tag:blogger.com,1999:blog-77721821134994516032024-03-19T04:21:16.207-05:00Real PsychiatryThe reality of psychiatry rather than the perceptionGeorge Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.comBlogger853125tag:blogger.com,1999:blog-7772182113499451603.post-87652346704188005272024-03-13T11:33:00.014-05:002024-03-14T10:59:17.071-05:00Two Million Reads - A Blogging Milestone of Sorts<p> <a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhsqmCCzBZpzrOl73lVL5hM55__GM64lUhHRx1x3dlpiebgPOW321qlTgvLu77jHCaZdUjwPdq-QkQqZeUHBE4gSqvXM3trNfpVrQLf5qMgHeAAkNnOMJO42ODXAK1Sd2piKhkKGu70-XRRjvup7CQBXZ3Tl7QREa5FbBNVCOA9wtiHE5Z4YSwAXEDxjsIg/s1272/No%20royal%20road.png" style="margin-left: 1em; margin-right: 1em; text-align: center;"><img border="0" data-original-height="376" data-original-width="1272" height="190" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhsqmCCzBZpzrOl73lVL5hM55__GM64lUhHRx1x3dlpiebgPOW321qlTgvLu77jHCaZdUjwPdq-QkQqZeUHBE4gSqvXM3trNfpVrQLf5qMgHeAAkNnOMJO42ODXAK1Sd2piKhkKGu70-XRRjvup7CQBXZ3Tl7QREa5FbBNVCOA9wtiHE5Z4YSwAXEDxjsIg/w640-h190/No%20royal%20road.png" width="640" /></a></p><p class="MsoNormal"><br /></p>
<p class="MsoNormal">Last night around midnight – I noticed that I had crossed
the 2 million reads mark on this blog.<span style="mso-spacerun: yes;">
</span>The <i>Google Blogger</i> interface that I use is not very granular so
it is difficult to tell how many of those hits are actual reads as opposed to
something else. By something else I mean hackers, bots, and people trying to
use my blog for free advertising.<span style="mso-spacerun: yes;"> </span>The
products are typically illegal or barely legal drugs or psychiatric services outside
of the US.<span style="mso-spacerun: yes;"> </span>The increase in VPNs is also
probably a factor.<span style="mso-spacerun: yes;"> </span>Over the years the
number of hits per page has flattened out while the overall number for the blog
has increased. My assumption is that individual page reads with a VPN are not
counted, but they are counted for the overall blog.<o:p></o:p></p>
<p class="MsoNormal">I am reassured and very grateful for the readers of this blog and have
corresponded in detail with many of them.<span style="mso-spacerun: yes;">
</span>They range from medical students considering a career in psychiatry to
very senior medical scientists with hundreds of research publications.<span style="mso-spacerun: yes;"> </span>In many cases they are advocating for a
specific viewpoint.<span style="mso-spacerun: yes;"> </span>In a few they want
me to change a blog post in some way.<span style="mso-spacerun: yes;">
</span>That rarely happens because of my level of experience and the degree of
research I put into these posts.<span style="mso-spacerun: yes;">
</span>Somewhere in the past I pointed out that one of my motivations for
writing this blog came from colleagues who asked me what I read, where I found
certain information, and how I came to know what I know. I hope I am successful
at getting that information out there. <o:p></o:p></p>
<p class="MsoNormal">I am also very grateful to the academics out there who share
their work and give me free advice.<span style="mso-spacerun: yes;"> </span>One
of the most striking examples was midnight correspondence with two philosophers
who wrote a book about diagnostic decision making in the late 1980s. I used it
to teach a course in not making diagnostic errors in medicine and psychiatry.
Both professors were retired and I sent them emails in a later time zone at
midnight. They gave me detailed responses within an hour. I don’t always get a
response, but when I do it is exhilarating to be a part of academic discussions
with some of the most accomplished people in the world. <o:p></o:p></p>
<p class="MsoNormal">It has not always been a walk in the park.<span style="mso-spacerun: yes;"> </span>I was confused about gaslighting initially
and tolerated too much of that activity before drawing a line. <o:p></o:p></p>
<p class="MsoNormal">I often wonder about why people read or do not read this
blog.<span style="mso-spacerun: yes;"> </span>The appearance is fairly basic
compared with other sites that offer better graphics.<span style="mso-spacerun: yes;"> </span>I think there is some reluctance or
resentment based on the idea that I am profiting from this blog.<span style="mso-spacerun: yes;"> </span>I can restate that this is completely
non-commercial and not-for-profit.<span style="mso-spacerun: yes;"> </span>I not
only have not made a cent writing this blog but have had to pay licensing costs
out-of-pocket for graphics and permissions.<span style="mso-spacerun: yes;">
</span>A friend and colleague recently told me that he never thought about
reading blogs.<span style="mso-spacerun: yes;"> </span>The era seems to be one
of podcasts and TikTok video clips. I have always found reading to be a lot
faster. <span style="mso-spacerun: yes;"> </span>And unlike TikTok I am
intentionally not provocative.<o:p></o:p></p>
<p class="MsoNormal">One of the recurrent themes here on my blog is that there is
no way to simplify psychiatry and do it well.<span style="mso-spacerun: yes;">
</span>A psychiatrist considering themselves to be primarily a
psychotherapist or primarily a psychopharmacologist is not considering large
areas of the discipline.<span style="mso-spacerun: yes;"> </span>The same is
true of the psychiatrist who ignores medicine and neurology.<span style="mso-spacerun: yes;"> </span>To paraphrase Euclid (325 BCE - 265 BCE) “There is no royal road
to psychiatry.”<span style="mso-spacerun: yes;"> </span>You must know it all to
do good work. <span style="mso-spacerun: yes;"> Complexity is good and necessary in human biology.</span></p><p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal">I currently have 123 folders in my <i>References 2024 Folder
</i>and it’s only March<i>.</i><span style="mso-spacerun: yes;"> </span>I am
working on a protocol that will allow me to submit research papers and blog
them if they are rejected.<span style="mso-spacerun: yes;"> </span>At the rate I
am going I will write my own textbook in psychiatry in another 20 years.<span style="mso-spacerun: yes;"> </span>Stay tuned!<o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal">And Thanks again!<o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal">George Dawson, MD, DFAPA <o:p></o:p></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com3tag:blogger.com,1999:blog-7772182113499451603.post-28571700964542715572024-03-12T14:43:00.017-05:002024-03-13T22:36:04.579-05:00An Unpublished NEJM Letter<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiHaTd9GapfdtfiKOzW8TFPHKEsJuPAlB5E1i4PQIhd8B3wYulKA6FCABIqnhd0v9nM4ntcVOQ5VlHnsW5uuVe0x7hqgpGL2Ts2e02D5Y7RgwHC2BJSZh0aTjqRYkYxI-rAVxAfHEuzWvz-QAdRoIEG3mMLRbBeBnX8gFxnm356xkDt8BO04GOQmuGlhKYf/s1024/RR%20workers%20LOC%20public%20domain.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="803" data-original-width="1024" height="502" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiHaTd9GapfdtfiKOzW8TFPHKEsJuPAlB5E1i4PQIhd8B3wYulKA6FCABIqnhd0v9nM4ntcVOQ5VlHnsW5uuVe0x7hqgpGL2Ts2e02D5Y7RgwHC2BJSZh0aTjqRYkYxI-rAVxAfHEuzWvz-QAdRoIEG3mMLRbBeBnX8gFxnm356xkDt8BO04GOQmuGlhKYf/w640-h502/RR%20workers%20LOC%20public%20domain.jpg" width="640" /></a></div><br /><br />
<p class="MsoNormal"><o:p> </o:p>I was notified this morning that a letter I sent in to the <i>New
England Journal of Medicine</i> would not be published because they had limited
space. Anyone sending a letter is
notified that if the letter does not respond to one of their articles you are
limited to 400 words. If your letter
does respond to an article the word limit is 200 words. I was responding to an essay by Lisa
Rosenbaum, MD (1) and whether medicine is <i>a calling</i> or just a vocation
and the implications that each of those categories have. My first attempt at the 400-word mark (374
actual) is below:</p><p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><i><o:p> </o:p></i><i>To The Editor: The
essay by Dr. Rosenbaum (1) highlights a critical issue in medical education,
research, and practice. Much of the
analysis is dependent on the concept that medicine is either a job or a
calling. The critical factor in all settings is the practice environment. Over the past 30 years we have seen a severe
deterioration in that environment and how it impacts physicians. </i></p>
<p class="MsoNormal"><i>Forty years ago – physicians were valued as knowledge
workers.<span style="mso-spacerun: yes;"> </span>Work quality was emphasized and
teaching departments were run by senior physicians who emphasized teaching and
research.<span style="mso-spacerun: yes;"> </span>They were models for focused
lifelong learning and were able to maintain interest and enthusiasm in their
departments by balancing clinical demands and those learning tasks. Trainees in
the department benefitted from identification with these physicians as well as
learning clinical approaches in their specialty.<span style="mso-spacerun: yes;"> </span>The department head often had a business
administrator in the department, but there was no doubt that the focus was
medicine first and business tasks were minimal. <o:p></o:p></i></p>
<p class="MsoNormal"><i>Over the past several decades, business and political
interests have changed the physician role to production workers. Physicians are
now valued in corporations for productivity and all the administrative time
that takes. Department heads are often more focused on business matters than
teaching and research.<span style="mso-spacerun: yes;"> </span>Meetings take on
a business rather than academic orientation.<span style="mso-spacerun: yes;">
</span>More time is spent learning about the business environment rather than learning medicine.<span style="mso-spacerun: yes;"> </span>The
administrative burden alone easily exceeds the time used in the past for
teaching rounds and conferences.<span style="mso-spacerun: yes;"> </span>This
burden has also decreased physician efficiency and added hours per day
producing documentation for billing purposes that is repetitive and excessive.
It also detracts from the physician patient relationship that is further
fragmented by physician extenders.<o:p></o:p></i></p>
<p class="MsoNormal"><i>The modern practice environment is not conducive to
producing and motivating physicians.<span style="mso-spacerun: yes;">
</span>Rather than an environment where experts can have spirited exchanges
about medical care – it is one where experts are second guessed by
administrators with no medical training.<span style="mso-spacerun: yes;">
</span>It is an environment that does not produce a calling. <o:p></o:p></i></p>
<p class="MsoNormal"><i>Recognition of the severe deterioration in the practice
environment is the first step in correcting the problem.<span style="mso-spacerun: yes;"> </span>Steps need to be taken to restore practice
environments to stimulating settings that can lead to a high level of
expertise, quality, and humanistic care.<span style="mso-spacerun: yes;">
</span><o:p></o:p></i></p>
<p class="MsoNormal"><i><o:p> </o:p></i></p>
<p class="MsoNormal"><i>George Dawson, MD, DFAPA<o:p></o:p></i></p>
<p class="MsoNormal"><i><o:p> </o:p></i></p>
<p class="MsoNormal"><i>References:<o:p></o:p></i></p>
<p class="MsoNormal"><i>1. <a name="_Hlk161091566">Rosenbaum L.<span style="mso-spacerun: yes;"> </span>On
calling – from privileged professionals to cogs of capitalism?<span style="mso-spacerun: yes;"> </span>N Engl J Med 2024; 390: 471-5.</a><o:p></o:p></i></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal">The final 200-word final submitted version is below:<o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal"><i>Rosenbaum argues doctors' declining job satisfaction
stems from corporatization, generational changes, and a shift to
production-style management.<sup>1</sup> Traditionally, senior physicians
oversaw the practice, fostering a learning and research environment. Forty
years later, business managers treat doctors as production workers<sup>2</sup>
in an increasingly inefficient environment. This clashes with physicians’ role
as knowledge workers, requiring intellectual stimulation, collegiality, and
patient-centered care.<o:p></o:p></i></p>
<p class="MsoNormal"><i>That change is responsible for a marked deterioration in
the training and practice environment.<span style="mso-spacerun: yes;">
</span>Business practices have been emphasized to the point that there has been
an adverse effect on physician time management for professional and personal
activities. It is also a direct cause of burnout.<sup>3 </sup><o:p></o:p></i></p>
<p class="MsoNormal"><i>Physicians function best as knowledge workers consistent
with their training. Physicians have been forced into the role of production
workers. The solution is not to develop a rhetorical response to being in that
role. The solution is not an idealization of the “good old days” – but
recreating and restoring the physician knowledge worker environment.<span style="mso-spacerun: yes;"> </span>That is the first step toward making
physician sacrifice meaningful again. <o:p></o:p></i></p>
<p class="MsoNormal"><i><o:p> </o:p></i></p>
<p class="MsoNormal"><i>George Dawson, M.D.<o:p></o:p></i></p>
<p class="MsoNormal"><i><o:p> </o:p></i></p>
<p class="MsoNormal"><i>1. Rosenbaum
L.<span style="mso-spacerun: yes;"> </span>On calling – from privileged
professionals to cogs of capitalism?<span style="mso-spacerun: yes;"> </span>N
Engl J Med 2024; 390: 471-5.<o:p></o:p></i></p>
<p class="MsoNormal"><i>2. <a name="_Hlk161146622">Drucker PF. Knowledge worker productivity – the biggest
challenge.<span style="mso-spacerun: yes;"> </span>California Management Review
1999; 41: 71-94.</a><o:p></o:p></i></p>
<p class="MsoNormal"><i>3. Lacy BE,
Chan JL. Physician burnout: the hidden health care crisis. Clinical
gastroenterology and Hepatology. 2018;16(3):311-7.<o:p></o:p></i></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal">It took me 5 rewrites to get to progressively less
words.<span style="mso-spacerun: yes;"> </span>When you tend to use as many
words as I do that was a painful process.<span style="mso-spacerun: yes;">
</span>If you are a blogger the pain is compounded by the fact that editorial
control is lost and you cannot publish your comments anywhere else (including a
blog) if you hope to get them published in a journal.<span style="mso-spacerun: yes;"> </span>The NEJM has a 3-week deadline for letters
based on their articles.<span style="mso-spacerun: yes;"> </span>It took them 5
weeks to reject it. They obviously can publish whatever they want and provide
whatever rationale that they want – but the space argument seems thin.<o:p></o:p></p>
<p class="MsoNormal">Let me suggest why I thought this letter – even pared down
to 170 words was important enough for me to send.<span style="mso-spacerun: yes;"> </span>A brief review of Dr. Rosenbaum’s essay is
necessary and if you have access, I encourage you to read it.<span style="mso-spacerun: yes;"> </span>The essay begins with standard blue-collar
rhetoric rooted in reality – basically that the working man is subjected to the
whims of corporations who rarely have their interests in mind. <span style="mso-spacerun: yes;"> </span>A young physician from that family concludes
that the idea of medicine as <i>a calling</i> is using that term “weaponized
against trainees as a means of subjugation— a way to force them to accept poor
working conditions.”<span style="mso-spacerun: yes;"> </span><o:p></o:p></p>
<p class="MsoNormal">The problem with that analysis is twofold.<span style="mso-spacerun: yes;"> </span>First, trainees do not have a monopoly on
subjugation by corporations or the government.<span style="mso-spacerun: yes;">
</span>It has been a decades long process directed at practicing physicians.<span style="mso-spacerun: yes;"> </span>Second, rhetorical “weaponization” of terms
applied to the profession is unnecessary.<span style="mso-spacerun: yes;">
</span>That <a href="https://real-psychiatry.blogspot.com/2013/11/accountability-last-refuge-of-scoundrel.html">battle
has already been lost</a>. The current work and training environment has been
deliberately shaped by the managed care business and like-minded governments
for the past 30 years. Businesses don’t have to use <i>weaponized </i>rhetoric.<span style="mso-spacerun: yes;"> </span>All they have to do is replace physicians
with non-physicians, tell them they can work somewhere else, or reduce their
compensation or just not pay them if they don’t meet their <i>productivity
expectations</i>.<i> </i>They can also use internal committees and business
practices to scapegoat and gaslight physicians who they do not like. <span style="mso-spacerun: yes;"> </span>There is essentially unlimited leverage to get
what they want.<span style="mso-spacerun: yes;"> </span>All those measures are
far more powerful in getting physician compliance than suggesting they need to
make sacrifices in the service of a <i>calling. </i><span style="mso-spacerun: yes;"> </span>Physicians today are expected to make
significant sacrifices or else – all in the service of their business masters.<span style="mso-spacerun: yes;"> </span>It is evident the young physician in the
essay knows nothings about it. The only practice and training environment that
he knows is the one that has been severely compromised. <o:p></o:p></p>
<p class="MsoNormal">From medicine-as-a-calling, Rosenbaum introduces us to <i>workism.
</i><span style="mso-spacerun: yes;"> </span>This term was coined in an <i>Atlantic
magazine</i> essay to suggest that somehow work is a central part of life,
identity, and meaningfulness is life.<span style="mso-spacerun: yes;">
</span>That author goes on to suggest that people born between 1981 and 1996
were encouraged in this attitude and found themselves instead in debt and with
no meaningful life work.<span style="mso-spacerun: yes;"> </span>That led to
demoralization and nihilism about capitalism.<span style="mso-spacerun: yes;">
</span>When I read these paragraphs, I had to wonder how naïve this generation
could be?<span style="mso-spacerun: yes;"> </span>How could they possibly think
that American capitalism and the economy was good for anybody? <span style="mso-spacerun: yes;"> </span>Don’t they read anything about the
environment, pollution, climate change, environmental catastrophes, unnecessary
wars, near economic catastrophes – all precipitated by American
capitalism?<span style="mso-spacerun: yes;"> </span>I don’t think the idealization
of work or capitalism explains the <i>lack of medicine-as-a-calling</i>.<o:p></o:p></p>
<p class="MsoNormal">There is a glimpse of reality in the next section when we
hear how of how a long-time residency director of internal medicine stepped
down due to a <i>misalignment</i> of the missions of hospitals and training
programs. That is really putting it mildly. In many cases that difference was
all it took to destroy training programs.<span style="mso-spacerun: yes;">
</span>It is common to hear how residents are just used as inexpensive labor –
but that has always been the case. The real problem is that the quality of
teaching is adversely affected when faculty are told that they must max out
their productivity and at the same time – get no credit at all for teaching. <span style="mso-spacerun: yes;"> </span><o:p></o:p></p>
<p class="MsoNormal">Rosenbaum’s essay depends on generational stereotypes and
barely touches the root of the problem.<span style="mso-spacerun: yes;">
</span>I reference the work of Peter Drucker – widely considered
a guru in business management. <span style="mso-spacerun: yes;"> </span>He
pointed out the differences between production workers and knowledge workers. Basically,
knowledge workers are quality focused in areas that they have more expertise than
the management does. They are generally felt to be critical to the business and
the idea is to retain them and give them adequate resources. Establishing a
culture of excellence in their knowledge base adds to the environment. Production
workers are engaged in repetitive tasks.<span style="mso-spacerun: yes;">
</span>Their supervisors generally have worked their way up from doing the same
tasks and therefore know as much about their work. Early experiments
in mass production showed that analysis of the repetitive tasks by so-called <i>efficiency
experts </i>could improve the overall production. <o:p></o:p></p>
<p class="MsoNormal">What has occurred in the past 30 years has been the mass
conversion of physicians from knowledge workers to production workers. The
associated practice and academic environments have suffered drastic changes.
Academic physicians have found that a major part of their work – teaching and
research has been devalued in many cases to nothing.<span style="mso-spacerun: yes;"> </span>In the meantime, they are expected to see many
more patients, often to the point that they find themselves in new clinics –
just to increase the overall billing. <span style="mso-spacerun: yes;"> </span>The electronic health record (EHR), billing,
and coding, and maintenance of certification are all added time penalties with
no associated productivity credit. They have little say about how they see
patients or how many patients they see.<o:p></o:p></p>
<p class="MsoNormal">I will cite one of many examples to highlight these points. Just 5 years ago, an internist I know was audited by his managers
who had him tracked from 8AM to 4PM by an efficiency expert. That time frame
encompassed 90% of his patient contacts, but only 66% of his workload.<span style="mso-spacerun: yes;"> </span>Every day when the efficiency expert left –
he would ask: “Where are you going? I am here for another 4 hours.”<span style="mso-spacerun: yes;"> </span>The managers wanted to use the efficiency expert
report to suggest that he was not efficient enough in seeing patients – but the
real problem was the lack of clerical support and the EHR. The exercise was enough
for the internist to realize he was working in a hostile environment and he
moved on.<span style="mso-spacerun: yes;"> </span>A clear loss of a knowledge
worker. <span style="mso-spacerun: yes;"> </span>The corporate myth that everyone
is replaceable missed again in this case. This internist had experience and skills
that could not be duplicated by anyone else in that clinic. This cycle of
corporate flexing repeats itself thousands of times per day. <o:p></o:p></p>
<p class="MsoNormal">There can be no <i>calling</i> to work in such an environment where your work is routinely denigrated and devalued.<span style="mso-spacerun: yes;"> </span>It plays out as a personal attack. You will
necessarily feel like a production worker and start to work on the goals of
production workers like standardized working conditions, hours, and
benefits.<span style="mso-spacerun: yes;"> </span>When you come home at night –
you will leave the job behind you and no longer think about the patients who
have problems with no solutions or what you need to know to do a better job. There
is no <i>esprit de corps </i>of cohesion, support, and invigoration necessary
for a stimulating knowledge worker environment. <o:p></o:p></p>
<p class="MsoNormal">That is the recent attitude and it correlates directly with
the business takeover of medicine – not the newest generations.<span style="mso-spacerun: yes;"> </span>It also correlates with prominent editorials
in the top journals of our field like the <i>New England Journal of Medicine</i>.<span style="mso-spacerun: yes;"> </span>These editorials illustrate on almost a
weekly basis that there is no end to the businessmen, politicians, and lawyers
who want to run and ruin our profession.<span style="mso-spacerun: yes;">
</span>To date – they have been tremendously successful.<span style="mso-spacerun: yes;"> </span>There is also no lack of evidence that the
medical profession has been completely inadequate advocating for a reasonable
practice and training environment.<o:p></o:p></p>
<p class="MsoNormal">Medicine will never be <i>a calling</i> again until the work
and practice environment has been repaired and removed from the complete
control of businesses and governments. <o:p></o:p></p>
<p class="MsoNormal">And yes – it is that simple. <o:p></o:p></p>
<p class="MsoNormal">George Dawson, MD, DFAPA</p><p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal"><i>References:</i><o:p></o:p></p>
<p class="MsoNormal">1:<span style="mso-spacerun: yes;"> </span>Rosenbaum L.<span style="mso-spacerun: yes;"> </span>On calling – from privileged professionals to
cogs of capitalism?<span style="mso-spacerun: yes;"> </span>N Engl J Med 2024;
390: 471-5.<o:p></o:p></p>
<p class="MsoNormal">2:<span style="mso-spacerun: yes;"> </span>Drucker PF.
Knowledge worker productivity – the biggest challenge.<span style="mso-spacerun: yes;"> </span>California Management Review 1999; 41: 71-94.<o:p></o:p></p><div class="separator" style="clear: both; text-align: left;"><i>Graphic Credit:</i></div><div class="separator" style="clear: both; text-align: left;"><br /></div><div class="separator" style="clear: both; text-align: left;">All details at this link. Coming from 4 generations of railroad workers it was a natural choice: </div><div class="separator" style="clear: both; text-align: left;">https://commons.wikimedia.org/wiki/File:Group_of_laborers_digging_through_dirt_pile_along_railway_bed_LCCN2016647134.jpg</div><br />George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com1tag:blogger.com,1999:blog-7772182113499451603.post-32383363476852982702024-03-02T22:00:00.009-06:002024-03-03T17:53:48.361-06:00Kendler Keeping It Real…..<p> </p>
<p class="MsoNormal"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiZfpKGYtboESIN27wdJ8IqfMjXe8DpjtK5zDsW7bpDbAXYwyZcueyoUOSwaKne4IEhXjl9qP-7qaiQ_EM0XPSbOrb2iU-qUkf0WFKyxHqI5OZ_-Fs3FoEn8ek4TD0AhPbxrZdNrJWPRX25pFDNCBjrYyhTi58tsd73LhOJI-7PDdvZ5k6yv6cCzN0BbK6s/s1772/Kendler%20quote%20March%202024.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="966" data-original-width="1772" height="348" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiZfpKGYtboESIN27wdJ8IqfMjXe8DpjtK5zDsW7bpDbAXYwyZcueyoUOSwaKne4IEhXjl9qP-7qaiQ_EM0XPSbOrb2iU-qUkf0WFKyxHqI5OZ_-Fs3FoEn8ek4TD0AhPbxrZdNrJWPRX25pFDNCBjrYyhTi58tsd73LhOJI-7PDdvZ5k6yv6cCzN0BbK6s/w640-h348/Kendler%20quote%20March%202024.png" width="640" /></a></div><div class="separator" style="clear: both; text-align: center;"><br /></div><div class="separator" style="clear: both; text-align: center;"><br /></div>Kenneth Kendler, MD needs no introduction to anyone even
vaguely familiar with the psychiatric literature.<span style="mso-spacerun: yes;"> </span>If you need to do your own research his
accomplishments and scientific papers are widely available on the Internet.
This post is to focus on his recent commentary in JAMA psychiatry (1) over the
issue of psychiatric diseases and whether or not they are brain diseases.<span style="mso-spacerun: yes;"> </span>He starts out with a 1867 quote from
Griesinger stating that the brain is the only logical origin for symptoms of
insanity. His analysis is at the level of “pathological and physiological”
factors. <o:p></o:p><p></p>
<p class="MsoNormal">He briefly reviews two common arguments about whether
psychiatric disorders are brain diseases.<span style="mso-spacerun: yes;">
</span>The first <i>Cartesian dualism</i> that a mind emerges from the brain
and is not the same as a brain. Since a brain is necessary for all mental
phenomenon there is no specific answer to the question about whether the
phenomenon observed with psychiatric disorders are diseases.<span style="mso-spacerun: yes;"> </span>The second common argument is that grossly
detectable brain diseases (lesions at autopsy and sophisticated
imaging) <span style="mso-spacerun: yes;"> </span>eventually became the purview
of neurology.<span style="mso-spacerun: yes;"> </span>To complement Kendler’s commentary,
I would add that this has never been strictly true since both overt lesions and
physiological brain dysfunction has always been studied by psychiatrists.<span style="mso-spacerun: yes;"> </span>It has been a common antipsychiatry argument
advanced by Szasz and others based on 19<sup>th</sup> century concepts.<span style="mso-spacerun: yes;"> </span>Ron Pies (2) has recently commented that it involved
a misunderstanding of Virchow’s work on pathophysiology. <span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span><o:p></o:p></p>
<p class="MsoNormal">An indirect way this problem has been handled is to suggest that
it has to do with the vague definitions of disease (3).<span style="mso-spacerun: yes;"> </span>Without a clear definition, anyone can use
their own to declare that psychiatric disorders are not diseases. That has been
a common tactic used to declare that not only that mental illnesses are not diseases
– because of the lack of clear gross pathology they do not exist.<span style="mso-spacerun: yes;"> </span>Dealing with the problem at this rhetorical
level has not been very successful largely due to the lack of interest in rhetoric
on the part of medical professionals and constant repetition by the rhetoricians.
<o:p></o:p></p><p class="MsoNormal">More practical philosophical attempts at disease definition like loss of function models seem to not have much traction. <a href="https://real-psychiatry.blogspot.com/2018/10/the-nejm-addiction-as-learning-and-not.html">Munson and Resnick</a> (4) proposed one of these models and also suggested that the loss of function is related to programming errors in biological processes. </p>
<p class="MsoNormal">Kendler suggests a clear path that has appeal to anyone who
has studied pathophysiology and treated illnesses without clear lesions or with
lesions that had to be the end product of some unknown pathophysiology.<span style="mso-spacerun: yes;"> </span>That group of people would be anyone who has
done an internship or residency in any medical field.<span style="mso-spacerun: yes;"> </span>Anyone with that experience has seen a wide array
of medical conditions that are polygenic in nature and have either an unknown
or highly speculative pathophysiology.<o:p></o:p></p>
<p class="MsoNormal">The suggested path is genetics-> pathophysiology or more
broadly “genetics -> brain -> schizophrenia.”<span style="mso-spacerun: yes;"> </span>Rather than bemoaning all of the failed GWAS
studies and Decade of the Brain, Kendler cites “the most robust empirical
findings in all of psychiatry—that genetic risk factors impact causally and
substantially on liability to all major psychiatric disorders.”<span style="mso-spacerun: yes;"> </span>More specifically he cites a 2022 report that
shows that gene expression (as mRNA levels) of risk variants for schizophrenia were
noted in the brain and no other tissue.<span style="mso-spacerun: yes;"> </span>That
brings the brain expression in his causal link into clear focus.<span style="mso-spacerun: yes;"> </span><o:p></o:p></p>
<p class="MsoNormal">At that point he hedges and suggests that this may not be
robust enough to suggest that a brain disease is occurring. For me it is plenty.<span style="mso-spacerun: yes;"> </span>He goes on to suggest that there are 5 advantages
of this approach including data driven rather than metaphysical, bypasses the
19<sup>th</sup> century need for gross lesions, fits with pluralism or multiple
possible etiologies, can potentially provide information about other diseases
affecting the brain, and avoids a hard line of demarcation between normal and
disease at the physiological level.<span style="mso-spacerun: yes;"> </span>The
last point has been elaborated in the more recent past as quantitative versus
qualitative diseases and the associated variants.<span style="mso-spacerun: yes;"> </span><o:p></o:p></p>
<p class="MsoNormal">On the limitation side – a genetics only approach is the main
consideration.<span style="mso-spacerun: yes;"> </span>The antipsychiatrists
that he has alluded to may be realizing that they need to finally modify their
19<sup>th</sup> century rhetoric and I have seen the equally absurd claims that
there are no genetic effects for psychiatric disorders.<span style="mso-spacerun: yes;"> </span>The difference is that Kendler is an expert
in the area – so only the most dedicated post modernists will claim that they
did their own research and came to a different conclusion.<span style="mso-spacerun: yes;"> </span>He does see the innovation of being able to
detect tissue levels effects of genetic variants as a good starting point.<span style="mso-spacerun: yes;"> </span>The goal is to elaborate the functional networks
affected by these variants, describe mechanisms at the molecular level, and how
those mechanisms are affected by variants (5).<o:p></o:p></p>
<p class="MsoNormal">This is really an inspiring commentary at a time when it is
getting more fashionable to attack basic science research in psychiatry. I saw
a comment just last week about how <i>biological psychiatry</i> was a drain on mental
health research.<span style="mso-spacerun: yes;"> </span>And there are frequent comments
about how there should be more psychosocial research, even though there is no
clear evidence that is necessary. <o:p></o:p></p>
<p class="MsoNormal">As a clinical psychiatrist and a physician first, my observations
have been that most people go to medical school to gain knowledge about the
human body and how to treat, prevent and where possible cure diseases. Speculative
pathophysiology and mechanisms are all part of that starting in the first two
years of basic science course and extending to clinical rounds at bedside during residency.<span style="mso-spacerun: yes;"> </span>Philosophy and endless arguments about the
nature of disease or psyche is not.<span style="mso-spacerun: yes;"> </span>Psychiatry
has lost its way many times due to an inability to recognize and respond to rhetoric.
Kendler’s solution to the question of whether mental disorders are brain diseases
is an elegant one and it is consistent with the way physicians are trained. <span style="mso-spacerun: yes;"> </span>It also establishes a boundary that some
questions in psychiatry are not answerable by philosophy. <o:p></o:p></p>
<p class="MsoNormal">Finally, what is still lacking?<span style="mso-spacerun: yes;"> </span>I think that ultimately, we want medicine and
psychiatry to be part of a comprehensive view of human biology. We need more comprehensive
theories about human biology and how things really work at the physiological
and molecular level.<span style="mso-spacerun: yes;"> </span>That knowledge is
currently spotty across all specialties. Biology theory rather than <i>biological
psychiatry</i> is really the goal here and we can use more input from theoretical
biologists of all specialties. <o:p></o:p></p>
<p class="MsoNormal">George Dawson, MD, DFAPA<o:p></o:p></p>
<p class="MsoNormal"><br /></p><p class="MsoNormal">References:<o:p></o:p></p>
<p class="MsoNormal">1:<span style="mso-spacerun: yes;"> </span>Kendler KS. Are
Psychiatric Disorders Brain Diseases?-A New Look at an Old Question. JAMA
Psychiatry. 2024 Feb 28. doi: 10.1001/jamapsychiatry.2024.0036. Epub ahead of
print. <o:p></o:p></p>
<p class="MsoNormal">2:<span style="mso-spacerun: yes;"> </span>Pies R.<span style="mso-spacerun: yes;"> </span>Did Szasz Misunderstand Virchow’s Concept of
disease? Psychiatric Times. Feb 21, 2024.<span style="mso-spacerun: yes;">
</span><a href="https://www.psychiatrictimes.com/view/did-szasz-misunderstand-virchow-s-concept-of-disease">https://www.psychiatrictimes.com/view/did-szasz-misunderstand-virchow-s-concept-of-disease</a><o:p></o:p></p>
<p class="MsoNormal">3:<span style="mso-spacerun: yes;"> </span>Pies RW, Dawson G.<span style="mso-spacerun: yes;"> </span>Epistemic Humility in Psychiatry: Why We Need
More Montaigne and Less Savonarola.<span style="mso-spacerun: yes;">
</span>Psychiatric Times.<span style="mso-spacerun: yes;"> </span>Oct 19,
2023.<span style="mso-spacerun: yes;"> </span><a href="https://www.psychiatrictimes.com/view/epistemic-humility-in-psychiatry">https://www.psychiatrictimes.com/view/epistemic-humility-in-psychiatry</a><o:p></o:p></p><p class="MsoNormal">4: <span face="Arial, Tahoma, Helvetica, FreeSans, sans-serif" style="background-color: white; color: #333333; font-size: 14.85px;">Albert DA, Munson R, Resnik MD. Reasoning in Medicine: An Introduction to Clinical Inference. Baltimore, Maryland: The Johns Hopkins University Press, 1988: 150-180.</span></p>
<p class="MsoNormal">5:<span style="mso-spacerun: yes;"> </span>van Dongen J,
Slagboom PE, Draisma HH, Martin NG, Boomsma DI. The continuing value of twin
studies in the omics era. Nat Rev Genet. 2012 Sep;13(9):640-53. <a href="https://www.nature.com/articles/nrg3243">https://doi:10.1038/nrg3243</a></p><p class="MsoNormal">. <o:p></o:p></p><br />George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com0tag:blogger.com,1999:blog-7772182113499451603.post-26831110472866080912024-02-28T12:44:00.015-06:002024-02-29T16:05:25.474-06:00A Trip To The Dermatologist<p> </p><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjq3pnTdS9y9ZtE7BfHDMNDTdzd5XFOUFWwWNTaKweKd-l8y8B501eLiCJ9sQ8orH_EiqA9i0pl6m6oB1RY5jcviomu0h9Cw0PTglZcT2ouVYYfM97YqqYH2yNf1rhRrfwiCkrC2Hy2G-1EbnXl1thc429xdLsQFgpG2043FNxVNUIA6utuaBQF__pXdLg9/s1872/Dermatology%20post%2002.28.2024.png" style="margin-left: 1em; margin-right: 1em; text-align: center;"><img border="0" data-original-height="1446" data-original-width="1872" height="494" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjq3pnTdS9y9ZtE7BfHDMNDTdzd5XFOUFWwWNTaKweKd-l8y8B501eLiCJ9sQ8orH_EiqA9i0pl6m6oB1RY5jcviomu0h9Cw0PTglZcT2ouVYYfM97YqqYH2yNf1rhRrfwiCkrC2Hy2G-1EbnXl1thc429xdLsQFgpG2043FNxVNUIA6utuaBQF__pXdLg9/w640-h494/Dermatology%20post%2002.28.2024.png" width="640" /></a><br />
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal">Pattern matching is an important skill for all
physicians.<span style="mso-spacerun: yes;"> </span>It is rarely discussed these
days despite all the continuous hype about artificial intelligence replacing
doctors by reading x-rays and other lab tests.<span style="mso-spacerun: yes;">
</span>I taught a course in diagnostic reasoning for about 12 years and the
examples of pattern matching I used were from dermatology and
ophthalmology.<span style="mso-spacerun: yes;"> </span>The dermatology
experiment was a straightforward comparison of dermatologists to primary care
physicians looking at the same slide set of rashes and skin lesions (1).<span style="mso-spacerun: yes;"> </span>The dermatologists were correct more often,
faster at diagnosing, and able to correctly diagnosis equivocal cases compared
with the primary care physicians. <o:p></o:p></p>
<p class="MsoNormal">I want to be clear that does not mean that primary care
doctors don’t do a good job.<span style="mso-spacerun: yes;"> </span>Some are so
good that dermatologists know that they need to attend to the diagnosis and
treatment of some physicians who refer them significant numbers of patients
with melanoma and other types of cancer.<span style="mso-spacerun: yes;">
</span>All these factors were probably in my subconscious when I decide to call
to see a dermatologist. <o:p></o:p></p>
<p class="MsoNormal">It was not easy.<span style="mso-spacerun: yes;"> </span>The
first appointment was a teleconference and I would call it a swing and a miss. I
was given a very expensive prescription for ocular rosacea that did nothing.
When I called again to be seen in person, I was given an elaborate algorithm based on how many problems I wanted to be seen about. The more problems – the
longer the wait.<span style="mso-spacerun: yes;"> </span>I decided to go outside
of my usual healthcare providers to a private clinic closer to my home.<span style="mso-spacerun: yes;"> </span><o:p></o:p></p>
<p class="MsoNormal">I have noticed a gradual accumulation of dermatology
problems with age. I have made every effort to avoid direct sunlight.<span style="mso-spacerun: yes;"> </span>If I must be outside at any time when my
shadow is shorter than my height, I am wearing a high SPF shirt and sunscreen,
a baseball cap, and wrap around polarized sunglasses. I have probably been
sunburned twice in my life and tanned once. About 2 years ago I noticed a
ring-shaped red lesion on my right forearm.<span style="mso-spacerun: yes;">
</span>Every now and then it seemed to burn but generally it was static.<span style="mso-spacerun: yes;"> </span>I saw my primary care MD and he did a
scraping and potassium hydroxide preparation to see if it was ringworm (<i>tinea
corporis</i>). It was not, so he told me to apply the betamethasone ointment
that I typically use for eczema to the area.<span style="mso-spacerun: yes;">
</span>I did for a couple of weeks and there was no effect. <o:p></o:p></p>
<p class="MsoNormal">At about the same time, I happened to notice a blue spot on
the lateral aspect of my left ankle.<span style="mso-spacerun: yes;">
</span>That is a difficult area to see.<span style="mso-spacerun: yes;">
</span>I went into see a primary care MD who used an ophthalmoscope for
magnification and concluded it was a collection of pigmented cells that did not
look like a melanoma.<span style="mso-spacerun: yes;"> </span>She said she would
describe it in my chart including recording the diameter so it could be followed
along by primary care.<span style="mso-spacerun: yes;"> </span><o:p></o:p></p>
<p class="MsoNormal">I described all these problems to the Dermatologist's assistant
before he walked in the room.<span style="mso-spacerun: yes;"> </span>I had
photos of all the dermatology products I had been using and what had been tried
in the past.<span style="mso-spacerun: yes;"> </span>Even though the pattern
matching diagnosis in Dermatology is good, like other areas of medicine – the treatments
seem to be hit or miss and even then the response seems to vary over time.<span style="mso-spacerun: yes;"> </span>I made a note to myself that I should look
for papers claiming that these are placebo treatments or it is just all
<i>regression to the mean</i>.<span style="mso-spacerun: yes;"> </span>But I doubt that
there are any anti-Dermatologists out there complaining about that and too many diagnoses and too many medications.<o:p></o:p></p>
<p class="MsoNormal">The intake form that I completed was just 2 pages long and
there was an occupation section probably to consider environmental
exposures.<span style="mso-spacerun: yes;"> </span>When the Dermatologist came
in he was very cordial and talkative.<span style="mso-spacerun: yes;"> </span>He
established that we both went to the same medical school (27 years apart),
lived in the same neighborhood while we attended, and knew some of the same
professors.<span style="mso-spacerun: yes;"> </span>He took the history and
clarified the technical points to his assistant who had now become his
scribe.<span style="mso-spacerun: yes;"> </span>He used a dermatoscope to inspect
the lesions and make rapid diagnoses on the right forearm (actinic keratosis), left ankle (fibroma secondary to trauma) and left
malar area (actinic keratosis).<span style="mso-spacerun: yes;"> </span>He recommended freezing the
malar area and forearm with liquid nitrogen and said the fibroma was just a
skin reaction to some trauma that did not require treatment. At that point we
went into a more detailed discussion of the rosacea and ocular rosacea and
failed treatments with doxycycline and tacrolimus.<span style="mso-spacerun: yes;"> </span>He recommended a compounded product of azelaic
acid, metronidazole, and ivermectin, advised me of the cost, and has his assistant
set that up. It was a very efficient process – the diagnoses, freezing
treatments, and discussion took about 20 minutes.<span style="mso-spacerun: yes;"> </span>At the end all of the follow up,
prescriptions, and documentation was done and he was moving on to the next
person. <o:p></o:p></p>
<p class="MsoNormal">There are times when it pays to see an expert and this is
an illustration of one of those times. <span style="mso-spacerun: yes;"> </span>I
had been looking at these lesions for 2 years and trying to take the next
steps.<span style="mso-spacerun: yes;"> </span>There are as many barriers to
seeing a Dermatologist as there are to seeing a psychiatrist.<span style="mso-spacerun: yes;"> </span>I knew enough to monitor these lesions and
they did not seem to get worse, but they were also not improving. After 2
years I got the definitive diagnoses and treatment I had been looking for as
well as reassurance that the ankle lesion was not a melanoma. <o:p></o:p></p>
<p class="MsoNormal">This is an impressive result compared with most physician
visits.<span style="mso-spacerun: yes;"> </span>Even considering that there were
a couple of things that did not fit.<span style="mso-spacerun: yes;"> </span>Sun
exposure for one.<span style="mso-spacerun: yes;"> </span>I am what is referred
to as a <i>white fish </i>in upper Midwest vernacular.<span style="mso-spacerun: yes;"> </span>That means apart from my blue veins and the
redness of rosacea – my skin is generally as white as the background of this page. <span style="mso-spacerun: yes;"> </span>I had some early exposure to people with skin
cancer and have been very diligent about keeping my skin and retinal exposure to
direct sunlight at a minimum.<span style="mso-spacerun: yes;"> </span>I suppose
there are other factors at play such as age and know there are <i>senile
keratoses</i> – but this did not resemble typical lesions in my dermatology texts
or online. The Dermatologist predicted that the freezing treatment would cause
these lesions to slough off and be replaced by normal smooth skin.<span style="mso-spacerun: yes;"> </span>I have a follow up in 3 months to see if that
happens and if the compounded topical rosacea medication works.<o:p></o:p></p>
<p class="MsoNormal">I am currently studying high prevalence polygenic diseases
and have included eczema on that list.<span style="mso-spacerun: yes;">
</span>Some estimates say that 20% of the population may have it.<span style="mso-spacerun: yes;"> </span>There is the association with asthma but in
my case as my asthma improved with age, I developed eczema and then worsening eczema.
<span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span>I
expect there will be many parallels with psychiatric disorders and diseases
when my comparison is done.<span style="mso-spacerun: yes;"> </span><o:p></o:p></p>
<p class="MsoNormal">In the meantime, a Dermatologist in the right setting is a good consultant to
have in your corner.<o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal">George Dawson, MD, DFAPA<o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal"><i>References:<o:p></o:p></i></p>
<p class="MsoNormal">1:<span style="mso-spacerun: yes;"> </span>Norman, G.R.,
Brooks, L.R., Rosenthal, D., Allen, S.W., & Muzzin, L.J. (1989). The
development of expertise in dermatology. Archives of Dermatology, 125,
1063–1068<o:p></o:p></p>
<p class="MsoNormal"><span style="mso-spacerun: yes;"><i> This is the original reference I used in my course on the diagnostic process and how not to make a mistakes. The first author has written significant papers about this. </i></span><o:p></o:p></p><p class="MsoNormal"><span style="mso-spacerun: yes;"><i>Graphic:</i></span></p><p class="MsoNormal"><span style="mso-spacerun: yes;">I mapped the dermatology conditions onto the body outline. If someone has a better body outline or one that they use on a standardized form and you want to send it my way - please do. I can make a much better graphic if the outline is a separate shape. The actinic keratoses areas on the map are probably both only 2 cm in diameter. The rosacea can happen anywhere on the face and most annoyingly on the eyelids. The eczema is a whole body condition that started out subtly as intense pruritis on the extremities and eventually spread to the abdominal area, chest, and back. Pruritis is the most significant symptom with occasional lesions that looks like abrasions. It can be exacerbated by skin contact with allergens like ECG electrodes. </span></p><br /><div class="separator" style="clear: both; text-align: center;"><br /></div><br />George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com0tag:blogger.com,1999:blog-7772182113499451603.post-87337991392832046332024-02-25T02:11:00.015-06:002024-03-06T00:06:41.347-06:00The Retired Consultant<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg-Zp8UM3hUkuo_0jQ_PU6U9ww2GfiBiMbOTa-eKY3pG9-Yhm2eWeZpwpE1BVxYnfteE7AmCBn8e8X_TukelRki93cXWk-aX6SrgLKlgA2qeZ0FHMSAGY4Dkg_XDLomQH4ThWRATk4SsBF6k1BxPcnsZ5NVvKncHds3p0Sw1IZ-kga-4z-2xEVxuWdsRWzp/s1024/Biscotti_1.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="576" data-original-width="1024" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg-Zp8UM3hUkuo_0jQ_PU6U9ww2GfiBiMbOTa-eKY3pG9-Yhm2eWeZpwpE1BVxYnfteE7AmCBn8e8X_TukelRki93cXWk-aX6SrgLKlgA2qeZ0FHMSAGY4Dkg_XDLomQH4ThWRATk4SsBF6k1BxPcnsZ5NVvKncHds3p0Sw1IZ-kga-4z-2xEVxuWdsRWzp/w640-h360/Biscotti_1.jpg" width="640" /></a></div><br /><p>I happened across <a href="https://real-psychiatry.blogspot.com/2016/07/closing-in-on-retirement.html">this old post</a> on approaching retirement today
and reread it. Of course, I am biased but it holds up well.<span style="mso-spacerun: yes;"> </span>It contains information about psychiatrists
retiring that you will not see anywhere else – including why we are happy.<span style="mso-spacerun: yes;"> </span>I currently spend much of my day doing the
usual chores, exercising, and writing.<span style="mso-spacerun: yes;"> </span>I
have several writing projects going and am near completing one that is unique.</p><p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal">I don’t get out much and I like it that way. I am an
introvert and have been subjected to the usual jokes about introversion.<span style="mso-spacerun: yes;"> </span>The pandemic was a factor but not the only
one.<span style="mso-spacerun: yes;"> </span>I just got back from working out in a
gym that has Cybex machines.<span style="mso-spacerun: yes;"> </span>After that
I went to Target to pick up a supply of blueberries and frozen burritos.<span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span><o:p></o:p></p>
<p class="MsoNormal">On the way out – I stopped to get a mocha and 2
biscottis.<span style="mso-spacerun: yes;"> </span>The barista was young and we talked
about the closing time of the coffee shop relative to the store. I associated
to what I was doing at that age.<span style="mso-spacerun: yes;"> </span>I was a
janitor in a dormitory. It was a thankless job.<span style="mso-spacerun: yes;">
</span>Luckily with increasing college experience I was able to move on to more
technical work as a lab and research assistant.<span style="mso-spacerun: yes;"> </span>I
wondered if she would reflect on her work as a barista when she got to be my
age and I sincerely hoped she would get to my age and beyond.<span style="mso-spacerun: yes;"> </span>I thought about writing a poem about that brief
encounter, probably because I had just read two Emily Dickinson poems and
have a history of writing free verse in the style of<i> ee cummings</i>.<o:p></o:p></p>
<p class="MsoNormal">On the drive home, public radio was playing election
coverage from South Carolina. <span style="mso-spacerun: yes;"> </span>It was the
GOP primary and I shut it off. I always have public radio in the background –
but listening to this is just too much.<span style="mso-spacerun: yes;">
</span>I drove, drank my mocha and crunched on my biscotti in silence. I had
some thoughts about biscotti.<span style="mso-spacerun: yes;"> </span>A competitor
has a much harder biscotti.<span style="mso-spacerun: yes;"> </span>It is so
hard the almonds are cut sharply with the slices.<span style="mso-spacerun: yes;"> </span>The biscotti I was eating was not as hard but
still had an almond and vanilla crunchy taste. <o:p></o:p></p>
<p class="MsoNormal">I started thinking about a paper I was writing. Even though
it was about rhetoric, it seemed quite exciting. <span style="mso-spacerun: yes;"> </span>I have not encountered any papers like
it.<span style="mso-spacerun: yes;"> </span>I thought about where it should be
submitted and how I should modify the introduction. One of the most insightful and
informative books I have read lately was about rhetoric. It tied together so
many things.<span style="mso-spacerun: yes;"> </span>The author was gracious
enough to respond to two of my emails.<span style="mso-spacerun: yes;"> </span>I
need to incorporate more of his concepts into the paper – but his book is encyclopedic.<o:p></o:p></p>
<p class="MsoNormal">I thought about some advice I had given lately.<span style="mso-spacerun: yes;"> </span>Even though I am retired and people know it –
they still call me.<span style="mso-spacerun: yes;"> </span>I tell them that
technically I am not treating them or directly giving them medical advice
because we do not have a physician patient relationship, I don’t have a working
office setting or records, and I don’t have malpractice coverage.<span style="mso-spacerun: yes;"> </span>They understand that and it doesn’t deter
them.<span style="mso-spacerun: yes;"> </span>I am licensed and recently contacted
the Board of Medical Practice about continuing medical education (CME) credit
reporting this summer. The pandemic created a lot of confusion about deferred
CME reporting.<span style="mso-spacerun: yes;"> </span>I need to report 75 credits and I
currently have 74 with a 6 CME credit conference in March. I wonder how long I will keep that up in retirement.<o:p></o:p></p>
<p class="MsoNormal">On the home stretch, I think about the advice I have given
people over the years. The qualified
advice on the system over the past 2 years tells me how bad things have
gotten. Parents calling me about their
adult children who are not doing well.
Adult children calling me about parents who are not doing well. The occasional email directly from a person
who is dissatisfied with treatment. Many calls about what happens in emergency
situations. Many calls about what specific diagnoses, imaging findings, and labs really mean. Was the emergency department
trying to talk me out of being admitted? Why wasn’t I treated with
anything? It just seems like I sat there
a long time, nothing happened, and they sent me home. Are these side effects that I am getting from
this medication and what can be done about it?
Are there any resources out there that can help me? I don’t seem to be
getting any help?<o:p></o:p></p>
<p class="MsoNormal">I try to help people negotiate available systems and help
them prioritize what should happen first.<span style="mso-spacerun: yes;">
</span>There is a general reluctance to call their clinic or doctor and report that
there are potential side effects. Overall, there is a lack of help for
people with psychiatric disorders. I know that is not strictly true and that
there are many large systems of psychiatric care nearby – but even when people
get in - there is difficulty getting what they need. I shock them with basic
information about when to call their doctor and what might be helpful to
discuss. I never second guess their doctor. I am focused on how to help them get the answers they need. It is not at all like practicing psychiatry. The most valuable product of that work is a patient who feels understood at the end of the session. None of the people calling me feel understood at even a superficial level.<o:p></o:p></p>
<p class="MsoNormal">Just a few years ago, I was an insider working in an intense
hospital environment. I was generally feeling the stress all day long. I had
the physical manifestations of that stress that were measurable – but I pushed
through every day and made it home to unwind.<span style="mso-spacerun: yes;">
</span>In some cases I could not unwind and ended up calling my nursing staff
at 2AM to make sure that things were going OK.<span style="mso-spacerun: yes;">
</span>I think about that right after thinking that I should still be working –
just based on all these systems problems that people are telling me about.<o:p></o:p></p>
<p class="MsoNormal">I come to the realization that I can’t do it anymore.
Cognitively and technically it is certainly not a problem. I have no doubts
that my diagnostic and treatment skills are still there. Physically it is an
interesting story.<span style="mso-spacerun: yes;"> </span>I just lifted plenty
of weights and will lift more tomorrow.<span style="mso-spacerun: yes;">
</span>My aerobic capacity is very good. I have posted some of my chronic
health problems here on this blog to illustrate diagnostic, pathophysiology,
and treatment concepts. So generally my health is pretty good. That can always turn on a dime.<span style="mso-spacerun: yes;"> </span>I can’t work anymore because of the stress response.<span style="mso-spacerun: yes;"> </span>The mental and emotional demands of work
become physical demands and that creates significant problems. Doctors reading
this in those environments know what I am talking about and I wish them the
best because I know nobody is trying to alleviate any of that pressure. <span style="mso-spacerun: yes;"> Nobody is trying to help them.</span><o:p></o:p></p>
<p class="MsoNormal">I finish off my mocha and biscotti as I am pulling into the
driveway. It is 7PM and dark out here in Minnesota.<span style="mso-spacerun: yes;"> </span>I had over 30 years of pulling in my driveway
in the dark after work and still feeling tense and in some cases jumpy about what happened that
day.<span style="mso-spacerun: yes;"> </span>Things are different now.<span style="mso-spacerun: yes;"> </span>I can decide how much pressure I am under and
when I can unwind. I wish I could do more for all these people who need help –
but I can’t. </p><p class="MsoNormal">It is time to finally take care of myself.<o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal">George Dawson, MD, DFAPA<o:p></o:p></p><p class="MsoNormal"><br /></p><p class="MsoNormal"><i>Supplementary:</i></p><p class="MsoNormal">@dahlle on Twitter read this post and posted the NASA Task Load Index - a workload measure that has been validated across a number of settings. Just looking at the scales - it is easy to see how physicians can max out almost every scale except for the physical demands (at least for non-surgeons). With enough stress - heart rate and blood pressure increase just like you are running. </p><p class="MsoNormal">It is also an illustration of how things can get rapidly complicated when there are people actively standing in your way and other people demanding that you do more. Work setting is critical here as well as adaptation to work. I have talked with hospitalists who told me their cognitive performance dropped off steeply on day 6 (of 7). On the other hand I have talked to physicians who were used to seeing 30 patients for a minute or two at a time in an afternoon who were not stressed at all. </p><p class="MsoNormal"><br /></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiziU5myT-D5XUB6Gl_kjlLPfg11Q3nch_fXO0u_-a6KL1DE-_U6WLPewUTehCCvrozaUNs7wU-Fm1nI-uqS8TukxJD2PPZKXrnYH_AA-EyVzg25nNQwl1A4v5g9YC2d40O-kBwgfMQ9bfkwnK3PPfkwAB9H_BmNcq7YocnPb_AO6mWSsjs6ne5xUuJQjit/s1534/NASA%20Task%20Load%20Index.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1534" data-original-width="1130" height="640" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiziU5myT-D5XUB6Gl_kjlLPfg11Q3nch_fXO0u_-a6KL1DE-_U6WLPewUTehCCvrozaUNs7wU-Fm1nI-uqS8TukxJD2PPZKXrnYH_AA-EyVzg25nNQwl1A4v5g9YC2d40O-kBwgfMQ9bfkwnK3PPfkwAB9H_BmNcq7YocnPb_AO6mWSsjs6ne5xUuJQjit/w472-h640/NASA%20Task%20Load%20Index.png" width="472" /></a></div>At least one study has established a dose response relationship between physician task load using this scale and burnout:<div><br /></div><div><span style="font-family: arial;"><span face="BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif" style="background-color: white; color: #212121;">Harry E, Sinsky C, Dyrbye LN, Makowski MS, Trockel M, Tutty M, Carlasare LE, West CP, Shanafelt TD. Physician Task Load and the Risk of Burnout Among US Physicians in a National Survey. Jt Comm J Qual Patient Saf. 2021 Feb;47(2):76-85. doi: 10.1016/j.jcjq.2020.09.011. </span><br /></span><p class="MsoNormal"><br /></p><p class="MsoNormal"><i>Graphics Credit:</i></p><p class="MsoNormal">Biscotti is via Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Biscotti_1.jpg</p><p class="MsoNormal">Mokkie, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons</p><p class="MsoNormal"><br /></p><p class="MsoNormal"><br /></p></div>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com6tag:blogger.com,1999:blog-7772182113499451603.post-61475788028314592722024-02-08T12:09:00.015-06:002024-02-14T10:55:19.954-06:00Blame Gun Extremists – Not Parents<p> </p> <div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh_fOfEsJhcunRU0AM6iHSJHPDtPcwp8axgdRs_nxvtUMW_GtDR3NkmS2xzZcbtyhf_Ds8CZr8iPLrHo58zqXdnwbm5iUwWyZUYAEmY7INUiKrJNB7eq3utXdMbFG3J8E5s7ehmriTyULvbrYKRoEBizcUPeCsOLixqr_byXx7JGnZ4xcpZlrEDLRsVocaT/s2048/MPLS%20street%20at%20night%20Oct%202022.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1536" data-original-width="2048" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh_fOfEsJhcunRU0AM6iHSJHPDtPcwp8axgdRs_nxvtUMW_GtDR3NkmS2xzZcbtyhf_Ds8CZr8iPLrHo58zqXdnwbm5iUwWyZUYAEmY7INUiKrJNB7eq3utXdMbFG3J8E5s7ehmriTyULvbrYKRoEBizcUPeCsOLixqr_byXx7JGnZ4xcpZlrEDLRsVocaT/w640-h480/MPLS%20street%20at%20night%20Oct%202022.jpg" width="640" /></a></div><br /><br />
<p class="MsoNormal"><o:p> </o:p>The Crumbley verdict is in and in the usual manner – the
media is either celebrating it or bothered by it. The bothered response is more muted this time
– probably because Americans have been conditioned to see national court cases
as vindication or rejection of whatever moral position they seem to have on the
issue. Without reading the court transcript – media reports suggest that the
prosecution in the case portrayed Jennifer Crumbley as a distracted mother who
did not pay adequate attention to her son – 15-year-old Ethan Crumbley’s mental
status. If she had - he would not have had access to the 9mm semiautomatic handgun that he used in the Oxford
school shootings. On November 30, 2021 –
he shot and killed 4 students and wounded 7.
The jury agreed with the prosecution despite Ms. Crumbley’s statement: "You
never would think you'd have to protect your child from harming somebody else. That’s
what blew my mind. That was the hardest I had to stomach is that my child
harmed and killed other people." She
was found guilty of 4 counts of involuntary manslaughter and the sentence is
pending. </p><p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal">Jennifer Crumbley is of course right.<span style="mso-spacerun: yes;"> </span>Professionals charged with assessing the
potential for harming others cannot accomplish this task with any degree of
certainty.<span style="mso-spacerun: yes;"> </span>Should untrained parents be
held to that standard, especially when they are emotionally involved with the
children they are supposed to assess?<span style="mso-spacerun: yes;"> </span>A
summary of her court testimony is available from several sites at this point.
It focuses on testimony and texts that suggest her son was having difficulty at
school and that other people noticed he was moody and depressed. The parents
were called in by school officials because they had noticed violent content in
his drawings, but after a meeting they did not insist that he be removed from
school.<span style="mso-spacerun: yes;"> </span>I do not know the school
professionals involved – but if there was that level of concern – why not
insist that the parents take their son home and give them a clear plan of care?
<o:p></o:p></p>
<p class="MsoNormal">With any criminal proceeding there are always a lot of
discrepancies. <span style="mso-spacerun: yes;"> </span>Jennifer Crumbley denied
that her son was symptomatic (hearing voices and depressed).<span style="mso-spacerun: yes;"> </span>She denied knowing anything about his
preoccupation with violent thoughts.<span style="mso-spacerun: yes;"> Ethan</span> Crumbley apparently intentionally injured birds and enjoyed doing
that.<span style="mso-spacerun: yes;"> </span>I do not know if the parents were
aware of this or not. There was some debate about the family’s health insurance
situation.<span style="mso-spacerun: yes;"> </span>Coverage for Ethan lapsed
when his father lost his job and his mother was trying to enroll him during the
next enrollment period in her plan. There is also the question of what is generally available for emergency psychiatric care for a 15 yr old. I don't know if that was bought up during the hearings or not. I can't speak to what is available in that specific area, but I can say that it is generally non-existent throughout much of the country. <o:p></o:p></p>
<p class="MsoNormal">There is some opinion in the media right now that this trial
is precedent setting in that it may translate to parents being held responsible
for the crimes of their children. Although I am not a lawyer – to me the
precedent seems to already have been set – parents are not responsible for the
crimes of their children.<span style="mso-spacerun: yes;"> </span>There have
been other parents convicted in cases where their children were involved in
school shootings.<span style="mso-spacerun: yes;"> </span>In one case the mother
of a 6-year-old who shot his teacher was sentenced to 21 months, but that was
for illegally obtaining a firearm by denying a that she had a drug
problem.<span style="mso-spacerun: yes;"> </span>In the other case, a father of
a shooter who killed 7 people was eventually charged with 7 counts of reckless
conduct for assisting his son in obtaining a firearm license even when he had
expressed thoughts about killing himself and others.<o:p></o:p></p>
<p class="MsoNormal">The critical events in the Crumbley case seem to be the
parent purchasing the handgun for their son as a way to lift his spirits, not
securing the gun when he was not under their direct supervision, and the two
meetings at school on the day before and the day of the shooting. On the first
of those days there was concern that he was researching ammunition on his phone
during class.<span style="mso-spacerun: yes;"> </span>He explained that he went
shooting with his mother and that was a hobby.<span style="mso-spacerun: yes;">
</span>The counselor called his mother who communicated by text and joked that
he had to learn to not get caught.<span style="mso-spacerun: yes;"> </span>On
the day of the shooting, his parents were called in after he was seen watching
a violent video in class, drawing guns and a bleeding body on a math worksheet
and writing several nihilistic statements. The counselor was concerned that he
might be suicidal. During the meeting the Dean of Students brought in Ethan’s
back pack but nobody searched it.<span style="mso-spacerun: yes;"> </span>The
handgun was in the backpack.<span style="mso-spacerun: yes;"> H</span>e
returned to school from that meeting with his backpack and started the shooting (2). <span style="mso-spacerun: yes;"> </span><o:p></o:p></p>
<p class="MsoNormal">In a related matter – there is a civil suit but the trail of
that paperwork is difficult to follow.<span style="mso-spacerun: yes;">
</span>The original suit against the school and staff was dropped but a
subsequent suit against the counselor and Dean of Students was allowed to
proceed. There was also a lawsuit against the Michigan State police. <o:p></o:p></p>
<p class="MsoNormal">From what I know about this case so far, it appears that
Jennifer Crumbley’s trial was primarily an attack on her character. Combined
with hindsight that is a powerful approach to find someone guilty of a
crime.<span style="mso-spacerun: yes;"> </span>I looked up the definition of
involuntary manslaughter in the state of Michigan according to <a href="https://www.findlaw.com/state/michigan-law/michigan-involuntary-manslaughter-law.html">this
reference</a> it requires proving one of 2 theories:<o:p></o:p></p>
<p class="MsoNormal">1:<span style="mso-spacerun: yes;"> </span>That the deaths
were caused by grossly negligent actions of the defendant<o:p></o:p></p>
<p class="MsoNormal">2:<span style="mso-spacerun: yes;"> </span>That the defendant
neglected her duty as a parent to “exercise reasonable care to control their
minor child so as to prevent the minor child from intentionally harming others
or prevent the minor child from conducting themselves in a way that creates an
unreasonable risk of bodily harm to others.”<o:p></o:p></p><p class="MsoNormal">There is a lot of room between "gross negligence" and "reasonable care." In this case the parents were responsive to school authorities and those responses at the time satisfied those authorities to the point that they allowed Ethan to return to school. </p>
<p class="MsoNormal">Applicable laws in the State of Michigan state that handgun
purchasers must be 18 years of age to purchase from a private seller and 21
years of age to purchase from a federal licensed firearms dealer (FFL).<span style="mso-spacerun: yes;"> </span>The handgun purchase in this case occurred
when Ethan Crumbley was 15 years of age.<span style="mso-spacerun: yes;">
</span>Michigan will not have a <a href="https://www.legislature.mi.gov/documents/2023-2024/billanalysis/House/pdf/2023-HLA-0079-8865F358.pdf">safe
storage law</a> for firearms until February 13, 2024.<span style="mso-spacerun: yes;"> </span>The law mandates that unattended firearms
must be locked and unloaded and it defines crimes and penalties for problems
that occur as a result of violations defined as behavior ranging from threats
to deaths resulting from unauthorized access to that firearm.<span style="mso-spacerun: yes;"> </span>Since the Oxford school shootings occurred in
November 2021 – that law does not apply.<span style="mso-spacerun: yes;">
</span><o:p></o:p></p>
<p class="MsoNormal">The medical literature has a few studies that appear to
address the issue of age-related firearm purchases and homicide and suicide.<span style="mso-spacerun: yes;"> </span>The authors of one study (6) found no correlation between higher age requirements and homicide rates of 18-20 year olds; but discuss the
reasons why that was the case.<span style="mso-spacerun: yes;"> </span>Most of
those reasons come back to the firearm density in the United States and how
easy it is to access firearms through back channels.<span style="mso-spacerun: yes;"> </span>Any casual inspection of those firearm
density figures in the United States – shows an incredible number of firearms
even relative to <a href="https://en.wikipedia.org/wiki/Estimated_number_of_civilian_guns_per_capita_by_country">war
zones across the globe</a>. The United States <a href="https://en.wikipedia.org/wiki/List_of_countries_by_guns_and_homicide">ranks
9<sup>th</sup> in gun homicides</a>.<span style="mso-spacerun: yes;"> </span>The
8 countries ranking higher all have significant amounts of gang and cartel
related violence, some to the point that it is driving the current immigrant
crisis at the southern border. <span style="mso-spacerun: yes;"> Five of those 8 countries have the <a href="https://worldpopulationreview.com/country-rankings/crime-rate-by-country">highest crime index</a>. Four have the <a href="https://worldpopulationreview.com/country-rankings/violent-crime-rates-by-country">highest homicide rates</a>. The US has</span> the gun homicide rate of lawless <a href="https://wellcome.org/grant-funding/guidance/low-and-middle-income-countries">low and middle income</a> (LMIC) countries. <span style="mso-spacerun: yes;"> </span><o:p></o:p></p>
<p class="MsoNormal">The cultural effects of gun extremism are never discussed as
being a cause of gun violence in the United States.<span style="mso-spacerun: yes;"> </span>Over the past 50 years, gun extremists have
pushed for increasing accessibility to firearms by shall issue laws, stand your
ground laws, fewer restrictions, and loopholes that allow back door access to
firearms. In the process, common sense gun laws that were developed in the 19<sup>th</sup>
century, like city ordinances that forbade carrying guns in town have fallen by
the wayside.<span style="mso-spacerun: yes;"> </span>Some gun extremists are pushing
to eliminate domestic violence charges as a disqualifier for gun possession. In
that landscape there is a subcultural effect that (for some) guns are a legitimate
way to express anger or dissatisfaction in school or the workplace. Nobody is
standing up against that myth.<span style="mso-spacerun: yes;"> </span>If anything,
the gun extremists are rationalizing it as mental illness or not enough guns
(arm the teachers) rather than far, far too many guns.<o:p></o:p></p>
<p class="MsoNormal">That is what I think about when I think about the Jennifer Crumbley
verdict. In many ways she was set up to take a fall for 50 years of gun
extremism. Certainly, her son should have never had a handgun. But do other parents buy firearms for their children? They certainly <a href="https://www.nbcnews.com/think/opinion/christmas-card-guns-lauren-boebert-thomas-massie-start-new-culture-ncna1285709">pose them with guns</a> on Christmas cards. When I was a kid
50 years ago – no kid had one and it was the law. There was a good reason for
it and that reason was not discovered until the 21<sup>st</sup> century.<span style="mso-spacerun: yes;"> </span>Teenagers may look like adults but they do
not have the brain development or judgment of adults. Combining that with a general
culture of gun extremism and a subculture of mass shootings is a recipe for
disaster. Until we recognize the cultural effects and how guns became part of
the culture wars – we will not be able to stop this violence and loss of life. <span style="mso-spacerun: yes;"> </span></p><p class="MsoNormal">Parents may have become the next casualty.<o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal">George Dawson, MD, DFAPA<o:p></o:p></p>
<p class="MsoNormal"><br /></p><p class="MsoNormal"><b>Photo Credit</b> to my colleague Eduardo A. Colon, MD</p>
<p class="MsoNormal"><br /></p><p class="MsoNormal"><b>References:</b><o:p></o:p></p>
<p class="MsoNormal">1:<span style="mso-spacerun: yes;"> </span>El-Bawab N.<span style="mso-spacerun: yes;"> </span>Jennifer Crumbley says she wishes son had
'killed us instead' as she took stand in manslaughter trial.<span style="mso-spacerun: yes;"> </span>February 1, 2024.<span style="mso-spacerun: yes;"> </span><a href="https://abcnews.go.com/US/jennifer-crumbley-takes-stand-manslaughter-trial-tied-sons/story">https://abcnews.go.com/US/jennifer-crumbley-takes-stand-manslaughter-trial-tied-sons/story</a><o:p></o:p></p>
<p class="MsoNormal">2:<span style="mso-spacerun: yes;"> </span>Snell R.<span style="mso-spacerun: yes;"> </span>Oxford school shooting victim's family sues
Michigan State Police in latest legal challenge.<span style="mso-spacerun: yes;"> </span>October 5, 2023<span style="mso-spacerun: yes;"> </span><a href="https://www.detroitnews.com/story/news/local/michigan/2023/10/05/oxford-school-shooting-victims-family-sues-michigan-state-police/71074873007/">https://www.detroitnews.com/story/news/local/michigan/2023/10/05/oxford-school-shooting-victims-family-sues-michigan-state-police/71074873007/</a><o:p></o:p></p>
<p class="MsoNormal">3:<span style="mso-spacerun: yes;"> </span>Stack MK.<span style="mso-spacerun: yes;"> </span>What Is This Mother Really Guilty Of?<span style="mso-spacerun: yes;"> </span>New York Times.<span style="mso-spacerun: yes;"> </span>Febnruary 1, 2024. <a href="https://www.nytimes.com/2024/02/01/opinion/mother-homicide-court-crumbley.html">https://www.nytimes.com/2024/02/01/opinion/mother-homicide-court-crumbley.html</a><o:p></o:p></p>
<p class="MsoNormal">4:<span style="mso-spacerun: yes;"> </span>Strom S. Michigan
Involuntary Manslaughter Law.<span style="mso-spacerun: yes;">
</span>FindLaw.<span style="mso-spacerun: yes;"> </span>February 7, 2024. <a href="https://www.findlaw.com/state/michigan-law/michigan-involuntary-manslaughter-law.html">https://www.findlaw.com/state/michigan-law/michigan-involuntary-manslaughter-law.html</a><o:p></o:p></p>
<p class="MsoNormal">5:<span style="mso-spacerun: yes;"> </span>Associated
Press.<span style="mso-spacerun: yes;"> </span>Timeline: Key moments surrounding
the 2021 Michigan high school shooting as mother of shooter is found guilty.<span style="mso-spacerun: yes;"> </span><a href="https://www.nbcchicago.com/news/local/timeline-key-moments-surrounding-the-2021-michigan-high-school-shooting-as-mother-of-shooter-is-found-guilty/3348384/">https://www.nbcchicago.com/news/local/timeline-key-moments-surrounding-the-2021-michigan-high-school-shooting-as-mother-of-shooter-is-found-guilty/3348384/</a><span class="MsoHyperlink"><o:p></o:p></span></p>
<p class="MsoNormal">6:<span style="mso-spacerun: yes;"> </span>Moe CA, Haviland
MJ, Bowen AG, Rowhani-Rahbar A, Rivara FP. Association of Minimum Age Laws for
Handgun Purchase and Possession With Homicides Perpetrated by Young Adults Aged
18 to 20 Years. JAMA Pediatr. 2020 Nov 1;174(11):1056-1062. doi: 10.1001/jamapediatrics.2020.3182.
Erratum in: JAMA Pediatr. 2020 Nov 1;174(11):1119. PMID: 32870238; PMCID:
PMC7489426.<o:p></o:p></p><div class="separator" style="clear: both; text-align: center;"><br /></div><br /><div class="separator" style="clear: both; text-align: center;"><br /></div><br /><div class="separator" style="clear: both; text-align: center;"><br /></div><br />George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com0tag:blogger.com,1999:blog-7772182113499451603.post-10323863128384925682024-02-04T14:21:00.013-06:002024-02-18T01:37:38.707-06:00Drugs from Gas Stations and Other Notes from the Field...<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgXRw3QHhnzgtjkwHXX4a_JZgEVV_9leLbmfHX22EWucUfIIA66GQ-cOZnugQa-wycm_1Tz-9dOHxl98mNZK1lhDpO-uGEl6erXpQRfnlA2czHTRUoBsCtrbAjTRcowTvwQegxzEP9gQF4fdSlTt867XIx3vUkvaItNCTZniEwFB_LGJarQ4x6XIjkOZd00/s3339/Gas%20station%20Kratom.JPG" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="3339" data-original-width="2561" height="640" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgXRw3QHhnzgtjkwHXX4a_JZgEVV_9leLbmfHX22EWucUfIIA66GQ-cOZnugQa-wycm_1Tz-9dOHxl98mNZK1lhDpO-uGEl6erXpQRfnlA2czHTRUoBsCtrbAjTRcowTvwQegxzEP9gQF4fdSlTt867XIx3vUkvaItNCTZniEwFB_LGJarQ4x6XIjkOZd00/w490-h640/Gas%20station%20Kratom.JPG" width="490" /></a></div><br /><p></p><p class="MsoNormal"><i>The Food and Drug Administration has not approved
tianeptine for use in the United States; however, it is readily purchased in
elixir formulations online or at gas stations informally referred to as “gas
station heroin” - </i>from reference 1</p>
<p class="MsoNormal"><o:p> </o:p>I shot the photo at the top of this post at my local gas
station. A couple of months ago they
installed this neon sign advertising <i>Kratom</i> for sale and another selling
<i>Delta-10 THC</i>. Both compounds are
intoxicants and are a part of the <a href="https://real-psychiatry.blogspot.com/2018/10/drug-overdoses-as-proxy-for-drug.html">multigenerational
drug epidemic</a> that the United States finds itself in. Depending on how you are reading about it
that epidemic may seem restricted to fentanyl or in some cases amphetamines –
but make no mistake about it there is a general trend in making all intoxicants
more easily accessible and even making it seem like they are a legitimate
business. Even the fentanyl story is only partially told. The backdrop of excessive prescription opioid
prescribing is rarely told – apart from a dramatized version. The only good that has come of this is that all
the hype about medicinal cannabis seems to be rapidly dwindling along with the
lack of medical evidence that it has any such properties.</p><p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal">That brings me to the latest gas station intoxicant – tianeptine.
It was originally intended to be an antidepressant based on a very general tricyclic structure.<span style="mso-spacerun: yes;"> </span>I made the graphic below for a rapid
structural comparison with standard tricyclic antidepressants (nortriptyline)
and selective serotonin reuptake inhibitors (escitalopram). It is obviously not
structurally like either class of compounds and has a unique moiety – the 5,5
dioxo structure on the central cycloheptane ring. <o:p></o:p></p><div class="separator" style="clear: both; text-align: left;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgCU-_Z0J3542EmJX__OK3TkLxdjVwIfXkXBQETX37_bdLpaLyKLfA8erU0fDDd4Dc8jZd8l_URICTqPkNzVyCb5yzz_6b9w2J7bvEwPwOQmB6Wk3yL8sLRLbgrEPGmEbLaWQDZ2yrD6glTIwgQu6_Sk_AjaAGRmhXucjhgvYnogpNeOTT7U9PlrjECOBJb/s2242/Tianeptine%20comparison%20slide.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1132" data-original-width="2242" height="324" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgCU-_Z0J3542EmJX__OK3TkLxdjVwIfXkXBQETX37_bdLpaLyKLfA8erU0fDDd4Dc8jZd8l_URICTqPkNzVyCb5yzz_6b9w2J7bvEwPwOQmB6Wk3yL8sLRLbgrEPGmEbLaWQDZ2yrD6glTIwgQu6_Sk_AjaAGRmhXucjhgvYnogpNeOTT7U9PlrjECOBJb/w640-h324/Tianeptine%20comparison%20slide.png" width="640" /></a></div><div class="separator" style="clear: both; text-align: left;"><span style="text-align: left;"><br /></span></div><div class="separator" style="clear: both; text-align: left;"><span style="text-align: left;">In terms of receptor affinities, the first property that
jumped out at me was that tianeptine had none of the usual receptor or
transporter affinities expected of typical antidepressants in the </span><a href="https://pdsp.unc.edu/databases/kidb.php" style="text-align: left;">PDSP database</a><span style="text-align: left;">.</span><span style="text-align: left;"> </span><span style="text-align: left;">The only affinity in that data set was for
the mu opioid receptor (MOR).</span><span style="text-align: left;"> </span></div><p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p>
<table border="1" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; mso-border-alt: solid windowtext .5pt; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-yfti-tbllook: 1184;">
<tbody><tr style="mso-yfti-firstrow: yes; mso-yfti-irow: 0;">
<td style="border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.75pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.75pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">NET<o:p></o:p></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">SERT<o:p></o:p></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">DAT<o:p></o:p></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">5-HT2A<o:p></o:p></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">5-HT1A<o:p></o:p></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">MOR<o:p></o:p></p>
</td>
</tr>
<tr style="mso-yfti-irow: 1;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.75pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">tianeptine<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.75pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">-<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">>10,000<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">>10,000<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">>10,000<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">>10,000<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">383 nM<o:p></o:p></p>
</td>
</tr>
<tr style="mso-yfti-irow: 2;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.75pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">nortriptyline<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.75pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">1.8 nM<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">15 nM<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">1,140 nM<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">294 nM<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">5 nM<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
</tr>
<tr style="mso-yfti-irow: 3; mso-yfti-lastrow: yes;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.75pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">escitalopram<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.75pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">6,514 nM<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">1.1 nM<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">>10,000<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">>10,000<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">>10,000<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 66.8pt;" valign="top" width="89">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
</tr>
</tbody></table>
<p class="MsoNormal">A recent CDC report (1) describes a spike in tianeptine
ingestions and complications due to contamination from synthetic cannabinoid
receptor agonists (SCRAs) between June and November 2023. Fourteen of the 17 exposure calls involved
patients drinking an elixir called Neptune’s Fix – a mixture of tianeptine and <i>kavain</i>
or Piper methysticum root. Six of the
patients ingested other compounds including benzodiazepines, Kratom, trazodone,
tramadol, and gabapentin. Nine had
previously used tianeptine. Thirteen of the 17 patients were admitted to
intensive care units (ICU) and 7 required intubation and ventilatory
support. There were cardiovascular
complications including conduction abnormalities, hypotension, tachycardia, and
a cardiac arrest. All the patients had altered mental status.</p><p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal">Six samples of the <i>Neptune’s Fix </i>preparation from 2
of the patients were analyzed by gas chromatography-(GS-MS) and compared with a
standard database of compounds of interest.
All of the bottles were labelled tianeptine and kavain. Two of the
samples contained THC and CBD. Two of
the samples contained the SCRAs ADB-4en-PINACA and MDMB-4en-PINACA. </p><p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal">The overall message of the report is that tianeptine preparations
available as unregulated preparations can potentially be addictive and may
contain adulterants that can produce severe adverse effects requiring resuscitation
or ICU admission.<span style="mso-spacerun: yes;"> </span>This has been noted in
previous literature about SCRAs including severe psychiatric effects.<span style="mso-spacerun: yes;"> </span>There have been <a href="https://real-psychiatry.blogspot.com/2017/01/jwh-compounds-make-nejm.html">144
synthetic cannabinoids</a> identified since 2014.<span style="mso-spacerun: yes;"> </span>In some circles these compounds are referred
to as JWH compounds after the organic chemist who first synthesized and
researched them. <o:p></o:p></p>
<p class="MsoNormal">The way that tianeptine is described in the literature seems
to parallel the interests of the authors.<span style="mso-spacerun: yes;">
</span>The FDA references are uniformly negative because they are focused on
severe side effects including death and addiction. Authors who are interested
in the opioidergic system in depression will describe how it is a legal antidepressant
in several countries and minimize both potential addiction and severe side
effects. Either way it maps well onto the current American pro-drug culture.
The sheer number of new intoxicants and widespread access to these intoxicants
is staggering. Hundreds of new compounds in the past ten years.<span style="mso-spacerun: yes;"> </span>Addictive compounds readily available at gas
stations?<span style="mso-spacerun: yes;"> </span>Those compounds laced with
additional problematic intoxicants?<span style="mso-spacerun: yes;"> The so-called War on Drugs is obviously non-existent at this time. </span><o:p></o:p></p><p class="MsoNormal"><span style="mso-spacerun: yes;"></span></p><p class="MsoNormal">One of the questions I always get from people in response to
posts about contaminated, adulterated, and counterfeit intoxicants is why? Why would drug dealers or semi-legitimate
businesses want to kill off or injure their customers? What is their motivation? The most obvious one
is that they don’t care. There always
seems to be a significant number of people out there interested in a new or
higher high so demand is never a problem.
The second is marketing. In a previous
post I described a case where fentanyl was being pressed into tablets that
looked like Xanax bars and the purchasers were not only aware of that but preferred
to purchase those tablets even after directly observing them being made. A third
possibility is ignorance. People looking to find intoxicants and sell them on
the street are not medicinal chemists – even though they may talk like it. Some
of these compounds vary in potency by a factor of a hundred or a thousand. The fourth is a lack of accountability. Even the most cynical conceptualization of
the pharmaceutical industry recognizes the fact that the products are approved,
manufactured, and monitored according to standards. Manufacturers are subject
to regulatory bodies, criminal and civil liability, and accountability at the business
level from a board of directors and at the shareholder level. It is fairly easy
to find that the industry has paid tens of billions of dollars in civil and
criminal penalties over the past 30 years. None of these incentives applies at
the level of small companies marketing unapproved but unregulated drugs or
street sales of illicit drugs. For that matter it probably also does not apply
at the level of legal cannabis dispensaries. Even though legally prescribed and
regulated medications have risks – unregulated and street drug risk is much
higher. As demonstrated in this post
that risk starts with what is really in the bottle complicated by even higher
risk adulterants. <o:p></o:p></p>
<p class="MsoNormal">I always think of the former President of Mexico Vincente
Fox in these situations.<span style="mso-spacerun: yes;"> </span>When asked
about the American drug problem and the involvement of Mexico he characterized
the problem as “America’s insatiable appetite for drugs.”<span style="mso-spacerun: yes;"> </span>When I think about people going into a <i>gas
station</i> and buying Neptune’s Fix or Kratom or Delta-10 THC and not really
knowing what they are getting in the bottle – he can’t be wrong.<o:p></o:p></p>
<p class="MsoNormal">George Dawson, MD, DFAPA</p><p class="MsoNormal"><i><br /></i></p><p class="MsoNormal"><i><br /></i></p><p class="MsoNormal"><i>Supplementary:</i>
On <i>not caring</i> that I mentioned in the above post. I think there is a case to be made that the
same attitude can fuel legitimate retail sales of drugs that reinforce their
own used including alcohol, cannabis, and tobacco. Increasing liquor stores will increase
alcohol consumption by increasing access.
That increased access comes with smaller distances to liquor stores, home delivery, placing
liquor stores in proximity to other retail stores and supermarkets, and the
<a href="https://real-psychiatry.blogspot.com/2023/01/the-curious-sober-movement.html">commoditization of alcohol</a> – you will always be able to find a cheaper drink.
Since a significant portion of any population are problematic drinkers all this
increased access directly impacts them. The people that create all this access,
typically argue that the intoxicants are legal, they run a legitimate business,
and not creating all this access puts them at a disadvantage compared to other
sellers. That argument leaves out the significant
morbidity and mortality associated with alcohol and ironically that argument is
typically used when advocates are trying to legalize another intoxicant as
in: “Our new intoxicant is not as
dangerous or lethal as alcohol.”<o:p></o:p></p><p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p><p class="MsoNormal"><o:p><i>References:</i></o:p></p>
<p class="MsoNormal">1:<span style="mso-spacerun: yes;"> </span>Counts CJ, Spadaro
AV, Cerbini TA, et al. Notes from the Field: Cluster of Severe Illness from
Neptune’s Fix Tianeptine Linked to Synthetic Cannabinoids — New Jersey,
June–November 2023. MMWR Morb Mortal Wkly Rep 2024;73:89–90. DOI: <a href="http://dx.doi.org/10.15585/mmwr.mm7304a5">http://dx.doi.org/10.15585/mmwr.mm7304a5</a>.<o:p></o:p></p>
<p class="MsoNormal">2:<span style="mso-spacerun: yes;"> </span>El Zahran T,
Schier J, Glidden E, et al. Characteristics of Tianeptine Exposures Reported to
the National Poison Data System — United States, 2000–2017. MMWR Morb Mortal
Wkly Rep 2018;67:815–818. DOI: http://dx.doi.org/10.15585/mmwr.mm6730a2<o:p></o:p></p>
<p class="MsoNormal">3:<span style="mso-spacerun: yes;"> </span>Samuels BA,
Nautiyal KM, Kruegel AC, Levinstein MR, Magalong VM, Gassaway MM, Grinnell SG,
Han J, Ansonoff MA, Pintar JE, Javitch JA, Sames D, Hen R. The Behavioral
Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor.
Neuropsychopharmacology. 2017 Sep;42(10):2052-2063. doi: 10.1038/npp.2017.60.
Epub 2017 Mar 17. PMID: 28303899; PMCID: PMC5561344.<o:p></o:p></p>
<p class="MsoNormal">4:<span style="mso-spacerun: yes;"> </span>Nobile B, Ramoz N,
Jaussent I, Gorwood P, Olié E, Castroman JL, Guillaume S, Courtet P.
Polymorphism A118G of opioid receptor mu 1 (OPRM1) is associated with emergence
of suicidal ideation at antidepressant onset in a large naturalistic cohort of
depressed outpatients. Sci Rep. 2019 Feb 22;9(1):2569. doi:
10.1038/s41598-019-39622-3. PMID: 30796320; PMCID: PMC6385304.<o:p></o:p></p>
<p class="MsoNormal">5: Wikipedia contributors. Nortriptyline. Wikipedia, The
Free Encyclopedia. December 20, 2023, 17:01 UTC. Available at: <a href="https://en.wikipedia.org/w/index.php?title=Nortriptyline&oldid=1190922632">https://en.wikipedia.org/w/index.php?title=Nortriptyline&oldid=1190922632</a><o:p></o:p></p>
<p class="MsoNormal"><i>Accessed February 4, 2024.<span style="mso-spacerun: yes;"> </span>Wikipedia table was used for nortriptyline because
the PDSP database was no longer working.<o:p></o:p></i></p>
<p class="MsoNormal">6:<span style="mso-spacerun: yes;"> </span>Jelen LA, Stone
JM, Young AH, Mehta MA. The opioid system in depression. Neurosci Biobehav Rev.
2022 Sep;140:104800. doi: 10.1016/j.neubiorev.2022.104800. Epub 2022 Jul 30.
PMID: 35914624; PMCID: PMC10166717.<o:p></o:p></p>
<p class="MsoNormal">7:<span style="mso-spacerun: yes;"> </span>FDA.<span style="mso-spacerun: yes;"> </span>Tianeptine Products Linked to Serious Harm,
Overdoses, Death.<span style="mso-spacerun: yes;"> </span><a href="https://www.fda.gov/consumers/consumer-updates/tianeptine-products-linked-serious-harm-overdoses-death">https://www.fda.gov/consumers/consumer-updates/tianeptine-products-linked-serious-harm-overdoses-death</a><o:p></o:p></p>
<p class="MsoNormal">8:<span style="mso-spacerun: yes;"> </span>FDA.<span style="mso-spacerun: yes;"> </span>Tianeptine in Dietary Supplements.<span style="mso-spacerun: yes;"> </span><a href="https://www.fda.gov/food/dietary-supplement-ingredient-directory/tianeptine-dietary-supplements">https://www.fda.gov/food/dietary-supplement-ingredient-directory/tianeptine-dietary-supplements</a><o:p></o:p></p>
<p class="MsoNormal">9:<span style="mso-spacerun: yes;"> </span>FDA.<span style="mso-spacerun: yes;"> </span>FDA warns consumers not to purchase or use
Neptune’s Fix or any tianeptine product due to serious risks.<span style="mso-spacerun: yes;"> </span><a href="https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-purchase-or-use-neptunes-fix-or-any-tianeptine-product-due-serious-risks">https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-purchase-or-use-neptunes-fix-or-any-tianeptine-product-due-serious-risks</a><o:p></o:p></p><br /><p></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com6tag:blogger.com,1999:blog-7772182113499451603.post-49651596852857710322024-01-26T00:14:00.014-06:002024-02-16T01:47:52.230-06:00More Fake Xanax....<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhTw4PpMqyNLaWlvetpoxeRVP_4gT4OYqgHy44GJn1J_Tws2Ca0Pp6Fui11OoJMYI5Jpo0rGEmC-556H45U3evESrsYvQCAUEoJuj8hzMuJMZnF09-sUhl6brNLVf_uPWxssl0pFOAOsCU5vq1SPsD8e151Xn4tTQb-7FeVEddGQCRIVcUT_D_j6d2XjAwd/s1796/alprazolam%20and%20bromazolam.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1006" data-original-width="1796" height="358" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhTw4PpMqyNLaWlvetpoxeRVP_4gT4OYqgHy44GJn1J_Tws2Ca0Pp6Fui11OoJMYI5Jpo0rGEmC-556H45U3evESrsYvQCAUEoJuj8hzMuJMZnF09-sUhl6brNLVf_uPWxssl0pFOAOsCU5vq1SPsD8e151Xn4tTQb-7FeVEddGQCRIVcUT_D_j6d2XjAwd/w640-h358/alprazolam%20and%20bromazolam.png" width="640" /></a></div><br /><div class="separator" style="clear: both; text-align: left;"><p class="MsoNormal">Xanax 2 mg “bars” are currency for drug users on the
street. Xanax or alprazolam is a
benzodiazepine like drug that has been around since 1981. That was my third year in medical school and
the intense marketing of the drug had just begun. A few years later as a psychiatry resident I
attended my first American Psychiatric Association (APA) convention in Los
Angeles. As I was walking around with 2 colleagues,
we noticed a large light show that consisted of a Xanax tablet inscribed on the
wall of the convention center in bright red laser light.<o:p></o:p></p>
<p class="MsoNormal">Like all new medications there is a period of
experimentation and off label use. In
that time some extraordinary doses of alprazolam were suggested to treat panic
attacks. There was also the suggestion
that alprazolam may have special properties and that it might be an
antidepressant because it was not structurally like the other
benzodiazepines. Over time it was
apparent that it was an addicting medication that could lead to tolerance and
withdrawal phenomena in the context of dose escalation and uncontrolled
use. I have never seen any good studies
looking at the addiction potential but it is highly desired and easily
accessible on the street and has significant street value. A good comparison molecule for addiction
potential is chlordiazepoxide. It is
also in the benzodiazepine class but is considerably less potent and probably
has a much longer time to effect. Both those properties make it far less euphorigenic
and lessen the addiction potential. Over the course of my career – I have never
seen a person using excessive amounts of chlordiazepoxide and when used for
detoxification from alcohol – even in high doses – it seems to work without any
euphoria or disinhibitory effect. <o:p></o:p></p>
<p class="MsoNormal">About ten years ago, the people I was assessing at the time
described a new trend. Fentanyl was
being pressed into tablets identical to Xanax bars. I asked several people how they knew that was
true and they personally witnessed the process. Of course, you must believe
that what is described as fentanyl really is.
For safety’s sake you also must believe that these street chemists know
the difference between milligrams and micrograms. I am not recommending that
anyone believe people dealing or distributing street drugs – I am just
explaining how the people I was seeing rationalized that decision. I was seeing
a skewed sample of people who had survived the experience of taking these fake
Xanax bars. They were also not <i>risk averse</i> – but were clearly looking
for higher highs after developing tolerance to opioids, benzodiazepines, or
both. Many sought out sources of fentanyl and fake Xanax bars was only part of
that scene.<o:p></o:p></p>
<p class="MsoNormal">Fentanyl is not the only way to make fake Xanax. The MMWR (1) describes 3 cases of bromazolam
being disguised as Xanax. As can be seen
from the structures at the top of this post – both molecules
are nearly identical. The only
difference is that alprazolam has a chlorine atom at the identical location
that bromazolam has a bromine atom. Despite
the similarity – chlorine is more electronegative and would be expected to
significantly alter the electron distribution and polarity of alprazolam - so
receptor binding would probably be affected.<o:p></o:p></p>
<p class="MsoNormal">The CDC paper says that bromazolam was synthesized in 1976 –
about the time that alprazolam was originally coming on the scene. I searched
my access to the medicinal chemistry literature and did not find any papers on
synthesis of series of these compounds with different properties. I did find a much more recent paper on the
search for Novel Psychoactive Substances (NPS) in the population-based
toxicology of British Columbia over a 2 year span from August 1, 2019 to August
31, 2021. During that time the researchers
focused on identifying novel compounds and plotting the percentage of positive samples
over time. In the case of bromazolam,
the percentage of samples increased from 0% to 5% (Figure 4). The CDC paper suggests a similar very rapid
increase in bromazolam on the street as evidenced by drug seizures and deaths
over the past three years. <o:p></o:p></p>
<p class="MsoNormal">The CDC paper also describes an intentional ingestion by two
25-year-old men and a 20-year-old woman of a substance they believed was
alprazolam. It was bromazolam. All three required emergency hospitalization
after they were found unresponsive 8 hours later.. They all developed seizures and one
progressed to status epilepticus and coma. Vital signs were variable with
tachycardia, hypertension, and hyperthermia. All three were intubated for
ventilatory support. All three had myocardial damage as indicated by elevated
troponin levels. One of the men had
persistent neurological deficits (aphasia) at the time of discharge on day 11. The other man was discharged on day 4 with
hearing deficits. The woman required transfer to another hospital on day 11 due
to status epilepticus despite multiple anticonvulsant medications. She was lost to follow up. Subsequent toxicology (serum or plasma)
showed bromazolam with no fentanyl or other opioids in all of their samples.<o:p></o:p></p>
<p class="MsoNormal">The case reports from the CDC are instructive because of the
relatively catastrophic outcomes at least in the short term in otherwise
healthy young adults.. We do not know
the specifics of the ingestion and what findings were directly attributable to
the drug as opposed to secondary effects like hypoxia. The relative lack of information about the
drug suggest to me that it was abandoned in early development for some
reason. None of these are good signs in
terms of the safety of the Xanax supply available through non-prescription sources.
It seems as likely that drug distributors are likely to substitute anything
ranging from fentanyl to non-approved benzodiazepines and both can have disastrous
consequences. <o:p></o:p></p>
<p class="MsoNormal">It is no secret that there is a never-ending stream of toxic
drugs being sold on the street as intoxicants. Bromazolam as Xanax is just the
latest iteration. We are in the midst of a <a href="https://real-psychiatry.blogspot.com/2018/10/drug-overdoses-as-proxy-for-drug.html">multi-decade drug epidemic</a> fueled by a combination of unlimited demand in the United States and
various criminal and state interests set to profit immensely off this problem.
We also now have people who are spinning drug dealers and the drug supply as a
harm reduction intervention that should go unchecked on that basis. All that I can do is remind people that
suppliers of these drugs are not your friends and they cannot be trusted. The
contents of this post are just a small part of that evidence. And a sober life
is a better life so that not starting to use these drugs at the outset is the
best path. <o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal">George Dawson, MD, DFAPA<o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p><p class="MsoNormal"><i>Supplementary:<o:p></o:p></i></p><p class="MsoNormal">
</p><p class="MsoNormal">A note on nomenclature.
Alprazolam or Xanax is commonly considered a benzodiazepine but it is
not. Complex molecules have naming conventions based on IUPAC (International
Union of Pure and Applied Chemistry) nomenclature. These are complicated, require some knowledge
of organic chemistry, and are hardly ever used in the medical literature. Organic chemists and medicinal chemists have advised me that they are also hardly ever used in their professions outside of publications where they are required. Structural formulas are generally more useful for direct comparisons. Chemistry publications typically have both. </p><p class="MsoNormal">What is used is a general classification
based on structures that are more readily identified. I will illustrate what I mean using
alprazolam, bromazolam, and a classic benzodiazepine – diazepam or Valium. In the table below both the IUPAC name and the
chemical structure shows that the key difference is the 1,2,4 triazolo moiety. Moieties in organic chemistry are
recognizable parts of molecules that are typically used in naming and designing syntheses. The triazolo structure
is a 5-member ring that consists of 3 nitrogen atoms and 2 carbon atoms. It is visible in the drawings of both
alprazolam and bromazolam in the lowest part of the drawing. The blue dots in these drawings are nitrogen
atoms. Technically alprazolam and bromazolam are triazolobenzodiazepines and
diazepam is a benzodiazepine. This may account for differences at the clinical
level in terms of cross reactivity for detoxification purposes and likelihood of
certain complications – like withdrawal seizures. <o:p></o:p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgK0oPqf7hSYX3f2jPz9Gs3NQLCEwihDvuxfpp6lHFnaTL73viETLKzGCNvVJ25yPsMj75MIC139ed6WSXRqK023-pWiexVCGkgqsQl2mjVL2iI4eHb-AYfRxPZKgEOXUVAnwWgFkR63SJpLF3D1FvzFopQXkLgULrCICKKBeXhRFHSep8ihauy4BXWPRwZ/s1268/alprazolam%20bromazolam%20diazepam%20comparison.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1182" data-original-width="1268" height="596" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgK0oPqf7hSYX3f2jPz9Gs3NQLCEwihDvuxfpp6lHFnaTL73viETLKzGCNvVJ25yPsMj75MIC139ed6WSXRqK023-pWiexVCGkgqsQl2mjVL2iI4eHb-AYfRxPZKgEOXUVAnwWgFkR63SJpLF3D1FvzFopQXkLgULrCICKKBeXhRFHSep8ihauy4BXWPRwZ/w640-h596/alprazolam%20bromazolam%20diazepam%20comparison.png" width="640" /></a></div><br /><p class="MsoNormal"><i>References:</i></p>
<p class="MsoNormal">1: Ehlers PF, Deitche
A, Wise LM, et al. Notes from the Field: Seizures, Hyperthermia, and Myocardial
Injury in Three Young Adults Who Consumed Bromazolam Disguised as Alprazolam —
Chicago, Illinois. February 2023. MMWR
Morb Mortal Wkly Rep 2024;72:1392–1393. DOI: <a href="http://dx.doi.org/10.15585/mmwr.mm725253a5">http://dx.doi.org/10.15585/mmwr.mm725253a5</a><o:p></o:p></p>
<p class="MsoNormal">2: Skinnider MA,
Mérette SAM, Pasin D, Rogalski J, Foster LJ, Scheuermeyer F, Shapiro AM.
Identification of Emerging Novel Psychoactive Substances by Retrospective
Analysis of Population-Scale Mass Spectrometry Data Sets. Anal Chem. 2023 Nov
28;95(47):17300-17310. doi: 10.1021/acs.analchem.3c03451. Epub 2023 Nov 15.
PMID: 37966487.<o:p></o:p></p>
<p class="MsoNormal">3: Mérette SAM,
Thériault S, Piramide LEC, Davis MD, Shapiro AM. Bromazolam Blood
Concentrations in Postmortem Cases-A British Columbia Perspective. J Anal
Toxicol. 2023 Apr 14;47(4):385-392. doi: 10.1093/jat/bkad005. PMID: 36715069.<o:p></o:p></p>
<p class="MsoNormal">4: Wagmann L, Manier
SK, Felske C, Gampfer TM, Richter MJ, Eckstein N, Meyer MR.
Flubromazolam-Derived Designer Benzodiazepines: Toxicokinetics and Analytical
Toxicology of Clobromazolam and Bromazolam. J Anal Toxicol. 2021 Nov
9;45(9):1014-1027. doi: 10.1093/jat/bkaa161. PMID: 33048135.<o:p></o:p></p>
<p class="MsoNormal">5: Papsun DM,
Chan-Hosokawa A, Lamb ME, Logan B. Increasing prevalence of designer
benzodiazepines in impaired driving: A 5-year analysis from 2017 to 2021. J
Anal Toxicol. 2023 Nov 1;47(8):668-679. doi: 10.1093/jat/bkad036. PMID:
37338191.<o:p></o:p></p><p class="MsoNormal"><i><br /></i></p><p class="MsoNormal"><i>Graphics Credit</i></p><p class="MsoNormal">I drew the molecules in the top drawing with MolView. The thumbnails in the table are from PubChem.</p><p class="MsoNormal"><br /></p><p class="MsoNormal"><br /></p></div><p></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com1tag:blogger.com,1999:blog-7772182113499451603.post-9209263148822210082024-01-19T22:30:00.013-06:002024-02-22T11:11:32.074-06:00Is Clozapine The Most Dangerous Drug?<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg81K5N1WLp-ysdF0Fe9PhZTienVxcOzgFcNOp5FuP_qDVgFQkho-3dJ3ttst9k9UVWfTlR-TzsGQCdsljCMflsq7frasDY1TjAIde9DY3QPafMkHAUdbt838x88fpOWk-YyAzRkpQ6sDQf0Y7Y7S8sL7xh4X8EqpLo5jCxjLjbPnUkO6_Q70Ns8Q1JdgSQ/s2048/TStorm2%2008.18.2022jpg.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1536" data-original-width="2048" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg81K5N1WLp-ysdF0Fe9PhZTienVxcOzgFcNOp5FuP_qDVgFQkho-3dJ3ttst9k9UVWfTlR-TzsGQCdsljCMflsq7frasDY1TjAIde9DY3QPafMkHAUdbt838x88fpOWk-YyAzRkpQ6sDQf0Y7Y7S8sL7xh4X8EqpLo5jCxjLjbPnUkO6_Q70Ns8Q1JdgSQ/w640-h480/TStorm2%2008.18.2022jpg.jpg" width="640" /></a></div><br /><p></p><br />
<p class="MsoNormal"><i>The Times </i>came out with an article<i> </i>last week
that did not get enough commentary.<span style="mso-spacerun: yes;"> </span>In
my opinion it was sensationalized and that was evident in both the title <i>Britain’s
most dangerous prescription drug — linked to 400 deaths a year </i>and subtitle
<i>Clozapine has transformed the lives of thousands of schizophrenia patients
but its dangers are not understood, say the families of those who have died
from it(1). </i><o:p></o:p></p>
<p class="MsoNormal">A good starting point is my experience with clozapine.<span style="mso-spacerun: yes;"> </span>When I was a research fellow in 1985, I was
interested in prescribing it for people with treatment resistant
schizophrenia.<span style="mso-spacerun: yes;"> </span>Those were the days
before atypical antipsychotics.<span style="mso-spacerun: yes;"> </span>The
first atypical was risperidone and that was not approved until 1993. I applied
for compassionate use of the medication to the FDA, but I was eventually called
by the company who manufactured it at the time.<span style="mso-spacerun: yes;">
</span>They told me that they had no intention of allowing me to prescribe the
medication before it was released to the public. That was eventually done in
1989, but it was under very tight regulations. A serious and potentially fatal
adverse drug effect was agranulocytosis and that caused a number of related
deaths in Finland. That meant every prescription was on a week-to-week basis
contingent on getting a CBC with differential count. There were parameters to
hold or discontinue the medication based on the ANC or absolute neutrophil
count. There were also several other serious side effects like excessive
fatigue, somnolence, significant weight gain, metabolic syndrome, diabetes
mellitus Type 2, sialorrhea, severe constipation that could lead to bowel
obstruction, hypotension, tachycardia, and myocarditis that required close follow
up. <o:p></o:p></p>
<p class="MsoNormal">The initial expense led to tight regulation of the drug at
the state level because a significant number of patients were disabled and on
public assistance. <span style="mso-spacerun: yes;"> </span>For years I had to
complete a form stating that the patient had schizophrenia, had been tried on
other medications, and needed clozapine. Even then it had to be approved by a
clinical pharmacist who was the head of the state program. Eventually as the
medication cost decreased specific retail and institutional pharmacies took
over and were focused primarily on coordinating the blood draws and week to
week prescriptions. A generic form of clozapine was released in 1999, but in a
randomized study of changing to the generic – outcomes were worse (2).<o:p></o:p></p>
<p class="MsoNormal">In addition to treatment resistant schizophrenia, movement
disorders could be treated by changing the antipsychotic medication to
clozapine. In those early days of treatment with only typical antipsychotics <i>tardive
syndromes</i> like tardive dyskinesia, tardive akathisia and tardive
Parkinson’s were apparent.<span style="mso-spacerun: yes;"> </span>Other
refractory syndromes like tremors, torticollis, and dystonias also occurred in
routine clinical practice. The patient population I was treating at the time
often experienced severe psychosis and movement disorders at the same and had
found no effective treatment. It is difficult to explain how disruptive severe
hallucinations and delusions can be. Many of these patients required total care
and could not function independently. It was clear that they were suffering and
distressed. Clozapine often provided the first relief they experienced in
years. <o:p></o:p></p>
<p class="MsoNormal">The combination of severe psychosis and the need for close
monitoring was not an easy task for the physician. The medical complications
needed to be avoided, but many of them depended on patient self-report and even
then, a high index of suspicion by the physician. A good example is clozapine
induced myocarditis.<span style="mso-spacerun: yes;"> </span>The typical early
symptoms including tachycardia, shortness of breath, and chest pain are
commonly reported in a patient population that includes people who are heavy
smokers, overweight or obese, and may have tachycardia as a drug side effect
rather than myocarditis.<o:p></o:p></p>
<p class="MsoNormal">The Times article looks at all deaths of people taking
clozapine as well as specific complaints to the regulatory agency and concludes
that 400 people die per year (7,000 deaths since 1990 when it was licensed for
use).<span style="mso-spacerun: yes;"> </span>There are an additional 2,400 reports
of severe side effects to the Medicines and Healthcare predicts Regulatory
agency (MHRA) per year. The following paragraph is the only qualifier:<o:p></o:p></p>
<p class="MsoNormal"><i>“The figures are not conclusive proof that clozapine is
the cause of death because they record deaths of people on the drug, not simply
because of it. Those people are already seriously ill and at risk.”<o:p></o:p></i></p>
<p class="MsoNormal">The current overall death rate in the UK is 337/100,000. The
article states there are 37,000 patients in the UK taking clozapine.<span style="mso-spacerun: yes;"> </span>The expected all cause death rate in the
clozapine cohort would be about 125 per year.<span style="mso-spacerun: yes;">
</span>We know from international studies that the life expectancy of patients with schizophrenia is about 25 years shorter than the adult cohort.<span style="mso-spacerun: yes;"> </span>With a median standardized mortality ratio
(SMR) in schizophrenia of 2.58 (3) the expected death rate in this population would
be 325 per year – but with the ranges noted in this review it could significantly
higher. The limitation with the <i>Times</i> estimate is that all-cause mortality is not
noted in the article since the assumption is that all the mortality is clozapine
related. <span style="mso-spacerun: yes;"> </span><o:p></o:p></p>
<p class="MsoNormal">Are there more likely direct cardiovascular causes of death?
Newcomer and Hennekens (4) pointed out the association between severe mental
illnesses and cardiovascular disease and potential modifying factors including
cigarette smoking, decreased likelihood of medical treatment for modifiable
risk factors including undiagnosed diabetes mellitus, and decreased likelihood
of acute care for cardiac events. They also cite the lack of coordination of
care among clinicians who are treating cardiovascular morbidity and psychiatric
clinicians. <o:p></o:p></p><p class="MsoNormal">It would be useful to know if regulatory agencies had clear
thresholds for recalling dangerous drugs. The reality is far from ideal. For example the FDA <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2249657/">recalled heparin</a>
after 4 deaths and 350 adverse events, but in the case of <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC534432/">rofecoxib</a> it
missed the fact that is may have caused 88,000 to 138,000 heart attacks and
strokes. In the case of rofecoxib the
company ended up voluntarily recalling the drug. That extreme range of complications suggests
that pharmacovigilance may only be a partial solution – but a lot depends on
getting clear data and doing the correct analysis. In pharmacology there is a concept called the <i>therapeutic index </i>(see the supplementary below) defined as the difference between the therapeutic range and toxic range for a particular medication. That range can be specified as the dose or plasma level. One limitation of that approach is that it lumps broadly toxic medications with those that only affect a few individuals. See the paragraph below for further discussion. It is difficult to find a measure that applies at both the individual and population wide level. <o:p></o:p></p>
<p class="MsoNormal">The remainder of the <i>Times</i> article focuses on the
impressions of the relatives of deceased patients and a series of “more
clozapine cases” from a preventable death registry. The relatives are
understandably upset by the death of their family members and point out that
they noticed problems for some time and in one case felt that clozapine was
forced on them. <span style="mso-spacerun: yes;"> </span>In the case reports/brief
vignettes – it is not clear if clozapine was the cause of death or not.<span style="mso-spacerun: yes;"> </span>The interaction between cigarette smoking and
clozapine plasma levels was included and this is very useful information for
the public. <span style="mso-spacerun: yes;"> </span>In the case reports – coroner
findings rather than autopsy results were reported. <o:p></o:p></p>
<p class="MsoNormal">I did not have any success in locating the information that
the Times had access to at the MHRA web site, but I am familiar with <a href="https://real-psychiatry.blogspot.com/2014/02/dangerous-medications-part-one.html">previous
pharmacovigilance research in the UK</a>.<span style="mso-spacerun: yes;">
</span>That study (5) reviewed 526,186 medication incident reports over a 5-year
period from 2005 to 2010.<span style="mso-spacerun: yes;"> </span>Seventy five
percent of the reports were from acute care hospitals and the remainder from primary
care clinics. There were 271 deaths and 551 incidents with severe
outcomes.<span style="mso-spacerun: yes;"> </span>The top 5 medications in terms
of deaths were (in descending order) opioids, antibiotics, warfarin, low molecular
weight heparin, and insulin.<span style="mso-spacerun: yes;"> </span>The
psychiatric medication on the list included benzodiazepines (15 deaths) and
antipsychotics (2 deaths) accounting for 3.28% and 0.85% of the combined death
and severe outcomes. I do not have access to the clozapine prescriptions per
year or any updated pharmacovigilance data from the NRLS system. <span style="mso-spacerun: yes;"> </span>It seems likely if clozapine was really
causing hundreds of deaths in the UK someone would have flagged this and had
the drug pulled off the market. <o:p></o:p></p>
<p class="MsoNormal">Apart from the analytical flaws in this article what might
be going on? <span style="mso-spacerun: yes;"> </span>As I have written about
many times on this blog – medical decision making both on the recommendation and
acceptance side is probabilistic and there is a lot of subjectivity.<span style="mso-spacerun: yes;"> </span>It can only be approached concretely as <i>error
</i>or <i>no error</i> after decisions have been made and outcomes determined.
Even the ideal informed consent does not assure anything near a good outcome. Physicians
who have seen suboptimal or overtly problematic outcomes know this – but patients
less so and are generally hopeful that the newest treatment has something more
to offer than what they have been doing. The equivalent bias in physicians is
deciding that you are using an evidence-based treatment that is the best and
wanting to maintain your patient on it when they are getting minimal benefit, significant
side effects, or both. These decisions are complicated in the case of severe
mental illness because of cognitive effects of the illness and possibly the
medication.<span style="mso-spacerun: yes;"> </span>It requires collateral
information from people who know the person well and then another discussion
with the patient.<o:p></o:p></p>
<p class="MsoNormal">Everything suggested in the previous paragraph takes time
and more specifically – time with the most experienced member of the team. If
my name is on the prescriptions, I want to be the person having these
discussions.<span style="mso-spacerun: yes;"> </span>I want to make sure that
the patient, their family, and caregivers all know that I will never hesitate
to discontinue a medication if it is not clearly more helpful than detrimental
to the patient. <span style="mso-spacerun: yes;"> </span>I want to make sure that
every person in the room knows that at the time of the original informed
consent discussion and that they can call me at any time with concerns. I want to
make sure that I have enough medical knowledge to have the <i>low threshold</i>
for diagnosing rare but serious complications and know what to do about them as
quickly as possible. <o:p></o:p></p>
<p class="MsoNormal">In terms of a system of care whether that is in the US or
the UK, all of that can be operationalized and monitored prospectively as a
quality assurance project. <span style="mso-spacerun: yes;"> </span>Even at that
level there is a tendency of clinical and regulatory systems to be excessively
rigid.<span style="mso-spacerun: yes;"> </span>There is really no substitute for
high quality treatment adhering to this cooperative process with ample
opportunity for the patient or their surrogates to provide feedback to the responsible
psychiatric staff and make active corrections – up to and including discontinuing
clozapine - a daily opportunity.<o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal">George Dawson, MD, DFAPA<o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p><p class="MsoNormal"><o:p><i>Addendum:</i> I contacted a clinical pharmacist recently who I had worked with in the past. I offered to work on a pharmacovigilance system for the healthcare system we used to work for. I think it is the best way to get answers to these questions about the complications of medications and the associated prescribing practices. I offered to work <i>for free</i>. So far no return call. </o:p></p><p class="MsoNormal"><i>Supplementary 1:</i>
One of the classic measures of a medication that may confer higher risk
is the <i>therapeutic index</i>. Therapeutic
index is defined as the range between a therapeutic effect and a toxic
effect. Toxicity in this case can mean
severe side effects that may be irreversible including possible death. That
range could be in dosage but more precisely measured as plasma concentration. This database lists 254 narrow therapeutic
range drugs. Clozapine is not on the
list but in terms of psychiatric medications lithium, some antipsychotics, some
anticonvulsants, and tricyclic antidepressants are. Inspecting the list shows immediate
limitations. The chemotherapeutic agents
listed are clearly more toxic than most of the other medications. Non-steroidal anti-inflammatory drugs or
NSAIDs are not listed despite significant mortality and morbidity. Acetaminophen is not listed despite it being
a leading cause of hepatic toxicity, liver transplantation and overdose death.<o:p></o:p></p><p class="MsoNormal">From a personal standpoint - I currently take 2 of the drugs on this list and use acetaminophen exclusively for pain.</p><p class="MsoNormal"><o:p>
</o:p></p><p class="MsoNormal"><a href="https://go.drugbank.com/categories/DBCAT003972">https://go.drugbank.com/categories/DBCAT003972</a><o:p></o:p></p>
<p class="MsoNormal"><i><br /></i></p><p class="MsoNormal"><i>References:</i></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal">1:<span style="mso-spacerun: yes;"> </span>O’Neill S.<span style="mso-spacerun: yes;"> </span>Britain’s most dangerous prescription drug —
linked to 400 deaths a year.<span style="mso-spacerun: yes;"> </span>The Times,
Sunday January 14, 2024.<o:p></o:p></p>
<p class="MsoNormal">2:<span style="mso-spacerun: yes;"> </span>Kluznik JC, Walbek
NH, Farnsworth MG, Melstrom K. Clinical effects of a randomized switch of
patients from clozaril to generic clozapine. J Clin Psychiatry. 2001;62 Suppl
5:14-7; discussion 23-4. PMID: 11305843.<o:p></o:p></p>
<p class="MsoNormal">3:<span style="mso-spacerun: yes;"> </span>Bushe CJ, Taylor
M, Haukka J. Mortality in schizophrenia: a measurable clinical endpoint. J
Psychopharmacol. 2010 Nov;24(4 Suppl):17-25. doi: 10.1177/1359786810382468.
PMID: 20923917; PMCID: PMC2951589.<o:p></o:p></p>
<p class="MsoNormal">4:<span style="mso-spacerun: yes;"> </span>Newcomer JW,
Hennekens CH. Severe mental illness and risk of cardiovascular disease. JAMA.
2007 Oct 17;298(15):1794-6. doi: 10.1001/jama.298.15.1794. PMID: 17940236.<o:p></o:p></p>
<p class="MsoNormal">5:<span style="mso-spacerun: yes;"> </span>Cousins DH,
Gerrett D, Warner B. A review of medication incidents reported to the National
Reporting and Learning System in England and Wales over 6 years (2005-2010). Br
J Clin Pharmacol. 2012 Oct;74(4):597-604. doi:
10.1111/j.1365-2125.2011.04166.x. PMID: 22188210; PMCID: PMC3477327.<o:p></o:p></p>
<p class="MsoNormal">6: <span style="mso-spacerun: yes;"> </span>Alvir JM,
Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA. Clozapine-induced
agranulocytosis. Incidence and risk factors in the United States. N Engl J Med.
1993 Jul 15;329(3):162-7. doi: 10.1056/NEJM199307153290303. PMID: 8515788.<o:p></o:p></p>
<p class="MsoNormal">7: <span style="mso-spacerun: yes;"> </span>La Grenade L,
Graham D, Trontell A. Myocarditis and cardiomyopathy associated with clozapine
use in the United States. N Engl J Med. 2001 Jul 19;345(3):224-5. doi:
10.1056/NEJM200107193450317. PMID: 11463031.<o:p></o:p></p>
<p class="MsoNormal">8: <span style="mso-spacerun: yes;"> </span>Siskind D, Sidhu
A, Cross J, Chua YT, Myles N, Cohen D, Kisely S. Systematic review and
meta-analysis of rates of clozapine-associated myocarditis and cardiomyopathy.
Aust N Z J Psychiatry. 2020 May;54(5):467-481. doi: 10.1177/0004867419898760.
Epub 2020 Jan 20. PMID: 31957459.<o:p></o:p></p>
<p class="MsoNormal">9:<span style="mso-spacerun: yes;"> </span>Medicines and
Healthcare products Regulatory Agency (MHRA) Drug Safety alerts issued on
clozapine<span style="mso-spacerun: yes;"> </span><a href="https://www.gov.uk/drug-safety-update?keywords=clozapine">https://www.gov.uk/drug-safety-update?keywords=clozapine</a><span style="mso-spacerun: yes;"> </span>Previous alerts issued on the risk and
dangers of smoking cessation, metabolic syndrome and weight gain, therapeutic
drug monitoring, intestinal obstruction, and drug interactions. All published
2020 or earlier.<o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p><p class="MsoNormal"><o:p><i>Photo Credit:</i></o:p></p><p class="MsoNormal"><o:p>Eduardo Colon, MD - much appreciated. </o:p></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com4tag:blogger.com,1999:blog-7772182113499451603.post-88632437243165983562024-01-16T12:59:00.006-06:002024-01-17T00:30:24.970-06:00 Serotonin Research Marches On or Why the Michaelis-Menten Equation is Important to Psychiatrists<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj_SHR66c3PsbWeLo2AVPAK_MGZy3B4q9tAtJ6_sdIksCleljcoN_ZaA1NeABum0jpAcHd94xld50qID_if5O4XqPEYTwGTxuYDR93Sd0AE6fANOeLLMFkAIWodpXcy6dN9oUh3dPn4DJwAslzc4shzwOY_jNCVc4EAVXOfmLhOO6Tt3DJ3J7-1GGgPney4/s1434/5-HT%20to%20quinoneimine.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="808" data-original-width="1434" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj_SHR66c3PsbWeLo2AVPAK_MGZy3B4q9tAtJ6_sdIksCleljcoN_ZaA1NeABum0jpAcHd94xld50qID_if5O4XqPEYTwGTxuYDR93Sd0AE6fANOeLLMFkAIWodpXcy6dN9oUh3dPn4DJwAslzc4shzwOY_jNCVc4EAVXOfmLhOO6Tt3DJ3J7-1GGgPney4/w640-h360/5-HT%20to%20quinoneimine.png" width="640" /></a></div><span style="font-family: arial;">As the old saying goes – the demise of serotonin (5-HT) in the psychiatric literature has been greatly exaggerated. Another worthwhile proposition would be to get to know the detractors and their work as well as the basic scientists doing the research. The criticism is predictable after a while. I made a <a href="https://real-psychiatry.blogspot.com/2015/05/the-heuristic-is-dead-long-live.html">comment about this back in 2015</a> and charted the Medline references for major depression and serotonin. The update of that chart is below and there has not been a steep decline in references to serotonin in depression. There are roughly three times as many serotonin references per year for psychiatric disorders. When you read the introductions to these papers – there is generally a restatement of the importance of serotonin in psychiatric disorders up to stating that serotonergic signaling is indispensable in considering antidepressant drug development. The bulk of this research is not done by psychiatrists – but by basic scientists interested in the study of mental disorders. That is the focus of this post.</span><p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhy_nGjQgINvbFd9Dv_Xv09J6Lbd1iwObF8u3uFnUjFzM15DmGNanOD5TmBkYcdV10I0-ebAzXe73TpygRKzmSIJIkIduXSHEnl3pM3fcrAtwEEEacrq57fGhyphenhyphenIfslTMwhCYHVBsWtmWbjnSE8eH3ab0_6htFzMsUyr8Xs-_2mV1lwyI2eYLHbpLaFA0Hjl/s1552/5HT%20Medline%20references.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="757" data-original-width="1552" height="312" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhy_nGjQgINvbFd9Dv_Xv09J6Lbd1iwObF8u3uFnUjFzM15DmGNanOD5TmBkYcdV10I0-ebAzXe73TpygRKzmSIJIkIduXSHEnl3pM3fcrAtwEEEacrq57fGhyphenhyphenIfslTMwhCYHVBsWtmWbjnSE8eH3ab0_6htFzMsUyr8Xs-_2mV1lwyI2eYLHbpLaFA0Hjl/w640-h312/5HT%20Medline%20references.png" width="640" /></a></div><p></p><p class="MsoNormal">The paper today (1) was of great interest to me for several
reasons.<span style="mso-spacerun: yes;"> </span>First, it was focused on
antidepressant mechanism of action and area that needs more work.<span style="mso-spacerun: yes;"> </span>Second, it employed physical chemistry
techniques (voltammetry and reaction kinetics) that have been of great interest
to me since I was exposed to them as a Physical Chemistry (PChem) undergraduate.<span style="mso-spacerun: yes;"> </span>Third, it discusses a system of 5-HT reuptake
that is relatively unknown to most psychiatrists – but clearly important.<span style="mso-spacerun: yes;"> </span>I hope to explain it all and provide the
necessary references for further study.<span style="mso-spacerun: yes;">
</span>And finally, it is the product of a lab and collaborators with a high
level of expertise in physiological chemistry including the technology
necessary for accurate measurement. I am referring to Hashemi Lab. That contrasts significantly with many
critics of serotonin work who have no similar expertise and typically do not do
original research in the field.</p><p class="MsoNormal"><o:p></o:p></p>
<p class="MsoNormal">Starting with the serotonergic systems – the paper is
focused on extracellular 5-HT signaling as a common feature of antidepressant
medications.<span style="mso-spacerun: yes;"> </span>Models of this process have
been around for a long time.<span style="mso-spacerun: yes;"> </span>A basic
assumption of the model is that presynaptic serotonin transporter (SERT)
terminates serotonergic neurotransmission by reuptake 5-HT from the synaptic
cleft to the intracellular space of the presynaptic neuron. One action of
antidepressants studied over the past three decades has been to block that process.<span style="mso-spacerun: yes;"> </span>When fluoxetine was initially marketed, there
was an emphasis on this process and the term selective serotonin reuptake
inhibitors (SSRIs) was born. As assays become more sensitive, it was shown that
medications from some other classes of antidepressants also blocked 5-HT reuptake.<span style="mso-spacerun: yes;"> </span><o:p></o:p></p>
<p class="MsoNormal">The authors describe two uptake systems.<span style="mso-spacerun: yes;"> </span>Uptake 1 consists of SERT and is
characterized as a high affinity low-capacity system. Uptake 2 consists of
norepinephrine transporter (NET), dopamine transporter (DAT), organic cation
transporter (OCT), and plasma membrane monoamine transporter (PMAT) as a low
affinity high-capacity system.<span style="mso-spacerun: yes;"> </span>There has
been a common view that transporters are restricted to blocking reuptake of the
named substance (ie. DAT will only transport dopamine).<span style="mso-spacerun: yes;"> </span>More recently it was discovered that these
proteins are not specific and will transport other monoamines.<span style="mso-spacerun: yes;"> </span>5-HT is taken up in both streams Uptake 1 via
SERT and Uptake 2 by DAT, NET, OCT, and PMAT.<span style="mso-spacerun: yes;">
</span>Characteristics of both systems are listed in the tables below.<o:p></o:p></p>
<table border="1" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; mso-border-alt: solid windowtext .5pt; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-yfti-tbllook: 1184;">
<tbody><tr style="mso-yfti-firstrow: yes; mso-yfti-irow: 0;">
<td style="border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">Transporter<o:p></o:p></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.9pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.9pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
</tr>
<tr style="mso-yfti-irow: 1;">
<td colspan="4" style="background: rgb(251, 228, 213); border-top: none; border: 1pt solid windowtext; mso-background-themecolor: accent2; mso-background-themetint: 51; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 467.5pt;" valign="top" width="623">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="color: black; mso-color-alt: windowtext;">Uptake
1</span><o:p></o:p></p>
</td>
</tr>
<tr style="mso-yfti-irow: 2;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">SERT<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.9pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.9pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
</tr>
<tr style="mso-yfti-irow: 3;">
<td colspan="4" style="background: rgb(251, 228, 213); border-top: none; border: 1pt solid windowtext; mso-background-themecolor: accent2; mso-background-themetint: 51; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 467.5pt;" valign="top" width="623">
<p align="center" class="MsoNormal" style="line-height: normal; margin-bottom: 0in; text-align: center;"><span style="color: black; mso-color-alt: windowtext;">Uptake
2</span><o:p></o:p></p>
</td>
</tr>
<tr style="mso-yfti-irow: 4;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">NET<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.9pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.9pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
</tr>
<tr style="mso-yfti-irow: 5;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">DAT<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.9pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.9pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
</tr>
<tr style="mso-yfti-irow: 6;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">OCT<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.9pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.9pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
</tr>
<tr style="mso-yfti-irow: 7; mso-yfti-lastrow: yes;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;">PMAT<o:p></o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.9pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 116.9pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><o:p> </o:p></p>
</td>
</tr>
</tbody></table>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal">Despite observed clinical differences in antidepressants,
physicians are generally taught to think of them by general class based on
binding studies.<span style="mso-spacerun: yes;"> </span>There is a tendency to
view all antidepressants within a class as having the same mechanism of
action.<span style="mso-spacerun: yes;"> </span>That illusion of equivalency can
give the impression that within a class – they are interchangeable apart from
pharmacokinetic parameters (half-life, time to max concentration, etc) and side
effects commonly attributed to effects at other receptors.<o:p></o:p></p>
<p class="MsoNormal">The more specific mechanism of action of antidepressants at
the binding site is often not mentioned.<span style="mso-spacerun: yes;">
</span>Reuptake proteins can be bound allosterically and orthosterically
(3).<span style="mso-spacerun: yes;"> </span>Orthosteric ligands bind to the
protein at the site of the natural endogenous ligand of interest - in this case
serotonin. Allosteric ligands or modulators bind to the protein at sites that
are peripheral to the site of interest and can be positive, negative, or silent
modulators based on their effect on their effect on the orthosteric ligand. In
some cases, a molecule can be both an allosteric and orthosteric modulator. In
the case of antidepressant medications that is true for escitalopram.<span style="mso-spacerun: yes;"> </span>Studying the complexity of 5-HT reuptake
systems has the potential to clarify mechanisms and potentially look at
mechanisms that remain unclear such as antidepressant withdrawal symptoms. <o:p></o:p></p>
<p class="MsoNormal">The main technology used in this study was fast scan cyclic
voltammetry (FSCV) to estimate the extracellular 5-HT in the hippocampus of
mice where 5-HT release has been stimulated via the median forebrain bundle
(MFB). <span style="mso-spacerun: yes;"> </span>FSCV is a technique where an
electrical current is applied and it oxidizes the compound in solution at the
electrode surface.<span style="mso-spacerun: yes;"> </span>Major
neurotransmitters like 5-HT, dopamine (DA), and norepinephrine (NE) oxidize
under these circumstances and the resulting current flow can be used to
estimate concentration.<span style="mso-spacerun: yes;"> </span>The lab involved
in the study and principal investigator developed the measurement technology
and calibrated it against standardized solutions of 5-HT (4) so that the control
detection was a clean square wave signal in a flow cell. <o:p></o:p></p>
<p class="MsoNormal">The authors performed FSCV analysis – pre and post drug in
the same mice and applied Michaelis-Menten (M-M) analysis of the resulting
curves from these experiments.<span style="mso-spacerun: yes;"> </span>The M-M
equation was originally derived to study enzyme kinetics.<span style="mso-spacerun: yes;"> </span>It shows the relationship between initial
reaction velocity to maximal velocity for a certain enzyme and substrate.<span style="mso-spacerun: yes;"> </span>The M-M equation is given below: <o:p></o:p></p>
<br />
<p class="MsoNormal"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEjMJLg1AW_NHsfwEVI5V_UjGQaWUwaII51L_srWcoLIuliMh1l-m8lQtY_qd71ACU5zJQcSEYBh21supvAyy2Ad88UD7Gnwjh7EHp6fBVjOp6qMkfwNuR3Voyuz5MMPIFH1ZVfDfgkqb--66a-iYCaHV67R7w8_OmTOv4qEJq5n7polrrQqh0DGc-rszOZm" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="438" data-original-width="1044" height="269" src="https://blogger.googleusercontent.com/img/a/AVvXsEjMJLg1AW_NHsfwEVI5V_UjGQaWUwaII51L_srWcoLIuliMh1l-m8lQtY_qd71ACU5zJQcSEYBh21supvAyy2Ad88UD7Gnwjh7EHp6fBVjOp6qMkfwNuR3Voyuz5MMPIFH1ZVfDfgkqb--66a-iYCaHV67R7w8_OmTOv4qEJq5n7polrrQqh0DGc-rszOZm=w640-h269" width="640" /></a></div><br />In enzyme work, M-M equations are
typically analyzed graphically (<i><span style="font-family: "Cambria Math",serif; font-size: 14pt; line-height: 107%; mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">y = mx + b</span></i>)
plotting <i><span style="font-family: "Cambria Math",serif; font-size: 14pt; line-height: 107%; mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">v<sub>ο</sub></span></i> vs [<i><span style="font-family: "Cambria Math",serif; font-size: 14pt; line-height: 107%; mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">S
</span></i>] or the inverse of <i><span style="font-family: "Cambria Math",serif; font-size: 14pt; line-height: 107%; mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">1/v<sub>ο</sub></span></i>
vs <i><span style="font-family: "Cambria Math",serif; mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">1/[S]</span></i>
to determine <i><span style="font-family: "Cambria Math",serif; font-size: 14pt; line-height: 107%; mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">V<sub>max</sub></span></i>
and <i><span style="font-family: "Cambria Math",serif; font-size: 14pt; line-height: 107%; mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">K<sub>M</sub></span></i>.<p></p>
<p class="MsoNormal"><span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">In previous work the authors developed an
expression for M-M kinetics for two reuptake mechanisms (7):<o:p></o:p></span></p>
<p class="MsoNormal"><span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;"><o:p> </o:p></span></p><p class="MsoNormal"><span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;"></span></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgoJt4ctHJUAtAa3fey3vLTz4rrBwlDP6Y5YZyBbd63wg2MAX_YN1udl5xYShugAHCSSqK2nmC123njQhY4aVV11qZbgvxeCS-BCCa9md4KHWDKY_4cgt7xbcg_Ooh92uvmgCfg2EQRfVCRpjyzIcsn3VmVuF0AR0N9qRFMIMsi6a1-1b-oEvfhXGf1AySq/s1064/MM%20complex%20eqn.png" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="144" data-original-width="1064" height="54" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgoJt4ctHJUAtAa3fey3vLTz4rrBwlDP6Y5YZyBbd63wg2MAX_YN1udl5xYShugAHCSSqK2nmC123njQhY4aVV11qZbgvxeCS-BCCa9md4KHWDKY_4cgt7xbcg_Ooh92uvmgCfg2EQRfVCRpjyzIcsn3VmVuF0AR0N9qRFMIMsi6a1-1b-oEvfhXGf1AySq/w400-h54/MM%20complex%20eqn.png" width="400" /></a></div><br /><o:p><br /></o:p><p></p>
<p class="MsoNormal"><!--[if gte vml 1]><o:wrapblock><v:shape id="Picture_x0020_1"
o:spid="_x0000_s1026" type="#_x0000_t75" style='position:absolute;
margin-left:0;margin-top:-22.8pt;width:267.8pt;height:36pt;z-index:251658240;
visibility:visible;mso-wrap-style:square;mso-width-percent:0;
mso-wrap-distance-left:9pt;mso-wrap-distance-top:0;mso-wrap-distance-right:9pt;
mso-wrap-distance-bottom:0;mso-position-horizontal:absolute;
mso-position-horizontal-relative:text;mso-position-vertical:absolute;
mso-position-vertical-relative:text;mso-width-percent:0;mso-width-relative:margin'>
<v:imagedata src="file:///C:/Users/dawso/AppData/Local/Temp/msohtmlclip1/01/clip_image009.emz"
o:title=""/>
<w:wrap type="topAndBottom"/>
</v:shape><![endif]--><!--[if !vml]--><span style="mso-ignore: vglayout;">
</span></p><table align="left" cellpadding="0" cellspacing="0">
<tbody><tr>
<td height="0" width="30"></td>
</tr>
<tr>
<td></td>
<td><br /></td>
</tr>
</tbody></table><span style="mso-ignore: vglayout;">
</span><!--[endif]--><!--[if gte vml 1]></o:wrapblock><![endif]--><br clear="ALL" style="mso-ignore: vglayout;" />
<span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;"><o:p></o:p></span><p></p>
<p class="MsoNormal"><span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">Where:<o:p></o:p></span></p>
<p class="MsoNormal"><i><span style="font-family: "Cambria Math",serif; font-size: 14pt; line-height: 107%; mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">R(t)</span></i><span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;"> = rate of release<o:p></o:p></span></p>
<p class="MsoNormal"><i><span style="font-family: "Cambria Math",serif; font-size: 14pt; line-height: 107%; mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">A(t)</span></i><span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;"> = fraction of
stimulated autoreceptors<o:p></o:p></span></p>
<p class="MsoNormal"><i><span style="font-family: "Cambria Math",serif; font-size: 14pt; line-height: 107%; mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">V<sub>max1</sub>, V<sub>max2</sub></span></i><span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">
= M-M </span><span style="font-family: "Cambria Math",serif; mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">Vmax</span><span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">
for each of the reuptake mechanisms (1-slow, 2-fast)<o:p></o:p></span></p>
<p class="MsoNormal"><i><span style="font-family: "Cambria Math",serif; font-size: 14pt; line-height: 107%; mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">K<sub>m1</sub>, K<sub>m2</sub></span></i><span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">
= Michaelis constant for each reuptake mechanism (1-slow, 2-fast) <o:p></o:p></span></p>
<p class="MsoNormal"><i><span style="font-family: "Cambria Math",serif; font-size: 14pt; line-height: 107%; mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">α</span></i><span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;"> and </span><i><span style="font-family: "Cambria Math",serif; font-size: 14pt; line-height: 107%; mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">β</span></i><span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">
are constants to differentially weight the reuptake mechanisms individually and
synergistically <o:p></o:p></span></p>
<p class="MsoNormal"><span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">In their paper the authors found that
escitalopram, fluoxetine, reboxetine, and ketamine all decreased 5-HT reuptake and
increased extracellular 5-HT.<span style="mso-spacerun: yes;"> </span>They have
an excellent graphic of their results as Figure S2 in the Supporting
information (10).<span style="mso-spacerun: yes;"> </span>Using the M-M
analysis, fluoxetine followed an orthosteric Uptake 1 mechanism.<span style="mso-spacerun: yes;"> </span>Reboxetine followed an Uptake 2 mechanism.
Escitalopram did not fit the standard M-M analysis suggesting a more complex mechanism
due to the combination of allosteric and orthosteric effects as well as SERT
trafficking (overexpression and internalization). Ketamine indirectly increased
extracellular 5-HT by effects of histamine.<span style="mso-spacerun: yes;">
</span>In view of their results, the authors conclude that the direct measurement
of serotonin may be an indicator of antidepressant potential.<o:p></o:p></span></p>
<p class="MsoNormal"><span style="mso-fareast-font-family: "Times New Roman"; mso-fareast-theme-font: minor-fareast;">To me this is a landmark work.<span style="mso-spacerun: yes;"> </span>Just the brief list of references below
indicates very active research in this area.<span style="mso-spacerun: yes;">
</span>It shows the amount of complexity involved in signaling at the neuronal
level. The authors speculate that in one case the suggested superior efficacy
of escitalopram may reflect the unique mechanism of action that they suggest. It
also suggests that a much more sophisticated approach is necessary when reading
the antidepressant literature. Are the suggested mechanisms of action for
ketamine through NMDA really the primary mechanism of action or is it the
effects of inhibitory H3 receptors on 5-HT neurons?<span style="mso-spacerun: yes;"> </span>And what about the issue of antidepressant withdrawal
phenomenon?<span style="mso-spacerun: yes;"> </span>Do the new pharmacodynamic insights
provided by the research have implications for withdrawal?<span style="mso-spacerun: yes;"> </span>That area has been primarily addressed by pharmacokinetics
in the past. <span style="mso-spacerun: yes;"> </span>Finally – even though we
have been getting glimpses of the importance of 5-HT over the past 70 years,
the complexity has not been sorted out. Contrary to some opinions – the is an exciting
area of research and the people involved are doing brilliant work. It raises
the bar for those engaged in clinical work interested in the associated
pathophysiology and pharmacology. <o:p></o:p></span></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal">George Dawson, MD, DFAPA<o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p>
<p class="MsoNormal">References:<o:p></o:p></p>
<p class="MsoNormal">1:<span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span>Witt CE, Mena S, Holmes J, Hersey M, Buchanan
AM, Parke B, Saylor R, Honan LE, Berger SN, Lumbreras S, Nijhout FH, Reed MC,
Best J, Fadel J, Schloss P, Lau T, Hashemi P. Serotonin is a common thread
linking different classes of antidepressants. Cell Chem Biol. 2023 Dec
21;30(12):1557-1570.e6. doi: 10.1016/j.chembiol.2023.10.009. Epub 2023 Nov 21.
PMID: 37992715.<o:p></o:p></p>
<p class="MsoNormal">2:<span style="mso-spacerun: yes;"> </span>Hexter M, van
Batenburg-Sherwood J, Hashemi P. Novel Experimental and Analysis Strategies for
Fast Voltammetry: 2. A Troubleshoot-Free Flow Cell for FSCV Calibrations. ACS
Meas Sci Au. 2023 Jan 11;3(2):120-126. doi: 10.1021/acsmeasuresciau.2c00059.
PMID: 37090258; PMCID: PMC10120031.<o:p></o:p></p>
<p class="MsoNormal">3:<span style="mso-spacerun: yes;"> </span>John CE, Jones SR.
Fast Scan Cyclic Voltammetry of Dopamine and Serotonin in Mouse Brain Slices.
In: Michael AC, Borland LM, editors. Electrochemical Methods for Neuroscience.
Boca Raton (FL): CRC Press/Taylor & Francis; 2007. Chapter 4. Available
from: https://www.ncbi.nlm.nih.gov/books/NBK2579/<o:p></o:p></p>
<p class="MsoNormal">4:<span style="mso-spacerun: yes;"> </span>Stucky C, Johnson
MA. Improved Serotonin Measurement with Fast-Scan Cyclic Voltammetry:
Mitigating Fouling by SSRIs. J Electrochem Soc. 2022 Apr;169(4):045501. doi:
10.1149/1945-7111/ac5ec3. Epub 2022 Apr 11. PMID: 36157165; PMCID: PMC9491377.<o:p></o:p></p>
<p class="MsoNormal">5:<span style="mso-spacerun: yes;"> </span>Jiang C, He X,
Wang Y, Chen CJ, Othman Y, Hao Y, Yuan J, Xie XQ, Feng Z. Molecular Modeling
Study of a Receptor–Orthosteric Ligand–Allosteric Modulator Signaling Complex.
ACS Chemical Neuroscience. 2023 Jan 24;14(3):418-34.<o:p></o:p></p>
<p class="MsoNormal">6:<span style="mso-spacerun: yes;"> </span>Weber BL, Beaver
JN, Gilman TL. Summarizing studies using constitutive genetic deficiency to
investigate behavioural influences of uptake 2 monoamine transporters. Basic
Clin Pharmacol Toxicol. 2023 Nov;133(5):439-458. doi: 10.1111/bcpt.13810. Epub
2022 Nov 20. PMID: 36316031; PMCID: PMC10657738.<o:p></o:p></p>
<p class="MsoNormal">7:<span style="mso-spacerun: yes;"> </span>Wood KM, Zeqja A,
Nijhout HF, Reed MC, Best J, Hashemi P. Voltammetric and mathematical evidence
for dual transport mediation of serotonin clearance in vivo. J Neurochem. 2014
Aug;130(3):351-9. doi: 10.1111/jnc.12733. Epub 2014 Apr 26. PMID: 24702305; PMCID:
PMC4107184.<o:p></o:p></p>
<p class="MsoNormal">8:<span style="mso-spacerun: yes;"> </span>Bunin MA, Wightman
RM. Quantitative evaluation of 5-hydroxytryptamine (serotonin) neuronal release
and uptake: an investigation of extrasynaptic transmission. J Neurosci. 1998
Jul 1;18(13):4854-60. doi: 10.1523/JNEUROSCI.18-13-04854.1998. PMID: 9634551; PMCID:
PMC6792557.<o:p></o:p></p>
<p class="MsoNormal">9.<span style="mso-spacerun: yes;"> </span>Matthäus F,
Haddjeri N, Sánchez C, Martí Y, Bahri S, Rovera R, Schloss P, Lau T. The
allosteric citalopram binding site differentially interferes with neuronal
firing rate and SERT trafficking in serotonergic neurons. European
Neuropsychopharmacology. 2016 Nov 1;26(11):1806-17.<o:p></o:p></p>
<p class="MsoNormal">10:<span style="mso-spacerun: yes;"> </span><a href="https://assets.researchsquare.com/files/rs-2741902/v1/6bbb2cbd79dc6d7e5e99b40d.pdf">Supporting
Information</a> for Serotonin is the Common Thread Linking Different Classes of
Antidepressants<span style="mso-spacerun: yes;"> </span>(see Figures S1 and S2).<o:p></o:p></p>
<p class="MsoNormal"><o:p> </o:p></p><div class="separator" style="clear: both; text-align: center;"><br /></div><br /><div class="separator" style="clear: both; text-align: center;"><br /></div><br /><div class="separator" style="clear: both; text-align: center;"><br /></div>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com0tag:blogger.com,1999:blog-7772182113499451603.post-63006671668490144872024-01-07T12:41:00.012-06:002024-01-09T12:17:32.937-06:00The Real Lesson of January 6th – How Fascism Works<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhdZeMTpgngwgZrG5Y_GQ_dYKEzZp9zbi2XK-rIZ6EG-Irp_9NGeL7n4MBAWuLmGHBFWWnm57phJifFMDSPY9fKVGW30ESeFt141_m3r5xRNhulif7q93MtUXIl3Vnx51mK0zP05633xEIs3Tkqfzwe2boO6vcAx9czz3iWKMpL6fvPVSNWbASTp4I89BO-/s1280/Insurrection%20overlay.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="720" data-original-width="1280" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhdZeMTpgngwgZrG5Y_GQ_dYKEzZp9zbi2XK-rIZ6EG-Irp_9NGeL7n4MBAWuLmGHBFWWnm57phJifFMDSPY9fKVGW30ESeFt141_m3r5xRNhulif7q93MtUXIl3Vnx51mK0zP05633xEIs3Tkqfzwe2boO6vcAx9czz3iWKMpL6fvPVSNWbASTp4I89BO-/w640-h360/Insurrection%20overlay.jpg" width="640" /></a></div><br /><p></p><p></p><p class="MsoNormal"><span face="Arial, sans-serif" style="font-size: 12pt;">Yesterday was the third anniversary of the Insurrection at
the Capitol.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">This event remains
prominent in the news due to ongoing civil and criminal litigation and the
overall meaning to culture and politics in the United States.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">At the level of accountability there are
striking discrepancies between those who were physically at the Capitol and
many who orchestrated the event. The most striking discrepancy and controversy
is former President Trump. He has currently been removed from the ballots in 2
states pending what will likely be Supreme Court decisions.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">The Supreme Court is clearly stacked in his
favor and one of his attorneys stated an explicit </span><i style="font-family: Arial, sans-serif; font-size: 12pt;">quid pro quo</i><span face="Arial, sans-serif" style="font-size: 12pt;"> this week
as in “this President appointed you - better get him back on the ballot.”</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">There have also been threats that Republicans
would remove Biden from the ballot to compensate for Trump being removed from
ballots as a 14</span><sup style="font-family: Arial, sans-serif;">th</sup><span face="Arial, sans-serif" style="font-size: 12pt;"> Amendment insurrectionist.</span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">There is striking video footage of Republican legislators
calling the initial event an insurrection and clearly stating that Trump was
responsible – but years later walking all of that back and saying the
Insurrection was just a protest – nothing to see here. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Former President Trump continues to promote <i>The Big Lie</i>
whenever he has access to an open microphone despite overwhelming evidence
being frequently recited that it is a lie. He continues to portray himself as a
victim of politics even when partisans from his own party and administration
recite why it is a good idea that he never be elected again. Since I ascribe to
the Goldwater Rule, I will avoid any psychiatric speculation.<span style="mso-spacerun: yes;"> </span>At an overt level, it is obvious he can keep
going and continue to attack and alienate people even when it is not in his
best interest. Many of his interviewed followers describe this as his best
trait.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">I happened to be watching a popular television show the
other night and they put up a recent poll about the Insurrection and whether it
was initiated by the FBI. Quite surprisingly 25% of the respondents were
convinced the FBI initiated it and 26% were unsure or did not comment. So even
though at this point 1200 people have been charged and 890 convicted of federal
crimes associated with the Insurrection – over half of Americans are either
certain that this was an FBI conspiracy or uncertain that it was not.<span style="mso-spacerun: yes;"> </span>What is happening here?<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Although much of politics is an irrational appeal to
emotion – it is clearly at an all time high in the United States.<span style="mso-spacerun: yes;"> </span>A recent <i>Foreign Affairs</i> article
describes this trend as coinciding with the US now being a major exporter of
white supremacist terrorism. Most Americans probably do not know that President
Grant </span><a href="https://www.foreignaffairs.com/united-states/american-hatred-goes-global"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">created
the Department of Justice</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"> to counter white supremacist terrorism by
the Ku Klux Klan in 1870.<span style="mso-spacerun: yes;"> </span>A group who
spread recruiting literature across Twin Cities suburbs in 2022 also promoted
antisemitism.<span style="mso-spacerun: yes;"> </span>Just the act of dispersing
that literature is a clear sign that something in the US has gone horribly
wrong. <span style="mso-spacerun: yes;"> </span>What is the problem?<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Listening to many of the supporters of these processes it
is easy to attribute the support for autocracy, the Insurrection, and the MAGA
movement to ignorance.<span style="mso-spacerun: yes;"> </span>They see the
former President as a strong man who speaks his mind and that is all that they
are interested in. They do not care about the book length criticisms of people
with worked closely with him during his Presidency.<span style="mso-spacerun: yes;"> </span>Many of those criticisms have been severe –
questioning his depth of knowledge and decision-making ability. They don’t care
about public remarks he has made that were basically false or dog
whistles.<span style="mso-spacerun: yes;"> </span>They say they care about the
economy but the Biden economy is clearly superior to the Trump economy and
easily exceeded any warnings Trump had about not re-electing him.<span style="mso-spacerun: yes;"> They don't care about the fact that Trump does not campaign on relevant domestic or foreign policy issues. </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The lack of a rational basis for supporting Trump and MAGA
suggest that other factors are at play. First and foremost is partisan
politics.<span style="mso-spacerun: yes;"> </span>Practically all the
Republicans that were skeptical or critical of Trump have fallen in behind him
– not wanting to provoke the ire of his MAGA loyalists.<span style="mso-spacerun: yes;"> </span>Their affiliation is with a seriously
compromised Republican party rather than the republic itself.<span style="mso-spacerun: yes;"> </span>Better to have a good career and government
job and let the Insurrection cards fall where they may.<span style="mso-spacerun: yes;"> </span>The Republicans walking away rather than make
that compromise are a small minority and deserve our gratitude.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Nihilism is a significant factor.<span style="mso-spacerun: yes;"> </span>Nihilism is a vague term, I am using the
existential meaning.<span style="mso-spacerun: yes;"> </span>In other words,
meaninglessness is pervasive both in terms of the truth being relative rather
than absolute and the same is true for institutions. This is a large part of
what Trump does on almost a daily basis.<span style="mso-spacerun: yes;">
</span>Using a shotgun approach he has attacked just about every aspect of the
government, military, public health, educational, and judicial systems and
continues to do so.<span style="mso-spacerun: yes;"> </span>Many of the attacks
have been personal and directed at people who have distinguished government
service. These attacks are unprecedented by any American president and
unquestionably erode the authority of these agencies – not just with his
followers but in general.<span style="mso-spacerun: yes;"> </span>Some have
endangered the people attacked and their families.<span style="mso-spacerun: yes;"> </span>Many of his supporters clearly want to burn
“the system” down and not replace it. Nihilism also reinforces many right-wing
conspiracy theories like the secret Deep State or the FBI orchestrating the
Insurrection. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The symbols of nihilism were prominent at the January 6
Insurrection and included a Confederate flag, a </span><a href="https://www.nytimes.com/2022/06/16/us/politics/jan-6-gallows.html"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">gallows
and a noose</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">, militia gear and paramilitary tactics.<span style="mso-spacerun: yes;"> </span>Since then, at least one Republican candidate
offered support for <i>Lost Cause</i> rhetoric that revises history to suggest
that aggressive northern states fought the Civil War to suppress states’ rights
in the south rather than end slavery. The idea of a rebellion is also suggested
rather than an insurrection and an attack on the legitimate government of the
United States.<span style="mso-spacerun: yes;"> </span>The Civil War was really
a war between the Confederacy and the United States rather than the North
versus the South. All that rhetoric is designed to render the real history of
the Civil War meaningless.<span style="mso-spacerun: yes;"> </span>It was no
accident that the Confederate flag appeared in the Capitol carried by insurrectionists.
<span style="mso-spacerun: yes;"> </span>There is nothing more nihilistic than
vigilante law as evidenced by the threat of hanging rationalized as “so the
traitors know the stakes” initially and then a site where insurrectionists
chanted to “Hang Mike Pence!” while searching for him in the Capitol Building. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“Nihilistic hooliganism” or “striving to create the
atmosphere of a street battle or barroom brawl” was a tactic used by Goebbels
in the Nazi propaganda paper <i>Der Angriff</i> because at the time he knew it
appealed to supporters (2). It seems obvious that several individuals and
factions in the Republican party are intent creating this kind of atmosphere.<span style="mso-spacerun: yes;"> </span>Late in 2023 it extended into Congress with
threat of physical violence against a witness in a hearing and alleged physical contact between Republican members of Congress in the hallways. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">In the vacuum of nihilism, the right does not hesitate to dictate
how people should think on culture war or hot button issues like guns,
abortion, LGBT issues, separation of church and state, control over education, climate change denial, and pandemic denial.<span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span>They
cast attempts to remove overt misinformation as censorship and a return to
rational gun control as a denial of Second Amendment rights.<span style="mso-spacerun: yes;"> </span>In many cases there is a “doubling down” on
any political gains made in these areas.<span style="mso-spacerun: yes;">
</span>This level of cynicism and disingenuousness keeps the threat of gun
violence very real for most Americans and has had a clear negative impact on
women’s health where abortion access is <a href="https://www.acog.org/advocacy/policy-priorities/abortion-access">considered
essential health care by experts</a>. This doubling down to the point of
criminalization is characteristic of autocracies that consider <i>winning</i> cultural
issues crucial for the survival of their ideology.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Trump and his supporters are using very well-known
propaganda techniques. <span style="mso-spacerun: yes;"> </span>The first is to
establish Trump as a cult of personality. He has certainly done this himself by
marketing himself as a superhero. Any search on superhero Trump merchandise
brings up pages of this stuff.<span style="mso-spacerun: yes;"> </span>He also
markets himself as being a genius and being tough and ruthless if necessary.
Practically all the drama surrounding the current court cases, including
sustained attacks on court officials is all part of that image. An average
citizen watching this unfold can only wonder why he can get away with behavior
that would cause anyone else to get contempt charges and incarceration. Since
this is also unprecedented behavior it is reminiscent of other negatively
charismatic leaders like Hitler who cultivated mythical images:<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“Hard, ruthless, resolute, uncompromising, and radical, he would
destroy the old privilege - and class-ridden society and bring about a new
beginning, uniting the people in an ethnically pure and socially harmonious 'national
community'.” (1)<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The entire MAGA movement and its associated “drain the
swamp” mottos are consistent with Trump’s cultivated image that has
successfully obliterated the fact that he has had far more privilege than
practically any other person in the MAGA movement.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">As in the case of Hitler, it takes more than a
self-cultivated mythical image to establish a following that will ignore
obvious deficits and vote for you no matter what. In the case of Republican
politicians – self-interest is the obvious motivation.<span style="mso-spacerun: yes;"> </span>If any other candidate has a chance in the
national elections, they would not all be in lock step behind Trump. The fall
out from that process has been astounding including continuing to support the
Big Lie strategies and making the original January 6<sup>th</sup> Insurrection
out to be a picnic.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">A pillar of the autocrat playbook is to attack everything
in the existing government and suggest all these problems will be solved when
the superior human being is elected.<span style="mso-spacerun: yes;">
</span>That involves significant distortion at three levels. <span style="mso-spacerun: yes;"> </span>First – it devalues clear accomplishments of
the existing government.<span style="mso-spacerun: yes;"> </span>Most serious
students of government would describe the Biden administration as one of the
most successful in modern history.<span style="mso-spacerun: yes;"> </span>Some
of that success depended on correcting the damage done by the last Trump administration.<span style="mso-spacerun: yes;"> Second - direct attacks on the opposition, unfounded accusations, and name calling. </span>Third – it depends on a distortion of the
abilities of their ideal candidate.<span style="mso-spacerun: yes;"> </span>In
the case of Trump there is a long list of deficiencies provided by members of
his own party and people who were in his own cabinet. Many of them are clear
that he should never be re-elected.<span style="mso-spacerun: yes;"> </span>That
stands in sharp contrast to the hyperbole candidate Trump and his dedicated followers. <span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The real lesson of January 6, 2021 is that American
democracy is under attack from one of the major
parties and a former President who is combative to the point of alienating members of his own party, never admits he is wrong, is hypersensitive to criticism, and is not honest with the American people.<span style="mso-spacerun: yes;"> </span>A significant part of the electorate finds
that attractive even though it is not clear what would happen if their
candidate is reelected. His stated first order of business is to get revenge on those who he feels
have slighted him. That image should give any rational voter pause.<span style="mso-spacerun: yes;"> </span>The only thing scarier is what happens when
autocrats implode (and they all do). <span style="mso-spacerun: yes;"> </span>It
is typically as a colossal failure – negatively impacting the entire country
for years. <span style="mso-spacerun: yes;"> </span>In the United States there is
a good chance that fall will be far greater than any other country.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">That is why the lessons of January 6 at the Capitol should
never be forgotten. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">George Dawson, MD, DFAPA<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p></o:p></span></p><p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Supplementary 1: </span></i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">How the FBI started the
Insurrection Conspiracy Theory got started was <a href="https://apnews.com/article/arizona-ap-fact-check-ted-cruz-congress-767d5dad0631f88bb0b10a45115a1bc6">discovered
and debunked in January 2022</a>. An Arizona
man named Ray Epps was filming the insurrection and apparently encouraging people
to enter the Capitol. Assuming he was an
FBI agent provided the basis for the conspiracy theory. When he was questioned by the January 6
Committee – Epps stated he was not working for law enforcement or a member of
the FBI. As the linked article states
prominent Republicans including Sen. Ted Cruz promoted this theory. <i><o:p></o:p></i></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The actual story:</span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-family: arial; line-height: 107%;"><span style="background-color: white; color: #232a31;">".....Fox News Channel and other right-wing media outlets amplified conspiracy theories that Epps, 62, was an undercover government agent who helped incite the Capitol attack to entrap Trump supporters. Epps </span><a class="link rapid-noclick-resp" data-rapid_p="24" data-v9y="1" data-ylk="slk:filed a defamation lawsuit;elm:context_link;itc:0" href="https://apnews.com/article/fox-news-epps-lawsuit-january-6-a4804aa115410ebc206ba6ee77d10270" rel="nofollow noopener" style="background-color: white; color: #0f69ff; cursor: pointer; text-decoration-line: none;" target="_blank">filed a defamation lawsuit</a><span style="background-color: white; color: #232a31;"> against Fox News last year, saying </span><a class="link rapid-noclick-resp" data-rapid_p="25" data-v9y="1" data-ylk="slk:the network was to blame;elm:context_link;itc:0" href="https://apnews.com/article/fox-tucker-carlson-capitol-riot-election-lies-b2471a41f5d1580218ff20b23901b530" rel="nofollow noopener" style="background-color: white; color: #0f69ff; cursor: pointer; text-decoration-line: none;" target="_blank">the network was to blame</a><span style="background-color: white; color: #232a31;"> for spreading baseless claims about him...."</span></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-family: arial; line-height: 107%;"><span style="background-color: white; color: #232a31;">Kunzelman M. </span></span>Ray Epps, a target of Jan. 6 conspiracy theories, gets a year of probation for his Capitol riot role. Associated Press January 9, 2024. https://www.yahoo.com/news/ray-epps-target-jan-6-164800399.html</p><p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><br /></span></i></p><p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">References</span></i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">:</span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">1:<span style="mso-spacerun: yes;"> </span>Kershaw I.<span style="mso-spacerun: yes;"> </span>The Hitler Myth.<span style="mso-spacerun: yes;"> </span>History Today. 1985; 35(11): 23-29.<span style="mso-spacerun: yes;"> </span></span><a href="https://www.historytoday.com/archive/hitler-myth"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">https://www.historytoday.com/archive/hitler-myth</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">2:<span style="mso-spacerun: yes;"> </span>Lemmons R.<span style="mso-spacerun: yes;"> </span>Goebbels and Der Angriff.<span style="mso-spacerun: yes;"> </span>1994.<span style="mso-spacerun: yes;">
</span>University of Kentucky Press. Lexington, Kentucky. p. 128-131.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Graphics Credit:<o:p></o:p></span></i></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">1:<span style="mso-spacerun: yes;"> </span>Main Graphic is:
DC Capitol Storming by TapTheForwardAssist, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>,
via Wikimedia Commons.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><a href="https://commons.wikimedia.org/wiki/File:DC_Capitol_Storming_IMG_7947.jpg"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">https://commons.wikimedia.org/wiki/File:DC_Capitol_Storming_IMG_7947.jpg</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Note the original was altered by me with the superimposed
transparency. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">2:<span style="mso-spacerun: yes;"> </span>Transparency
is:<span style="mso-spacerun: yes;"> </span>WWII, Europe, Germany, "Nazi
Hierarchy, Hitler, Goering, Goebbels, Hess", The Desperate Years p143 –
NARA by National Archives and Records Administration, Public domain, via
Wikimedia Commons </span><a href="https://commons.wikimedia.org/wiki/File:WWII,_Europe,_Germany,_%22Nazi_Hierarchy,_Hitler,_Goering,_Goebbels,_Hess%22,_The_Desperate_Years_p143_-_NARA_-_196509.jpg"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">https://commons.wikimedia.org/wiki/File:WWII,_Europe,_Germany,_%22Nazi_Hierarchy,_Hitler,_Goering,_Goebbels,_Hess%22,_The_Desperate_Years_p143_-_NARA_-_196509.jpg</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p><br /><p></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com1tag:blogger.com,1999:blog-7772182113499451603.post-18138884709243209262023-12-31T22:30:00.004-06:002024-01-01T11:33:43.903-06:00Misinformation X<p></p><div class="separator" style="clear: both;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiuSqRN76Q0dphf0vnOOaBEMc9W11EFtUS_aCU8Rn-KhDMdiOw5rM3w2SZvZ5XSYj4g5da7hveV1A37YFphbXQ-8g3sOrTAFcVasxT0gcDhiVkNX9rEGzvEOnPQfZXxef6LzBz_aKgvdBCL-wvZogveznsOV98cOHFt0mCmCBf9m2H5m8L4kdb3qSkS6ZyN/s792/happy%20new%20year%202024.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="282" data-original-width="792" height="228" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiuSqRN76Q0dphf0vnOOaBEMc9W11EFtUS_aCU8Rn-KhDMdiOw5rM3w2SZvZ5XSYj4g5da7hveV1A37YFphbXQ-8g3sOrTAFcVasxT0gcDhiVkNX9rEGzvEOnPQfZXxef6LzBz_aKgvdBCL-wvZogveznsOV98cOHFt0mCmCBf9m2H5m8L4kdb3qSkS6ZyN/w640-h228/happy%20new%20year%202024.png" width="640" /></a></div><div class="separator" style="clear: both;"><br /></div><div class="separator" style="clear: both;">I have a lot of blog posts in the works right now. That strategy works for me because my attention has always been a problem and it works better to work on many things at once rather than bogging down on one. I decided to post on this topic and the one that may be the most relevant. The content of my blog tends to go from scientific and medical topics, to social topics, to a lot of posts that address current misinformation. The Information Age has become the Misinformation Age and there is probably no better example than the platform formerly known as Twitter. </div><p></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Twitter used to be an invigorating and informative place
for physicians. I could count on reasonable discussions and literature
references by daily participation and focusing on specific colleagues. In
psychiatry – there is a chronic misinformation problem dating back to Szasz,
Foucault, and others in the 1970s.<span style="mso-spacerun: yes;"> </span>They
created tropes and memes that are still repeatedly used by antipsychiatrists
today to deny the reality of mental illness and the real function and value of
psychiatry. In many ways this sort of criticism has generalized to the rest of
medicine and that became very clear during and after the pandemic. <span style="mso-spacerun: yes;"> </span>The takeover of Twitter by Elon Musk and his
so-called “free speech” policies made that site a fountain of
misinformation.<span style="mso-spacerun: yes;"> </span>The amount of
misinformation would be embarrassing to anyone concerned with the truth or
reality but these days those constraints clearly do not apply. <span style="mso-spacerun: yes;"> </span>The truth is of little value in much of what
can be read on X.<span style="mso-spacerun: yes;"> </span>I would go as far as
saying the truth is actively devalued on X and you can read falsehoods about
settled areas of science, medicine, and public policy.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">There is a clear positive correlation between the
transition in management and an increase in misinformation, hate speech, hate
speech and antisemitism.<span style="mso-spacerun: yes;"> </span>Problems also
existed before that transition and some were highlighted during the pandemic.
Misinformation about vaccinations, masks, and public health personnel were
clear problems. Despite what happened during the pandemic that misinformation
has clearly increased.<span style="mso-spacerun: yes;"> </span>The day before I
started writing this post there was a great deal of misinformation about how
“jabs” (misinfospeak for COVID immunizations) cause blood clots and that there
would be a tsunami of deaths from thromboembolic diseases.<span style="mso-spacerun: yes;"> </span>Several physicians posted clearcut evidence
to refute this misinformation.<span style="mso-spacerun: yes;"> </span>Most physicians
are also aware of the fact that immunization are the single most effective
intervention to prevent death in large populations. That evidence, including
the evidence for COVID-19 immunization effectiveness is indisputable.<span style="mso-spacerun: yes;"> </span>Medical research on Long-COVID or chronic
symptoms following infection with the virus is also clearer now. Trying to
avoid that chronic state and the associated disability is another good reason
to get immunized.<span style="mso-spacerun: yes;"> </span>Practicing
physicians have a healthy respect for respiratory viruses.<span style="mso-spacerun: yes;"> </span>We have all seen healthy young people die
from infections with what are considered common cold viruses.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">A great solution for physicians and scientist would be a
medical or scientific Twitter.<span style="mso-spacerun: yes;"> </span>It seems
like a simple matter but I suppose maintenance and day-to-day fees would need
to be covered in addition to the original programming. To prevent the <i>vulgarians
shouting in the city square</i> behavior of X – a simple model of behavior
consistent with what would be expected in a medical or scientific staff meeting
should suffice. No personal attacks, gaslighting, ridiculing, etc. and active
moderation.<span style="mso-spacerun: yes;"> </span>People would certainly be
able to debate the merits of climate change and other controversial topics –
but the arguments would need to be based on facts and scientific merit rather
than political rhetoric. People would not be allowed to post baseless claims
about another person, a theory, or a piece of research.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The defenders of name calling, gaslighting, and
misinformation all tend to hide behind the First Amendment. There is plenty of
evidence in the current news that there is no absolute right to say whatever
you want to say about a person or a business.<span style="mso-spacerun: yes;">
</span>Hundreds of millions of dollars have been assessed as legal penalties
for those statements in several high-profile civil suits. Litigation is a crude
and expensive instrument for keeping discourse focused and civil.<span style="mso-spacerun: yes;"> </span>A specific environment is a much better approach.
Instead of proclaiming a web site as having absolute free speech – it is far
better to have the exchanges moderated according to specific rules. Hence the
staff meeting approach.<span style="mso-spacerun: yes;"> </span>I have certainly
been in staff meetings where tempers flared, but there was no name calling or
threatening behavior. There was disagreement about information but at no point
was there any question about deliberately misrepresenting the information or
repeatedly lying about it.<span style="mso-spacerun: yes;"> </span>The largest
professional staff I worked with was about 35 psychiatrists.<span style="mso-spacerun: yes;"> </span>The entire time I worked there I had no doubt
about the integrity or sincerity of my colleagues – even though some of the disagreements
were intense.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Who might run such a Twitter-like operation?<span style="mso-spacerun: yes;"> </span>The American Psychiatric Association (APA)
ran an email listserv that I participated in for decades.<span style="mso-spacerun: yes;"> </span>They decided to stop this in the past
year.<span style="mso-spacerun: yes;"> </span>It had probably run its
course.<span style="mso-spacerun: yes;"> </span>The number of new participants and
total participants was low.<span style="mso-spacerun: yes;"> </span>Discussion
by email tends to become too diffuse and they are difficult to reference later.
There were also limitations on discussions based on the charitable status of
the organization – no political discussions.<span style="mso-spacerun: yes;">
</span>Twitter seemed like an ideal format for discussions, educational
threads, and daily reviews. I doubt that the APA or AMA have the resources for
a Twitter like platform but they might and it could be seen as a benefit to
potential members. Doximity comes to mind.<span style="mso-spacerun: yes;">
</span>Currently Doximity has threads that are posted as news updates
presumably by their editors. They tend to be much less interesting than good
Twitter threads and discussions.<span style="mso-spacerun: yes;"> </span>A
Twitter like platform would be a greater asset in attracting physicians to the
site.<span style="mso-spacerun: yes;"> </span>LinkedIn tends to have the same
constraints as Doximity but it does allow member to start new threads. All of
the commercial threads suffer from commercialization and overly intrusive
members.<span style="mso-spacerun: yes;"> </span>I don’t want to see an endless
sequence of friend or connection requests when it is obvious that I have
nothing in common with those requestors.<span style="mso-spacerun: yes;">
</span>On Twitter – the commonalities were obvious and I knew who to
follow.<span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The competitors that were started based on Twitter’s
obvious demise – Blue Sky, Threads, and Mastodon just don’t seem to have active
physician communities at this point.<span style="mso-spacerun: yes;"> </span>As
more physicians leave Twitter – there is a clear socialization and discussion
gap. It is probably obvious that I have no clear solutions for that gap – other
than a hope that somebody with enough resources and insight to the value of
Twitter for physicians can get a platform established.<span style="mso-spacerun: yes;"> </span>Alternately – more networked and focused
discussions on Blue Sky and Threads is still a possibility.<span style="mso-spacerun: yes;"> </span>Either way – I think we need a functional
blue bird back in one form or another….<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Happy New Year!<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">George Dawson, MD, DFAPA<span style="mso-spacerun: yes;">
</span><o:p></o:p></span></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com0tag:blogger.com,1999:blog-7772182113499451603.post-83320971188427446242023-12-25T12:23:00.008-06:002023-12-27T14:52:22.165-06:00Counterfeit Ozempic is NOT Off-Label Ozempic<p> </p><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgGx09uTtBKIrvWzZOJ0Tvq0cJLv9IsitMY3rNBbl7K6IIZY7ONXE1BG4Rq8iTAnFmYCXjxsSliz1zyCUOnfpYqyXnFZelcNjqgLY3ZTOFN8fR37Qsv3RTU0Kd0K6BpqlLejxWv3tlkBwKnhyphenhyphen9dJ_1D2-KNomLl4ttRG9yBX2J3gN5eEaNrWGsKnyLH_iBv/s2472/GLP.png" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="432" data-original-width="2472" height="112" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgGx09uTtBKIrvWzZOJ0Tvq0cJLv9IsitMY3rNBbl7K6IIZY7ONXE1BG4Rq8iTAnFmYCXjxsSliz1zyCUOnfpYqyXnFZelcNjqgLY3ZTOFN8fR37Qsv3RTU0Kd0K6BpqlLejxWv3tlkBwKnhyphenhyphen9dJ_1D2-KNomLl4ttRG9yBX2J3gN5eEaNrWGsKnyLH_iBv/w640-h112/GLP.png" width="640" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><span style="font-family: arial;">Glucagon like peptide (GLP)<br /><br /><br /></span><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhaDSsmGwRMZsvkhBlVHwZ_86qDKYptJtGGwRnl2tWvg42dXpJFyp-BDEuAHtJU1D310ZW_JPw_AM31uqT-aC9qvtr38Agf6cv2qexcKtVjAcTfgJ6rdG3WqX91_gHHNx-KtslSPMXC6cVKPp0x5ZyOvg-ekZp2NTiz2b3PZ4CwlDnDmYHGKdsMsk0aPtAj/s1362/GLP-1%20agonists%2012.25.2023.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="938" data-original-width="1362" height="440" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhaDSsmGwRMZsvkhBlVHwZ_86qDKYptJtGGwRnl2tWvg42dXpJFyp-BDEuAHtJU1D310ZW_JPw_AM31uqT-aC9qvtr38Agf6cv2qexcKtVjAcTfgJ6rdG3WqX91_gHHNx-KtslSPMXC6cVKPp0x5ZyOvg-ekZp2NTiz2b3PZ4CwlDnDmYHGKdsMsk0aPtAj/w640-h440/GLP-1%20agonists%2012.25.2023.png" width="640" /></a></div><br /></td></tr></tbody></table><p class="MsoNormal"><span style="font-size: 12pt;">I was content to let the FDA release and the news media
handle this problem until I watched a TV news person say the following:</span><span style="font-size: 12pt; mso-spacerun: yes;"> </span><span style="font-size: 12pt;">“Counterfeit Ozempic or off label Ozempic is
potentially dangerous…..”</span><span style="font-size: 12pt; mso-spacerun: yes;"> </span><span style="font-size: 12pt;">Off label
Ozempic is </span><i style="font-size: 12pt;">NOT</i><span style="font-size: 12pt;"> counterfeit Ozempic.</span><span style="font-size: 12pt; mso-spacerun: yes;">
</span><span style="font-size: 12pt;">Off label medications are FDA approved medications that are prescribed
for indication other than what is listed in the package insert.</span><span style="font-size: 12pt; mso-spacerun: yes;"> </span><span style="font-size: 12pt;">Based on a <a href="https://real-psychiatry.blogspot.com/2023/12/the-ultimate-key-opinion-leader.html">recent table</a> that I made from
package insert information practically all GLP-1 agonists like Ozempic are
prescribed off label because the FDA indication is Type 2 diabetes mellitus
rather than weight management. The FDA news release is all about Ozempic look
alikes being sold as the real
product.</span><span style="font-size: 12pt; mso-spacerun: yes;"> In some cases they do not contain any active ingredient and in the majority of cases what they actually contain is currently unknown. </span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The FDA warning (1) about counterfeit Ozempic surfaced on
12/21/2023.<span style="mso-spacerun: yes;"> </span>Ozempic and many drugs in
this class come in an injection device, since most of the dosing is by
subcutaneous (SC) injection. The FDA also warned that the needles in these
devices were counterfeit and their safety and sterility could not be
guaranteed.<span style="mso-spacerun: yes;"> </span>In the warning in reference
1 they describe 5 incidents of adverse effects – none life threatening.<span style="mso-spacerun: yes;"> </span>The confiscated pens are being analyzed to
determine what is being used rather than Ozempic.<span style="mso-spacerun: yes;"> </span>Counterfeit pens were found in at least 9
countries and in some – insulin was found (2). The FDA provides lot and serial
numbers of the counterfeit medication and advises pharmacies not to use it. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The same day as this release, the FDA also warned about
compounded GLP-1 agonists (3).<span style="mso-spacerun: yes;"> </span>Compounded
products are prepared by compounding pharmacies.<span style="mso-spacerun: yes;"> </span>If medications are in short supply –
compounding pharmacies can produce them. Ozempic and Wegovey are both on that
list.<span style="mso-spacerun: yes;"> </span>Both are semaglutides and adverse
events have occurred with the compounded versions.<span style="mso-spacerun: yes;"> </span>Some of the counterfeit versions contain the
salt form of semaglutide compared with the FDA approved medication that is the
base form.<span style="mso-spacerun: yes;"> </span>This warning also describes
counterfeit semaglutide being marketed online, concerns about counterfeit
Ozempic in the US, and it encourage patients to protect themselves by only
purchasing semaglutides through state licensed pharmacies. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Although it is not emphasized in the warnings, I also have
concern about the injection pen device that the semaglutide is contained
in.<span style="mso-spacerun: yes;"> </span>The injectors are calibrated to
deliver 0.25. 0.5, and 1 mg doses according to the prescription for each
patient.<span style="mso-spacerun: yes;"> </span>The device is supposed to click
when it is at the corrected dose. <span style="mso-spacerun: yes;"> </span>This
medication and unique injector is reminiscent of other medications where the patented
delivery system was so critical to the medication that it essentially extended
the patent. <span style="mso-spacerun: yes;"> </span>Unless the counterfeiters
are using a very similar device the recommended doses of medication might not
be delivered correctly.<span style="mso-spacerun: yes;"> </span>Exactly how
problematic that will be depends on the medication or substance that has been
substituted for the semaglutide.<span style="mso-spacerun: yes;"> </span>Even if
the counterfeiters can produce a semaglutide like name brand Ozempic or Wegovey
– there is no guarantee that the pen device they are using can guarantee
accurate delivery of the dose.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">At this time, I have not heard that there has been an attempt
to synthesize the actual medication. With today’s technology I would not be
surprised if that attempt was made at some point.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">That led me to think about the issue of legal and illicit
drugs. At some point – knowledge obtained in the past century seems to have
been replaced by the rhetoric of drug legalization. These arguments are always
about drugs that reinforce their own use or what are commonly referred to as
addictive drugs. The legalization myth generally skips over the harms of these
drugs directly to what is often referred to as harm reduction.<span style="mso-spacerun: yes;"> </span>That generally means that it is more harmful
to insist that people stop using these drugs than providing them with safe
forms to continue using or in the more extreme case to leave drug dealing and all
the illicit forms intact. In the latter case, methods to test the drugs and provide
safer methods of delivery offer the users an opportunity to protect themselves
from suppliers who may add adulterants to the drugs or substitute a more
dangerous drugs without informing them.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">GLP-1 agonists are clearly not addictive drugs as far as
anyone knows at this point. But the issue I attempted to cover in this post is drug safety – specifically the safety of the drug supply to patients with a prescription.
Despite the provocative way the pharmaceutical industry is covered and often villainized
in the press – there is no doubt that they can and have provided a safe supply
of medication to the public. There are lapses and inadequate inspections and
recalls.<span style="mso-spacerun: yes;"> </span>The current system is far from
perfect. But it is clearly superior to any system being run by a criminal
enterprise supplying illicit drugs. It is hard to imagine a system where you
would have to personally run a chemical test on your prescription medications
to make sure they were safe.<span style="mso-spacerun: yes;"> </span>It is
equally hard to imagine producing counterfeit drugs and selling them to the
public like the real thing. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">That is what the FDA is trying to prevent with this warning.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">George Dawson, MD, DFAPA<o:p></o:p></span></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></i></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p><i>Supplementary: </i>Aware of counterfeit<i> Ozempic </i>or<i> Wegovey? </i>Can you get it without a prescription?</o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p>It has come to my attention that many people are aware of the availability of counterfeit <i>Ozempic</i> and <i>Wegovey</i> thorough their social networks. I am very interested in how widespread this problem is right now. Please report your experience here anonymously in the comments section or by emailing me.</o:p></span></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">References:<o:p></o:p></span></i></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">1:<span style="mso-spacerun: yes;"> </span>FDA.<span style="mso-spacerun: yes;"> </span>FDA warns consumers not to use counterfeit
Ozempic (semaglutide) found in U.S. drug supply chain.<span style="mso-spacerun: yes;"> </span>December 21, 2023 </span><a href="https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-use-counterfeit-ozempic-semaglutide-found-us-drug-supply-chain"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-use-counterfeit-ozempic-semaglutide-found-us-drug-supply-chain</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">2:<span style="mso-spacerun: yes;"> </span>National
Association of Boards of Pharmacy.<span style="mso-spacerun: yes;">
</span>Counterfeit Ozempic Found in US Retail Pharmacy.<span style="mso-spacerun: yes;"> </span>August 7, 2023 </span><a href="https://nabp.pharmacy/news/blog/regulatory_news/counterfeit-ozempic-found-in-us-retail-pharmacy/"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">https://nabp.pharmacy/news/blog/regulatory_news/counterfeit-ozempic-found-in-us-retail-pharmacy/</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">3:<span style="mso-spacerun: yes;"> </span>FDA.<span style="mso-spacerun: yes;"> </span>Medications Containing Semaglutide Marketed
for Type 2 Diabetes or Weight Loss.<span style="mso-spacerun: yes;">
</span>December 21, 2023 </span><a href="https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/medications-containing-semaglutide-marketed-type-2-diabetes-or-weight-loss"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/medications-containing-semaglutide-marketed-type-2-diabetes-or-weight-loss</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><span style="mso-spacerun: yes;"><i>Peptide Structure:</i></span><o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><span style="mso-spacerun: yes;">Drawn with PepDraw: https://pepdraw.com/</span></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com0tag:blogger.com,1999:blog-7772182113499451603.post-33122187333464242392023-12-19T22:11:00.021-06:002023-12-21T01:31:18.331-06:00The Ultimate Key Opinion Leader?<p>
<a href="https://commons.wikimedia.org/wiki/File:Oprah_at_her_50th_birthday_party_(210467069).jpg" title="photo by Alan Light, CC BY 2.0 <https://creativecommons.org/licenses/by/2.0>, via Wikimedia Commons"><img alt="Oprah at her 50th birthday party (210467069)" src="https://upload.wikimedia.org/wikipedia/commons/thumb/b/bd/Oprah_at_her_50th_birthday_party_%28210467069%29.jpg/512px-Oprah_at_her_50th_birthday_party_%28210467069%29.jpg" width="512" /></a>
<br /></p><p><br /></p><p class="MsoNormal"><span face="Arial, sans-serif" style="font-size: 12pt;">Key Opinion Leader or KOL is an interesting myth. In the
long era of the </span><i style="font-family: Arial, sans-serif; font-size: 12pt;">pharmascolds</i><span face="Arial, sans-serif" style="font-size: 12pt;">, it was frequently stated that all you
needed to successfully market a drug was a KOL paid by the company to sell it
to the unknowing clinicians who were just waiting to prescribe in lock step
with whatever was suggested.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">KOLs were
typically academics with research and lecturing credibility but also included
clinicians who may have had some experience with the drug in clinical trials.
The KOL/clinician interface frequently occurred over pharmaceutical company
sponsored CME events or meals. KOLs in psychiatry were treated more harshly
than those in any other field when a US Senator decided to investigate their individual
employment arrangements. An explanation was never given about that selectivity,
but I did notice some other specialists were added – probably for cover.</span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The myth of KOL as Pied Piper encouraging mass
prescriptions always struck me as absurd for several reasons. First, I know the psychiatrists. It might be possible that the psychiatrists I
know are more enlightened than most – but my contact with them in numerous
clinic, hospital, academic and non-academic settings treating diverse groups of
patients makes that unlikely. As a group they are looking for inexpensive continuing
medical education (CME) credits, hearing about the latest developments, and
getting better treatments to their patients. Better in this case means more
efficacy, fewer side effects, or both. With
direct-to-consumer advertising in the US, patients coming to appointments
requesting a new drug is a common occurrence and a fast way to learn about
those drugs was listening to a KOL and picking up an FDA approved package
insert at the same time. That confluence of factors can make it seem like this
is all a great conspiracy that includes physicians – but it is not. The clinicians involved are as skeptical
about new drugs as they want something that works better. Second, pharmaceutical
companies aggressively market drugs.
Most physicians are aware of this and the fact that people in the US pay
much more for medications than is paid anywhere else in the world. Most
physicians are also aware of the mechanisms that lead to those higher prices
and must deal with the administrative costs and their patients going without
needed medications. Third, physicians have limited control over the prescription of newly released expensive drugs. Rationing these drugs is a separate for-profit business. Those businesses have gone as far as rationing low cost generic medications and they will make it painful for any physician to prescribe a new medication if there are cheaper alternatives. Fourth, working as a
KOL (or more probably a sponsored lecturer) can give a sense of satisfaction in
terms of continuing use of basic science and discussions with experts. All these factors lead to skepticism rather
than uncritical acceptance of a sales pitch. I don’t know of any celebrity
level psychiatrist who could endorse a pharmaceutical product that would lead
it to be immediately and universally adopted.
<o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">That leads me to the Ultimate KOL (UKOL). For the past few weeks Oprah Winfrey has been
in the news for a significant and visible weight loss. There was immediate
suspicion in the gossip media that she was using weight loss drugs –
specifically glucagon-like peptide (GLP-1) agonists. She initially said that she lost the weight
with the usual methods and that using a drug would be “cheating”. She has had similar weight losses in the past
and in one case ran the New York City marathon.
The photo of her at the top of
this post was for her 50<sup>th</sup> birthday when she lost all the weight
through diet and exercise. More recently - she was at an opening and said she did use a
medication and added that she was tired of being shamed for excessive weight
and being treated differently at a higher body weight than a lower
body weight. She has not disclosed the
name of the medication.<o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Oprah has unique status as a celebrity. According to <i>Time</i>
magazine - she was one of three and four most influential people in the 20th
and 21st century respectively (1). She
had a product endorsement segment on her daily show called Oprah’s Favorite
Things that greatly increased sales for many products. Her endorsement of Barack Obama produced an
additional 1 million votes in the Democratic primaries (2). At first glance,
Oprah’s statement about weight loss medication seems consistent with her past
promotions of products, books, and her self-improvement brand. <o:p></o:p></span></p><p class="MsoNormal">
<span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%; mso-ansi-language: EN-US; mso-bidi-language: AR-SA; mso-fareast-font-family: Calibri; mso-fareast-language: EN-US; mso-fareast-theme-font: minor-latin;">In this case things
are a bit more complicated. In October
2015, she purchased 6.4 million shares or $43.2 million ($6.79 a share) of
Weight Watchers (WW) stock. She sold
about a million shares when the stock appreciated and was given an option to
purchase an additional 3.3 million shares. (5). According to the latest SEC document WW is in
a Strategic Collaboration Agreement with Oprah that began in 2015 that has been
extended to 2025. In the annual report
she is listed as one of 9 Directors. Her
last stock purchase was in January and April of 2023 (5,067 and 2,053 shares
respectively). In April of 2023 Weight Watchers acquired the telehealth company
Weekend Health/Sequence described in their press release as “a subscription
telehealth platform offering access to healthcare providers specializing in
chronic weight management.” They now
offer weight loss medications including GLP-1 agonists <a href="https://www.weightwatchers.com/us/clinic/weight-loss-medication">directly
through their web site</a>. I did not go
through the process because a name was required, but several sources suggest
this is a monthly subscription service</span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Prior to Oprah’s self-disclosure demand for GLP-1 agonists
was very high and there was concern that weight loss demand would reduce
availability of these medications for people with diabetes mellitus. Some medications are approved for weight
management only and others for treating diabetes mellitus only. During the last
3 months of 2022 there were and estimated 9 million prescriptions for both
branded version of semaglutide - Ozempic and Wegovey. At the time, the average cost of Ozempic was
about $800/month and Wegovey was $270/week.
Doing the arithmetic, at that rate of prescribing the costs of these prescriptions
could easily exceed $100 billion per year. That would make them the </span><a href="https://real-psychiatry.blogspot.com/2023/05/top-selling-drugs-and-market-hype.html"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">highest
selling drugs of all time</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">. <o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">GLP-1 agonists are unique medications. They have a polypeptide structure and a much higher
molecular weight than typical medications. That protein structure makes them more likely
to trigger antibody formation and an immune response. The main side effects are gastrointestinal –
nausea, vomiting, diarrhea, constipation and abdominal pain and a significant
number of patients in the clinical trials withdrew due to these side effects. Hypoglycemia can be a problem especially if
there is concurrent oral hypoglycemic use. Dehydration is also a common problem
accompanying acute weight loss and starvation. That combination of problems leads
to a warning about needing to monitor for dehydration in patients being treated
with these medications especially because there is a higher incidence of renal
damage in that patient group. There are
warnings about pancreatitis, thyroid C-cell carcinoma, acute renal injury, diabetic
retinopathy complications, and hypoglycemia. There was also a recent report of <a href="https://www.novomedlink.com/semaglutide.html">increasing calls to poison
control centers about semaglutides</a> and counterfeit products. The therapeutic
effects of these drugs include glycemic control and weight loss although most
of these drugs have an indication for Type 2 diabetes mellitus only. <o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">I plan a more detailed post on the standard and more
interesting pharmacological properties of these medications in the new
year. So far, I have compiled a table
and will be working from an enhanced version of that. The goal of this post is to document the
effect of who is probably the single most important influencer in American
society and her impact on the sales of this class of medication in the United
States. Just the events that have occurred so far will probably be far reaching
– limited only by the supply and the availability of prescribers. I expect that there will be many online
prescribers available since the advent of telemedicine has led to specialty
prescribing of a few drugs to many recipients. <o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">There are currently unanswered questions. Will Oprah disclose the medication she
used? Will she endorse a specific
drug? We have recently seen Kareen Abdul
Jabbar in </span><a href="https://www.fiercepharma.com/marketing/hall-famer-assists-bms-pfizer-latest-no-time-wait-eliquis-heart-health-push"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">NOAC
commercials</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"> for apixaban.
Secondarily – how will this issue be studied? The typical studies that purported to show
that physicians were influenced by trinkets or KOLs were poorly done and any
increase in prescribing was taken as evidence of influence. How can the Oprah factor be studied to reduce
confounders like the American fantasy of weight loss without effort or the
debate that being overweight or obese is a disease rather than a personal
responsibility. From an ethical standpoint, are there problems with conflict of
interest given the share that Oprah has in a company that is promoting and profiting
from weight loss drugs? The scale of
potential profit is enormous compared with what most physicians are reported to
the <a href="https://openpaymentsdata.cms.gov/summary-by-state">CMS Open
Payments database</a>. In 2022, the
median payment to physicians who received payments from pharmaceutical
manufacturers or device makers was $161. <o:p></o:p></span></p><p>
</p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">For the record, at this point I am completely neutral on
the issue of GLP-1 agonists for weight loss. I am very familiar with the
previous literature and pharmacology of weight loss drugs. I was an early witness to the failed attempt
to use stimulants to treat obesity and treated many of those patients for
amphetamine dependence. It is clear to me that there is a lot of hype about
these medications right now and how they are the best medications ever invented
to treat obesity. Since the previous medications were mildly effective to not
effective that is a low bar. Just
reading the available package inserts suggests to me that a significant number
of people will not be able to tolerate them and many will probably tolerate
significant side effects to maintain a lower body weight. And with all new
medications, the real question is what happens to the population taking the
drug with wider and longer exposure. Will there be
adverse effects not seen in shorter clinical trials? So, stay tuned for more detailed pharmacology
and theory about the GLP-1 agonists. In
the meantime, see if Oprah has a palpable impact on the market. My
guess is that her effect will easily surpass any thousand or more physician lecturers
and KOLs. </span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><br /></span></p><p><span style="font-family: arial;">George Dawson, MD, DFAPA</span></p><p><span style="font-family: arial;"><br /></span></p><p><span style="font-family: arial;">References:</span></p><p class="MsoNormal"><span style="line-height: 107%;"><span style="font-family: arial;">1: Garthwaite CL.
You Get a Book! Demand Spillovers, Combative Advertising, and Celebrity
Endorsements. National Bureau of Economic Research; 2012 Mar 15.<o:p></o:p></span></span></p><p>
</p><p class="MsoNormal"><span style="line-height: 107%;"><span style="font-family: arial;">2: Garthwaite C,
Moore T. The role of celebrity endorsements in politics: Oprah, Obama, and the
2008 democratic primary. Department of Economics, University of Maryland. 2008
Sep:1-59.<o:p></o:p></span></span></p><p class="MsoNormal"><span style="line-height: 107%;"><span style="font-family: arial;">3: O'Connell B. Oprah's Weight Loss Company Adds a Prescription Drug Feature. May 7, 2023. https://www.thestreet.com/personalities/oprahs-weight-loss-company-adds-a-prescription-drug-feature</span></span></p><p class="MsoNormal"><span style="font-family: arial;"><span style="line-height: 107%;"><span>4: Summers J, Marquez Janse A, Ermyas T. </span></span>Oprah and Weight Watchers are now embracing weight loss drugs. Here's why. Dec 18, 2023.</span> <span style="font-family: arial;">https://www.npr.org/2023/12/18/1219710239/weightwatchers-oprah-ozempic-drugs-wegovy</span></p><p class="MsoNormal"><span style="font-family: arial;">5: </span><span face="Arial, sans-serif" style="font-size: 12pt;">Fitzgerald M.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">WW
International extends Oprah Winfrey deal to 2025, shares rise.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">CNBC</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><a href="https://www.cnbc.com/2019/12/16/ww-international-extends-oprah-winfrey-deal-to-2025-shares-rise.html" style="font-family: Arial, sans-serif; font-size: 12pt;">https://www.cnbc.com/2019/12/16/ww-international-extends-oprah-winfrey-deal-to-2025-shares-rise.html</a></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p></o:p></span></p><p class="MsoNormal"><span style="line-height: 107%;"><span style="font-family: arial;"> </span></span></p><p class="MsoNormal"><span style="line-height: 107%;"><span style="font-family: arial;"><i>Supplementary:</i></span></span></p><p><span style="font-family: arial;">Current GLP-1 agonists - all data taken from FDA approved package inserts.</span></p><p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjFYwMbNlT1o6q6Drr08r8rloij4X-IlDdjKo5QX5MRMQl6xmHP6CAnXyZvc0riTbawTYRGTDjPOatJx7MjzZ8pYFTMXuWytkfgxMPEIz9QymWwKzum-xIH82YRTA3Pr-pm9CVCL-vCK_4BgZdv13gNlKvgDWiMjKhAQgH7xzspq5tB-l0jSFr40MGQfwql/s1312/GLP-1%20agonists.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="904" data-original-width="1312" height="440" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjFYwMbNlT1o6q6Drr08r8rloij4X-IlDdjKo5QX5MRMQl6xmHP6CAnXyZvc0riTbawTYRGTDjPOatJx7MjzZ8pYFTMXuWytkfgxMPEIz9QymWwKzum-xIH82YRTA3Pr-pm9CVCL-vCK_4BgZdv13gNlKvgDWiMjKhAQgH7xzspq5tB-l0jSFr40MGQfwql/w640-h440/GLP-1%20agonists.png" width="640" /></a></div><br /><span style="font-family: arial;"><br /></span><p></p><p><span style="font-family: arial;">Photo Credit:</span></p><p><span style="font-family: arial;">Photo by Alan Light, CC BY 2.0 <https://creativecommons.org/licenses/by/2.0>, via Wikimedia Commons</span></p>
George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com0tag:blogger.com,1999:blog-7772182113499451603.post-3696254033158497452023-12-09T12:03:00.004-06:002023-12-12T14:44:45.216-06:00Merry Christmas From Your PBM<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhR3G98uPKfFCznuuN0-6EhLB6YyjFhzkEcn1jGJ3L4JV2XNKWdZkNDJPPTIkaFjBECKiMBCcE3Fq_aRBRe7-HTI6_cih5P4bOY8JJw8jLiSaSzLp-k3qs0uekKpxN8zSi08oooiawS_FSP3tTvM8fp_US_rGIoTPzbdZ2FkcwNtBAEBozKDciMRz0rtEEq/s723/Lindas%20pill%20tree.jpg" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" data-original-height="723" data-original-width="710" height="320" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhR3G98uPKfFCznuuN0-6EhLB6YyjFhzkEcn1jGJ3L4JV2XNKWdZkNDJPPTIkaFjBECKiMBCcE3Fq_aRBRe7-HTI6_cih5P4bOY8JJw8jLiSaSzLp-k3qs0uekKpxN8zSi08oooiawS_FSP3tTvM8fp_US_rGIoTPzbdZ2FkcwNtBAEBozKDciMRz0rtEEq/s320/Lindas%20pill%20tree.jpg" width="314" /></a></div><br /><div class="separator" style="clear: both; text-align: left;"><br /></div><p></p><p class="MsoNormal"><br /></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">After some deliberation I went into my local Walgreens for
an RSV immunization.<span style="mso-spacerun: yes;"> </span>I have multiple
unpredictable allergies and have had both anaphylaxis and significant local
reactions to vaccinations in the past. Like 20% of the population, I have
eczema and there is some research on flareups of this skin disease with
vaccinations.<span style="mso-spacerun: yes;"> </span>And like many people with
eczema, I also have asthma and had a severe flare-up of asthma when I got a
viral infection on a flight back from Alaska about 5 years ago. My primary care
physician recommended it last week so I scheduled it.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">As I was sitting there waiting for them to prepare the
shot, I was able to observe patients coming and going to pick up their
prescriptions. This is a busy Walgreens and there are people going past the
drive-up window as fast as they are showing up in line.<span style="mso-spacerun: yes;"> </span>Most people at there in the early afternoon
are retirees.<span style="mso-spacerun: yes;"> </span>There was an informal
retirement poll of the old guys in line and it was unanimous – we were all
quite happy to be retired. The people gathered were upbeat. I recalled being at
a 24-hour pharmacy in 2002.<span style="mso-spacerun: yes;"> </span>My late
father-in-law was visiting and forgot all his cardiac medications.<span style="mso-spacerun: yes;"> </span>I went over at midnight to pick them up and
it was an ugly scene.<span style="mso-spacerun: yes;"> </span>There were about
60 people there and the pharmacist was not filling the prescriptions fast
enough. From where I was seated – I could see him working furiously.<span style="mso-spacerun: yes;"> </span>The crowd was so agitated about this it
seemed like they were ready to riot. If that wasn’t enough a rather cranky lady
sitting next to me started to goad them and call them names.<span style="mso-spacerun: yes;"> </span>Luckily, I got the medicine and got out of
there as soon as possible.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><span style="mso-spacerun: yes;"> </span>The atmosphere today
was much better – but like most scenes in American health care it was far from
perfect. <span style="mso-spacerun: yes;"> </span>There were no simple
transactions. In the transactions I witnessed, very few people walked away with
the prescription medication ordered by their doctors. The most common problem
as a lack of prior authorization. People were advised that their doctor had to
get the prior authorization. Several were advised that they needed a new prior
authorization. I remember all the messaging that people hear when they need a
prescription refill.<span style="mso-spacerun: yes;"> </span>Call your doctor’s
office.<span style="mso-spacerun: yes;"> </span>Don’t call your doctor’s
office.<span style="mso-spacerun: yes;"> </span>Call the pharmacy.<span style="mso-spacerun: yes;"> </span>Don’t call the pharmacy.<span style="mso-spacerun: yes;"> </span>Today 75% of that messaging was
incorrect.<span style="mso-spacerun: yes;"> </span>And it wasn’t like the
medications were an option.<span style="mso-spacerun: yes;">
</span>Antihypertensives, diabetes medications, prostatic hypertrophy
medications – every medication name I heard had me hoping these impasses would
be resolved as soon as possible for the patient’s sake. The related quality
issue is that most of these medications were maintenance medications and yet
they required reauthorization – in some cases just because of an insurance
change.<span style="mso-spacerun: yes;"> </span>I didn’t see anyone get hit with
the <a href="https://real-psychiatry.blogspot.com/2023/08/the-donut-hole-gets-real.html">Medicare
Donut Hole</a>. I have been twice in the past 3 months with a copay for
apixaban ballooning up to $400 or roughly 7 times the usual amount just because
of the way the rules are written to favor pharmaceutical companies and pharmacy
benefit managers (PBMs). I am sure it would have happened if I had been there
longer. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">But 20 minutes was up and I did not have an anaphylactic
reaction. Another immunization I can take.<span style="mso-spacerun: yes;">
</span>I jumped in my car, turned the radio on, and thought about what I had
just witnessed.<span style="mso-spacerun: yes;"> </span>I am certainly no
stranger to it. As a physician I have been harassed by PBMs.<span style="mso-spacerun: yes;"> </span>They put me on hold for hours only to
eventually connect me with a clerk with no medical training or credentials that
would either approve or reject my recommended prescription.<span style="mso-spacerun: yes;"> </span>PBMs are not some quality improvement project
– they are patient and physician harassment to see who blinks first and loses
the time and money.<span style="mso-spacerun: yes;"> </span>They are
multibillion dollar companies that add to the cost of medications rather than
reducing the cost. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Overall prescription drug pricing in the United States is
much higher than in comparable countries both on an overall basis and a brand
name basis.<span style="mso-spacerun: yes;"> </span>A study (1) that looked at
2018 data showed that all drug pricing ranged average 258% higher than
comparable drugs purchased in Mexico, Canada, France, Germany, Italy, Japan and
the UK.<span style="mso-spacerun: yes;"> </span>Comparable brand name
medications averaged 344% higher.<span style="mso-spacerun: yes;"> </span>All of
that translates to much larger copays for Americans and often an inability to
purchase the medication. I saw that happening a lot today.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Advocacy from the physician side has been weak. After
decades of no action on the prior authorization issue some professional
organizations are now saying that it needs to be controlled. The problem with
that position is that it is so ratchetted down on patients and physicians that
any controls in the right direction will be trivial.<span style="mso-spacerun: yes;"> </span>The only solution is to eliminate prior
authorization completely. If pharmaceutical companies want to deny payment for
prescription medications – they can do it directly without using the physician
and pharmacist for cover. Beyond that the appeal can go through a state
administrative authority independent of the pharmacy business. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">I have written extensively in the past about the sheer
amount of resources that are wasted on prior authorization and the associated
pharmacy rationing strategies.<span style="mso-spacerun: yes;"> </span>I have
written about how pharmacists take a significant hit and their professionalism
is adversely affected by poor PBM reimbursement and conflict of interest –
especially when the PBM owns their own chain of pharmacies. Today as I was
waiting for clearance after an immunization it was all about the human cost.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">That never seems to get better, although the Obama and
Biden administrations have provided some <a href="https://real-psychiatry.blogspot.com/2023/09/the-true-big-pharma-backers-show.html">significant
relief to Medicare recipients</a>. Everyone involved would be happier if this
system was just gone.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">George Dawson, MD, DFAPA<o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><br /></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><i>Supplementary 1:</i> Additional inefficiencies - a couple of days after writing this post my wife got a text message that one of her prescriptions was ready and she could "pick it up after Sunday." She asked me to pick it up on Monday because I was driving by the pharmacy. I pulled up to the window and asked for the prescription and was told - "it is ready but you are one day early. You can pick it up tomorrow." Not the first time that has happened. The pick up rule seems to vary by PBM, insurance, and pharmacy but the automatic messaging obviously does not take it into account. Just another reason for going to the pharmacy and leaving without the prescription. </span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><i>References:</i><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">1:<span style="mso-spacerun: yes;"> </span>Mulcahy AW,
Whaley C, Tebeka MG, Schwam D, Edenfield N, Becerra-Ornelas AU.<span style="mso-spacerun: yes;"> </span>International Prescription Drug Price Comparisons
Current Empirical Estimates and Comparisons with Previous Studies.<span style="mso-spacerun: yes;"> </span>Rand Corporation Research Report. 2021.<o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">2: Yetter DM. </span><span color="var(--black)" style="background-color: white; font-family: arial;">Reprieve for Kentucky’s independent pharmacies is saving Medicaid millions. Kentucky Lantern. October 5, 2023. </span><span style="font-family: arial;">https://kentuckylantern.com/2023/10/05/reprieve-for-kentuckys-independent-pharmacies-is-saving-medicaid-millions/</span></p><p class="MsoNormal"><span style="font-family: arial;">This is the story of how Kentucky eliminated PBMs in their state and saved $283M in three years. </span></p><p class="MsoNormal"><span style="font-family: arial;"><br /></span></p><p class="MsoNormal"><span style="font-family: arial;"><i>Graphic credit:</i></span></p><p class="MsoNormal"><span style="font-family: arial;">Me - my wife reshot the photo.</span></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com1tag:blogger.com,1999:blog-7772182113499451603.post-27872435387250144882023-12-03T12:11:00.015-06:002023-12-19T10:30:26.544-06:00We Need More Unapologetic Psychiatrists…..<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhRAXHKezhtA0uyWUn2UBEP4zY6u5S6RToa1rtZF-eja1DxHwOZcWAuCHgoS7FDXbYQYrGQdIbveVo97u_auD-7cbV5Svf9iS8UpbfAViuBdEJeh3qh_UWhk78rVTRJtAIT5tY48nKNr1gLWj10uIDt_QZUNPIf3ldpifpU1VlkAlN1cfBWY9nwXB5mOTfS/s960/sunrise%20shot.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="720" data-original-width="960" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhRAXHKezhtA0uyWUn2UBEP4zY6u5S6RToa1rtZF-eja1DxHwOZcWAuCHgoS7FDXbYQYrGQdIbveVo97u_auD-7cbV5Svf9iS8UpbfAViuBdEJeh3qh_UWhk78rVTRJtAIT5tY48nKNr1gLWj10uIDt_QZUNPIf3ldpifpU1VlkAlN1cfBWY9nwXB5mOTfS/w640-h480/sunrise%20shot.jpg" width="640" /></a></div><p class="MsoNormal"><span face="Arial, sans-serif" style="font-size: 12pt;">I am not sure he would agree with the characterization but
I came up with this title when I decided to comment on Daniel Morehead,
MD.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">I have never met him but I have read
everything he has written in the </span><i style="font-family: Arial, sans-serif; font-size: 12pt;">Psychiatric Times. </i><span face="Arial, sans-serif" style="font-size: 12pt;">He is director of residency training in
general psychiatry at Tufts</span><i style="font-family: Arial, sans-serif; font-size: 12pt;">. </i><span face="Arial, sans-serif" style="font-size: 12pt;">In the most recent column, I notice the
heading </span><i style="font-family: Arial, sans-serif; font-size: 12pt;">Affirming Psychiatry</i><span face="Arial, sans-serif" style="font-size: 12pt;"> – that I wish I had thought of. </span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">That was one of the primary goals of this blog
when I started writing it 13 years ago.</span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">This month’s column was titled <i>Psychotherapy: Lies Cost
Lives</i> (1).<span style="mso-spacerun: yes;"> </span>He starts writing about a
New York Times column about psychotherapy that starts positive but rapidly
shifts to ambivalent. He points out that this is characteristic of most
headings that have to do with psychiatry and speculates about the origins.<span style="mso-spacerun: yes;"> </span>Controversy, mouse clicks, and advertising
dollars for sure.<span style="mso-spacerun: yes;"> </span>He lists several
titles and several themes of articles that with similarities and points out the
only logical conclusion:<o:p></o:p></span></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“The take-home message is that psychiatry rests
on shaky foundations and does not quite know what it is doing, rather like
someone feeling their way through a darkened room. Psychiatry, as usual, lags
behind the breezy confidence of other medical fields, where no one wrings their
hands about whether antihypertensives really work or whether surgery is just a
lingering form of inhuman medieval butchery.”<o:p></o:p></span></i></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">That is certainly one way to describe journalistic
gaslighting. I have offered several explanations for it on this blog.<span style="mso-spacerun: yes;"> </span>First, folk psychology. Trying to figure out
basic motivations and behavior of the people we encounter on a day-to-day basis
is an adaptive human skill.<span style="mso-spacerun: yes;"> </span>Many people
think that psychiatry is therefore just common sense and that anyone can do it
– at least until they encounter problems severe enough to where that level of
common sense fails completely.<span style="mso-spacerun: yes;"> </span>Second, there is the impression that anyone who prescribes psychiatric medications is basically equivalent to a psychiatrist. That is a trivialization of the psychiatric skill set and training. Third, antipsychiatry is a cottage industry in the US and other countries and our
detractors have had an inordinate amount of success in getting their rhetoric
published in both the popular press and professional publications. The previous
post on this blog was all about that. There are no other equivalent movements
attacking other medical specialties even though their good outcomes are
equivalent and their bad outcomes are generally much worse.<span style="mso-spacerun: yes;"> Fourth, </span>, the reality is that about 40,000
psychiatrists go to work every day in the US.<span style="mso-spacerun: yes;">
</span>The demand for psychiatrists is high. That demand is fueled by
successful treatment and a niche that is unfilled by other medical staff. Fifth, at least part of that demand is because
psychiatrists have unique skills. We are the treatment providers of last
resort, and other specialists know that and refer patients at all levels of
acuity. The only way that happens is if you know what you are doing.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Psychotherapy is part of that skill set and that is the
focus of Dr. Morehead’s column.<span style="mso-spacerun: yes;"> </span>The
science is there, even though there is a constant debate about clinical trial
design and replicability.<span style="mso-spacerun: yes;"> </span>Specific
brands of psychotherapy have been investigated and shown to work.<span style="mso-spacerun: yes;"> </span>There is also research into important
non-specific factors in psychotherapy that branded therapies have in common.
Even more basic than that are the interviewing techniques and courses taught to
second year psychiatric residents focused on facilitating information exchange
with patients for both diagnostic formulation and intervention. Communication
is a critical skill in psychiatry.<span style="mso-spacerun: yes;"> </span>In
this era of checklists, screening, and electronic health records – it is easy
to forget there is a much larger set of important information and like all
things it requires a lot of training to do it right. It is that body of information that allows for the treatment of each patients as a unique person. Personalized medicine has become a buzzword lately but from a communication perspective psychiatrists have been providing that for decades. </span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">These basic skills in
talking with people and talking in therapeutic ways are hardly ever mentioned
in discussions about psychiatrists. Criticism of psychiatry commonly seeks to
portray psychiatrists unidimensionally - as excessive prescribers of medication
rather than communicators. <span style="mso-spacerun: yes;"> </span>Throughout my
career the number one reason I was consulted was to establish communication
with a person and figure things out where nobody else could. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Even in the case of prescribing medications, there is
typically a lot more going on than a discussion of medications. One of my colleagues
established the largest clozapine clinic and long-acting injectable medication
clinics I have ever seen.<span style="mso-spacerun: yes;"> </span>When he moved
on, his patients asked me regularly where he was and how he was doing.<span style="mso-spacerun: yes;"> </span>They valued the relationship with him even
when he was providing a unique medical service. Ghaemi has written about existential
psychotherapy and how it can occur during appointments that are medication
focused (2,3). <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The overall message that Dr. Morehead is trying to convey
is that psychiatrists cannot let others characterize what we do.<span style="mso-spacerun: yes;"> </span>When that happens there are multiple agendas
operating that can lead to the clear distortion that psychiatry is not quite up
to the level of other medical disciplines.<span style="mso-spacerun: yes;">
</span>There is typically an overidealization of those other branches of
medicine with a focus on innovations that often do not materialize.<span style="mso-spacerun: yes;"> </span>The real message rarely gets out and that is –
psychiatrists are uniquely trained, we are interested in problems that nobody
else is and that other physicians often avoid, and we are good at what we
do.<span style="mso-spacerun: yes;"> </span>It is highly problematic that
journalists seem reluctant to get that message out to the public. When I first
read Dr. Morehead’s writing I found it refreshing because there are very few psychiatrists who want to get that message out. Most will cave in to
the first suggestion of a level of uncertainty that every specialist in
medicine has to deal with – the persistent risk no matter how small and the
lack of a guaranteed outcome. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">I look forward to a new generation of psychiatrists who can
start to set the record straight.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">George Dawson, MD, DFAPA<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p><p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Supplementary:<o:p></o:p></span></i></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Decided to add this explanation anticipating the typical criticism: “Well he is arrogant isn’t he? We always knew he was arrogant. All psychiatrists are arrogant!” When I say unapologetic – I mean <i>unapologetic
for just existing and trying to help people</i>. That is the level that psychiatrists are forced
to operate at that no other medical specialist is. There are the usual
misunderstandings, errors, and adverse outcomes in psychiatry that there are in
any other medical specialty. There are psychiatrists who are burned out, forced to practice in a way that they would rather not, and even personality disordered - just like any other specialty. But in
those other specialties the assumption is that these problems are handled on a case-by-case
basis by the responsible physician, clinic or hospital administrative structure, or medical board. There is no similar assumption in
psychiatry. Instead, there is an
assumption that the entire profession can be condemned for some adverse
outcome, unprofessional conduct, historical event, or any unreasonable criticism that someone can
come up with. As I have pointed out in the previous post - many criticisms are fabricated or <a href="https://real-psychiatry.blogspot.com/2023/02/the-arbitrary-and-often-absurd.html">just absurd.</a><o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">
</span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">So when you read these unrealistic criticisms about
psychiatry in the papers – keep in mind that there has been a doubling down on
the rhetoric unlike what happens with any other specialty in medicine. Use that
knowledge to moderate your reaction to it. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><i><br /></i></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><i>References:</i><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">1:<span style="mso-spacerun: yes;"> </span>Morehead D. Psychotherapy:
Lies Cost Lives. Psychiatric Times 40(11).<span style="mso-spacerun: yes;">
</span>Published online on November 10, 2023<span style="mso-spacerun: yes;">
</span><a href="https://www.psychiatrictimes.com/view/psychotherapy-lies-cost-lives">https://www.psychiatrictimes.com/view/psychotherapy-lies-cost-lives</a><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">2:<span style="mso-spacerun: yes;"> </span>Ghaemi SN.
Rediscovering existential psychotherapy: The contribution of Ludwig Binswanger.
American journal of psychotherapy. 2001 Jan;55(1):51-64.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">3:<span style="mso-spacerun: yes;"> </span>Ghaemi SN, Glick
ID, Ellison JM. A Commentary on Existential Psychopharmacologic Clinical
Practice: Advocating a Humanistic Approach to the" Med Check". The
Journal of Clinical Psychiatry. 2018 Apr 24;79(4):6935.<o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><br /></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><i>Photo Credit:</i></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Many thanks to Eduardo Colon, MD</span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com1tag:blogger.com,1999:blog-7772182113499451603.post-30296197188822191022023-11-28T18:12:00.020-06:002024-02-16T01:51:31.518-06:00Benjamin Rush - Myths Turned Into Propaganda<p style="text-align: center;"> <a href="https://commons.wikimedia.org/wiki/File:Benjamin_Rush_Painting_by_Peale_1783.jpg" title="Charles Willson Peale
, Public domain, via Wikimedia Commons"><img alt="Benjamin Rush Painting by Peale 1783" src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/da/Benjamin_Rush_Painting_by_Peale_1783.jpg/256px-Benjamin_Rush_Painting_by_Peale_1783.jpg" width="256" /></a>
</p><p style="text-align: left;"></p><p class="MsoNormal"><br /></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">If you are a casual reader of this blog, you may not have
noticed a <a href="https://real-psychiatry.blogspot.com/2021/08/drapetomania-lack-of-relevance-to.html">large
post in the past</a> that was dedicated to countering common antipsychiatry
propaganda that involved Benjamin Rush (1746-1863).<span style="mso-spacerun: yes;"> </span>Rush was a physician who was a participant in
the Continental Congress and a signer of the Declaration of Independence. He is
considered both a Founding Father and the Father of American psychiatry.<span style="mso-spacerun: yes;"> </span>In the latter case, I have expressed the
opinion that he was not really a psychiatrist and that his methods as a
physician were somewhat primitive – particularly the propensity for
bloodletting that he encouraged his own physician to use. Of course, writing
this in 2023 and calling his 18<sup>th</sup> century methods primitive is an
easy task and I am sure that if civilization lasts – 24<sup>th</sup> century
physicians may say the same thing about the current practice of medicine.<span style="mso-spacerun: yes;"> </span>The reason why Rush’s connection to
psychiatry has persisted is that he was an important historical figure and prolific writer, he made useful
observations about alcoholism and the care of patients with mental illnesses in his time
and provided asylum care.<span style="mso-spacerun: yes;"> He was considered one of the most prominent physicians of his time. </span>There is also
overlap between Rush’s lifetime and the <i>American Journal of Insanity</i>
(1844-1943) – the precursor to the <i>American Journal of Psychiatry</i>.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><span style="mso-spacerun: yes;">His historical prominence was probably the reason the American Psychiatric Association (APA) incorporated Rush and his image into various seals, certificates, and awards. As an example, I have two medals and two certificates that contained his embossed image and name from the APA. These same considerations are probably why the detractors of psychiatry have either made up stories about him or interpreted his work in the most negative possible light. Much of that rhetoric has been so successful that it now exists in the psychiatric literature. In a 2015 rebranding the <a href="https://psychnews.psychiatryonline.org/doi/full/10.1176/appi.pn.2015.6a14#">APA dropped Rush's image</a> from its logo - but retained the image for ceremonial purposes. </span></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Rush has been a target of antipsychiatry criticism and
rhetoric since the 1970s. Some of the most enduring but inaccurate tropes have
been about him – most notably involving the invention of the condition <i>negritude</i>
and being affiliated with Samuel Cartwright – a southern proslavery physician
who promoted the concept of <i>drapetomania</i> or a disease that caused slaves
to want to run away and the need to treat that condition with physical
coercion. <span style="mso-spacerun: yes;"> </span>Szasz successfully developed
both conditions into antipsychiatry tropes in a 1971 paper.<span style="mso-spacerun: yes;"> </span>Both are still actively used today as
antipsychiatry critics seek to tie modern day psychiatrists with
racism and social injustice as well as early physicians who were not really
psychiatrists. By my estimate the discipline has existed in the US for about
100 years.<span style="mso-spacerun: yes;"> </span>These tropes have been so
successful that they have found their way into professional literature
including the flagship journal of the American Psychiatric Association – The
American Journal of Psychiatry. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Here are a few examples of the inaccuracies:<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“<i>Of particular interest was Benjamin Rush (considered
the father of American psychiatry), who believed that Black skin was a mild
form of leprosy <span style="color: red;">that he called “negritude,” </span>which
could be cured only by becoming White. <span style="color: red;">An apprentice of
his, Samuel Cartwright, coined the diagnosis “drapetomania,” </span>a mental
illness that caused Black slaves to flee captivity. After the Civil War, the
frequency that severe mental illness was found in the diagnoses of patients
admitted in the country’s first psychiatric hospital for Blacks
patients—Central Lunatic Asylum in Petersburg, Va.—raises an important question
about whether Black patients were overdiagnosed with severe mental illness, as
they have been in modern times. In addition, numerous references can be found
to</i> <i>the hypothesis that mental illness in the Black population increased
substantially with the end of slavery.” </i>(1)</span></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“In 1851, Samuel Cartwright, a prominent
Louisiana physician <span style="color: red;">who had studied under Benjamin Rush</span>
but was not a psychiatrist, identified two mental disorders peculiar to slaves:
Drapetomania, or the disease causing blacks to run away, and Dysaethesia
Aethiopica, or the condition that accounted for laziness among slaves. Such
diagnoses, of course, were racist pathologizing of reasonable behavior.” </span></i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">(2)</span></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“Cartwright’s theories were embraced in the
slave states and mocked in the free states, including in medical journals,”
Geller said. <span style="color: red;">“APA was silent, and that is our shame.
They were silent then, and we have been silent for 176 years.”</span><o:p></o:p></span></i></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">In fact, Cartwright’s theory was not embraced in either group
of states, it was not a diagnosis that was used. The APA and psychiatry did not exist. (3)</span></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“Over 60 years after the ratification of the
U.S. Constitution, physician Samuel <span style="color: red;">Cartwright played a
prominent role in the rise of racism in the field of psychiatry</span>. His
descriptions and characterizations of mental health conditions in enslaved
Africans, particularly drapetomania, which he described as the illness of
enslaved people wanting to run away and escape captivity, and dysaesthesia
aethiopica, a disease of “rascality” or laziness in enslaved Africans, were the
beginning justifications of pathologizing normal behavioral responses to trauma
and oppression. These “diseases” paved the way for long-standing
rationalization of harsh, inhumane treatment of mental illnesses in communities
of color; Cartwright’s prescribed treatment for both conditions was whipping
(22). <span style="color: red;">The historical origins of racism in psychiatry
set the stage for instances of structural racism that impact the diagnosis,
management, and treatment of mental illnesses and substance use disorders to
this day.”</span><o:p></o:p></span></i></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">If you consider Cartwright to set the “historical origins
of racism in psychiatry” then there is no structural racism in psychiatry. (4)</span></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“In 1792 Benjamin Rush, considered the father
of American psychiatry and the best known physician throughout America in his
era, proclaimed that Black skin was actually a disease. Rush was a remarkable
mix of contradictions. He was an ardent abolitionist who owned a slave. He
spoke out on the position that Blacks were of equal intelligence and morality
as whites. <span style="color: red;">Nonetheless, he created a disease called
negritude,</span> a disease whose cure was turning a Black person white.” </span></i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">(5)</span></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“I consider Cartwright's "Report,"
and especially the two diseases afflicting the Negro that he discovered, of
special interest and importance to us today for the following reasons: first,
because Cartwright invoked the authority and vocabulary of medical science to
dehumanize the Negro and justify his enslavement by the white man; second, <span style="color: red;">because the language and reasoning he used to justify the
coercive control of the Negro are identical to those used today by mental
health propagandists to justify the coercive control of the madman </span>(that
is, the so-called "psychotic," "addict," "sexual
psychopath," and so forth); and third, because <span style="color: red;">Cartwright's
"Report" is the sort of medical document that has, for obvious
reasons, been systematically ignored or suppressed in standard texts on medical
and psychiatric history</span><o:p></o:p></span></i></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="color: red; font-size: 12pt; line-height: 107%;">One such omission, discussed in
detail in The Manufacture of Madness, is Benjamin Rush's theory of Negritude, </span></i><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">according
to which the black skin and other physical "peculiarities" of the
Negro are due to his suffering from congenital leprosy (1, pp. 153-159).”<o:p></o:p></span></i></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Any serious historical look at the diagnosis of
drapetomania would show that it was ignored – even by southern physicians
interested in racial medicine. Szasz's analogy of slavery and mental illness is purely rhetorical. (6)<o:p></o:p></span></p>
<p class="MsoNormal"><span face="Arial, sans-serif" style="font-size: 12pt; line-height: 107%;">The tropes about Rush and his relationship to
Samuel Cartwright and racial medicine seem entrenched at all levels of
discussion of psychiatry including writing by psychiatrists. From
a rhetorical standpoint they are used to legitimize an argument that the
profession is either racist, built on a racist foundation, or did not actively
counter racism when the opportunity presented itself. They are also used to suggest that psychiatric diagnoses are invalid - even though these pseudo-diagnoses by a non-psychiatrist were never used by any physicians. Those specific narratives
are false at best and fabricated at the worst.
This historical record is now clearly available and should be consulted
in the future when writing on this topic at the </span><a href="https://guides.library.upenn.edu/benjamin-rush/Benjamin_Rush_Mythology"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">University
of Pennsylvania Benjamin Rush Portal</span></a><span face="Arial, sans-serif" style="font-size: 12pt; line-height: 107%;">. If you read all the segments what I have
written in this post covers only a portion of the myths. You will also note that some of the myths are
described as <i>villainizing</i> Rush. I
think the same characterization could apply to Szaszian rhetoric that has been
applied to the entire profession of psychiatry in modern times on a repetitive
basis.</span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">While it may be unrealistic to think that historically
accuracy will have much of an impact in this era of for-fame-and-profit-misinformation,
I am suggesting a higher standard.<span style="mso-spacerun: yes;"> </span>That
standard is that members of the psychiatric profession and the editors of that
literature should be aware of it and make the necessary changes.<span style="mso-spacerun: yes;"> </span>I am fully aware of the current concerns
about structural racism and building diversity. That cannot be based on a false
narrative.<span style="mso-spacerun: yes;"> </span>In fairness to Rush, I think
it is necessary to set the historical record straight as his biographer Stephen
Fried has done. Like most of the historical figures I write about on this blog
– I see him just as that - with no relevance to modern day psychiatry.<span style="mso-spacerun: yes;"> </span>Anyone reading Fried’s detailed biography of
Rush will see him as a progressive thinker that would probably easily maintain
that description even in today’s polarized political climate.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">George Dawson, MD, DFAPA<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">References:<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">1:<span style="mso-spacerun: yes;"> </span>Dike CC.<span style="mso-spacerun: yes;"> </span>Misuse of Psychiatry.<span style="mso-spacerun: yes;"> </span>Psychiatric News. Published Online:23 Apr
2022 <a href="https://doi.org/10.1176/appi.pn.2022.05.5.30">https://doi.org/10.1176/appi.pn.2022.05.5.30</a><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">2:<span style="mso-spacerun: yes;"> </span>Jeffrey Geller,
MD, MPH. The Rise and Demise of America’s Psychiatric Hospitals: a Tale of
Dollars Trumping Decency.<span style="mso-spacerun: yes;"> </span>Published
Online:26 Feb 2019 <a href="https://doi.org/10.1176/appi.pn.2019.3a36">https://doi.org/10.1176/appi.pn.2019.3a36</a><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">3:<span style="mso-spacerun: yes;"> </span>D’Arrigo T. Black
Psychiatrists Call on White Colleagues To Dismantle Racism in Profession,
APA.<span style="mso-spacerun: yes;"> </span>Psychiatric News Published
Online:23 Jun 2020 <a href="https://doi.org/10.1176/appi.pn.2020.7a34">https://doi.org/10.1176/appi.pn.2020.7a34</a><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">4:<span style="mso-spacerun: yes;"> </span>Shim RS.
Dismantling Structural Racism in Psychiatry: A Path to Mental Health Equity. Am
J Psychiatry. 2021 Jul;178(7):592-598. <a href="https://doi:%2010.1176/appi.ajp.2021.21060558">https://doi:
10.1176/appi.ajp.2021.21060558</a><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">5:<span style="mso-spacerun: yes;"> </span>Geller J.<span style="mso-spacerun: yes;"> </span>Structural Racism in American Psychiatry and
APA: Part 1.<span style="mso-spacerun: yes;"> </span>Psychiatric News.<span style="mso-spacerun: yes;"> </span>Published Online:23 Jun 2020 <a href="https://doi.org/10.1176/appi.pn.2020.7a18">https://doi.org/10.1176/appi.pn.2020.7a18</a><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">6:<span style="mso-spacerun: yes;"> </span>Szasz TS. The
sane slave: An historical note on the use of medical diagnosis as justificatory
rhetoric. American Journal of Psychotherapy. 1971 Apr;25(2):228-39.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Supplementary:<o:p></o:p></span></i></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">I decided to include a section on Rush’s theory of black skin
color to avoid the typical gotcha arguments from antipsychiatrists.<span style="mso-spacerun: yes;"> </span>These arguments are contained in the
reference below and I have supplied a link where you can download the entire
paper. Context is always important when considering the medical, social, or
political opinions from over 200 years ago. <span style="mso-spacerun: yes;"> </span>The important contexts would include prevalent
racial bias that obviously persists today, and the lack of important medical
advances including germ theory, general pathophysiology, and medical genetics.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">He opens by referencing <i>An Essay On the Causes Of The
Variety Of Complexion and Figure In The Human Species</i> by Rev. Samuel
Stanhope Smith, DD – a professor of moral philosophy.<span style="mso-spacerun: yes;"> </span>The essay is a book the content of which was
based on a previous lecture given on February 28, 1787.<span style="mso-spacerun: yes;"> </span>Rush touches on the four main causes listed
in this text – climate, state of society, diet, and diseases. Citing a moral philosopher and clergyman is not an ideal start to an opinion piece on pathology or pathophysiology, but it forms the main outline of his essay.</span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">He suggests that
the color and figure “of that part of our fellow creatures who are known by the
epithet of negroes, are derived from a modification of that disease, which is known
by the name of Leprosy.”<span style="mso-spacerun: yes;"> </span>He says the
leprosy outbreaks in Europe in the 13<sup>th</sup> and 14<sup>th</sup>
centuries were caused by “unwholesome diets.”<span style="mso-spacerun: yes;">
</span>He observes that “in some instances” leprosy causes a black color of the
skin and that some Africans have other symptoms. He notes Biblical and real world
observations describing inconsistencies in skin color. He suggests that
“insensibility” as a feature of leprosy (meaning sensory neuropathy) may
explain why people with African origins have a lower pain sensitivity.<span style="mso-spacerun: yes;"> </span>He also connects leprosy with “strong
venereal desires” and suggests this is also true in people of African
origin.<span style="mso-spacerun: yes;"> </span>He comments that leprosy can
produce characteristic skin changes in whites as well and notes that matted hair
in people of Polish descent is a sign.<span style="mso-spacerun: yes;"> </span>He
notes the longevity of the illness and that it took 3 to 4 generations to clear
in Iceland.<span style="mso-spacerun: yes;"> </span>He gives other examples of
physical signs that are locally transmitted among ethnic groups. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">He anticipates the objection that leprosy is an infectious
disorder but that does not appear to be the case in Africans by saying that it
has “ceased to be infectious” but also that there are exceptions in the case of
mixed-race couples where white women acquired the features and skin color of
their black husbands. Since he expects that leprosy does not significantly
affect longevity he expects these traits to continue. The causative bacterium for leprosy (</span><span style="background-color: white; color: #202124;"><span style="font-family: arial;">Mycobacterium leprae) </span></span><span style="font-size: 12pt;">was eventually discovered in 1873 by Hansen. The genetics of skin coloration was <a href="https://real-psychiatry.blogspot.com/2016/07/what-is-missing-from-divisiveness-debate.html">not discovered until the 21st century</a>.</span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">These are clearly very weak and biased observations.<span style="mso-spacerun: yes;"> </span>Rush’s conclusions based on these observations
are interesting.<span style="mso-spacerun: yes;"> </span>First, claims of
superiority of whites based on skin color are “founded in ignorance and
inhumanity.” He suggests that if a disease is causing this difference “it should
entitle them to a double portion of our humanity, for disease all over the
world has always been the signal for immediate and universal compassion”.<span style="mso-spacerun: yes;"> </span>Second, the facts outlined should teach white
people to not keep intergenerational prejudices. Third, science and humanity
should unite to find a cure for the disease, but the science at the time was
non-existent. He goes on to list several anecdotal approaches.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Rush ends his paper speculating about how curing this
disease of leprosy producing blackness would add greatly to the happiness in
the world and that of people with African ancestry.<span style="mso-spacerun: yes;"> </span>He qualifies that by noting that black people
seem to prefer their skin color to white. He wraps it up in a Biblical myth at the
end to say:<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“We shall render the belief of the whole human race being
descended from one pair, easy, and universal, and thereby not only add weight
to the Christian revelation, but remove a material obstacle to the exercise of
that universal benevolence which is inculcated by it.”<span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><span style="mso-spacerun: yes;">This was 60 years before Darwin's <i>Origin of the Species</i>. It is doubtful than anyone at the time had a theory of how isolated groups of humans might evolve with different characteristics.</span><o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-size: 12pt;">Although Rush did not technically invent a disease or word
called </span><i style="font-size: 12pt;">negritude</i><span style="font-size: 12pt;"> or suggest that it was responsible for skin color in
African Americans – he certainly proposed what I would characterize as an
off-the-wall theory.</span><span style="font-size: 12pt; mso-spacerun: yes;"> </span><span style="font-size: 12pt;">His writing further
suggests that a solution of universal white skin would allow for a more
harmonious existence – with less discrimination and that would be a solution to
the problem of racism. It is an overly simplified and biased solution
by today’s standards.</span><span style="font-size: 12pt; mso-spacerun: yes;"> </span><span style="font-size: 12pt;">Since Rush was
obviously not racist the logical explanation for this opinion is a significant
knowledge deficit and speculating outside of his lane.</span><span style="font-size: 12pt; mso-spacerun: yes;"> </span><span style="font-size: 12pt; mso-spacerun: yes;"> </span><span style="font-size: 12pt; mso-spacerun: yes;"> </span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Rush B: Observations intended to favour a supposition that
the black color (as it is called) of the Negroes is derived from the leprosy.
American Philosophical Society Transactions 4 (old series): 289-297, 1799.<span style="mso-spacerun: yes;"> </span>Link directly loads PDF:<span style="mso-spacerun: yes;"> </span></span><a href="https://canvas.emory.edu/courses/86982/files/5134312/download?download_frd=1"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">https://canvas.emory.edu/courses/86982/files/5134312/download?download_frd=1</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p></o:p></span></p>
<p class="MsoNormal"><br /></p><p></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com3tag:blogger.com,1999:blog-7772182113499451603.post-86830380064567246212023-11-19T22:34:00.030-06:002023-12-02T22:40:37.203-06:00The Times They Are A-Changin’ – or Are they?<p style="text-align: center;"><br /></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjxPQyl8VzQGVbX_56wGBh0GN21njH7Id9JLwBtJUGgTbuFX2aOVdo0Ya-i-QCubcknwGg5YdygCp81si81BgL2W9KGkfLre10MB-OwO-9RaEUmzixGtPJGXM-7KzUmbkw7xodo3KVh4TMC51FqSXIiOGLTinITYq72S5GLSiv8WfmnJDjFLY_6CVdKq7fg/s1818/2024%20Presidential%20Campaign%20graphic%2011.24.2023.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1274" data-original-width="1818" height="448" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjxPQyl8VzQGVbX_56wGBh0GN21njH7Id9JLwBtJUGgTbuFX2aOVdo0Ya-i-QCubcknwGg5YdygCp81si81BgL2W9KGkfLre10MB-OwO-9RaEUmzixGtPJGXM-7KzUmbkw7xodo3KVh4TMC51FqSXIiOGLTinITYq72S5GLSiv8WfmnJDjFLY_6CVdKq7fg/w640-h448/2024%20Presidential%20Campaign%20graphic%2011.24.2023.png" width="640" /></a></div><br /><div class="separator" style="clear: both; text-align: center;"><br /></div><span style="font-family: arial;">I was walking around last week at dusk on a couple of nights. For the first time I decided to listen to some music as I walked. I would never do this if I was cycling because you need to hear the tire noise of approaching vehicles and I was using noise cancellation headphones tied into my music library. I also decided to use shuffle mode and that is also unusual – I typically repeat tracks until I get tired of them and that often takes a long time. For some reason, my phone kept playing Dylan songs. It reminded me of how I really did not like Dylan when I was young and listening to Hendrix and the Who. My interest peaked when he got the Noble Prize for Literature. It peaked again when I heard him interviewed and he talked about how easy it was to write music when he was younger. The music just seemed to flow and all he had to do was write it down. It was how mathematicians were described in Nasar’s biography of John Nash. Young mathematicians typically produced most of the ideas that advanced the field. </span>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="font-family: arial;"><span style="color: #202124;">A lot
of the songs were melancholy tunes about relationships gone bad.</span><span style="color: #202124; mso-spacerun: yes;"> </span><span style="color: #202124;">Some were lessons in how not to be
codependent. I was acutely aware of being an old man dressed in black listening
to this music and free associating to similar events in my life from long ago.
Before it got too maudlin - </span><i style="color: #202124;">The Times They Are A-Changin’</i><span style="color: #202124;"> came on:</span></span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><i style="background-color: transparent;">Come gather 'round people</i></p><i>Wherever you roam <br />And admit that the waters <br />Around you have grown <br />And accept it that soon <br />You'll be drenched to the bone <br />If your time to you is worth savin' <br />And you better start swimmin' <br />Or you'll sink like a stone<br />For the times they are a-changin'</i>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">I could have sworn that what I heard walking around in the dark was a direct
reference to the United States in that song. But looking it up later - it was
not there. The song snapped me out of interpersonal reflection and into the current
threat to American democracy.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">For the
past several days I had been responding to social media posts about the
disconnect between what </span><i style="color: #202124; font-size: 12pt;">appears</i><span style="color: #202124; font-size: 12pt;"> to be going on in national presidential
politics and the reality of the situation. Just that day I responded to a
poster questioning why Christians appear to be in lock step with a candidate
who does not appear to have similar values and how Biden has done very well in
the White House but seems to be struggling in the polls against a candidate
with a known poor record who orchestrated an insurrection against the US
government? A candidate who has been charged with 91 felonies. Even more
mysteriously, the entire Republican party with rare exceptions is supporting
Trump and most want his endorsement in local and state elections. How can a
candidate with that many flaws still be in contention at this point and
dominating a party that was originally abolitionist and got Lincoln elected as
their first President before the start of the Civil War? </span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">It does not make any sense and I will look at
the hypotheticals below.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">I tried to put
as many as possible into the graphic at the head of this post – but only the coarsest
details are possible:</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">1:</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><i style="color: #202124; font-size: 12pt;">A general lack of critical thinking:</i></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">It has
been a long time since I took a high school English class, but from what I
recall even back in those days there was very little emphasis on rhetoric.
Critical thinking generally involved the decoding the author’s intent,
detection of symbolism and defending an opinion on a theme: “Do you find Lord
of the Flies to be optimistic or pessimistic and why?”</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">Rhetoric was largely confined to debate teams
that a small percentage of students participated in.</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">It has
never been more important for the average citizen to be informed and aware of
what might be rhetorical distortions. There used to be some level of assistance
from professionally edited news, but that is no longer reliably available.
Today it is possible to get all your news from a site that you agree with on
ideological grounds – no matter how far from reality that site gets. Apart from
these echo chambers on the Internet, the main street news offers minimal
assistance.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">You might find stories about
the </span><i style="color: #202124; font-size: 12pt;">polarized electorate</i><span style="color: #202124; font-size: 12pt;"> with no discussion of what that means or if one
side is more polarized than the other. </span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">Threats and overt violence were introduced
into the political scene with no comment that this is almost an entirely right-wing
phenomenon that is often tied in with gun rights and bragging about who owns
the most guns. The right wing owns both moral and gun extremism in the US and
yet there no criticism of this in mainstream media. Most importantly, political
violence against specific groups should be unacceptable in the US and it is
increasingly apparent.</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">2:</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><i style="color: #202124; font-size: 12pt;">President Biden is too old:</i><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">This
seems to be a popular trope in both campaign propaganda and as material for
comedians.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">Bill Maher for example, will
often detail the accomplishments of the Biden administration as being some of
the most significant in decades only to incorporate polling questions about his
age and conclude he should step down and let someone else run. No suggestions
about who that should be and judging from the declared candidates there is no
one of suitable name recognition or accomplishment who could run and expect to
get support equal to Trump’s locked in MAGA constituency. If you look at my
graphic – any candidate the Democrats advance will not have the amount of leverage
with the voters based on the factors listed.</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">But
backing up – is 80 years old – too old?</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;">
</span><span style="color: #202124; font-size: 12pt;">I saw President Biden on the bike and I saw him fall. It was clearly a
mistake that people make when they are not used to toe clip pedals. The part
that most people seem to ignore is that he got up with no problems. That is not
the mark of a feeble old man and neither is the current schedule he has been
keeping. More to the point – he has an awareness of how things need to run in
the Executive Branch, how information needs to be managed, how consultation
with staff is a critical function, and how to manage alliances.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">There is minimal evidence that his
predecessor has that level of awareness. </span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">There
is certainly no current evidence that Biden cannot do the job given his list of
accomplishments and some high-profile incidents – most notably his performance
at the last State of the Union address. Ageism is certainly a prominent
cultural bias in the US.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">If I were a
foreign actor wanting to manipulate the American electorate – I would use it,
especially if I knew the opposition party could easily be convinced to use it. </span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">The current group of Republicans could be
expected to jump on it even though some of their members of Congress are older than Biden.</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">3:</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><i style="color: #202124; font-size: 12pt;">The Republican base has been manipulated
and brain washed by culture war tropes</i><span style="color: #202124; font-size: 12pt;">:</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">This
is undoubtedly a factor at some level.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">I
have written on this blog about how the GOP has become a party of gun and moral
extremists – not out of some strict Constitutional interpretation or religious
belief, but out of political expediency. It is easy to manufacture some
ideological position to elicit emotional responses from some voters and get
them to believe they are in a morally or Constitutionally superior position.
Fortunately, that is not how democracy works but it is how the current crop of
Republicans want it to work. In the meantime, public safety, education, and
women’s health have all been compromised. On the day I am typing this a
Constitutional Amendment for reproductive rights was passed in Ohio blocking
attempts to pass restrictive abortion laws. Whether this can be a rallying
point against moral extremism is an open question at this point.</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><i><span style="color: #202124; font-size: 12pt;">4:</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span></i><span style="color: #202124; font-size: 12pt;"><i>Fragmentation among Democrats:</i> </span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">There is some
concern that progressives within the party have gone too far in areas of social
consciousness particularly social justice issues involving race and the LGBT
community. The concern is amplified by the Republican’s rhetorical use of the
term </span><i style="color: #202124; font-size: 12pt;">woke</i><span style="color: #202124; font-size: 12pt;"> as a pejorative. That has allowed them to indiscriminately use
the term to criticize health care, educational, social, and economic policies
as being </span><i style="color: #202124; font-size: 12pt;">too woke</i><span style="color: #202124; font-size: 12pt;"> (translation politically correct) and simultaneously
suggest that most Americans would not find it to be acceptable. That can range
from books in a high school library that were read by several older generations
to college admission policies to protests about excessive use of force by the
police.</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">The
current war between Israel and Hamas is a similar flashpoint. One analysis
suggests that progressives see the world though a simple lens of colonizers and
victims. That has been spun into Israel starting a genocidal war in Gaza or
even the US starting or backing such a war. In the most extreme case, social
media was abuzz with young people supporting a letter allegedly written by a
famous terrorist, blaming the United States for terrorist attacks. That has
also led to protests and threats to Jewish college students in the United
States. All of that misses the point that violence is being incited against US
citizens who happen to be Jewish and that Hamas clearly started the war and clearly
stated their ongoing goal is to destroy Israel and kill their citizens.</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="color: #202124; font-size: 12pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;"><i>5:<span style="mso-spacerun: yes;"> </span>Activation of far right white supremacist and
antisemitic groups:</i><span style="mso-spacerun: yes;"><i> </i> </span></span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="color: #202124; font-size: 12pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">There is no doubt
that </span><span style="color: black; mso-color-alt: windowtext;"><a href="https://www.splcenter.org/20200810/when-alt-right-hit-streets-far-right-political-rallies-trump-era"><span face=""Arial",sans-serif" style="font-size: 12pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;">fringe groups that
were essentially silenced for many years</span></a></span><span face=""Arial",sans-serif" style="color: #202124; font-size: 12pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;"> were
activated during the Trump administration and actively support him. In my own
neighborhood there was widespread dissemination of white supremacist literature
for tens of miles in all directions.<span style="mso-spacerun: yes;">
</span>That has <i>never</i> happened in the Midwest during my lifetime. Further
investigation linked the same group spreading that literature to
antisemitism.<span style="mso-spacerun: yes;"> </span>Investigation by local
officials and law enforcement did not identify the specific perpetrators and no
charges were ever filed.</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><i><span style="color: #202124; font-size: 12pt;">6:</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">Activation of antisemitism in younger
generations: </span></i></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">The facts are not disputed and various theories have been
proposed. The </span><i style="color: #202124; font-size: 12pt;">history is forgotten</i><span style="color: #202124; font-size: 12pt;"> explanation seems to have a lot of
traction.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">At least it seems to have
garnered the most speculation. In other words, with less exposure to Holocaust
survivors and the history of World War II, younger generations are unlikely to
believe the actual historical events – a clearly documented genocide against
the Jewish people. That seems to minimize any role of activated antisemitic
hate groups and social media. Many of these groups are now at the point that
they show up in public demonstrations and are attempting to recruit new members
from suburban neighborhoods. The wave of antisemitism in the younger generation
has had far reaching effects on college campuses, in some cases to the point
that departments and administrations failed to condemn the recent terrorist
attack against Israel or an obvious problem of antisemitism on their campuses.
This generation uses TikTok as a preferred social media site. In a recent press
release they described removing tens of thousands of antisemitic posts.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">Just how long that posting has occurred is
unknown.</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">I
think it is also useful to recall that political violence directed at minority
groups is a well-known tactic of fascist and totalitarian states.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">In the early days of the Internet online
discussions often became heated to the point that accusations of Naziism were
often made.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">This led to Godwin’s Rule </span><i style="color: #202124; font-size: 12pt;">or
as an online discussion grows longer (regardless of topic or scope), the
probability of a comparison to Nazis or Adolf Hitler approaches 1.<span style="mso-spacerun: yes;"> </span></i><span style="color: #202124; font-size: 12pt;">That is basically nerd speak to say that
analogies to Nazis based on Internet discussions is probably absurd. What I
have seen lately suggests to me that we are beyond the absurd stage when people
are injured and living in fear.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">If it walks
and talks </span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">like a Nazi….</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><i><span face=""Arial",sans-serif" style="color: #202124; font-size: 12pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;"><o:p> </o:p></span><span style="color: #202124; font-size: 12pt;">7:</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">The social media propaganda machine:</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span></i></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">Social media seems to always be in the news.
The common topic is how it is a malignant force in the lives of teenagers and
children. There is concern that you can get “addicted” to rapidly scrolling and
clicking on too many sites. People talk about the dopaminergic effects of this
activity – like the neuroscience is known. Even though we had a foreign
government actively interfering in the last Presidential election through
social media and email hacks – nobody seems focused on that happening again. US
Intelligence agencies predicted that it would happen again and it would
probably be more vigorous than the last time. It is also more difficult to
detect because the foreign actors are all using servers within the United
States. Several agencies are responsible for detecting and monitoring this
activity – but 1 year out none of them are reporting on what they see or what
kind of misinformation is being posted. You don’t have to be a secret agent to
think about who these foreign actors are. Russia was clearly involved in the
last Presidential election and given the situation in Ukraine – they would
clearly prefer Trump over Biden.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">Putin
has actively encouraged Russian hackers at all levels including those who steal
money from average Americans.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">Trump has
made it clear that he would not support Ukraine and he clearly had a negative
impact on NATO.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">Biden has been able to
reverse most of that damage and unify NATO.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;">
</span><span style="color: #202124; font-size: 12pt;">Iran, China, and North Korea also have an interest in a Trump
presidency. </span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">These countries either have
a direct interest in supporting Trump based on his probable policies or just
weakening the US by more divisiveness in the electorate.</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><i><span face=""Arial",sans-serif" style="color: #202124; font-size: 12pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;"><o:p> </o:p></span><span style="color: #202124; font-size: 12pt;">8:</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">Uncritical voters:</span></i><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">I heard Iowa voters asked about why they are
voting for Trump and why he is so popular in their state.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">I heard the following responses:</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="color: #202124; font-size: 12pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;"><o:p> </o:p></span><span style="color: #202124; font-size: 12pt;">“He is
a businessman.”</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="color: #202124; font-size: 12pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;"><o:p> </o:p></span><span style="color: #202124; font-size: 12pt;">“He
says what is on his mind.”</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="color: #202124; font-size: 12pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;"><o:p> </o:p></span><span style="color: #202124; font-size: 12pt;">“I
don’t care what he has said or done – I am voting for him.”</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">These
responses and his previous performance – all indicate that many Trump voters
are not focused on any policy.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">It would
probably be difficult because most of the policies that Trump seems focused on
at this point have to do with revenge against his perceived enemies.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">That is typically a low bar – they are people
who either disagree with him or want accountability.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">That leads me to a previously stated
conclusion I made that a lot of Trump’s base are nihilists who just want to
burn the system down. It is difficult to find more nihilistic behavior than
orchestrating an insurrection against the US government and refusing the
peaceful transfer of power.</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">Given
the above analysis – I think the negative sentiment about President Biden is
primarily the product of foreign actors manipulating the American electorate.
That also explains the disconnect between many of the demographic features of
Trump voters and their candidate.</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">I do
not want to put all of this on young voters.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;">
</span><span style="color: #202124; font-size: 12pt;">There are clearly older voters who demonstrate similar levels of
cluelessness, probably borne out of long-standing biases.</span><span style="color: #202124; font-size: 12pt; mso-spacerun: yes;"> </span><span style="color: #202124; font-size: 12pt;">It is up to voters of all ages to not believe
what you see in social media echo chambers, clear propaganda from hate groups,
and similar attitudes that may have existed in your culture for generations. We
cannot turn the United States over to a man and a party of extremists who have
proven time again that they have no vision for the country or where it is
headed. In Congress the Republican majority has clearly demonstrated that they cannot govern. We cannot be influenced by groups seeking to divide Americans
and destroy the values that this country was founded on.</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">We all
must start swimmin’ to save American democracy.</span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="color: #202124; font-size: 12pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;"><o:p> </o:p></span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;">George
Dawson, MD, DFAPA</span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;"><i><br /></i></span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;"><i>References:</i></span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="font-family: arial;"><span style="color: #202124;">1: </span><span style="background-color: #fefefe; color: #0a0a0a;">Hotez, Peter. "On Antiscience and Antisemitism." </span><i style="background-color: #fefefe; box-sizing: inherit; color: #0a0a0a; line-height: inherit;">Perspectives in Biology and Medicine</i><span style="background-color: #fefefe; color: #0a0a0a;">, vol. 66 no. 3, 2023, p. 420-436. </span><i style="background-color: #fefefe; box-sizing: inherit; color: #0a0a0a; line-height: inherit;">Project MUSE</i><span style="background-color: #fefefe; color: #0a0a0a;">, </span><a href="https://doi.org/10.1353/pbm.2023.a902035" style="background-color: #fefefe; box-sizing: inherit; color: #1a4c8c; cursor: pointer; line-height: inherit; outline-width: 0px; overflow-wrap: break-word; text-decoration-line: none;">https://doi.org/10.1353/pbm.2023.a902035</a><span style="background-color: #fefefe; color: #0a0a0a;">.</span></span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="font-family: arial;"><span style="background-color: #fefefe; color: #0a0a0a;">2: </span><span style="background-color: transparent;"><span style="color: #0a0a0a;">Scherer, Nancy & Miller, Banks. (2009). The Federalist Society's Influence on the Federal Judiciary. Political Research Quarterly - Polit Res Quart 62. 366-378. <a href="https://doi.org//10.1177/1065912908317030">https://doi.org//10.1177/1065912908317030</a>. </span></span></span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;"><br /></span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124; font-size: 12pt;"><i>Graphic Credit: </i>I made this graphic </span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124;"><span style="font-size: 12pt;"><i>Supplementary 1:</i> Why I wrote this post - this post is not an analysis of the psychiatric status of either candidate. I am on record on this blog that the role of assessing the President's fitness to work in that office is supposed to be </span>assumed<span style="font-size: 12pt;"> by lay people working with him or her. Many people working with Trump have provided scathing critiques of what they observed. I have not seen any from the Biden administration. </span></span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124;"><span style="font-size: 12pt;">This post was written basically as an exploration of how a candidate who seems so </span>intellectually<span style="font-size: 12pt;">, emotionally, and temperamentally unfit for the office (as determined by multiple independent assessments by non-mental health professionals) has such a draw with the electorate. It seems mystifying until you look at the diagram and realize that more of the factors that leverage the electorate are stacked against Biden rather than Trump. In fact - replacing Biden in the graphic results in minimal gains. If I had to </span>speculate<span style="font-size: 12pt;"> on the biggest effect I would see it as all of the factors impinging on the social media on Trump's side. </span></span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span style="color: #202124;"><span style="font-size: 12pt;">For the record, I am not a life long Democrat and in fact ran as an Independent in 2000 for the US Senate from Minnesota. As a life long skeptic of both major parties, that was an eye opening experience. I am currently highly motivated to write about political extremism that I see from Republicans and the fact that it is only getting worse. Giving Trump the job again when we already know what happened the last time is a clear mistake. Allowing the Republican Party to maintain a nongoverning, culture wars, nihilistic response is also a massive mistake for the Republic. </span></span></p>
<p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="color: #202124; font-size: 12pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;"><span style="mso-spacerun: yes;"> </span></span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="color: #202124; font-size: 12pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;"><span style="mso-spacerun: yes;"><i>Supplementary 2:</i></span></span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="color: #202124; font-size: 12pt; mso-fareast-font-family: "Times New Roman"; mso-font-kerning: 0pt; mso-ligatures: none;"><span style="mso-spacerun: yes;">Will add some examples to highlight the graphic as the I see them on a day to day basis:</span></span></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><a href="https://www.tmz.com/2023/11/21/taylor-lorenz-biden-meme-birthday-cake-wont-help-win-young-voters/">Taylor Lorenz </a>- excellent example that I saw today on TMZ is this interview. Before this the TMZ crew showed Biden's attempt at humor with a birthday cake and they continue this into the interview like he is trying to win young voters with jokes. Ms. Lorenz of course jumps on the opportunity to point out that Biden has not been focused on what Millennials or Gen Z want. She cites an example of student loan forgiveness was not a focus apparently forgetting that his $430B student loan forgiveness plan was shot down by the right wing Supreme Court. All three justices appointed by Trump (Gorsuch, Kavanaugh, Barrett) voted against the plan in a 6-3 vote (<i>Biden v. Nebraska</i>). Instead she praises Trump for being "authentic." With brilliant analyses like that Biden does not stand a chance. </p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><a href="https://en.wikipedia.org/wiki/Adam_Kinzinger">Adam Kinzinger</a> - seems like a rare positive force in American politics today. I saw him on <a href="https://www.hbo.com/real-time-with-bill-maher/season-21/21-november-17-2023-rob-reiner-and-albert-brooks-donna-brazile">Real Time</a> with Bill Maher last week where he clearly stated that there was only one pro-democracy political party in the US and it was the Democrats. The former Republican Congressman clearly described why fanaticism is a negative coercive force in politics and that is why it needs to be eliminated. He also founded the Country First PAC as a way to distance himself from right wing extremists and conspiracy theories. </p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><a href="https://www.youtube.com/watch?v=jaYI1cxUE1o">Gen. Mark Milley</a> - questioned about President Biden's performance by 60 minutes.</p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><br /></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><br /></p><p class="MsoNormal" style="background: white; line-height: normal; margin-bottom: 0in;"><br /></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com1tag:blogger.com,1999:blog-7772182113499451603.post-73846810914507482592023-11-12T14:09:00.006-06:002023-11-13T12:28:07.197-06:00Hierarchical Diagnoses<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiLT10AGHQEZbf5kpTPqPJ70mdxi3nnDiqlDyQ8AtXDlXag7aH-af9FAwHSWcQu2H7Kaq4K93wQ-6i5M05n22gdrbgcMntx8RJvyE8XS_GDbrXZr-EIYG48jd493PC974lfOWYfiRfPDd8qdLYy7hoVohlN9QHrVrH_DIBdbJY37KWH1B1flE0o5pZuejF7/s1338/Clinincal%20hierarchy%20versus%20nomenclature%20hierarchies.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1338" data-original-width="1302" height="640" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiLT10AGHQEZbf5kpTPqPJ70mdxi3nnDiqlDyQ8AtXDlXag7aH-af9FAwHSWcQu2H7Kaq4K93wQ-6i5M05n22gdrbgcMntx8RJvyE8XS_GDbrXZr-EIYG48jd493PC974lfOWYfiRfPDd8qdLYy7hoVohlN9QHrVrH_DIBdbJY37KWH1B1flE0o5pZuejF7/w622-h640/Clinincal%20hierarchy%20versus%20nomenclature%20hierarchies.png" width="622" /></a></div><p class="MsoNormal"><span face="Arial, sans-serif" style="font-size: 12pt;"><br /></span></p><p class="MsoNormal"><span face="Arial, sans-serif" style="font-size: 12pt;">The notion of hierarchical diagnoses comes up from time to
time, so it is about time that I made some comments about it. Like most
criticism of psychiatry, I think the concept is overblown and will illustrate
why that is. The idea of hierarchies in diagnosis is basic.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">It means prioritizing the most clearly
defined illness.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">Clearly defined in this
case may mean a clearcut phenotype or disease mechanism.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">In the psychiatric examples provided that
generally means a feature high in the hierarchy that is not replicated at lower
levels, but many features at lower levels that overlap. </span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The overall goal is to not end up with a long list of
conditions or diseases that could fit the presenting problems and end up
treating everything on the list rather than the <i>most likely</i> cause of the
problem.<span style="mso-spacerun: yes;"> </span>I think of it as second year
med student differential diagnosis.<span style="mso-spacerun: yes;"> </span>When
you are learning physical diagnosis you take an exhaustive history, review of
systems, and physical exam and try to come up with a <i>differential diagnosis</i>
list.<span style="mso-spacerun: yes;"> </span>Even with that beginning level of
knowledge in medicine you start to realize that diagnosis number 3 to 8 are
improbable and start to focus just on the top 2. By the time you are an intern
those lengthy differential diagnoses lists are a remote memory. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">It also involves the application of the parsimony
principle.<span style="mso-spacerun: yes;"> </span>Is there a single diagnosis
that incorporates all the features of the observed disorder rather than a list
of conditions?<span style="mso-spacerun: yes;"> </span>I can illustrate this
with an example right out of my physical diagnosis text from medical school (1):<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“In selecting the diagnosis from a list of hypotheses, the
physician is to choose a single disease to explain all of the patient’s
manifestations rather than explain them by the coincidence of several
diseases.<span style="mso-spacerun: yes;"> </span>This is called the <i>law of
parsimony</i>. For example, when a patient is found to have a dilated heart,
hepatomegaly, ascites, and pedal edema, the single diagnosis of cardiac failure
explains all of the findings. It is more likely to be the true diagnosis than
to suppose a coincidence of heart disease producing cardiac enlargement,
cirrhosis of the liver producing hepatic enlargement, and nephrosis leading to
edema from hypoproteinemia.<span style="mso-spacerun: yes;">
</span>Nevertheless. The “law” must be applied cautiously.<span style="mso-spacerun: yes;"> </span>The experienced clinician realizes that in
the process of aging the patient accumulates the more debilitating conditions
the longer he lives, and his demise is often accompanied by a combination of
several diseases.” (p. 3-4)<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">And from a comparable section of DSM-II (2):<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“The diagnostician, however, should not lose sight of the <i>rule
of parsimony</i> and diagnose more conditions than are necessary to account for
the clinical picture. The opportunity to make multiple diagnoses does not
lessen the physician's responsibility to make a careful differential diagnosis.”<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">This excerpt on strictly physical diagnoses of
non-psychiatric conditions illustrates a couple of points.<span style="mso-spacerun: yes;"> </span>First is that disease states in general do
accumulate over time.<span style="mso-spacerun: yes;"> </span>Some are more
likely to occur during different time frames during a life time.<span style="mso-spacerun: yes;"> </span>The age at onset is a relevant concept but
even then, there are exceptions. Secondly, transdiagnostic symptoms (covering
many diagnoses) are common in the physical world. In the example edema and
ascites are the obvious example but even the gross organ findings can be
considered transdiagnostic signs. <span style="mso-spacerun: yes;"> </span>For
example, there are hundreds of possible causes of cardiomegaly and
hepatomegaly, even though from a clinical standpoint the majority are not all
fully investigated.<span style="mso-spacerun: yes;"> </span>Once heart failure
develops it is treated as a syndrome without a specific pathophysiological
cause.<span style="mso-spacerun: yes;"> </span>That illustrates a third point in
the diagnostic process and that is the <i>triage</i> aspect.<span style="mso-spacerun: yes;"> </span>Whatever is acute and life threatening gets
priority and is diagnosed and treated first. I will illustrate how all these
concepts apply directly to psychiatric disorders. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Hierarchies are thought to be more important in psychiatry
because of symptom overlaps as well as certain diagnoses being more important
not to miss. A common problem is the overlap of anxiety and depression. Some
people have long history of both disorders concurrently or one morphing into
another. Ghaemi (3) has suggested that mood disorders should be prioritized
over anxiety disorders in the hierarchy.<span style="mso-spacerun: yes;">
</span>He stresses the importance of diagnosis in this process and suggests
that treatment of depression in this case would be the priority. He also
briefly reviews some evidence in diagnostic hierarchies that basically show
that they can be arranged so that diagnoses at the top of the hierarchy would
contain the symptoms of every lower level in the hierarchy. For example, if
bipolar disorder with psychosis is at the top of the hierarchy those patients
would also have the symptoms seen at defined lower levels in the hierarchy like
unipolar depression, schizoaffective disorder, schizophrenia, anxiety
disorders, and personality disorders.<span style="mso-spacerun: yes;"> </span>He
claims that there is a current emphasis to make every possible diagnosis rather
than a hierarchical approach, but does acknowledge that some psychiatrists
“intuitively practice this way.” (p. 223).<span style="mso-spacerun: yes;">
</span>Treatment setting is an obvious factor – with acute care psychiatrists
seeing clear presentations of the more severe forms of schizophrenia, unipolar
depression, and bipolar disorder. <span style="mso-spacerun: yes;"> </span>They
would be most likely to treat these acute forms and the pharmacotherapies are
very similar. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">It is always good to remember the task of the psychiatrist
in all these academic exercises particularly when they are coupled with
criticism of the psychiatrist in the field. What is the task of that
psychiatrist?<span style="mso-spacerun: yes;"> </span>That task varies with
setting but after 22 years in acute care, the job is to recognize the acute
illness and treat it while keeping the patient and the staff safe.<span style="mso-spacerun: yes;"> </span>How well does a bipolar disorder->unipolar
disorder->schizophrenia-> obsessive compulsive disorder-> anxiety
disorder-> personality disorder->attention deficit~hyperactivity disorder
(BUSOAPA) hierarchy hold up in that setting? <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Probably not very well. That psychiatrist is confronted
with an entirely different hierarchy. The first syndromic level encountered:
“Is this patient medically stable? Are these symptoms I am seeing
manifestations of an intoxication, withdrawal, or secondary medical condition?”
<span style="mso-spacerun: yes;"> </span>I routinely encountered these cases and
often had to send them directly to the intensive care unit for both acute
conditions threatening the life of the patient and acute conditions creating
the psychiatric symptoms. The second syndromic level: “Is this patient
responsive to me during the interview?<span style="mso-spacerun: yes;">
</span>If not, are they delirious, catatonic, or is there another psychiatric
reason?<span style="mso-spacerun: yes;"> </span>Did I miss an acute medical
condition like a stroke and aphasia at the first syndromic level?<span style="mso-spacerun: yes;"> </span>The third syndromic level: “Is this person
able to produce an accurate history that I need to make a diagnosis and
formulate a treatment plan? Does the history that they are giving me sound
plausible?”<span style="mso-spacerun: yes;"> </span>If not why not why - and
what needs to be done?<span style="mso-spacerun: yes;"> </span>Do I need to
gather a lot of collateral history to get the full picture?<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">These considerations place the BUSOAPA hierarchy at the
minimum as a hierarchy within a hierarchy that contains about 40 or 50
psychiatric diagnoses and many more if all possible medical diagnoses
masquerading as psychiatric diagnoses are considered. The diagnoses also have
clear implications for Ghaemi’s concern that a hierarchical model would reduce
misdiagnosis and polypharmacy.<span style="mso-spacerun: yes;"> </span>Patients
with alcohol use disorder (AUD) can experience psychotic symptoms and mood
symptoms.<span style="mso-spacerun: yes;"> </span>I have seen them misdiagnosed
as having schizophrenia and bipolar disorder. Does that mean AUD should be at
the top of the hierarchy?<span style="mso-spacerun: yes;"> </span>Placing it
there would skew the data because most people with AUD do not have those severe
symptoms, but on the other hand if they were misdiagnosed with schizophrenia or
bipolar disorder – appropriate treatment with benzodiazepines for alcohol
withdrawal may be held to the detriment of the patient. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">A recent exercise was sent to me to see if it suggested a
need to modify DSM criteria for major and mild neurocognitive disorder.<span style="mso-spacerun: yes;"> </span>The patient was described as having Alzheimer’s
disease, cerebrovascular disease, an HIV infection, and heavy chronic alcohol
use.<span style="mso-spacerun: yes;"> </span>They had symptoms of
psychosis.<span style="mso-spacerun: yes;"> </span>They were coded as having
major neurocognitive disorder due to all the listed etiologies.<span style="mso-spacerun: yes;"> </span>The problem is that the current diagnostic
criteria use a hierarchical approach and state that for probable Alzheimer’s
Disease in both the major and mild neurocognitive disorder categories the mixed
etiologies need to be ruled out or eliminated. That is currently difficult to
do on a clinical basis and will lead to more uncertainty in the Alzheimer’s
Disease diagnosis using these criteria. In terms of the BUSOAPA hierarchy – it
is an argument to put the neurodegenerative disorders diagnoses at the top
since they frequently contain most of the symptoms of psychosis, mood
disorders, and anxiety while having unique cognitive profiles that would not be
seen at lower levels. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Getting back to Ghaemi’s original argument for empirically
studied hierarchies in psychiatry to reduce misdiagnosis and improve treatment
by reducing polypharmacy – is that likely? They might work at the level of
nomenclature only. <span style="mso-spacerun: yes;"> </span>Hierarchies might
work in highly selected environments with low acuity patients.<span style="mso-spacerun: yes;"> </span>I am thinking about an outpatient psychiatric
teaching clinic. It might be easy to illustrate how the patient population matches what is happening hierarchically.<span style="mso-spacerun: yes;"> </span>In other settings looking at higher levels of
acuity – the acuity becomes the hierarchy. Residents in acute care should learn
almost immediately that pharmacotherapy in the inpatient setting needs to be
directed at the likely acute diagnosis.<span style="mso-spacerun: yes;">
</span>Even then that clearcut diagnosis can be obscured in the outpatient
setting. The best example I can think of is women with postpartum bipolar
disorder +/- psychosis who are stabilized and eventually readmitted with
diagnoses of schizophrenia or schizoaffective disorder. In that case, the
diagnosis was in the top spot of the BUSOAPA hierarchy based on the direct
observations of the inpatient psychiatrist, but it was modified on an
outpatient basis by staff who did not directly observe the acute manic episode.
A violation of the hierarchical model to be sure, but also poor continuity of
care and ignoring what happens in acute care.<span style="mso-spacerun: yes;">
</span><span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">That brings me to the issue of hierarchies in previous versions
of the DSM. I will focus on DSM-II because it is the most clearcut.<span style="mso-spacerun: yes;"> </span>The explicit hierarchies in DSM-II included both
acuity and severity.<span style="mso-spacerun: yes;"> </span>Specifically:<o:p></o:p></span></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“1. The condition which most urgently requires
treatment should be listed first.”<o:p></o:p></span></i></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">And:<o:p></o:p></span></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“2. When there is no issue of disposition or
treatment priority, the more serious condition should be listed first.”<o:p></o:p></span></i></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">And:<o:p></o:p></span></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“It is recommended that, in addition to
recording multiple disorders in conformity with these principles, the
diagnostician underscore the disorder on the patient's record that he considers
the underlying one.”<o:p></o:p></span></i></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">These three sentences from DSM-II capture what appears to
be the concern about diagnostic hierarchies in subsequent versions of the
DSM.<span style="mso-spacerun: yes;"> </span>They easily map on to what happens
clinically as depicted in my diagram at the top of this post. It is also consistent
with the general approach to all medical diagnoses and the training of
psychiatrists. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">A long list of diagnoses is a rookie mistake. Experienced
psychiatrists are generally trying to address the main problem and the urgent
problem. There is some evidence for that in </span><a href="https://gdpsychtech.blogspot.com/2023/05/counting-dsm-diagnoses.html"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">the
numbers of diagnoses that are used in clinical practice</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"> and those
numbers are considerably lower than the usual DSM-5 count. That does not mean
that polypharmacy will not be involved, but it does mean that any polypharmacy
used is there to address the main problem and not multiple separate diagnoses
all at once. <span style="mso-spacerun: yes;"> </span>The concepts of comorbidity
and transdiagnostic symptoms are discussed these days like they represent new
ideas. Any physician trained in a medical school and residency program knows
about both starting with medical and surgical diagnoses and progressing to
psychiatric diagnoses. The general concepts are the same. The necessary
evaluation in psychiatry should adequately reflect the complexity of the
situation and that means a detailed longitudinal history and that can include
disorders that are commonly viewed as symptoms – like primary insomnia.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">A detailed longitudinal history may not lead to a correct
current diagnosis until the symptom patterns change. The best example in the
case of a pure psychiatric disorder is bipolar disorder.<span style="mso-spacerun: yes;"> </span>Goodwin and Jamison (4) make this point in
their discussion of <i>false unipolar disorder</i> – people with recurrent unipolar
depressive episodes until the first episode of mania occurs. In their table
they show that according to three different longitudinal studies, patients experience
1 to 5 episodes of unipolar depression without a manic episode and they
constituted a significant portion of the unipolar sample.<span style="mso-spacerun: yes;"> </span>A hierarchical rule in this case results in
misclassification until a manic episode occurs.<span style="mso-spacerun: yes;">
</span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">A strictly hierarchical diagnosis will also not capture
clinic reality.<span style="mso-spacerun: yes;"> </span>It can potentially lead
to catastrophic results.<span style="mso-spacerun: yes;"> </span>The best
example I can think of is schizophrenia and depression. If you consider
schizophrenia in a hierarchy independent of depression, you will miss the
opportunity to treat serious depression in patients with a schizophrenia
diagnosis.<span style="mso-spacerun: yes;"> </span>It is also a case of seeing a
new patient treated for both diagnoses and considering what medication to
stop.<span style="mso-spacerun: yes;"> </span>The features of schizophrenia are
such that the presentation of depression is very subtle and medication changes
of antidepressants and antipsychotics should only be changed with extreme
caution and after adequate collateral history has been obtained. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Criticizing DSMs is a popular American sport. That has
resulted in elevating the DSM to levels that are really not consistent with the
way these documents are viewed by psychiatrists. The documents are generally limited
by the fact that they are not treatment manuals and do not incorporate
considerable amounts of research that could provide guidance in these areas. With
a document that is limited to nomenclature – any changes including hierarchies
will result in a loss of information at another level. To me this seems like an endless exercise in trying to reduce uncertainty to an unachievable level. </span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">That is why
psychiatrists need to be trained and don’t result from reading a manual. <span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">George Dawson, MD, DFAPA<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">References:<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">1:<span style="mso-spacerun: yes;"> </span>DeGowin RL.<span style="mso-spacerun: yes;"> </span>Bedside Diagnostic Exam.<span style="mso-spacerun: yes;"> </span>3<sup>rd</sup> ed.<span style="mso-spacerun: yes;"> </span>Macmillan Publishing Company, New York, 1976:
3-4.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">2:<span style="mso-spacerun: yes;"> </span>Diagnostic and
Statistical Manual of Mental Disorders. 2<sup>nd</sup> ed. Washington, DC.<span style="mso-spacerun: yes;"> </span>American Psychiatric Association. 1968: 2-3.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">3:<span style="mso-spacerun: yes;"> </span>Ghaemi SN.<span style="mso-spacerun: yes;"> </span>The concept of a diagnostic hierarchy. In:
Ghaemi SN.<span style="mso-spacerun: yes;"> </span>Clinical Psychopharmacology:
Principles and Practice.<span style="mso-spacerun: yes;"> </span>New York.<span style="mso-spacerun: yes;"> </span>Oxford University Press. 2019: 222-230.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">4:<span style="mso-spacerun: yes;"> </span>Goodwin FK,
Jamison KR.<span style="mso-spacerun: yes;"> </span>Manic-Depressive Illness.
New York.<span style="mso-spacerun: yes;"> </span>Oxford University Press. 2009:
66.<o:p></o:p></span></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com1tag:blogger.com,1999:blog-7772182113499451603.post-41761613751985488712023-11-08T02:24:00.008-06:002023-11-18T12:16:34.181-06:00Buspirone and Gepirone<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg5BpWtiY6QUaFEkF66dSL4IkUCwd0jwCmarFl0JtSPuTvQjJEQU_kb_qYhw8SL_YK3G8vWP428tnhl_Ctme1Bsqx5OxNR9yeerdE-ngRVv3h98bmh88a-9rF94WSAEEB8YWmwfEJhdW5kje9BhgEAUjJajtvvYZjPWHm92U8KAktvoenY3kxuqj0UmaHGT/s1280/Buspirone%20versus%20gepirone%20best%20slide.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="720" data-original-width="1280" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg5BpWtiY6QUaFEkF66dSL4IkUCwd0jwCmarFl0JtSPuTvQjJEQU_kb_qYhw8SL_YK3G8vWP428tnhl_Ctme1Bsqx5OxNR9yeerdE-ngRVv3h98bmh88a-9rF94WSAEEB8YWmwfEJhdW5kje9BhgEAUjJajtvvYZjPWHm92U8KAktvoenY3kxuqj0UmaHGT/w640-h360/Buspirone%20versus%20gepirone%20best%20slide.jpg" width="640" /></a></div><br /><p></p><p class="MsoNormal"><br /></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Buspirone and gepirone are interesting compounds.<span style="mso-spacerun: yes;"> </span>As shown in the above 2D structures they are structurally
similar -<span style="mso-spacerun: yes;"> </span>with the main difference being
a cyclopentane ring in the azapirone structure in buspirone and two methyl
groups at the same atom in gepirone. That results in the molecular formulas of
both compounds to be slightly different.<span style="mso-spacerun: yes;">
</span><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Buspirone was initially proposed as an antipsychotic
medication (2) but it showed no efficacy in clinical trials.<span style="mso-spacerun: yes;"> </span>Buspirone was FDA approved for the treatment
of anxiety on September 29, 1986.<span style="mso-spacerun: yes;">
</span>Gepirone was approved for treatment of depression on September 28, 2023.
The 37-year lag time for approving gepirone has always been a mystery to me,
especially given the amount of buspirone I have prescribed over the years.<span style="mso-spacerun: yes;"> </span>Buspirone came out during an <a href="https://real-psychiatry.blogspot.com/2021/03/the-new-black-box-warnings-on.html">era of benzodiazepine prescribing</a> that at times was excessive.<span style="mso-spacerun: yes;"> </span>Alprazolam or Xanax was heavily marketing
just prior to the release of buspirone and it did not take long for some
experts to recommend using higher doses than the package insert to treat
anxiety and panic attacks. That led to complications including excessive use
and in some cases withdrawal seizures.<span style="mso-spacerun: yes;">
</span>When buspirone was marketed, there was emphasis placed on the fact that
it did not lead to excessive use, it did not affect the GABA receptor like
benzodiazepines, it did not have synergism with beverage alcohol, and it did
not have any withdrawal liability.<span style="mso-spacerun: yes;"> </span>As a
result, many primary care physicians tried to use it as a substitute for
patients taking benzodiazepines. It was ineffective when used in that manner because
of the behavioral pharmacology.<span style="mso-spacerun: yes;"> </span>A person
taking buspirone did not notice any immediate effects, unlike benzodiazepines
and it did not reinforce its own use. <span style="mso-spacerun: yes;"> It also did not start to work immediately and had an onset of action more like an antidepressant. </span>These properties had the effect of creating the perception that it was an ineffective
medication and that was reinforced by some experts – who claimed that
only benzodiazepines were useful for anxiety.<span style="mso-spacerun: yes;">
</span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Historically the enthusiasm for benzodiazepines decreased
over time with antidepressants (SSRIs, SNRIs, and TCAs) being recommended for anxiety
and panic rather than benzodiazepines. Some psychiatrists (like myself) used
buspirone for both primary anxiety without panic and antidepressant augmentation. I found that it was an effective medication for those indications
but it required a detailed discussion with the patient, especially if they had
previous benzodiazepine exposure. The very favorable side effect profile –
including no intoxication or withdrawal effects were an important
consideration.<span style="mso-spacerun: yes;"> </span>Generally, people exposed
to that discussion did well on buspirone and were able to avoid
benzodiazepines. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The activity of both compounds is thought to be mediated by
5-HT1A agonism as noted in the table below.<span style="mso-spacerun: yes;">
</span>Using the PDSP Ki database as the source, more detailed receptor
information is available for buspirone than gepirone, probably because the
latter approval date.<span style="mso-spacerun: yes;"> </span>Partial data is
also given for 2 metabolites of gepirone one of which is active at the 5-HT1A
receptor. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<table border="1" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; mso-border-alt: solid windowtext .5pt; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-yfti-tbllook: 1184;">
<tbody><tr style="mso-yfti-firstrow: yes; mso-yfti-irow: 0;">
<td style="border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Receptor<o:p></o:p></span></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Buspirone<o:p></o:p></span></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Gepirone<o:p></o:p></span></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">3’-OH-gepirone<o:p></o:p></span></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">1-PP-gepirone<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 1;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 2;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">5-HT1A<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">5 - 77<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">38<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">58<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 3;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">5-HT1B<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">>10,000<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">>10,000<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 4;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">5-HT1D<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">>10,000<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 5;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">5-HT2A<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">138<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">3,630<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 6;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">5-HT2B<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">213.8<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 7;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">5-HT2C<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">489<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">>10,000<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 8;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">5-HT3<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">>10,000<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 9;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">5-HT4<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">>10,000<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 10;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">5-HT6<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">398<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 11;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">5-HT7<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">375<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 12;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">DA D4.2<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">78-136<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">58<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 13;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">DA D2 like<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">1,210<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 14; mso-yfti-lastrow: yes;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 100.85pt;" valign="top" width="134">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">α-2<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 103.9pt;" valign="top" width="139">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">>1,042<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 101.25pt;" valign="top" width="135">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">>1,042<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 88.3pt;" valign="top" width="118">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt; width: 73.2pt;" valign="top" width="98">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">42<o:p></o:p></span></p>
</td>
</tr>
</tbody></table>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><span style="mso-spacerun: yes;"> </span></span><span face=""Arial",sans-serif" style="font-size: 9pt; line-height: 107%;">All
receptor affinities are Ki as nM from </span><span style="font-size: 9pt; line-height: 107%;"><a href="https://pdsp.unc.edu/databases/kidb.php"><span face=""Arial",sans-serif">PDSP Ki database</span></a></span><span face=""Arial",sans-serif" style="font-size: 9pt; line-height: 107%;">.
Affinities for human receptors included where available. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">What is the evidence these medications are effective?<span style="mso-spacerun: yes;"> </span>The real mystery for these medications is
their efficacy and favorable side effect profile compared with clinical use. In
terms of side effects – I don’t think it is an overstatement to say that they
have the most favorable side effect profile of any psychiatric medications. In
my experience, it was rare for anyone to get a side effect.<span style="mso-spacerun: yes;"> </span>If it happened it was most likely
dizziness.<span style="mso-spacerun: yes;"> </span>In prescribing to hundreds of
people – I can recall exactly one person who got sedated. When used for antidepressant
augmentation I have observed two people become hypomanic and that resolved with
discontinuation of the buspirone. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">I have no real information to explain the partial and
delayed approvals. Most of the clinical trials for both medications occurred in
the late 1980s and early 1990s. At that time there was clear evidence that both
were effective for anxiety and depression and yet only buspirone was approved
at the time for an anxiety indication. Psychiatrists are more typically aware
of the off-label use of buspirone as an antidepressant augmenting agent from
the Star*D study protocols (3).<span style="mso-spacerun: yes;"> </span>At
the time buspirone was described as one of the three best studied augmentation
strategies for treatment resistant depression with lithium and thyroid hormone
being the other two. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Interestingly – I am not aware of any head-to-head comparisons
of azapirones to typical antidepressants for the treatment of depression. There
are currently 67 studies on ClinicalTrials.gov with <a href="https://clinicaltrials.gov/search?intr=Buspirone&page=1">buspirone</a>
listed as an intervention. Most of these studies investigate the use in novel
clinical situations or mechanism of action.<span style="mso-spacerun: yes;">
</span>There is one study about anxiety and quality of life when it is used to
treat depression and that currently has no publications.<span style="mso-spacerun: yes;"> </span>Another references the Star*D study from 20
years ago.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The best single source for the efficacy of azapirones in
depression, anxiety, and some novel situations is a chapter by Ninan and
Muntasser(4). Their general conclusions are that buspirone is effective in
treating generalized anxiety disorder (GAD), GAD with depression, and is more effective
in treating the depression associated with anxiety than benzodiazepines. In
studies with a crossover design and initial benzodiazepine exposure – response to
buspirone was reduced but not eliminated. In a head-to-head comparison of
buspirone 30 mg and venlafaxine ER (75 or 150 mg) for GAD both were superior to
placebo but venlafaxine was superior to buspirone.<span style="mso-spacerun: yes;"> </span>Buspirone has demonstrated efficacy in studies
of both non-melancholic and melancholic depression. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Gepirone ER was studies in 3 RCTs for major depression and
was effective in all three. One of those studies was a dose ranging study and
only the higher dose was noted to be effective.<span style="mso-spacerun: yes;">
</span>Gepirone was also studied in GAD with diazepam as a comparator.<span style="mso-spacerun: yes;"> </span>Both medications were efficacious, but diazepam
had a more rapid onset and consistent effects.<span style="mso-spacerun: yes;">
</span>The anxiolytic effects of gepirone occurred at 6 weeks. When both medications
were discontinued rebound anxiety occurred with diazepam but not gepirone.<span style="mso-spacerun: yes;"> </span>There is some evidence from the buspirone
trials that the anxiolytic effect of these medications improves over time. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The current azapirones are interesting and neglected compounds
in clinical psychiatry.<span style="mso-spacerun: yes;"> </span>They have not
been vigorously studied for their primary indications of GAD and major
depression.<span style="mso-spacerun: yes;"> </span>Most of the interest in this
class of medications was generated in studies that look at antidepressant
augmentation. Although there is always a lack of pharmacosurveillance data in
the US, my speculation is that second and third generation antipsychotics
(aripiprazole, brexpiprazole) are much more likely to be prescribed as
augmenting agents – despite the risk of tardive dyskinesia and metabolic effects
(the azapirones have neither). In my experience with buspirone, I found it to
be effective for GAD and antidepressant augmentations.<span style="mso-spacerun: yes;"> </span>Despite the theoretical risk of serotonin
syndrome – I never saw any symptoms of serotonin toxicity.<span style="mso-spacerun: yes;"> </span>If gradually titrated - side effects were rare.<span style="mso-spacerun: yes;"> </span>In any detailed informed consent discussion, the
azapirones come across as having distinct advantages over other medication
classes - primarily from the side effect perspective. With all medication there
is a question of efficacy – but in relatively non-urgent situations most people
prefer to try the medication with the lowest risk of adverse events – first. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">George Dawson, MD, DFAPA<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">References:<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">(1) Piercey MF, Smith MW, Lum-Ragan JT. Excitation of
noradrenergic cell firing by 5-hydroxytryptamine1A agonists correlates with
dopamine antagonist properties. Journal of Pharmacology and Experimental
Therapeutics. 1994 Mar 1;268(3):1297-303.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">(2) Le Foll B, Payer D, Di Ciano P, Guranda M, Nakajima S,
Tong J, Mansouri E, Wilson AA, Houle S, Meyer JH, Graff-Guerrero A. Occupancy
of dopamine D3 and D2 receptors by buspirone: A [11C]-(+)-PHNO PET study in humans.
Neuropsychopharmacology. 2016 Jan;41(2):529-37.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Modest occupancy of D2/D3 receptors cannot R/O MOA of this
plus 5-HT1A as MOA.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">(3)<span style="mso-spacerun: yes;"> </span>Fava M, Rush AJ,
Trivedi MH, Nierenberg AA, Thase ME, Sackeim HA, Quitkin FM, Wisniewski S,
Lavori PW, Rosenbaum JF, Kupfer DJ. Background and rationale for the sequenced
treatment alternatives to relieve depression (STAR</span><span style="font-family: "Cambria Math",serif; font-size: 12pt; line-height: 107%; mso-bidi-font-family: "Cambria Math";">∗</span><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"> D) study. Psychiatric
Clinics. 2003 Jun 1;26(2):457-94.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">(4)<span style="mso-spacerun: yes;"> </span>Ninan PT,
Muntasser S.<span style="mso-spacerun: yes;"> </span>Buspirone and gepirone. In:
Schatzberg AF, Nemeroff CB.<span style="mso-spacerun: yes;"> </span>The American
Psychiatric Publishing Textbook of Psychopharmacology.<span style="mso-spacerun: yes;"> </span>3<sup>rd</sup> ed. Washington DC, American
Psychiatric Publishing, 2004: 391-404.<o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">(5)<span style="mso-spacerun: yes;"> </span>Robinson DS,
Rickels K. Buspirone.<span style="mso-spacerun: yes;"> </span>In:<span style="mso-spacerun: yes;"> </span>Schatzberg AF, Nemeroff CB.<span style="mso-spacerun: yes;"> </span>The American Psychiatric Publishing Textbook
of Psychopharmacology.<span style="mso-spacerun: yes;"> </span>5th ed.
Washington DC, American Psychiatric Publishing, 2017: 585-600.<o:p></o:p></span></span></p><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“We speculate that had buspirone’s sponsor persuaded
a depression rather than a GAD indication, buspirone might have well become the
first 5-HT1A partial agonist developed as an antidepressant. At present,
however, buspirone exists in the shadow of numerous approved antidepressant drugs
with high clinical exposure and promotion”.</span></i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"> (p. 591-592) <span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p><br /></span><p></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com0tag:blogger.com,1999:blog-7772182113499451603.post-2547365427007427622023-10-31T23:07:00.006-05:002024-01-19T18:17:12.680-06:00A New Superfluorinated Medication<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhQjz3d56WGYq2iN6z1kuE-enDFDicSij9BTkZ7r1sgR3AjXhxA04Ewja8iMS-3ZlYXFjOL69W5XraC6OpeuKxR7WBikih5dsINeDsEXDitwYi05H2FLowm21ldBLo7DttPfM1UwJM81PrMZCeelyYKXCl-loqSNU2JDdQP68p66efutm2H4-9ZmT8dwTrb/s1694/perflurohexyloctane.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="636" data-original-width="1694" height="240" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhQjz3d56WGYq2iN6z1kuE-enDFDicSij9BTkZ7r1sgR3AjXhxA04Ewja8iMS-3ZlYXFjOL69W5XraC6OpeuKxR7WBikih5dsINeDsEXDitwYi05H2FLowm21ldBLo7DttPfM1UwJM81PrMZCeelyYKXCl-loqSNU2JDdQP68p66efutm2H4-9ZmT8dwTrb/w640-h240/perflurohexyloctane.png" width="640" /></a></div><br /><div class="separator" style="clear: both; text-align: center;"><br /></div><br /><p><span style="font-size: 12pt;">As a biology and chemistry major with ongoing interest –
fluorinated medications have been an interest of mine for some time.</span><span style="font-size: 12pt; mso-spacerun: yes;"> </span><span style="font-size: 12pt;">If you have taken organic chemistry – you know
that fluorination significantly alters the properties of molecules due to the electronegativity
of the fluorine atom. </span><span style="font-size: 12pt; mso-spacerun: yes;"> </span><span style="font-size: 12pt;">If you are
interested in the chemistry of compounds in nature – you may know none of them
are fluorinated.</span><span style="font-size: 12pt; mso-spacerun: yes;"> </span><span style="font-size: 12pt;">I pointed that out in a
</span><a href="https://real-psychiatry.blogspot.com/2021/02/fluorinated-medications-revisited.html" style="font-size: 12pt;">previous
post about fluorinated molecules</a><span style="font-size: 12pt;"> that are used as medications.</span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">You can imagine my surprise when I received a solution of 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorotetradecane
in the mail yesterday. That’s right C<sub>14</sub>H<sub>17</sub>F<sub>13</sub></span>.<span style="mso-spacerun: yes;"> </span><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">It’s not that people are mailing me random
fluorinated compounds – this is a prescription from a dry eye specialist on the
latest in dry eye care. It all started as a conversation at our last
appointment.<span style="mso-spacerun: yes;"> </span>He knows I am a nerd and I
stared talking about the lack of available treatments and how it made no sense
to me from a chemical perspective:<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Me:<span style="mso-spacerun: yes;"> </span>“It seems like a
straightforward problem to me,<span style="mso-spacerun: yes;"> </span>Current chemical
analysis should be able to very accurately characterize the tear film including
the lipid layer and just mix it up as eye drops.”<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">OD: “I hear you George – and we are getting close to that –
in fact a new drug has just been released that is supposed to keep the tear
layer from breaking up.<span style="mso-spacerun: yes;"> </span>Are you
interested in trying it?”<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Of course, I was.<span style="mso-spacerun: yes;">
</span>Dry eye disease in my case is multiple diagnoses and there seem to be no
good solutions for any of them. I end up using non-preservative artificial tears
6 - 8 times per day and even then, get burning and foreign body sensations in the
eye. <span style="mso-spacerun: yes;"> Worst case - my eyes start burning to the point that I can't focus and have to stop what I am doing. </span>Finding out that the new medication
was a poly fluorinated alkane was a surprise. For the past two weeks I have been
negotiating with the only pharmacy in the country that dispenses this product
along with the pharmacy benefit manager. At one point a retail price of $950/3
ml was quoted and I am in the Medicare doughnut hole. For some unknown reason
and appeal of the denial was granted and I got the prescription mailed to
me.<span style="mso-spacerun: yes;"> </span>I started it yesterday.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The accompanying package insert is only 2 pages in length.
That is brief relative to most medications.<span style="mso-spacerun: yes;">
</span>The results of two clinical trials are described (total of 1,217
patients). The studies were described as multicenter, randomized controlled
clinical trails with a saline placebo. The trials were 57 days in duration. Toxicology
has all been preclinical and mostly bioassays (Ames assay and <i>in vitro</i>
chromosome aberration assay using human peripheral lymphocytes and in <i>vivo
bone</i> micronucleus assays in rats). Long term toxicity studies have not been
done.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">I looked at what is known about the lipid layer that is provided
by Meibomian glands in the eyelid.<span style="mso-spacerun: yes;"> </span>The
resulting secretion <i>mebum </i>is a complex mixture of lipids, waxes, and
other organic molecules that provide a layer over the tear layer so that it
does not evaporate and dissipate as quickly.<span style="mso-spacerun: yes;">
</span>For all those details see the open access reference below.<span style="mso-spacerun: yes;"> </span>One of the advantages of polyfluorination is
that it greatly augments the lipid solubility of organic molecules. <span style="mso-spacerun: yes;"> </span>That is good if you happen to want a
controllable lipid layer over and aqueous layer, but it may cut both ways.
There is plenty of lipid content in the human body where these compounds can enter.
per- and poly-fluoroalkyl substances (PFAS) are examples of industrial chemicals
that have become environmental contaminants in drinking water, food, and
air.<span style="mso-spacerun: yes;"> </span>A 2015 study looking at 2011 data
suggested that <a href="https://www.niehs.nih.gov/health/topics/agents/pfc/index.cfm#footnote1">97%
of American had PFAS in their blood</a>, although there is some suggestion that
these numbers have been decreased with less production and removals from
products.<span style="mso-spacerun: yes;"> </span>Technically the dry eye
medication that I have reviewed here is a polyfluorinated alkyl product.<span style="mso-spacerun: yes;"> </span>I will be following this release closely especially
any after market adverse events and the literature on whether there is concern
that this molecule might accumulate in lipid tissue in the body.<span style="mso-spacerun: yes;"> </span>Ideally a product will be available that will
mimic Meibomian gland secretion in terms of the lipids that are naturally
there.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The potential dual nature of this medication highlights a
dilemma that many people face every day.<span style="mso-spacerun: yes;">
</span>Do you try a medication with potential downsides when the information
about those downsides will take a while to accumulate? <span style="mso-spacerun: yes;"> </span>To me that is always an informed consent
discussion and it depends a lot on expectations and risk/benefit
considerations.<span style="mso-spacerun: yes;"> </span>In this case, dry eyes
is a tremendous problem and there seem to be no other reasonable solutions. My
answer currently is a qualified yes.<span style="mso-spacerun: yes;">
</span>That may change as more is known about alternative medications that
resemble the natural secretions or the toxicology of the current medication. I
would characterize the level of severity of the problem as moderate. <span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span>There
are more toxic medications out there and more severe conditions. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">George Dawson, MD, DFAPA<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><i><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">References:<o:p></o:p></span></i></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">1:<span style="mso-spacerun: yes;"> </span>Chen J, Panthi S.
Lipidomic analysis of meibomian gland secretions from the tree shrew:
Identification of candidate tear lipids critical for reducing evaporation. Chem
Phys Lipids. 2019 May;220:36-48. doi: 10.1016/j.chemphyslip.2019.01.003. Epub
2019 Jan 17. PMID: 30660743; PMCID: PMC6600086.<o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">2: FDA page on PFAS: https://www.fda.gov/food/environmental-contaminants-food/and-polyfluoroalkyl-substances-pfas</span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">3: FDA page on further PFAS study: https://www.fda.gov/news-events/press-announcements/statement-fdas-scientific-work-understand-and-polyfluoroalkyl-substances-pfas-food-and-findings</span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">4: CDC page on Per- and Polyfluoroalkanes and Health: https://www.atsdr.cdc.gov/pfas/resources/pfas-faqs.html</span></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com0tag:blogger.com,1999:blog-7772182113499451603.post-73504347843217502252023-10-22T23:18:00.007-05:002023-10-23T21:28:53.014-05:00Library Access Problem Solved?<div style="text-align: center;"><a href="https://commons.wikimedia.org/wiki/File:Statsbiblioteket_l%C3%A6sesalen-2.jpg" title="Villy Fink Isaksen, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons"><img alt="Statsbiblioteket læsesalen-2" src="https://upload.wikimedia.org/wikipedia/commons/thumb/6/60/Statsbiblioteket_l%C3%A6sesalen-2.jpg/512px-Statsbiblioteket_l%C3%A6sesalen-2.jpg" width="512" /></a></div>
<p> </p><p class="MsoNormal"><br /></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">I have a <a href="https://real-psychiatry.blogspot.com/2021/04/medical-library-access-for-everyone.html">couple</a> of <a href="https://real-psychiatry.blogspot.com/2023/04/medical-library-access-revisited.html">previous</a> posts here about the
disappointment of losing online access to medical journals.<span style="mso-spacerun: yes;"> </span>The loss was due mainly to the arbitrary
decisions of administrators and their lack of any ability to compromise. I offered
several times to pay $1,000/year for online access to journals at the Biomed
Library and was told that was not possible. More recently I donated $100 to
become a Friends of the Library member with the benefit of online access to
University of Minnesota Libraries. After the donation I learned that access to
only occur through a terminal in a U of MN library. So every time I needed to
read a paper – I would have to drive 40 miles (round trip) to get that level of
access.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">I read hundreds of papers per year – several of them more
than once.<span style="mso-spacerun: yes;"> </span>I must stay current and
research topics for my blog and presentations. Reading one paper often results
in needing to read many of the references – the amount of reading can snowball.
Driving every day for access and probably having to print those references out in
this age wastes both time and resources. It is still hard for me to believe that University library systems cannot charge for at home access that I can get for free through a county library. I think they are trying to maintain a tradition that you can only get this as a perk if you are affiliated with our institution. That minimizes the role of the people paying the taxes to keep the institution afloat. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Luckily I have patched together a system that seems to work
fairly well to get the research papers that I need.<span style="mso-spacerun: yes;"> </span>This is a Minnesota solution so although I
would see if similar systems exist in your home state – there is no guarantee. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The centerpiece of the plan is my county library (Anoka
County).<span style="mso-spacerun: yes;"> </span>I tried this about 5 years ago
and they did not have the necessary systems in place – but now they do. <span style="mso-spacerun: yes;"> </span>The main option was affiliation with a much
larger library system in Ramsey County. Once I was registered in both places –
I had access to much more current digital media at the Ramsey County Library and
the interlibrary loan system Minnesota Link (mnlink.org). Now if I am searching
for a reference my Zotera app takes me to any full text references at either
Ramsey County Library or Minnesota Link if I am logged in. If there are no full
text references immediately available – I can search for them at Minnesota Link
and expand that search if necessary to a national interlibrary loan system. The
search returns a formatted reference that allows me to request the PDF and I
typically get that the next business day.<span style="mso-spacerun: yes;">
</span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">County library access is generally good but not 100%.<span style="mso-spacerun: yes;"> </span>I would estimate it is in the 80-90% range
for most medical and psychiatric references.<span style="mso-spacerun: yes;">
</span>Many of the papers I have requested are from esoteric journals.<span style="mso-spacerun: yes;"> </span>To cite one example – I had immediate access
to a 1999 paper from the journal <i>Depression and Anxiety</i> today when doing
some research for a friend.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">I continue to maintain my American Medical Association
(AMA) and American Psychiatric Association (APA) memberships and the associated
subscriptions.<span style="mso-spacerun: yes;"> </span>The AMA subscriptions are
a bonus because of the JAMA Network of subspeciality journals in 14 different
specialties and access to the precursor journal Archives in Neurology and
Psychiatry. The APA is much more restrictive than it used to be. Access as part
of membership is restricted to the <i>American Journal of Psychiatry (AJP)</i>. <span style="mso-spacerun: yes;"> That includes access to the <i>American Journal of Insanity</i> (AJI) - the forerunner before the AJP. The AJI is indispensable in looking at historical trends in the field in the 19th and early 20th century. Researching </span>The precursor journal of <i>Psychiatric Services</i>
used to be included in the membership but no longer. There are an additional 4 journals
that could be provided but they all require an additional subscription fee. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">I have standing subscriptions to <i>Nature</i> and <i>Science</i>
magazine. I also invested in a <i>Nature+</i> subscription for $30/month.<span style="mso-spacerun: yes;"> </span>That allows me to access 55 journals
published by that group but there are significant limitations. For example, I
only have access to the past 5 years of journals and not older archives.<span style="mso-spacerun: yes;"> </span>There are also some high-quality journals
like <i>Neuropsychopharmacology</i> that are not included. In those cases I am
hoping for an open access article or the authors sending me a copy of their paper
through ResearchGate.<o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">An additional bonus is that these libraries also allow access to a number of popular media sites that would otherwise require a paid online subscription of payment per view. That includes major newspapers and popular magazine that often include articles that I respond to on my blog. </span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">That is where my research access stands today.<span style="mso-spacerun: yes;"> </span>It is a significant improvement at anytime
since this became a problem 8 years ago.<span style="mso-spacerun: yes;">
</span>The access to research journals through two county libraries and
interlibrary loan was a game changer.<span style="mso-spacerun: yes;">
</span>Although it is free to county residents it is paid for by property
taxes and state income taxes and and I pay my fair share there. It also takes me back to my hometown county
library where I worked during my college days. I was the audio-visual guy at
that time and mailed materials out to different counties and individuals in a
multi-county area. When I was not mailing, I was repairing 16 mm films for
mailing. <span style="mso-spacerun: yes;"> </span>Libraries provided critical
access by both direct mailing and bookmobiles that travelled to different towns
to provide access. It is good to see libraries providing modern access to
necessary research materials and relieving some of the burden of publishing profit motives on the public. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">George Dawson, MD, DFAPA <o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><br /></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Graphics Credit: Click on the photo or complete information, graphics credits, and open access licensing information. This is </span><span face="sans-serif" style="background-color: white; color: #202122; font-size: 14px;">A reading room in the State and University Library (Statsbiblioteket- now Royal Danish Library) in Aarhus, Denmark.</span></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com0tag:blogger.com,1999:blog-7772182113499451603.post-70021681787048282262023-09-30T11:17:00.017-05:002023-10-06T23:45:03.255-05:00Are there potential problems in the latest study on antipsychotic medication reduction and discontinuation?<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi0FSTQnX6R0bMKYFaMNkIMIIYbQvEoSk6w7L0oPV8_ZB1X8_1AUgxVl5dhm5uN9M3f_bX92Fz2GYQ8EDGXw5LgMluKQr-Hu330HS9f24oQqgcbf0aAUcbZ59R31J7eR8rMYfTd5wGHMGX8m5ua-fs-Mqy7PposxUp3Eampl5K82YS8g3GjpcSZ7NuFUwd2/s2048/striking%20MPLS%20sunset%2002.19.2022.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1536" data-original-width="2048" height="480" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi0FSTQnX6R0bMKYFaMNkIMIIYbQvEoSk6w7L0oPV8_ZB1X8_1AUgxVl5dhm5uN9M3f_bX92Fz2GYQ8EDGXw5LgMluKQr-Hu330HS9f24oQqgcbf0aAUcbZ59R31J7eR8rMYfTd5wGHMGX8m5ua-fs-Mqy7PposxUp3Eampl5K82YS8g3GjpcSZ7NuFUwd2/w640-h480/striking%20MPLS%20sunset%2002.19.2022.jpg" width="640" /></a></div><br /><p class="MsoNormal"><span face="Arial, sans-serif" style="font-size: 12pt;">A study on antipsychotic medication reduction and
discontinuation came out yesterday with fanfare.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">The fanfare was basically because the principal
investigator is a self-proclaimed critical psychiatrist with many criticisms
of psychiatric medication and the results of her trial contradicted the primary
hypothesis of the study and that was:</span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“Our hypothesis was that antipsychotic reduction would improve
social functioning with only a small increase in relapse rate.” <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Relapse rate in this case was defined as rehospitalization
and the authors subsequently state that they thought a 10% rate of relapse
would be “acceptable.”<span style="mso-spacerun: yes;"> </span>The irony of this
situation (ideology versus real world treatment) was not lost on anyone.
Several people seemed to congratulate the authors on publishing results inconsistent with their ideology although the study was so embedded in the UK
research infrastructure – I doubt that not publishing it would have been an
option. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">As a clinical trialist myself – the research seems to
present several problems and creates several questions that could suggest that
it was designed to optimize the likelihood that antipsychotic medication could
be reduced and possibly discontinued. Before I get into those scenarios let me briefly summarize the results.<span style="mso-spacerun: yes;"> </span>The </span><a href="https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(23)00258-4/fulltext"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">paper
is open access</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"> and can be downloaded as well as </span><a href="https://bmjopen.bmj.com/content/9/11/e030912.long"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">another
paper that describes the research protocol</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">In the study there were two arms an antipsychotic maintenance
arm (N=127) and a reduction arm (N= 126). Diagnoses were taken from clinical
information and the clinical staff had treatment responsibility for the patients.<span style="mso-spacerun: yes;"> </span>In those patients who were randomized to dose
reduction, a tapering protocol was suggested to the clinical staff and if it went well at some point the option for a more rapid taper or discontinuation was offered.<span style="mso-spacerun: yes;"> </span>The
research staff monitored the protocol. Baseline and outcome measure included a
number of checklists to assess side effects, sexual side effects, positive and
negative symptoms, quality of life, and social outcomes at the reassessment points. Raters were blinded but the measures are essentially self report. The ultimate result was
that the risk of adverse outcomes was worse in the reduction arm with no
associated improvement in social functioning. <span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal">He are some potential issues that I noticed based on my experience in clinical trial design and on research review boards.</p><p class="MsoNormal"><span face="Arial, sans-serif" style="font-size: 12pt;">1.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><i style="font-family: Arial, sans-serif; font-size: 12pt;">Recruitment</i><span face="Arial, sans-serif" style="font-size: 12pt;">
– described in the following:</span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“Participants were recruited from 19 National Health
Service Trust mental health organisations across England. Potential participants
were identified initially by clinical staff or recruited through advertisements
placed in clinical settings and social media; those patients who expressed an
interest in participating were sent further information”.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Not enough information. What did the advertisements say?
Were subjects aware of who was running this trial and what the goal of the
research was? Were the patients asked why they were interested in participating
in this trial?<span style="mso-spacerun: yes;"> Were they asked what they think about taking a medication? </span>Did the subjects have any
exposure to the considerable press that the critical psychiatry group and the principal
investigator generate? <span style="mso-spacerun: yes;"> </span>Descriptions in
the lay press have been demonstrated to have significant effects on perceived
side effects – even to the point of creating a nocebo effect (6) – is there any
reason to think that a group emphasizing side effects and minimizing any therapeutic
effects might have a similar impact? If that is the case – how would it affect
this trial? <span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">2.<span style="mso-spacerun: yes;"> </span><i>Inclusion/Exclusion
criteria</i> – <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“Exclusion criteria included being considered by a
clinician to pose a serious risk of harm to self or others were the individual
to reduce their antipsychotic medication, being mandated to take antipsychotic
medication under a section of the Mental Health Act, having been admitted to
hospital or treated by a crisis service for a mental disorder within the last
month, lacking capacity to consent, having insufficient spoken English,
pregnancy, breastfeeding, and being involved in another trial of an
investigational medical product; eligibility was assessed by researchers and
confirmed by the Principal Investigator for the site.”<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Practically all the exclusion criteria result in a
population that may be more likely to discontinue antipsychotic medications
with less difficulty. Consistent with this is the antipsychotic doses of both
the reduction and maintenance arm of 300 mg <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696254/">chlorpromazine
equivalents</a> (on average).<span style="mso-spacerun: yes;"> </span>According
to the Maudsley Prescribing Guidelines (4) 300 mg chlorpromazine is considered the
minimally effective dose of medication for relapsing schizophrenia. Whether
this was a representative sample of the 4109 patients put forward for research
by clinicians a comparison of the demographics and medication doses would have
been of interest. <span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><span style="mso-spacerun: yes;"></span></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Selection bias may also be evident in the Consort diagram
(page 4). After subjects consented to be
contacted by the research team (N= 958) – a total of 562 declined participation.
Was that because they did not want to take the chance of randomization to a
medication reduction?<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">3.<span style="mso-spacerun: yes;"> </span><i>Diagnoses</i> –
the diagnosis required was schizophrenia or non-affective psychoses with recurrent
episodes. The diagnoses were taken from clinical records.<span style="mso-spacerun: yes;"> </span>Considerable heterogeneity is introduced with
the non-specific category of psychoses with an unpredictable course for which
the concept of maintenance medication was not intended. <span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">4.<span style="mso-spacerun: yes;"> </span>The <i>Dose Reduction
</i>-<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The description of the dose reductions in the paper is
confusing.<span style="mso-spacerun: yes;"> </span>It starts out describing
individualized reductions every 2 months based on starting doses but at some
point states the patient is allowed to discontinue the medication if the dose
reduction has been going well or reduce at a rate of the equivalent of 2 mg haloperidol/day.
<span style="mso-spacerun: yes;"> </span>2 mg/day of haloperidol is not a slow
reduction and it is a departure from reduction every 2 months. Some of the
authors here have written about antipsychotic withdrawal reactions – how is the
more rapid dose reduction or optional abrupt discontinuation justified?<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">4.<span style="mso-spacerun: yes;"> </span><i>Safety
Monitoring/Informed Consent:</i><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The more clinical trials I read (and I have read thousands)
– the more I want to see the consent form that each patient signs. Some of the
authors here continuously talk about medication side effects.<span style="mso-spacerun: yes;"> </span>In fact – the principle investigator (PI) has
stated that in her opinion that modern psychiatric medications work in a "drug
centered" rather than a disease centered model by producing side effects like sedation,
cognitive impairment, dysphoria, and loss of libido (5).<span style="mso-spacerun: yes;"> </span>In that model, symptoms of mental illness are
muted by side effects rather than effectively treated. The model essentially
denies the possibility of effective treatment without medication side effects. <span style="mso-spacerun: yes;"> </span>Of course, there are medication side effects
but consent forms also must contain a discussion of the risks of the
intervention. How are they listed when the investigators do not believe they
can be directly addressed?<span style="mso-spacerun: yes;"> </span>Were the
subjects told about the risk from medication discontinuation of recurrent
psychosis, suicidal thinking, and death?<span style="mso-spacerun: yes;">
</span>That seems especially relevant in a study where the intervention arm had
twice as many deaths as the maintenance arm (see Table 4).<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Along those same lines – the protocol paper for the study
(2) states that a Data Safety and Monitoring Board (DSMB) assessed the ongoing
safety of the protocol and made recommendation to a Programme Steering
Committee providing independent oversight – even to the point of stopping the
protocol if there was a substantial increase in adverse events related to the
intervention. Was there a threshold? In this case why was that threshold not
met?<span style="mso-spacerun: yes;"> </span>In the trials I have been involved
with the PI and the physician responsible for monitoring safety (typically me)
had to clearly delineate a safety plan if any of the research subjects
developed medical or psychiatric complications from the intervention.<span style="mso-spacerun: yes;"> </span>In this case that responsibility seems to
have been delegated to the clinicians originally treating the patient. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">In the reported causes of death of the trial participants –
how is the death of a research subject in the reduction arm attributed to
antipsychotic medication when they have been on a low dose, were being followed
clinically in an outpatient clinic, and their dose was presumably being
reduced? <span style="mso-spacerun: yes;"> </span>One patient in each arm died of
an “accidental overdose”. What medication was implicated in the accidental
overdoses?<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">This protocol is also a case of shifting risk for the
research to the clinicians.<span style="mso-spacerun: yes;"> </span>Here the
research staff designs an intervention that likely will lead to worsening clinic
status and the subjects are followed in a treatment as usual manner. Were any
additional safeguards in place for that eventuality?<span style="mso-spacerun: yes;"> </span>For example – were the subjects informed that
they could contact the principal investigator or research coordinator if things
were not going well?<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">These all seem like significant safety questions to me.<o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">5. Social Functioning Scale (SFS) to measure the primary outcome - </span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The measured results with this scale are in the top line of Table 2 at 6, 12, and 24 months. The scale has 79 items that are assigned to assess social functioning. Is there a problem with taking a cross sectional sample of people stabilized on medications and hypothesizing they will function better being tapered off antipsychotic medication? There is an obvious problem and that is there is no accounting for the improvement in social functioning due to the medication in the first place. In other words - what would the subjects have scored leading up to and during the episode of acute or recurrent psychosis - the reason they are taking the medication in the first place. What would the trajectory of these scores be over time? Stabilization of psychosis involves a lot more than treating hallucinations, delusions, and thought disorder symptoms. With stabilization there is an improvement in social behavior. The design of the trial suggests that the problem began with medications rather than a significant psychiatric disorder. </span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">There is a concept in clinical psychiatry and that is trying to get the patient as close as possible to their baseline level of functioning. That requires a knowledge of what they were like before the onset of illness and restoring as much functional and social capacity as possible. That also typically means minimal to no medication side effects if possible.</span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">6.<span style="mso-spacerun: yes;"> </span>What is <i>supported
reduction</i> of antipsychotic medication?<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Is there a protocol that I missed?<span style="mso-spacerun: yes;"> </span>I could not find what this means anywhere in
either the protocol or final paper or in the supplementaries.<span style="mso-spacerun: yes;"> </span>If I was tapering an antipsychotic medication
I would meet more frequently with the patient, inform them of what we
need to watch for, have additional caregiver and family involvement, and encourage
them to call me at specific signs of early problems due to the dosage
reduction. In a research protocol, research staff would call and check on how the
subject was doing. I would call all of that treatment as usual (TAU) when it
comes to antipsychotic medication reduction. Is supported reduction more than
that?<span style="mso-spacerun: yes;"> </span>Even TAU has been implicated as a
potential placebo enhancing effect. Did it have that effect on the intervention
in this case?<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">7.<span style="mso-spacerun: yes;"> </span>The overstated
conclusion:<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">“Our findings provide information for people with schizophrenia
and related conditions about the probable medium-term impact of reducing the
dose of their antipsychotic medication, and they highlight the need for collaborative
decision making based on the sharing and careful consideration of all the
evidence.”<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Actually, it doesn’t.<span style="mso-spacerun: yes;">
</span>This is what clinical psychiatrists do and more specifically it is what
I did for 35 years of practice. I can still recall community psychiatry
seminars with Len Stein, talking about dosage reductions of antipsychotic
medications and the implication of a WHO international study looking at that
problem in schizophrenia.<span style="mso-spacerun: yes;"> </span>That seminar
was in 1986. Collaborative decision making seems to be the latest term for informed consent and therapeutic alliance. Informed consent means that the patient is given enough information and discussion so that they can make a decision about the direction of their care including any medications, tests, or other interventions used. The therapeutic alliance is the affiliative relationship between the patient and physician aligned to address the patient's problems and diagnoses. It is by longstanding definition a collaboration.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">What the authors did encounter but did not discuss was the
tendency of people on antipsychotics to just discontinue them (several in the maintenance
group did this), how much withdrawal was encountered, and why there were no
group categorical differences in side effects with the taper. According to the </span><span style="background-color: white; color: #202124;"><span style="font-family: arial;">Glasgow Antipsychotic Side-effect Scale</span></span><span face=""Google Sans", arial, sans-serif" style="background-color: white; color: #202124; font-size: 20px;"> (</span><span style="font-family: arial;">GASS)</span><span style="font-size: 12pt;"> guidelines all subjects remained in the moderate side effect range. And if medications work through side effects as the critical psychiatrists say why did the subjects in the dose reduction group worsen? </span><span style="font-size: 12pt; mso-spacerun: yes;"> </span><span style="font-size: 12pt; mso-spacerun: yes;"> </span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Those are a few of the problems that jumped out at me as I
read this paper and the associated backgrounder. As can be seen from the above
discussion many of these design factors potentially optimize the intervention
group in the direction of proving the authors’ hypothesis. It also limits generalizability to other clinical settings. That makes the
result of the trial even more significant.<span style="mso-spacerun: yes;">
</span>It also raises some issues that seem more prominent in recent years as pharmaceutical
conflict of interest seems to ring hollow.<span style="mso-spacerun: yes;">
</span>Is there an ideological conflict of interest and how is it determined?<span style="mso-spacerun: yes;"> </span>How does it affect research design, results, and the discussion of research findings? <span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">George Dawson, MD, DFAPA<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">References:<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">1:<span style="mso-spacerun: yes;"> </span>Moncrieff J,
Crellin N, Stansfeld J, Cooper R, Marston L, Freemantle N, Lewis G, Hunter R, Johnson
S, Barnes T, Morant N, Pinfold V, Smith R, Kent L, <span style="mso-spacerun: yes;"> </span>Darton K, <span style="mso-spacerun: yes;"> </span>Long M, Horowitz M, Horne R, Vickerstaff V, Jha
M, Priebe S.<span style="mso-spacerun: yes;"> </span>Antipsychotic dose
reduction and discontinuation versus maintenance treatment in people with
schizophrenia and other recurrent psychotic disorders in England (the RADAR
trial): an open, parallel-group, randomised controlled trial. Lancet Psychiatry
September 28, 2023DOI:https://doi.org/10.1016/S2215-0366(23)00258-4.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">2:<span style="mso-spacerun: yes;"> </span>Moncrieff J,
Lewis G, Freemantle N, Johnson S, Barnes TR, Morant N, Pinfold V, Hunter R,
Kent LJ, Smith R, Darton K. Randomised controlled trial of gradual
antipsychotic reduction and discontinuation in people with schizophrenia and
related disorders: the RADAR trial (Research into Antipsychotic Discontinuation
and Reduction). BMJ open. 2019 Nov 1;9(11):e030912.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">3:<span style="mso-spacerun: yes;"> </span>Danivas V,
Venkatasubramanian G. Current perspectives on chlorpromazine equivalents:
Comparing apples and oranges! Indian J Psychiatry. 2013 Apr;55(2):207-8. doi:
10.4103/0019-5545.111475. PMID: 23825865; PMCID: PMC3696254.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">4:<span style="mso-spacerun: yes;"> </span>Taylor D, Paton
C. The Maudsley prescribing guidelines. CRC press; 2009 Oct 30.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">5:<span style="mso-spacerun: yes;"> </span>Middleton H,
Moncrieff J.<span style="mso-spacerun: yes;"> </span>Critical psychiatry: a
brief overview. BJPsych Advances (2019), vol 25, 45-54.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">6:<span style="mso-spacerun: yes;"> </span>Colloca L, Barsky
AJ. Placebo and Nocebo Effects. N Engl J Med. 2020 Feb 6;382(6):554-561. doi:
10.1056/NEJMra1907805. PMID: 32023375.<o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><br /></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Photo Credit:</span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Many thanks to my colleague Eduardo A. Colon, MD for the photograph at the top of this blog.</span></p>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com4tag:blogger.com,1999:blog-7772182113499451603.post-10351981055484985822023-09-26T12:01:00.015-05:002023-09-26T21:04:07.213-05:00The Recent Takedowns of Adult ADHD<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhBnAjnp4tOAc0agoQtnMMd7m_hlly55mMVjzIQkfMZgH6BSD8sQVT9ElmxLfZShWb1rv_bVOqV12O4oBmQXPabpUd9iCcXORMYkT1_SC929whWEBZHIfnP2NvVgK9MeT091bf10W9ABLmjNLu649Ar5HCCezdKpUaETYGnmktwTEtoVb1eis4wlwScuZzV/s1528/ADHD%20Ghaemi%20infographic%2009.26%209PM.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1372" data-original-width="1528" height="574" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhBnAjnp4tOAc0agoQtnMMd7m_hlly55mMVjzIQkfMZgH6BSD8sQVT9ElmxLfZShWb1rv_bVOqV12O4oBmQXPabpUd9iCcXORMYkT1_SC929whWEBZHIfnP2NvVgK9MeT091bf10W9ABLmjNLu649Ar5HCCezdKpUaETYGnmktwTEtoVb1eis4wlwScuZzV/w640-h574/ADHD%20Ghaemi%20infographic%2009.26%209PM.png" width="640" /></a></div><br /><div class="separator" style="clear: both; text-align: center;"><br /></div><br /><div class="separator" style="clear: both; text-align: center;"><span face="Arial, sans-serif" style="font-size: 12pt; text-align: left;"><br /></span></div><span style="font-family: arial;">Psychiatry seems doomed to argue endlessly about whether certain conditions exist or not and whether they can be characterized by written criteria. The latter condition is the most easily dismissed since clinical training is necessary to recognize conditions. You cannot just sit in an office, read the DSM and call yourself a psychiatrist. Whether conditions exist or not is more debatable but often slides into rhetoric that suggests inadequate training, ignorance, and/or significant conflict of influence or undue influence by the pharmaceutical industry. Consideration of the undue influence can easily be applied at the global level since Pharma has massive marketing efforts, direct to consumer advertising in the US, and at least <a href="https://real-psychiatry.blogspot.com/2023/09/the-true-big-pharma-backers-show.html">one major political party</a> pulling for them.</span>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="line-height: 107%;"><span style="font-size: 12pt;">That brings me to the recent commentaries about adult ADHD
(1, 2). The first reference (1) doubts that adult ADHD exists for the most part
and sees the diagnosis primarily as the result of a marketing scheme by Eli
Lilly for atomoxetine and ignoring affective temperaments and other states that
may affect attention. Atomoxetine was invented as a norepinephrine reuptake
inhibiting antidepressant and like other members of this class of drugs – it
did not work for depression. Since it is not technically a stimulant it was
tested for ADHD and found to be effective. It is unique relative to other ADHD
medications and not surprisingly it was heavily marketed while on patent. The
patent expired on May 2017. The years on the market patent protected were
2002-2017. The first references to the diagnosis of adult ADHD were noted in
the 1980s. Reference 2 suggests that the diagnosis of ADHD in children in the
US is around 2-3% with adult numbers half that based on the work of one
author.</span><span style="font-size: 12pt; mso-spacerun: yes;"> </span><span style="font-size: 12pt;">Contrasting numbers of a
lifetime prevalence in adults as 8.1% and surveys estimating current prevalence
at 4.4% are described as “absurdly high” but qualified on methodology (surveys
vs interviews). </span><span style="mso-spacerun: yes;"><span style="font-size: 12pt;"> Some authors have the opinion that books published about adult ADHD like Ratey and Hollowell's </span><i style="font-size: 12pt;">Driven to </i><i>Distraction </i>were a major source of public interest in the diagnosis<i> </i>and instrumental in getting it into the public vernacular.<i> </i></span><o:p style="font-size: 12pt;"></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Before I get started – let me say that the only stake I
have in this argument is making sure that the complexity of the situation is
adequately described. Practically all the pro/con arguments in psychiatry are
gross oversimplifications and based on what I know about the literature – I had
no reason to expect that this was any different.<span style="mso-spacerun: yes;"> </span>I am already on record on this blog
describing how to diagnose and treat ADHD and not fall into the common problems
of misdiagnosis, prescribing to people with substance use problems, or
prescribing to people who view these medications as performance enhancers. I
have successfully treated adult ADHD with both on and off label medications and
can attest to the fact that it is a valid and treatable diagnosis.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Let me start out by looking at the prevalence estimates.
These figures are very popular in the press to indict diagnosticians in the
United States compared with some European countries and sell more papers. The
problem with prevalence estimate is that the range can vary significantly due
to methodological differences in the surveys. That question was looked at (3)
and the title of that paper asked if ADHD was “an American condition”.<span style="mso-spacerun: yes;"> </span>The authors reviewed 22 studies based on
DSM-III criteria and 19 studies based on DSM-IV criteria.<span style="mso-spacerun: yes;"> </span>Twenty prevalence estimates were done on the
US and 30 were done in other countries.<span style="mso-spacerun: yes;">
</span>They demonstrated that the range of prevalence across all studies was
approximately the same and that ADHD was not just an American condition. Since
then numerous prevalence studies have been done in other countries – more recently
using DSM-5 criteria showing similar ranges.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">On the issue of adult ADHD, a recent review looked at the
issue adult ADHD and symptomatic adult ADHD prevalence by the </span><a href="https://en.wikipedia.org/wiki/List_of_WHO_regions"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">6 WHO
regions</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"> (4).<span style="mso-spacerun: yes;"> </span>Their overall
goal was to determine the worldwide prevalence of adult ADHD. They looked at
the issue of persistent or childhood onset ADHD and symptomatic adult ADHD with
no evidence of childhood onset and estimated the prevalence of those two groups
separately.<span style="mso-spacerun: yes;"> </span>The pooled prevalence of
persistent adult ADHD was 4.6% and for symptomatic ADHD it was 8.83%.<span style="mso-spacerun: yes;"> </span>These authors also looked at prevalence by a
list of demographic factors, diagnostic criteria, addition to geographic areas
as well as the decreasing prevalence by age groups. <span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<table border="1" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse: collapse; border: none; mso-border-alt: solid windowtext .5pt; mso-padding-alt: 2.9pt 5.4pt 2.9pt 5.4pt; mso-yfti-tbllook: 1184; width: 654px;">
<tbody><tr style="mso-yfti-firstrow: yes; mso-yfti-irow: 0;">
<td style="border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; padding: 2.9pt 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Study<o:p></o:p></span></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 2.9pt 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Target Population<o:p></o:p></span></p>
</td>
<td style="border-left: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 2.9pt 5.4pt; width: 256.55pt;" valign="top" width="342">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Prevalence % (US vs
Non-US) ranges or pooled<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 1;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 2.9pt 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Faraone, et al (2002)<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 2.9pt 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">DSM-III ADHD<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">DSM-III-R ADHD<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">DSM-IV<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 2.9pt 5.4pt; width: 256.55pt;" valign="top" width="342">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">(9.1-12.1) vs.
(5.8-11.2)<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">(7.1-12.8) vs.
(3.9-10.9)<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">(11.4-16.1) vs.
(2.4-19.8)<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 2;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 2.9pt 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Polanczyk, et al <o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">(2007)<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 2.9pt 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Pooled prevalence
estimates of ADHD by geographic location.<span style="mso-spacerun: yes;">
</span>N= number of studies in each WHO designated location<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 2.9pt 5.4pt; width: 256.55pt;" valign="top" width="342">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">North American
(N=32)<span style="mso-spacerun: yes;"> </span>6%<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Europe (N=32)<span style="mso-spacerun: yes;"> </span>4.5%<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Oceana (N=6) 4.5%<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">South American (N=9)
12%<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Asia (N=15) 4%<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Africa (N=4) 8%<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Middle East (N=4)
2.5%<o:p></o:p></span></p>
</td>
</tr>
<tr style="mso-yfti-irow: 3; mso-yfti-lastrow: yes;">
<td style="border-top: none; border: 1pt solid windowtext; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 2.9pt 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Song, et al (2021)<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 2.9pt 5.4pt; width: 116.85pt;" valign="top" width="156">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Pooled estimates and
ranges of <i>Adult ADHD</i> worldwide by WHO designated geographic areas<o:p></o:p></span></p>
</td>
<td style="border-bottom: 1pt solid windowtext; border-left: none; border-right: 1pt solid windowtext; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 2.9pt 5.4pt; width: 256.55pt;" valign="top" width="342">
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">North America (N=3)
6.06%<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Europe (N=10) 7.12%<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Oceana (N=4) 9.67%<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">South America (N=3)
6.06%<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Asia (N=1) 25.6%<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Africa (N=1) 9.17%<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;">Middle East (N=2)
16.58%<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: normal; margin-bottom: 0in;"><span face=""Arial",sans-serif" style="font-size: 12pt;"><o:p> </o:p></span></p>
</td>
</tr>
</tbody></table>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">This study raises the issue of whether ADHD can be acquired
rather than be a childhood onset illness. The reality is that there are many
paths to acquired attentional deficit that have been treated over the course of
my 35 years in the field.<span style="mso-spacerun: yes;"> </span>The best
examples are neurodegenerative diseases, strokes, and brain injuries.
Neuropsychiatrists have written about treating the associated cognitive, mood,
and motivational deficits with stimulants.<span style="mso-spacerun: yes;">
</span>But a more relevant question is whether mechanisms exist that can result
in people with none of these acquired brain injuries.<span style="mso-spacerun: yes;"> </span>The answer comes from modern genetics.
Polygenic risk scores (of all diseases) suggest that there are high risk
individuals who show no evidence of an illness as adults. These examples of </span><a href="https://www.nature.com/scitable/topicpage/same-genetic-mutation-different-genetic-disease-phenotype-938/"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">incomplete
penetrance</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"> are usually explained as environmental factors, additional
genetic dynamics such as aging or protective factors. I see no reason why these
factors could not occur in an ADHD genotype after childhood. The other
significant genetic factor is spontaneous mutation or as a recent commentator
put it: “You don’t die with the genome you were born with.” Psychiatry has
focused on familial studies for the past 50 years, but it is likely that
significant numbers of most conditions occur as the result of spontaneous
mutations rather than strictly hereditary transmission. That is borne out in
clinical practice every day. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The authors (1) make the argument that ADHD is not a
“scientifically valid” diagnosis. They explain “these symptoms have not been
shown to be the result of a scientifically valid disease (adult ADHD) and
better explained by more classic and scientifically validated psychiatric
conditions, namely diseases or abnormalities of mood, anxiety, or mood
temperament.”<span style="mso-spacerun: yes;"> </span>Mood temperament is a
stretch.<span style="mso-spacerun: yes;"> </span>It is rarely commented on in
adult psychiatry and then in extreme cases.<span style="mso-spacerun: yes;">
</span>It is not contained in the DSM. Part of the reason is selection
bias.<span style="mso-spacerun: yes;"> </span>Psychiatrists are seeing people
who have failed multiple other treatments and I have referred to this as being
the treatment provider of last resort.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Another factor is that ADHD is a <i>quantitative</i>
rather than <i>qualitative</i> disorder – that is the cognitive symptoms are at
the extreme end of normalcy and it is difficult to draw a line to demarcate
illness from normal in many cases. A comparable example from medicine is
hypertension.<span style="mso-spacerun: yes;"> </span>The cutoff for what is
considered hypertension has varied significantly over the decades (9, 10) and
even now considers antihypertensive side effects as a qualifier for
treatment.<span style="mso-spacerun: yes;"> </span>That means that for any 2
people with the same marginally elevated blood pressure only one might get
consistently treated. At one point hypertension was considered by some
physicians to be a necessary compensatory mechanism that should not be treated
(10). On the issue of quantitative aspects of psychiatric disorders in general
– dimensional approaches are often suggested as a solution and the question is
whether they work any better than the impairment criteria used in the DSM.<span style="mso-spacerun: yes;"> </span>That is especially true in a clinical setting
where a patient is presenting with a clear problem that they are asking for
help with<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">On the issue of validity, studies have been done
demonstrating reliability and validity (8) on both the DSM criteria as well as
various rating scales for adult ADHD that are consistent with the diagnosis. There
have also been detailed discussions of how to approach the problem clinically
(11).<span style="mso-spacerun: yes;"> </span>Those discussions include how to
differentiate mood disorders from ADHD and how to approach the functional impairment criteria in the clinical interview.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">That brings me to the issue of temperaments mentioned in
reference 1.<span style="mso-spacerun: yes;"> </span>Temperaments have been
researched in various contexts in psychiatry over the past decades.<span style="mso-spacerun: yes;"> </span>Most psychiatrists of my generation first
heard about them on child psychiatry rotations and the work of Stella and
Chess. In adults, temperaments are more descriptions of hyperthymia,
cyclothymia, and dysthymia and are generally considered in the differential
diagnosis of subclinical mood disorders.<span style="mso-spacerun: yes;">
</span>The best example is hyperthymia and it has been referred to both as a
temperament and a personality. Hyperthymic people are generally high energy,
require less sleep, and are social, talkative, and outgoing. They may be very
productive and have increased libido relative to their peers. In clinical
interviews they may say that their friends think they are “bipolar” and need to
be treated. But careful interviewing demonstrates that they lack the symptom
severity and degree of impairment necessary for a diagnosis of bipolar
disorder.<span style="mso-spacerun: yes;"> </span>Ideally the initial interview
results in that formulation and the psychiatrist can advise the person about
why treatment is not necessary. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Reference 12 looks at the issue of temperaments in a
retrospective controlled study of patients being treated with stimulants who
were referred to a mood disorders clinic.<span style="mso-spacerun: yes;">
</span>The authors acknowledge the selection bias in their study design. I can
not think of a better design to pick up misdiagnosed patients than this one. To
cite one example – of the 87 amphetamine treated referrals only 50% had a past
diagnosis of ADHD. The authors acknowledge that there is no standard way to
determine affective temperaments and decide to use the TEMPS-A with a cutoff of
75% of the items. If you are able to find a copy of the TEMPS-A (it is not
easy) – you will find a list of 50 true-false questions like “I’m usually in an
upbeat or cheery mood.” The questions are reminiscent of the Minnesota Multiphasic
Personality Inventory (MMPI) except there are far fewer questions. The scoring
guide suggests that the TEMPS-A can discriminate between hyperthymic,
cyclothymic, dysthymic, and irritable temperaments. It is validated in the
usual ways.<span style="mso-spacerun: yes;"> </span>The relevant question is
whether any diagnosis made with this checklist would deter you from treating a
comorbid condition - like Adult ADHD? It is one thing to survey a misdiagnosed group with the
TEMPS-A and consider the clinical implications, but another to consider the presenting problem possible ADHD and whether it should be treated.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The arguments in reference 2 about overdiagnosis, the
existence of adult ADHD, and the idea that ADHD can occur in adults without a
childhood diagnosis can be challenged with the facts and references provided here.<span style="mso-spacerun: yes;"> </span>The fact that we are in the midst of a <a href="https://real-psychiatry.blogspot.com/2018/10/drug-overdoses-as-proxy-for-drug.html">multigenerational
drug epidemic</a> in an increasingly intoxicant permissive society does not mean that a
diagnosis, treatment, or problem does not exist. It does mean that all
psychiatrists from the moment they enter practice must exercise extreme caution
when prescribing substances that reinforce their own use.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The most likely cause of overdiagnosis is not because adult
ADHD does not exist, not because of drug promotion (most are generic including the
non-stimulant alternatives), or because MDs are careless.<span style="mso-spacerun: yes;"> </span>There are basically two reasons.<span style="mso-spacerun: yes;"> </span>First – the difficulty of diagnosing quantitative
conditions. Second – sociocultural factors that exist in the US. Performance
enhancement is built on the myth that you can tune your brain (or any organ) with
supplements, nutrients, or medications to become a superior human being. The reality is you
can alter your conscious state to believe that – but in the case of stimulants
it is unlikely. The only real performance enhancement occurs because you
can stay awake longer to read more and there is some evidence that <a href="https://real-psychiatry.blogspot.com/2018/03/take-your-meds.html">your
belief system is altered so that you believe you are smarter</a> (14). These are
just two of the reinforcing properties of stimulants that can lead to
accelerated use and addiction. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">That is my brief summary of the complexity of this situation.
For more on my approach to adult ADHD (I only treat adults) – see <a href="https://real-psychiatry.blogspot.com/2023/05/adhd-28-discussion-points.html">this
post</a>. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">George Dawson, MD, DFAPA<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">References:<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">1:<span style="mso-spacerun: yes;"> </span>Ruffalo ML,
Ghaemi N.<span style="mso-spacerun: yes;"> </span>The making of adult ADHD: the
rapid rise of a novel psychiatric diagnosis.<span style="mso-spacerun: yes;">
</span>Psychiatric Times 2023 40(9): 1, 18-19.<o:p></o:p></span></p>
<p class="MsoNormal"><a href="https://www.psychiatrictimes.com/view/the-making-of-adult-adhd-the-rapid-rise-of-a-novel-psychiatric-diagnosis"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">https://www.psychiatrictimes.com/view/the-making-of-adult-adhd-the-rapid-rise-of-a-novel-psychiatric-diagnosis</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">2:<span style="mso-spacerun: yes;"> </span>Frances A.<span style="mso-spacerun: yes;"> </span>Containing The Adult ADHD Fad — With a
Rejoinder from ChatGPT. 9/21/23.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><a href="https://www.psychotherapy.net/blog/title/containing-the-adult-adhd-fad-with-a-rejoinder-from-chatgpt"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">https://www.psychotherapy.net/blog/title/containing-the-adult-adhd-fad-with-a-rejoinder-from-chatgpt</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">3:<span style="mso-spacerun: yes;"> </span>Faraone SV,
Sergeant J, Gillberg C, Biederman J. The worldwide prevalence of ADHD: is it an
American condition? World Psychiatry. 2003 Jun;2(2):104-13. PMID: 16946911<span style="mso-spacerun: yes;"> </span></span><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1525089/"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1525089/</span></a><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">4:<span style="mso-spacerun: yes;"> </span>Song P, Zha M,
Yang Q, Zhang Y, Li X, Rudan I. The prevalence of adult attention-deficit
hyperactivity disorder: A global systematic review and meta-analysis. J Glob
Health. 2021 Feb 11;11:04009. doi: 10.7189/jogh.11.04009. PMID: 33692893;
PMCID: PMC7916320.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">5: Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde
LA. The worldwide prevalence of ADHD: a systematic review and metaregression
analysis. Am J Psychiatry. 2007 Jun;164(6):942-8. doi: 10.1176/ajp.2007.164.6.942.
PMID: 17541055. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">6:<span style="mso-spacerun: yes;"> </span>Kim DS, Burt AA,
Ranchalis JE, Wilmot B, Smith JD, Patterson KE, Coe BP, Li YK, Bamshad MJ,
Nikolas M, Eichler EE. Sequencing of sporadic Attention</span><span style="font-family: "Cambria Math",serif; font-size: 12pt; line-height: 107%; mso-bidi-font-family: "Cambria Math";">‐</span><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Deficit Hyperactivity Disorder
(ADHD) identifies novel and potentially pathogenic de novo variants and
excludes overlap with genes associated with autism spectrum disorder. American
Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2017
Jun;174(4):381-9.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">7: McGough JJ, Barkley RA. Diagnostic controversies in
adult attention deficit hyperactivity disorder. Am J Psychiatry. 2004
Nov;161(11):1948-56. doi: 10.1176/appi.ajp.161.11.1948. PMID: 15514392.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">8: Kooij JJ, Buitelaar JK, van den Oord EJ, Furer JW,
Rijnders CA, Hodiamont PP. Internal and external validity of attention-deficit
hyperactivity disorder in a population-based sample of adults. Psychol Med.
2005 Jun;35(6):817-27. doi: 10.1017/s003329170400337x. PMID: 15997602. <span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">9:<span style="mso-spacerun: yes;"> </span>Saklayen MG,
Deshpande NV. Timeline of History of Hypertension Treatment. Front Cardiovasc
Med. 2016 Feb 23;3:3. doi: 10.3389/fcvm.2016.00003. PMID: 26942184; PMCID:
PMC4763852.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">10:<span style="mso-spacerun: yes;"> </span>Kotchen TA.
Historical trends and milestones in hypertension research: a model of the
process of translational research. Hypertension. 2011 Oct;58(4):522-38. doi:
10.1161/HYPERTENSIONAHA.111.177766. Epub 2011 Aug 22. PMID: 21859967.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">11:<span style="mso-spacerun: yes;"> </span>Murphy KR,
Gordon M.<span style="mso-spacerun: yes;"> </span>Assessment of adults with
ADHD. In: Barkley RA. Attention-Deficit Hyperactivity Disorder, 3<sup>rd</sup>
edition.<span style="mso-spacerun: yes;"> </span>The Guilford Press, New York,
2006: 425-450.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">12:<span style="mso-spacerun: yes;"> </span>Mauer S,
Ghazarian G, Ghaemi SN. Affective Temperaments Misdiagnosed as Adult Attention
Deficit Disorder: Prevalence and Treatment Effects. J Nerv Ment Dis. 2023 Jul
1;211(7):504-509. doi: 10.1097/NMD.0000000000001626. Epub 2023 Apr 11. PMID:
37040539. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">13:<span style="mso-spacerun: yes;"> </span>Akiskal HS,
Mendlowicz MV, Jean-Louis G, Rapaport MH, Kelsoe JR, Gillin JC, Smith TL.
TEMPS-A: validation of a short version of a self-rated instrument designed to
measure variations in temperament. J Affect Disord. 2005 Mar;85(1-2):45-52.
doi: 10.1016/j.jad.2003.10.012. PMID: 15780675.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">14:<span style="mso-spacerun: yes;"> </span>Ilieva I, Boland
J, Farah MJ. Objective and subjective cognitive enhancing effects of mixed
amphetamine salts in healthy people. Neuropharmacology. 2013 Jan;64:496-505.
doi: 10.1016/j.neuropharm.2012.07.021. Epub 2012 Aug 1. PubMed PMID: 22884611.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p><div class="separator" style="clear: both; text-align: center;"><br /></div><br />George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com6tag:blogger.com,1999:blog-7772182113499451603.post-51487384891886232182023-09-22T14:50:00.004-05:002023-09-29T13:40:35.697-05:00Heart Rate Variability<p> </p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiFnWlfcvgguH1UPswhtSjZUmHq7O07XhuwI_dbC8htS_OB_gkjN0Jyao3xu7jtfqxhGJCXoP_bvUubYiRoRb_fKeMVbT5BcDXepJTUfclfhkt46ijEjk5RjhRWpUxi-BDubNf5dke6yoSHHuxHYmxZehfuv_W4AF6p42reKb_YcFNpQld6xN1u0vbMRHhf/s1680/RR%20Interval.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="394" data-original-width="1680" height="150" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiFnWlfcvgguH1UPswhtSjZUmHq7O07XhuwI_dbC8htS_OB_gkjN0Jyao3xu7jtfqxhGJCXoP_bvUubYiRoRb_fKeMVbT5BcDXepJTUfclfhkt46ijEjk5RjhRWpUxi-BDubNf5dke6yoSHHuxHYmxZehfuv_W4AF6p42reKb_YcFNpQld6xN1u0vbMRHhf/w640-h150/RR%20Interval.jpg" width="640" /></a></div><br /><p></p><p class="MsoNormal"><span face="Arial, sans-serif" style="font-size: 12pt;">I have been following heart rate variability (HRV) on my
watch and three different apps for the past several years. HRV is defined as
the slight variations between R waves in the standard ECG recording.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">I have included an example below,
illustrating the R-R’ intervals (or RRI) and how they might vary over time.</span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Since HRV became widely available as a measurement off a
watch that is commonly worn by millions of people, the research on this
measurement and the variable studied has increased significantly.<span style="mso-spacerun: yes;"> </span>For my purposes – HRV is thought to be an
indicator of heart health and conditioning and possibly a marker of
overtraining – but advice about that varies significantly. Some studies have
shown that decreased HRV is associated with an increased risk of arrhythmias.<span style="mso-spacerun: yes;"> </span>My recent cardiac ablation and cardioversion
seemed to present an ideal situation for further study.<span style="mso-spacerun: yes;"> </span><o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Before getting into those details the physiology of HRV
needs to be considered. The dominant heart rhythm of a normal heart is
determined by the sinoatrial (SA) node. This node contains a population of
spontaneously depolarizing cells that determine the rhythm and rate of the
heartbeat. In addition to the neurophysiology of that cell population several
additional factors affect both the rate and HRV.<span style="mso-spacerun: yes;"> </span>Primary among them is autonomic innervation
from both the sympathetic and parasympathetic systems and their effect at the
SA node. Parasympathetic fibers from the vagus nerve modulate slower firing
through the neurotransmitter acetylcholine (ACh). Sympathetic fibers increase
the rate of firing through the neurotransmitter norepinephrine (NE).<span style="mso-spacerun: yes;"> </span>NE has a longer half-life than ACh, but vagal
tone is thought to be the most significant determinant of HRV.<span style="mso-spacerun: yes;"> </span>That is in line with several clinical
observations including lower baseline heart rates in conditioned athletes and
higher heart rates in people with less conditioning or in stressful situations.
<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">What happened to my heart rate and HRV during the recent
cardiac ablation for atrial fibrillation and subsequent cardioversion?<span style="mso-spacerun: yes;"> </span>To answer that question, I had to figure out
how to get the data off my Apple Watch 5.0.<span style="mso-spacerun: yes;">
</span>The only approach I could find was to downloaded all of the collected
Health App data as a CSV file and then plot it in Excel.<span style="mso-spacerun: yes;"> </span>There are some online sites that you can
download the data to and then use the remote software for plotting, but I
preferred to retain control over the data. If you decide to do that and have
several years of data like I did – it takes a long time.<span style="mso-spacerun: yes;"> </span>It took about 5 hours in my case to download
about 1G of data to a zip file.<span style="mso-spacerun: yes;"> </span>From
there it is easy to open that file with Excel or other software and do the
plots. A useful addition to the Health App would be able to download specific
time intervals.<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">I have done 2 plots so far based on average daily HRV and
hourly HRV as shown below. <o:p></o:p></span></p><p class="MsoNormal"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgW3gifxap9UwEppBkWIPYRHnI5DahMrRWQwmQ0_i2-ixeHg7IsdGp-HtKSfVoUfK5a5_0Jc1GVBTLeCHPXlszd_T8h8jRfDFGY1OKgY9_pjWkDW_MqjMVRj6EEHrHHonG_Y6DSjlGGNVf0NeRe_NCKqJtjGs0KanBWrYypVKk0v9zkp7I6i5964gr0zn20/s1454/HRV%20Daily%20x%201%20year.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1098" data-original-width="1454" height="484" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgW3gifxap9UwEppBkWIPYRHnI5DahMrRWQwmQ0_i2-ixeHg7IsdGp-HtKSfVoUfK5a5_0Jc1GVBTLeCHPXlszd_T8h8jRfDFGY1OKgY9_pjWkDW_MqjMVRj6EEHrHHonG_Y6DSjlGGNVf0NeRe_NCKqJtjGs0KanBWrYypVKk0v9zkp7I6i5964gr0zn20/w640-h484/HRV%20Daily%20x%201%20year.jpg" width="640" /></a></div><p class="MsoNormal"><br /></p><br /><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgZY_8qTcWRAd3M0uV2aJGUCcRbgqFZUr1rofSwjKG8oSt4RkFIx5kVkLWOONGLiQ30PANupyMPgqqfNce80x2yn9gJQNA6WCA7Z7o1LR-cmjkoTogi4GjPrtTWgjK6QAbcPlS75fbVq501zxPrY2pcr3db5OuZ9YgX7oreP6N_j0lcpd4XsjlQ7AD0PDjO/s1514/HRV%20hourly%20x%201%20year.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1158" data-original-width="1514" height="490" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgZY_8qTcWRAd3M0uV2aJGUCcRbgqFZUr1rofSwjKG8oSt4RkFIx5kVkLWOONGLiQ30PANupyMPgqqfNce80x2yn9gJQNA6WCA7Z7o1LR-cmjkoTogi4GjPrtTWgjK6QAbcPlS75fbVq501zxPrY2pcr3db5OuZ9YgX7oreP6N_j0lcpd4XsjlQ7AD0PDjO/w640-h490/HRV%20hourly%20x%201%20year.jpg" width="640" /></a></div><br /><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><br /></span><p></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span><span face="Arial, sans-serif" style="font-size: 12pt;">The plots are interesting because it clearly shows an
effect from the ablation, a 96-hour period of atrial fibrillation and atrial
flutter, and the cardioversion. At the minimum the baseline HRV drops to a
different baseline after the ablation. That is followed by a significant spike
with the recurrence of afib/flutter.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">And
then there is a return to the lower baseline after the electrical
cardioversion.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">I rarely had any
significant episodes over the course of a year and whenever I went back and
reviewed HRV it was not significantly changed. Since all those episodes were
typically less than 2 or 3 hours it may not have been long enough to see an HRV
effect.</span><span face="Arial, sans-serif" style="font-size: 12pt;"> </span><span face="Arial, sans-serif" style="font-size: 12pt;">Conversely spikes of 50-100 msec
in the HRV recording were common and not associated with arrhythmias. In the
case of the post ablation period the sustained rates were associated with
spikes, but since atrial flutter is regular, the associated R-R’ intervals
probably showed a more characteristic HRV.</span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">I would expect to see an increase in vagal tone and
therefore HRV just related to the sustained high rates over 4 days. If
increased vagal tone correlates with increased HRV that does not seem to be the
case in these graphs. The graphs also seem to indicate to me that there may be
a structural element to HRV – either in the anatomical configuration of the
conducting cells, their altered physiology, or a combination. <o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">The main implication for me at this point is to cautiously
restart my conditioning efforts and see what impact that has on the HRV
baseline.<span style="mso-spacerun: yes;"> </span>A second question is whether
my HRV will approach the pre-ablation baseline.<span style="mso-spacerun: yes;">
</span>Electrocardiograms (ECG) may provide some clues in that direction.<span style="mso-spacerun: yes;"> </span>I have listed them below for references.
Significant changes occurred in the immediate post ablation ECG and the post
cardioversion ECG. <o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">An additional thought is whether non linear analysis of the RR intervals would yield more information and easily interpretable graphics. I have used some of these attractor plots in the past and also applied them to single electrode analyses of normal controls and patients with Alzheimer's disease. In terms of ECG analysis - see figure 5 in reference 2. In terms of theory - these attractor diagrams also imply changes in biological complexity at either the structural or functional level - see the diagrams at the bottom of <a href="https://real-psychiatry.blogspot.com/2015/02/junk-neuroscience.html">this post</a>. </span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">George Dawson, MD, DFAPA<o:p></o:p></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><br /></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">ECG time course (1 -> 5 are in sequence):</span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">1. Baseline - preop ECG </span></p><p class="MsoNormal"></p><div class="separator" style="clear: both; text-align: center;"><br /></div><p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiHD9NOPHRXST9bneKliVTdf0txJEr9rjzSeq3wVvu8CvvYgBoSgC9wOZicukU3JnDaz-FgYIlQfE8f5KLrPEQKd1LSvr8IaMe8tAMo3R4Q_CGUsBLFx29sBu6a0_ZdA3clJ2M_KEWV_q_w8jFRs0pkh8byVAYVzdQeC3lcsyv9IAtrMYZ3-4if7JGcBwS8/s1280/Atrial%20fibrillation%20and%20biological%20complexity%20baseline%20FF.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="720" data-original-width="1280" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiHD9NOPHRXST9bneKliVTdf0txJEr9rjzSeq3wVvu8CvvYgBoSgC9wOZicukU3JnDaz-FgYIlQfE8f5KLrPEQKd1LSvr8IaMe8tAMo3R4Q_CGUsBLFx29sBu6a0_ZdA3clJ2M_KEWV_q_w8jFRs0pkh8byVAYVzdQeC3lcsyv9IAtrMYZ3-4if7JGcBwS8/w640-h360/Atrial%20fibrillation%20and%20biological%20complexity%20baseline%20FF.jpg" width="640" /></a></div><br /><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><br /></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">2. Post ablation ECG (following day):</span></p><p class="MsoNormal"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgBnhxw6sTuMgmBdNReefm1pUtH0srM47dE3pwDD5GXzhzBgs4TiUfR9YiseFIva9oWfIZASGxT7zpITylA3nIXaA4bh-AylkXLFUDla0C5x3oSZW0LARFXbMs8qKqVPLrSX8avvFAIqk1dGmX7ECwMQDqYV6IxUqDM7G38KQVSaWRbCr7TIp4MMeKS0j4Z/s1280/Atrial%20fibrillation%20and%20biological%20complexit%202.jpg" style="font-family: Arial, sans-serif; font-size: 12pt; margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="720" data-original-width="1280" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgBnhxw6sTuMgmBdNReefm1pUtH0srM47dE3pwDD5GXzhzBgs4TiUfR9YiseFIva9oWfIZASGxT7zpITylA3nIXaA4bh-AylkXLFUDla0C5x3oSZW0LARFXbMs8qKqVPLrSX8avvFAIqk1dGmX7ECwMQDqYV6IxUqDM7G38KQVSaWRbCr7TIp4MMeKS0j4Z/w640-h360/Atrial%20fibrillation%20and%20biological%20complexit%202.jpg" width="640" /></a></div><p></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p>3. Post ablation ECG - note anterior T wave changes thought to be consistent with procedure.</o:p></span></p>
<p class="MsoNormal"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh6q34zbj6cVnjC0_fBN534dP7JmD64mBiIYdMN1FPSdGjez8Kk9AaXf8ivlVaEJuh0EgHzb-IBOxSdlodCeJEhOo5adxadvyph_5sO6RYjwBPgeowynqv7kz0WRzX7n36pdCrSMMj8J0q-Zl_D0UeHKLZhGeer4-wNLlk3ITXMZI4xPPSOrutu1ZVhj6yb/s1280/Atrial%20fibrillation%20and%20biological%20complexity%203.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="720" data-original-width="1280" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh6q34zbj6cVnjC0_fBN534dP7JmD64mBiIYdMN1FPSdGjez8Kk9AaXf8ivlVaEJuh0EgHzb-IBOxSdlodCeJEhOo5adxadvyph_5sO6RYjwBPgeowynqv7kz0WRzX7n36pdCrSMMj8J0q-Zl_D0UeHKLZhGeer4-wNLlk3ITXMZI4xPPSOrutu1ZVhj6yb/w640-h360/Atrial%20fibrillation%20and%20biological%20complexity%203.jpg" width="640" /></a></div><br /><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">4. Precardioversion ECG showing atrial flutter at a high rate (day 5 of this arrhythmia; post op day 14).</span><p></p><p class="MsoNormal"></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjdpjtO9WW9fYPVqvaNuqR0qqbGyiGCcZBZz0rD92VPBDsZCSB-28jG1V2cl3hlB_bGFzz_NCIxT0M3VXC_OcJeGYbRKgD1KDy-DnaWvXCWuB1ovH6KpgA2l-ykU7F5fktInPBDGirV9DIeP8V5j2V0jNraCfGxsG2ssT5_Ca1xXIhYO_hlWanoJfs1Acbs/s1280/Atrial%20fibrillation%20and%20biological%20complexity%204.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="720" data-original-width="1280" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjdpjtO9WW9fYPVqvaNuqR0qqbGyiGCcZBZz0rD92VPBDsZCSB-28jG1V2cl3hlB_bGFzz_NCIxT0M3VXC_OcJeGYbRKgD1KDy-DnaWvXCWuB1ovH6KpgA2l-ykU7F5fktInPBDGirV9DIeP8V5j2V0jNraCfGxsG2ssT5_Ca1xXIhYO_hlWanoJfs1Acbs/w640-h360/Atrial%20fibrillation%20and%20biological%20complexity%204.jpg" width="640" /></a></div><p class="MsoNormal"><br /></p>5. Post cardioversion ECG showing NSR but flipped T waves in V1-V3.<p></p><p class="MsoNormal"><br /></p><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg-HjEIFFTjtnGm8FWNCAH5O6fq8zBDhRStdW_CkJiU7ts4_vk1Q2cJw-GNo2xRCnDo6D6B0G2G0xjMm3fe9UPhgkp9UY7B56YcgYFXlaYDY-0rdURw4SZ_gc1EJ-z47k7Rv4cPBt1SKLa06ewHnlOrDmUOHUGnTkrzpqccAXFHv9X9ZQFaGjMsVxDeGFu6/s1280/Atrial%20fibrillation%20and%20biological%20complexity%205.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="720" data-original-width="1280" height="360" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg-HjEIFFTjtnGm8FWNCAH5O6fq8zBDhRStdW_CkJiU7ts4_vk1Q2cJw-GNo2xRCnDo6D6B0G2G0xjMm3fe9UPhgkp9UY7B56YcgYFXlaYDY-0rdURw4SZ_gc1EJ-z47k7Rv4cPBt1SKLa06ewHnlOrDmUOHUGnTkrzpqccAXFHv9X9ZQFaGjMsVxDeGFu6/w640-h360/Atrial%20fibrillation%20and%20biological%20complexity%205.jpg" width="640" /></a></div><div><br /></div><div><br /></div>6. ECG follow up 2 weeks after cardioversion showing T wave normalization in anterior leads.<div><br /></div><div><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiFGKJWCx-dhgLKIYp_LTcAvmcFSKhjJRNwwAT3bT7f_0Xu7al6vi2uQf1y33M5dN-EJ8Obq9ov5VNQxpsS-wb5CmSIfrUcfRqzHBAyzDBHHkgayS865X7kZX9MCVz2GCnUxMjQZJvehBo9m-t8TaI-ZDfq1xFm4Fsk2KuzhpMISXcNDIPdQrylLowvrxAZ/s2058/ECG-09-28%202023.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1102" data-original-width="2058" height="342" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiFGKJWCx-dhgLKIYp_LTcAvmcFSKhjJRNwwAT3bT7f_0Xu7al6vi2uQf1y33M5dN-EJ8Obq9ov5VNQxpsS-wb5CmSIfrUcfRqzHBAyzDBHHkgayS865X7kZX9MCVz2GCnUxMjQZJvehBo9m-t8TaI-ZDfq1xFm4Fsk2KuzhpMISXcNDIPdQrylLowvrxAZ/w640-h342/ECG-09-28%202023.png" width="640" /></a></div><br /><div class="separator" style="clear: both; text-align: center;"><br /></div><div><br /><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><br /><i>Heart Rate Variability</i></span><div><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><i><br /></i></span></div><div><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">Some recent recovery in HRV after a long period of low numbers in the 7-37 msec range following ablation and cardioversion.</span></div><div><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><br /></span></div><div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhyf42wgT-4vzwGwLpph-b-Awf73Vh0ZYpCQSVGta6jUcvPrdpwjw1bOpPaaXtamfxZnJJKKgVtvL0eVTYzgsKYOItFIjw42sIYtJfb02VzRaJmGYQaBbqeIV0VKabKZ0ZF3LHgpOVDaHs6AXAEquqfbCj0wLpjvRbOCyRHeO9iiOwPrZ-R4og83N0Eg9xy/s1696/HRV%2009.26.2023.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1334" data-original-width="1696" height="252" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhyf42wgT-4vzwGwLpph-b-Awf73Vh0ZYpCQSVGta6jUcvPrdpwjw1bOpPaaXtamfxZnJJKKgVtvL0eVTYzgsKYOItFIjw42sIYtJfb02VzRaJmGYQaBbqeIV0VKabKZ0ZF3LHgpOVDaHs6AXAEquqfbCj0wLpjvRbOCyRHeO9iiOwPrZ-R4og83N0Eg9xy/s320/HRV%2009.26.2023.png" width="320" /></a></div><br /><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><br /></span><p></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><br /></span></p><p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;">References:<o:p></o:p></span></p>
<p class="MsoNormal"><span face=""Arial",sans-serif" style="font-size: 12pt; line-height: 107%;"><o:p> </o:p></span></p>
<p class="MsoNormal"><span style="font-family: arial; line-height: 107%;">1: Fojt O, Holcik J. Applying nonlinear dynamics to ECG signal
processing. Two approaches to describing ECG and HRV signals. IEEE Eng Med Biol
Mag. 1998 Mar-Apr;17(2):96-101. doi: 10.1109/51.664037. PMID: 9548087.<o:p></o:p></span></p>
<p class="MsoNormal"><span style="font-family: arial; line-height: 107%;">2: Nayak SK, Bit A, Dey A, Mohapatra B, Pal K. A Review on the
Nonlinear Dynamical System Analysis of Electrocardiogram Signal. J Healthc Eng.
2018 May 2;2018:6920420. doi: 10.1155/2018/6920420. PMID: 29854361; PMCID:
PMC5954865.<o:p></o:p></span></p><p class="MsoNormal"><span style="font-family: arial;"><span face=""Arial",sans-serif" style="line-height: 107%;">3: </span><span style="background-color: white; color: #212121;">Aston PJ, Christie MI, Huang YH, Nandi M. Beyond HRV: attractor reconstruction using the entire cardiovascular waveform data for novel feature extraction. Physiol Meas. 2018 Mar 1;39(2):024001. doi: 10.1088/1361-6579/aaa93d. PMID: 29350622; PMCID: PMC5831644.</span></span></p></div></div>George Dawson, MD, DFAPAhttp://www.blogger.com/profile/03474899831557543486noreply@blogger.com0