Serotonin Research Marches On or Why the Michaelis-Menten Equation is Important to Psychiatrists

 

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 comment about this back in 2015 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.

 

The paper today (1) was of great interest to me for several reasons.  First, it was focused on antidepressant mechanism of action and area that needs more work.  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.  Third, it discusses a system of 5-HT reuptake that is relatively unknown to most psychiatrists – but clearly important.  I hope to explain it all and provide the necessary references for further study.  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.

Starting with the serotonergic systems – the paper is focused on extracellular 5-HT signaling as a common feature of antidepressant medications.  Models of this process have been around for a long time.  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.  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. 

The authors describe two uptake systems.  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.  There has been a common view that transporters are restricted to blocking reuptake of the named substance (ie. DAT will only transport dopamine).  More recently it was discovered that these proteins are not specific and will transport other monoamines.  5-HT is taken up in both streams Uptake 1 via SERT and Uptake 2 by DAT, NET, OCT, and PMAT.  Characteristics of both systems are listed in the tables below.

Transporter
Uptake 1
SERT
Uptake 2
NET
DAT
OCT
PMAT

 

Despite observed clinical differences in antidepressants, physicians are generally taught to think of them by general class based on binding studies.  There is a tendency to view all antidepressants within a class as having the same mechanism of action.  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.

The more specific mechanism of action of antidepressants at the binding site is often not mentioned.  Reuptake proteins can be bound allosterically and orthosterically (3).  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.  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.

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).  FSCV is a technique where an electrical current is applied and it oxidizes the compound in solution at the electrode surface.  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.  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.

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.  The M-M equation was originally derived to study enzyme kinetics.  It shows the relationship between initial reaction velocity to maximal velocity for a certain enzyme and substrate.  The M-M equation is given below:

In enzyme work, M-M equations are typically analyzed graphically (y = mx + b) plotting v_ο vs [S ]  or the inverse of 1/v_ο vs 1/[S] to determine V_max and K_M.

In previous work the authors developed an expression for M-M kinetics for two reuptake mechanisms (7):

 

Where:

R(t) = rate of release

A(t) = fraction of stimulated autoreceptors

V_max1, V_max2 = M-M Vmax for each of the reuptake mechanisms (1-slow, 2-fast)

K_m1, K_m2 = Michaelis constant for each reuptake mechanism (1-slow, 2-fast)

α and β are constants to differentially weight the reuptake mechanisms individually and synergistically

 

In their paper the authors found that escitalopram, fluoxetine, reboxetine, and ketamine all decreased 5-HT reuptake and increased extracellular 5-HT.  They have an excellent graphic of their results as Figure S2 in the Supporting information (10).  Using the M-M analysis, fluoxetine followed an orthosteric Uptake 1 mechanism.  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.  In view of their results, the authors conclude that the direct measurement of serotonin may be an indicator of antidepressant potential.

To me this is a landmark work.  Just the brief list of references below indicates very active research in this area.  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?  And what about the issue of antidepressant withdrawal phenomenon?  Do the new pharmacodynamic insights provided by the research have implications for withdrawal?  That area has been primarily addressed by pharmacokinetics in the past.  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.

 

George Dawson, MD, DFAPA

 

References:

1:   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.

2:  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.

3:  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/

4:  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.

5:  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.

6:  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.

7:  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.

8:  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.

9.  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.

10:  Supporting Information for Serotonin is the Common Thread Linking Different Classes of Antidepressants  (see Figures S1 and S2).

 

The Real Lesson of January 6th – How Fascism Works

 

Yesterday was the third anniversary of the Insurrection at the Capitol.  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.  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.  The Supreme Court is clearly stacked in his favor and one of his attorneys stated an explicit quid pro quo this week as in “this President appointed you - better get him back on the ballot.”  There have also been threats that Republicans would remove Biden from the ballot to compensate for Trump being removed from ballots as a 14^th Amendment insurrectionist.

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.

Former President Trump continues to promote The Big Lie 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.  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.

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.  What is happening here?

Although much of politics is an irrational appeal to emotion – it is clearly at an all time high in the United States.  A recent Foreign Affairs 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 created the Department of Justice to counter white supremacist terrorism by the Ku Klux Klan in 1870.  A group who spread recruiting literature across Twin Cities suburbs in 2022 also promoted antisemitism.  Just the act of dispersing that literature is a clear sign that something in the US has gone horribly wrong.  What is the problem?

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.  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.  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.  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.  They don't care about the fact that Trump does not campaign on relevant domestic or foreign policy issues.  

The lack of a rational basis for supporting Trump and MAGA suggest that other factors are at play. First and foremost is partisan politics.  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.  Their affiliation is with a seriously compromised Republican party rather than the republic itself.  Better to have a good career and government job and let the Insurrection cards fall where they may.  The Republicans walking away rather than make that compromise are a small minority and deserve our gratitude.

Nihilism is a significant factor.  Nihilism is a vague term, I am using the existential meaning.  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.   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.  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.  Some have endangered the people attacked and their families.  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.

The symbols of nihilism were prominent at the January 6 Insurrection and included a Confederate flag, a gallows and a noose, militia gear and paramilitary tactics.  Since then, at least one Republican candidate offered support for Lost Cause 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.  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.  It was no accident that the Confederate flag appeared in the Capitol carried by insurrectionists.  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.

“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 Der Angriff 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.  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.

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.   They cast attempts to remove overt misinformation as censorship and a return to rational gun control as a denial of Second Amendment rights.  In many cases there is a “doubling down” on any political gains made in these areas.  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 considered essential health care by experts. This doubling down to the point of criminalization is characteristic of autocracies that consider winning cultural issues crucial for the survival of their ideology.

Trump and his supporters are using very well-known propaganda techniques.  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.  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:

“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)

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.

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.  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^th Insurrection out to be a picnic.

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.  That involves significant distortion at three levels.  First – it devalues clear accomplishments of the existing government.  Most serious students of government would describe the Biden administration as one of the most successful in modern history.  Some of that success depended on correcting the damage done by the last Trump administration.  Second - direct attacks on the opposition, unfounded accusations, and name calling.   Third – it depends on a distortion of the abilities of their ideal candidate.  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.  That stands in sharp contrast to the hyperbole candidate Trump and his dedicated followers.   

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.  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.  The only thing scarier is what happens when autocrats implode (and they all do).  It is typically as a colossal failure – negatively impacting the entire country for years.  In the United States there is a good chance that fall will be far greater than any other country.

That is why the lessons of January 6 at the Capitol should never be forgotten.

 

George Dawson, MD, DFAPA

 

Supplementary 1:  How the FBI started the Insurrection Conspiracy Theory got started was discovered and debunked in January 2022.  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. 

The actual story:

".....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 filed a defamation lawsuit against Fox News last year, saying the network was to blame for spreading baseless claims about him...."

Kunzelman M.   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

References:

1:  Kershaw I.  The Hitler Myth.  History Today. 1985; 35(11): 23-29.  https://www.historytoday.com/archive/hitler-myth

2:  Lemmons R.  Goebbels and Der Angriff.  1994.  University of Kentucky Press. Lexington, Kentucky. p. 128-131.

 

Graphics Credit:

1:  Main Graphic is: DC Capitol Storming by TapTheForwardAssist, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons. 

https://commons.wikimedia.org/wiki/File:DC_Capitol_Storming_IMG_7947.jpg

Note the original was altered by me with the superimposed transparency.

2:  Transparency is:  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 https://commons.wikimedia.org/wiki/File:WWII,_Europe,_Germany,_%22Nazi_Hierarchy,_Hitler,_Goering,_Goebbels,_Hess%22,_The_Desperate_Years_p143_-_NARA_-_196509.jpg

 

 

 

Misinformation X

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.

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.  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.  The takeover of Twitter by Elon Musk and his so-called “free speech” policies made that site a fountain of misinformation.  The amount of misinformation would be embarrassing to anyone concerned with the truth or reality but these days those constraints clearly do not apply.  The truth is of little value in much of what can be read on X.  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.

There is a clear positive correlation between the transition in management and an increase in misinformation, hate speech, hate speech and antisemitism.  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.  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.  Several physicians posted clearcut evidence to refute this misinformation.  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.  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.    Practicing physicians have a healthy respect for respiratory viruses.  We have all seen healthy young people die from infections with what are considered common cold viruses.  

A great solution for physicians and scientist would be a medical or scientific Twitter.  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 vulgarians shouting in the city square 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.  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. 

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.  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.  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.  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.  The largest professional staff I worked with was about 35 psychiatrists.  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. 

Who might run such a Twitter-like operation?   The American Psychiatric Association (APA) ran an email listserv that I participated in for decades.  They decided to stop this in the past year.  It had probably run its course.  The number of new participants and total participants was low.  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.  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.  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.  A Twitter like platform would be a greater asset in attracting physicians to the site.  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.  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.  On Twitter – the commonalities were obvious and I knew who to follow.   

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.  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.  Alternately – more networked and focused discussions on Blue Sky and Threads is still a possibility.  Either way – I think we need a functional blue bird back in one form or another….

 

Happy New Year!

 

George Dawson, MD, DFAPA 

Counterfeit Ozempic is NOT Off-Label Ozempic

 

Glucagon like peptide (GLP)

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:  “Counterfeit Ozempic or off label Ozempic is potentially dangerous…..”  Off label Ozempic is NOT counterfeit Ozempic.  Off label medications are FDA approved medications that are prescribed for indication other than what is listed in the package insert.  Based on a recent table 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.  In some cases they do not contain any active ingredient and in the majority of cases what they actually contain is currently unknown. 

The FDA warning (1) about counterfeit Ozempic surfaced on 12/21/2023.  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.  In the warning in reference 1 they describe 5 incidents of adverse effects – none life threatening.  The confiscated pens are being analyzed to determine what is being used rather than Ozempic.  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.

The same day as this release, the FDA also warned about compounded GLP-1 agonists (3).  Compounded products are prepared by compounding pharmacies.  If medications are in short supply – compounding pharmacies can produce them. Ozempic and Wegovey are both on that list.  Both are semaglutides and adverse events have occurred with the compounded versions.  Some of the counterfeit versions contain the salt form of semaglutide compared with the FDA approved medication that is the base form.  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.

Although it is not emphasized in the warnings, I also have concern about the injection pen device that the semaglutide is contained in.  The injectors are calibrated to deliver 0.25. 0.5, and 1 mg doses according to the prescription for each patient.  The device is supposed to click when it is at the corrected dose.  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.  Unless the counterfeiters are using a very similar device the recommended doses of medication might not be delivered correctly.  Exactly how problematic that will be depends on the medication or substance that has been substituted for the semaglutide.  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.

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. 

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.  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. 

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.  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.  It is equally hard to imagine producing counterfeit drugs and selling them to the public like the real thing.

That is what the FDA is trying to prevent with this warning. 

  

George Dawson, MD, DFAPA

 

Supplementary:  Aware of counterfeit Ozempic or Wegovey?  Can you get it without a prescription?

It has come to my attention that many people are aware of the availability of counterfeit Ozempic and Wegovey 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.

References:

1:  FDA.  FDA warns consumers not to use counterfeit Ozempic (semaglutide) found in U.S. drug supply chain.  December 21, 2023 https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-use-counterfeit-ozempic-semaglutide-found-us-drug-supply-chain

2:  National Association of Boards of Pharmacy.  Counterfeit Ozempic Found in US Retail Pharmacy.  August 7, 2023 https://nabp.pharmacy/news/blog/regulatory_news/counterfeit-ozempic-found-in-us-retail-pharmacy/

3:  FDA.  Medications Containing Semaglutide Marketed for Type 2 Diabetes or Weight Loss.  December 21, 2023 https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/medications-containing-semaglutide-marketed-type-2-diabetes-or-weight-loss

 

Peptide Structure:

Drawn with PepDraw:  https://pepdraw.com/

 

 

 

The Ultimate Key Opinion Leader?

Key Opinion Leader or KOL is an interesting myth. In the long era of the pharmascolds, 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.  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.

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. 

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^th 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.

Oprah has unique status as a celebrity. According to Time 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. 

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 directly through their web site.  I did not go through the process because a name was required, but several sources suggest this is a monthly subscription service

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 highest selling drugs of all time.

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 increasing calls to poison control centers about semaglutides 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.  

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.   

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 NOAC commercials 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 CMS Open Payments database.  In 2022, the median payment to physicians who received payments from pharmaceutical manufacturers or device makers was $161.  

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.  

George Dawson, MD, DFAPA

References:

1:  Garthwaite CL. You Get a Book! Demand Spillovers, Combative Advertising, and Celebrity Endorsements. National Bureau of Economic Research; 2012 Mar 15.

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.

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

4:  Summers J, Marquez Janse A, Ermyas T.  Oprah and Weight Watchers are now embracing weight loss drugs. Here's why.  Dec 18, 2023. https://www.npr.org/2023/12/18/1219710239/weightwatchers-oprah-ozempic-drugs-wegovy

5:  Fitzgerald M.  WW International extends Oprah Winfrey deal to 2025, shares rise.  CNBC  https://www.cnbc.com/2019/12/16/ww-international-extends-oprah-winfrey-deal-to-2025-shares-rise.html

 

Supplementary:

Current GLP-1 agonists - all data taken from FDA approved package inserts.

Photo Credit:

Photo by Alan Light, CC BY 2.0 <https://creativecommons.org/licenses/by/2.0>, via Wikimedia Commons