Over the past week a review was published in Molecular
Psychiatry that claimed to discredit nearly all of the previous work on
serotonin hypotheses of depression (there are far more than one).Ron W. Pies, MD, and I wrote a rejoinder to this review. Whenever you consider a commentary about a published paper the
level needs to be considered.For
example, if the paper is a polemic – responding to the rhetoric is one approach. For those not familiar with the rhetoric around this issue take a look at this previous post on Chemical Imbalance Theory and you will be brought up to speed. If you need additional information here is a second, more recent post. If the paper is primarily scientific then
responding to the science and measurements in the paper is another. These days,
responding to the statistics is a third option and in the case of specialized
reviews like an “umbrella review” commentary on the methodology is a
third.For our initial effort we made a
conscious decision not to go “to far into the weeds” of science or statistics.
On that basis, we respond to a fair amount of rhetoric and
science. I refer interested readers to our paper published this morning on the Psychiatric
Times. On that page the study I am
referring to is reference 1, The serotonin theory of depression: a systematic
umbrella review of the evidence. The serotonin
theory of depression is just like Fight Club – there is no serotonin theory
of depression and that is one of the first points we make in the paper.
As far as the science of serotonin goes – it is fairly
intense. Since 1957 when there were only 2 known serotonin receptors types, we
have developed a lot of knowledge about this system. With that knowledge there has been a mind-boggling
amount of system complexity that nobody has been able to explain to date. We
are basically getting glimpse of how the entire system works. It is highly
likely that there are behavioral, cognitive, and autonomic correlates of these
systems – but we have a way to go. Back in the day when I was a research fellow in neuroendocrinology I tried (in vain) to find out how serotonin signaling affected the HPA axis. Practically all researchers at the time considered monoaminergic hypotheses of mood disorders to have heuristic value (see the quote below). The intervening 30 years of advanced research proved them correct. The authors of the umbrella review conclude
that it is time to acknowledge that the serotonin theory of depression is
unsubstantiated despite a large research effort and that this should be
acknowledged. That is difficult to do
when they seem to be the only people promoting this theory.
For those interested in excellent summaries of current
serotonin research I suggest the following volumes written by 41 and 128
scientists respectively.
At some point, I will take a much closer look at the
methodology used in this study. Just looking at the PRISMA diagram and 360
reviews being pared down to 17 with just a few in some categories – suggests that
the umbrella has collapsed.
George Dawson, MD, DFAPA
Reference:
Ron W. Pies, George Dawson. The Serotonin Fixation: Much Ado About Nothing New, Psychiatric Times. August 3, 2022
When I first started to respond to the chemical imbalance theory rhetoric - I took all of the psychopharmacology books off my shelves from the past 35 years to illustrate that in all of those texts on the subject there were no references to a chemical imbalance theory and that I had never been taught such a theory by my professors (many of whom were leading psychopharmacologists). Since the original photo, my stack of psychopharmacology journals has increased about 3/4 of a foot and that would bring the stack up to about 5 feet. I am not going to pull them all down to remeasure so I just made this graphic.
Graphics Credit:
The iceberg graphic at the top of this post was done by the following authors and I added the text only. Full credit is listed below per Wikimedia and CC licensing:
Created by Uwe Kils (iceberg) and User:Wiska Bodo (sky)., CC BY-SA 3.0 , via Wikimedia Commons
I had this
letter published today with my co-author Ron Pies, MD. It is basically a
rebuttal to a more elaborate article (linked at the top of the letter) on chemical
imbalance theory. I encourage any interested reader to look at that argument
and then read our brief essay on why none of it supports a chemical imbalance
theory.Both Dr. Pies and I have written
about this in the past – me on this
blog and Dr. Pies in other literature (5-8).Several other authors have also discussed related issues (1-4, 9). I think the refutation is fairly straightforward so this blog will be
about the process. Why does this along with many other inaccurate portrayals of
psychiatry continue to come up in the literature? What follows is a few very clear answers but I
fully realize that theses and explanations are rarely adequate to counter
rhetoric.
1: Repeating
inaccurate claims is a standard strategy these days – it actually has been for
decades. The clearest modern example if
the Big Lie of the last Presidential election.
Even a comprehensive presentation of the real evidence by the January 6th
Congressional Panel is not enough to shake the belief of election
deniers. In fact – election denial has
become the latest cottage industry delivering hundreds of local lectures across
the country. Chemical imbalance theory
has a similar life of its own and a group of proselytizers. If the political comparison is too harsh – consider
the advertising approaches. Any number of products that make health claims are
sold every day based on repeating the same messages. For years alcohol carried the message that it
was a heart healthy product that increased HDL cholesterol and reduced the risk
of heart attacks. Now we know that those studies were biased because they
included alcohol users in recovery in the control group. Dietary supplements are a $62
billion dollar industry despite questionable value and some concerns about
toxicity in healthy populations with no clear nutritional deficiencies. All of
these examples illustrate the power of repetitive messaging.
2: It appeals to
anecdotal experience – a common response is “well I heard somebody say it”, “I
saw it posted on a web site”, or “my psychiatrist said it to me.” Anecdotal experiences exist and obviously we
cannot examine the intent of every statement. The reality for psychiatrists is
that in psychopharmacology and biological psychiatry lectures, in textbooks,
and in the published literature there is no reference to “chemical imbalance
theory”. In fact after reviewing the literature I
concluded that comprehensive theories really don’t exist in psychiatry. On the
other hand, over the past 40 years there have been over a hundred hypotheses
about the causes of depression.
3: There are clear
biases against psychiatry as a field – when reading authors whether in
professional journals, periodical, or books it is always useful to consider
what else they have written. Is the book or paper a one-sided harsh
criticism? Does their previous work seem
to make similar statements about the field?
It is already known that psychiatry gets much more than the expected levels
of criticism in the press. Is that
criticism warranted? In many areas of this blog, I have pointed out that it is
not warranted and, in many cases - it is grossly inaccurate.
4: There have been
no accurate histories of the intellectual development of the field. To be sure there are specialized biographies
of prominent historical figures and some of their influences but no clear
timeline of how developments build on previous thought. I recently read that
now that one of these historical figures has “scholars” rather than clinicians
describing his work – we could expect much more, but I am not seeing it. To me –
people who train and teach in the field are still the primary keepers of the working
intellectual development of the field and everything that is relevant.
Given all of these factors what can readers of our
published letter do with that information?
If you are a psychiatrist or a physician – think carefully about your
use of terms. If you have used the term “chemical
imbalance theory” or just “chemical imbalance” as a metaphor or something else –
please reconsider. I think it is more useful to patients to let them know that
depression or other clinical entities cannot be reduced to a single chemical event
and I would invite you to use a statement from Nicholas Giarman – a noted
neuropharmacologist:
“…nosologically it might be fair to compare the
depressive syndrome with the anemias. Certainly, no self-respecting
hematologist would subscribe to a unitary biochemical explanation for all of
the anemias.”
Nicholas J Giarman (1920-1968) – The Biochemical
Basis of Neuropharmacology – Fourth Edition 1982. p. 212
An explanation of heterogeneity and brain function would be
ideal, but given time constraints and variable expectations of patients – an
illustration of biological complexity is superior to a hopelessly inadequate
metaphor. The same is true for literature that is handed out to patients. In
that case, quoting the typical disclaimers in FDA approved package inserts as
well as a brief summary of the research evidence for specific patients is a
more optimal approach.
That is the real take home message.
George Dawson, MD, DFAPA
Supplementary 1: What about advice to patients? If you are considering taking an antidepressant
or any other medication as a patient that usually means you are having a
significant problem that you expect help with. The literature critical of
psychiatry often suggests that this decision is casually made but that is not
my experience either as a patient or a prescribing physician. Consider what is
written about the mechanism of action of antidepressants. Chemical Imbalance
Theory often implies that there has been dishonesty in presenting how a
medication works and by extrapolation that psychiatrists don’t know much about
anything. In fact, there are probably very few medications that you take where
the mechanism of action is known with any high degree of certainty. Aspirin was used for 70 years before its mechanism
of action was determined (10). Acetaminophen was first used clinically in
1887 and a preliminary report suggesting several potential mechanisms of action
became available in 2009 (11). Most decisions to take medications are not
made based on knowing a mechanism of action. The overemphasis on mechanism of
action of antidepressants is most likely based on pharmaceutical company
advertising in the 1980s and 1990s. At
that time, the manufacturers of newer antidepressants emphasized that they were
novel agents that probably worked through different mechanisms than the older
medications and had a more favorable side effect profile.
As a patient you are entitled to as much detail on
mechanism of action as you want and I hope that you will be able to get it
directly from your physician or from other sources. I have treated basic scientists
for depression and bipolar disorder and was able to give them adequate
information – so it is definitely out there. But at a practical level – every person
with a significant problem wants relief from that problem and no additional
problems. The clinical discussion needs to be focused on whether the medication
is working and the side effects are either non-existent or tolerable. Further – informed consent means that you
should have adequate information to make a decision about taking a medication. That includes the likelihood of severe
adverse drug events as well as more common side effects. Another common discussion
in the media these days is withdrawal from antidepressant medications. A prescribing
physician should be able to discuss that side effects in detail as well as rare
events and a plan to address them.
Credits:
1: My co-author Ron Pies, MD read this post and made valuable suggestions for modifications. It is difficult to indicate but he is a co-author of this post.
2: Eduardo A. Colon, MD took the photograph used at the top of this post.
10: Montinari MR,
Minelli S, De Caterina R. The first 3500 years of aspirin history from its
roots - A concise summary. Vascul Pharmacol. 2019 Feb;113:1-8. doi:
10.1016/j.vph.2018.10.008. Epub 2018 Nov 2. PMID: 30391545.
11: Smith HS.
Potential analgesic mechanisms of acetaminophen. Pain Physician. 2009
Jan-Feb;12(1):269-80. PMID: 19165309.
After a protracted discussion on the previous post, I thought I would go down to the University of Minnesota Biomed library today and look at the drug ads in psychiatric journals at about the time Prozac came out in 1987. I was interested in the trends before and after so I picked the years 1985 to 1995. I also picked the journals the American Journal of Psychiatry, Archives of General Psychiatry (currently JAMA Psychiatry), and the Journal of Clinical Psychiatry. I was going to include JAMA and the New England Journal of Medicine. They had about the same number of ads but none of them in that year contained ads for psychiatric medications.
This kind of search is labor intensive these days. There was a time on the early days of the Internet when entire journals with all of the ads were scanned in. As a subscriber I could have run that search from home. These days, all of the ads are gone and the references are saved as text files only. In order to see historical ads - the hard copy of the original journal needs to be examined. Even then there are some problems. I encountered some bound volumes where the ads were physically removed. There were two to three bound volumes per year and additional copies of the NEJM and JAMA - I may have looked at 75 bound volumesover 4 hours.
In many ways it was a walk down memory lane. Clozaril and Haldol Decanoate ads were especially heavy in the early 1990s. There were ads for medications that I prescribed all of the time like Navane and Pamelor and ads for drugs that I seldom prescribed like Stelazine, Serzone and Luvox. There were ads for new drugs that I would prescribe once like Paxil. It was a reminder that despite all of the advertising - a lot of drugs end up never being prescribed by physicians. My reason for being there was to look for the origins of the term "chemical imbalance" in this advertising.
I decided to embark on this project because of all of the inaccuracy about the term, especially the tendency to blame psychiatrists for it. In my previous post, I attempted to point out that it is a fairly straightforward process to conclude that the human brain does not run on chemical imbalances - just based on the average scientific knowledge of physicians. On the advertising side, I was there for the first National Depression Screening Day in 1990 and that was the first time I heard the term. The event has been criticized as a venue for allowing a pharmaceutical company to showcase their product. I participated in the event for 3 years and the advertising involved was much more subtle than is found today at NAMI walks for example. But the question is whether the advertising meme "chemical imbalance" was introduced at that time. Any event that happened 30 years ago is very hard to track. As the Public Affairs Rep for my District Branch of the APA, I had a lot of files about it that I subsequently trashed. I am guessing there were also some files on disk drives that would have been helpful. This is a reconstruction without that data.
I successfully located the first Prozac ad in AJP from 1988. The graphics are all iPhone photos so there is some distortion. Chemistry is emphasized on page one as in the chemical structure, chemically unrelated to other antidepressants, distinctive chemistry, and the first highly specific and highly potent blocker of serotonin reuptake.
Why is this important? At the time most of the antidepressants being used were tricyclic antidepressants. They could not claim any specificity and in subsequent ads manufacturers start to compare possible side effects based on transporter monoamine protein and receptor affinities. The Prozac molecule was being hyped as being chemically unique and with a better side effect profile. As Prozac started to sell more it became a blockbuster drug for Eli Lilly and at that point the manufacturers of other new antidepressants noted and the competition heated up. There were some direct references to Prozac in the ads from competitors.
The best example is this Wellbutrin ad from AJP in 1991. Prozac is directly mentioned in the ad and reasons are given for choosing Wellbutrin over Prozac. Being non-serotonergic is one of them and this is more of a counter to Prozac advertising as being a unique first highly selective serotonergic drug. It gives little or no weight gain as a reason, but at the time I was seeing obese patients who were taking 80 mg of Prozac because their primary care physicians told them they could lose weight taking it. Of the other bullet points it seems that lack of sexual dysfunction would be the most relevant. The marketing decision in this case was a conscious decision to go after the purported serotonergic effects of Prozac rather discuss the hypothetical mechanism of Wellbutrin. The side effect of Wellbutrin that most physicians are concerned about - seizures - is in the smaller print below the bullet points.
Effexor came up with similar ads. In the late 1980s and early 1990s, synaptosome technology was invented to look at binding affinities of central nervous system medications to specific receptor sites. The quantitative aspects of these studies were generally globalized in the psychiatric literature to qualitative ballpark effects. For example a plus or minus grading system could be used ranging from no effect at a receptor (-) to a robust effect (++++). Effexor advertising used this to compare side effect profiles among the competitive antidepressants at the time.
This ad emphasizes that Effexor is "a structurally novel antidepressant and is chemically unrelated to any other available antidepressant." It shows the table with comparisons to tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) and what might be predicted based on the in vitro synaptosome data with the qualifier that the clinical significance of that data is unknown. Clinically most people are able to tolerate all three classes of medication but some will not. The differences can't be predicted on the basis of the receptor binding studies because of receptor heterogeneity and differences in drug metabolism. For example, I still prescribe TCAs. It is nortriptyline and it is the only one I have ever prescribed. At the doses I prescribe and per the table in the ad - it is as well tolerated as SSRIs and SNRIs (Effexor). The ad appeared in the AJP in April of 1994. On that basis the argument could be made that it is an appeal to the technical expertise of psychiatrists and it should contain this information. That also points to a weakness in my informal advertising study and that is a lack of ads from the non-technical consumer literature from the same period. (see supplementary on a proposal).
I have 30 additional ads from the journals but the themes are roughly the same. An emphasis on medicinal chemistry and the suggestions that some chemistry is better than others. Interestingly, in my previous post the whole point was that this is the kind of argument that would not fly based on what the average physician knows about chemistry and molecular biology. Psychiatrists should know a lot more because the evidence for and against these theories had been reviewed in the psychiatric literature 20 years before these ads came out (1974-2002) (1). And they are engaged in clinical practice and need to be skeptical of newly introduced products and claims.
What I did find so far is unequivocal evidence that the chemical imbalance meme was used to directly market antidepressants to the public. The Zoloft ad embedded at the top of this page from 2001 is the first example. The second example is this Paxil ad from the same year.
That is what I have so far. See the Supplementary below to find out what you can do to complete the story. I don't have a problem with people telling me that their doctor told them that they have a chemical imbalance and their antidepressant is supposed to treat that. I don't have a problem with people saying that their psychiatrist told them that. I do have a problem with people saying that all or even most psychiatrists say this and that psychiatrists are behind this meme.
There is an exaggerated focus on the mechanism of action of medications used for psychiatric indications. I have never heard anyone say their doctor told them about the mechanism of action of antibiotics or even their blood pressure medications. In the case of antibiotics it is clear that people demand them and they don't care what the risks or mechanisms are. This advertising campaign may have something to do with the conversion of folk psychologists to folk psychopharmacologists. A friend of mine also brought up an important aspect of this campaign that is also addressed by these manufacturers and that is legitimacy. For decades people with depression and anxiety were viewed as weak people with a questionable problem. My friend told me that these ads confirmed that she had a serious problem that needed a serious solution and that it was finally acceptable to talk about it. Say whatever you want about Big Pharma advertising but it apparently carried the message that current "Let's Talk About Mental Health" programs do - but over 15 years ago.
The attribution of an advertising meme to psychiatry and psychiatrists despite the fact it has never appeared in 30 years of psychopharmacology texts is not a trivial fact. The advertising videos posted here were viewed by tens of millions of people. I hope to get more information and still have some people to contact. With any luck I will be able to fill in the additional data between the release date of Prozac in 1987 and the ads posted here from 2001.
Please send me anything you might have from those dates.
George Dawson, MD, DFAPA
References:
1. Nathan KI, Schatzberg AF. Mood disorders. in Review of Psychiatry, vol 13. American Psychiatric Press, Washington DC(1994): p.171-184 Supplementary 1:
From the information I posted above it is clear that chemical imbalance was an advertising meme introduced during the height of competition of blockbuster antidepressant drugs. The common Wall Street definition of a blockbuster pharmaceutical is a product that generates sales of a billion dollars a year. There are two important pieces of data that would be useful to complete the story.
The first is earlier ads with the term chemical imbalance. So far, I have two from 2001, but I am certain it appeared before that. I don't have time to search all of the popular literature. If you subscribe to a magazine that has pharmaceutical advertising and keep all of the old volumes - take a look at the editions from about 1987 to 1995. If you see the term chemical imbalance please send me the image with the name and date of the periodical. Let me know if you want credit for finding the image and I will give you full credit.
If you are a current or former pharmaceutical rep or marketing person and have access to any documents or videos with the chemical imbalance phrase please send it to me with the date it was being used. If you have recollections of how it was implemented and when I can also use that information but I am most interested in clear documentation like the videos I have posted. I have no interest in vilifying the pharmaceutical industry and understand the need for marketing and advertising. I am just interested in the origins of this term and how it was implemented.
If you are an APA member and you were involved in the original National Depression Screening Day in 1990 - you may also have some information about this. Please send it to me.
Thanks!
Supplementary 2:
All of the name brand drugs/medications mentioned in this post are currently generics or are no longer manufactured. I have no affiliation with the original manufacturers or the generic drug industry.
Supplementary 3:
There are various Internet sites that attribute the term chemical imbalance to Pfizer or Lilly but they do not appear to be reliable - many appear to be antipsychiatry sites. I would like to hear from people who were there at the time and can provide the necessary proof. In those days (1986-1996) it would have been an internal memo or presentation. Send me a copy if you have it.
Supplementary 4:
I had the opportunity to discuss this issue with a corporate attorney - especially the issue of available emails and memoranda dating back to 1987. He told me that corporations hold this data only as long as the law states they needs to. For example, if the law states the data must be held for 4 years it will be held exactly that long and then everything will be shredded. If this information exists it will probably be in private hands.
Supplementary 5:
I got the expected low level feedback from a Twitter poster who thought he was making some point about this link on the Royal College of Psychiatrists web site suggesting that at least one of the causes of schizoaffective disorder was "a chemical imbalance". I guess he really thought he had made me look foolish especially with the proclamation "You aren't psychiatry - they are."
In fact, I can't tell who wrote this and whether or not it is a psychiatrist. I don't know what the RCP official position is. I was happy to see that they are much more flexible than the anti-psychiatry Twitter posters I encounter. There was a feedback form that I completed and advised them to lose the "chemical imbalance" and that replacing it with "unknown etiology" was preferable. What I would like to see is an exposition of the latest theories and a suggestion that the critics actually read psychiatric literature. They would be less likely to perseverate the same criticism they have used for year after year. This poster also seemed to ignore the fact that the RCP public information was posted in 2015 - that's 14 years after the television ad posted at the top of this page. Royal College of Psychiatrists - the ball is in your court.
Supplementary 6: (added on 1/11/2020): I just learned today from an advertising expert in antidepressants that there was also a Zoloft ad from 2004 that used the term:
"While the cause is unknown, Zoloft can help. It works to correct a chemical imbalance in the brain that may be related to these symptoms."
Reference:
Cristina Hanganu-Bresch. Treat Her with Prozac: Four Decades of Direct-to-Physician Antidepressant Advertising in Drugs Media: New Perspectives on Communication, Consumption, and Consciousness (Hardback) (1st Edition) by Robert C. Macdougall (Editor), Drugs &. Media-Pasta Dura, 340 Pages, Published 2011 ISBN-10: 1-4411-1988-4 / 1441119884 ISBN-13: 978-1-4411-1988-9 / 9781441119889:
I keep looking for
it and can never find it. The above picture is my stack of
psychopharmacology texts dating back to about 1980 and none of them mentions
"chemical imbalance". I could add another foot or two to that
stack and there still would be no mention of this theory.
Why
is that important? The main reason is that one of the favorite arguments by
anti-psychiatrists is that real psychiatrists believe that psychiatric disorders
are caused by a “chemical imbalance” in the brain. This criticism showed up on
this blog several years ago in a post that I critiqued that was largely a
screed against psychiatrists. Accusing psychiatrists of promoting a chemical
imbalance theory is an almost perfect rhetorical strategy. It uses what
essentially was a marketing device for antidepressants in the late 1980s to
portray psychiatrists as excessively reductionist at the minimum and at the
worst biologically naïve and dishonest.
My
colleague Ron Pies, MD has written a recent piece on the historical,
philosophical, and rhetorical aspects of this argument. What I hope to
accomplish in this post is taking a look at the science behind why no
psychiatrist would consider the brain to be a substrate run by “chemical
imbalances”. Some might find this argument to be quite boring but I can attest
to the fact that the premises used allowed me to state unequivocally to the
first pharmaceutical rep to use the term that no such state exists in the
brain.
The
main factor has to do with how physicians are trained. There’s still a lot of
confusion about whether a psychiatrist is a physician or not. I can assure
anyone reading this that we all are. That means in order to get into medical
school certain prerequisites at the undergraduate level have to be completed.
That includes a year of general chemistry, a year of organic chemistry, and a
year of general physics. A significant number of psychiatrists that I have
encountered were chemistry majors. That training means that physicians in
general have had exposure to physical science and how chemistry works in
solutions and gases. In these basic two
or three component systems there are limited possibilities in terms of reaction
outcomes. Even electrochemical reactions produce electron flow that decays
predictably over time but that is not able to transmit any nuanced signal. In other words the information content in
these systems is low – too low to run biological organisms.
In
the basic science years of medical school biochemistry, neuroanatomy,
neurophysiology, pharmacology, and all of the associated molecular biology
provided medical framework that all of the physical science can be mapped onto.
The study of enzyme and receptor systems highlight the basic concept that the
chemistry involved can only occur because it is in a specific microenvironment.
That microenvironment includes the protein structure of the enzyme or receptor molecules
as well as associated membrane components and cell signaling components. The
intracellular and extracellular environments are exquisitely controlled as is
the synaptic cleft. Many of the reactions involve additional acid-base and
ionic gradients. The degrees of freedom in these many component and many phase
systems are large. They are so large in fact that I have been unable to find an
estimate of degrees of freedom for neurobiological systems.
A good example of the kind of microenvironments and complex interactions that I am taking about is the GABAA receptor depicted diagrammatically below. The GABAA receptor is a transmembrane cylindrical receptor that is a member of the pentameric ligand-gated ion channel superfamily. The diagram is a top down view of the receptor complex cylinder highlighting that it is composed of 5 glycoprotein subunits. Each subunit is composed of 4 domains with one domain that lines the chloride ion channel through the center of the receptor complex. Binding sites on these protein allow for allosteric modification of the cylindrical receptor to facilitate chloride ion influx and fast inhibition of neuronal signals. Allosteric modulation of enzymes and receptors occurs when a molecule reversibly binds to the protein molecule resulting in inhibition or stimulation of the overall process. For example, benzodiazepines bind to a specific site at the α-γ interface leading to increased affinity for GABA at the receptor sites and increased chloride ion influx. Benzodiazepines are the classic allosteric modulators of the GABAA receptor but there are others. Barbiturates, anesthetic agents, neurosteroids and ethanol are also allosteric modulators at the GABAA receptor. The detailed structure of both the benzodiazepine and flumazenil binding sites on the human synaptic GABAA receptor have only recently been detailed (1).
The above paragraph is a glance into the types of systems that modern psychiatry is focused on. In the case of the GABAA receptor global inhibitory effects can be expected at some point, but there are not the product of chemicals floating about inside the body or brain. They are the effects of complex interactions between proteins, positive and negative modulators, neurotransmitter effects, ion fluxes, and additional signaling. The effects result from where these receptors are located in the brain and central nervous system. The education of physicians assures that this level of complexity in the brain is appreciated as both the basis for normal physiology and also the basis for pharmacology and toxicology. It may be tempting to try to simplify things - but real brain function defies simplification. The basic working of the GABA receptor was discovered when I was in medical school back in the 1980s. The lectures in those days showed a simple structure with an arrow showing increased chloride ion permeability but nowhere near the structure that we currently have. This is one set of receptors and modulators very simplified. To get more of the story read the 22 pages of reference 1. To understand the brain and modern pharmacology much more needs to be understood. Forgetting about the term "chemical imbalance" is a good first step. George Dawson, MD, DFAPA
References:
1: Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE. Structure of a human synaptic GABA(A) receptor. Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27. PubMed PMID: 29950725; PubMed Central PMCID: PMC6220708. 2: Human GABA-A receptor alpha1-beta2-gamma2 subtype in complex with GABA and flumazenil, conformation A. Detailed structure from the above paper.
One of the criticisms of psychiatric treatment in particular
drug therapies is that essentially nothing is known about psychopathology,
neurobiology, or human genetics and therefore claiming that drug therapy is
treating a pathological state is erroneous (1). "Chemical imbalance" can
be used as a red herring along the way and I will try to address that in a
later post. In that post, I also hope to
address the issue of disease states and whether or not they need to be strictly
measurable.
For now, I want to discuss a model that I have used in
clinical practice for the past decade that addresses both the issues of
recovery and whether or not the drug altered state or treating an underlying
pathological state is really the issue. Let me start by saying I think it is
irrelevant for the purposes of treatment. I am first and foremost a clinical
psychiatrist and not a researcher and my priority is at all times patient care.
My
goal is to treat alterations in a person’s conscious state and restore their
level of functioning with medications and/or psychotherapy that have been shown to work. My goal is also not to introduce any new
problems such as sedation, mood changes, rage, perceptual problems, ataxia, false
memories, vertigo, or any number of subjective changes commonly seen as
"side effects".
I found that the best way to proceed is to have an explicit
discussion of the person’s conscious state and whether it has undergone any
transformation associated with the reasons why they are seeing me. I focus on the typical stream of consciousness
that occurs each and every day and how it may have changed over the previous
weeks or months or years. I ask about
whether or not getting back to that conscious state is a reasonable goal. I point out that the phenomenology associated
with a person's cognitive and emotional changes (2) can be followed in at least two
dimensions at once - the psychopathological and the normal.
There are obviously problems with my approach. The
subjective assessment of a psychopathological state and the subjective
assessment of the baseline conscious state are difficult to do and they take
time. There are a large number of
markers of psychopathological states but not so many for normal conscious
states. I often end up discussing broad
outlines that include the typical stream of consciousness, fantasies,
daydreams, defense mechanisms, distracting thoughts and typical thought patterns in certain situations such as driving
into work each day. I also ask about
a global assessment and whether at any point during treatment the person feels
like their original conscious state has been restored. It adds
another goal to treatment that is focused on restoring the self rather than
just treating symptoms.
