Showing posts with label chemical imbalance. Show all posts
Showing posts with label chemical imbalance. Show all posts

Wednesday, August 3, 2022

The Umbrella Review of Serotonin


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

https://www.psychiatrictimes.com/view/the-serotonin-fixation-much-ado-about-nothing-new


Supplementary Graphic:

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 

Thursday, June 30, 2022

Chemical Imbalance Theory – Again and Again

 


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.


References:

1:  Morehead D. It’s Time for Us To Stop Waffling About Psychiatry. Psychiatric Times.  Dec 2, 2021  https://www.psychiatrictimes.com/view/its-time-for-us-to-stop-waffling-about-psychiatry

2:  Morehead D.  It’s Time for Us to Realize We Are All on the Same Side.  Psychiatric Times. Jan 18, 2022  https://www.psychiatrictimes.com/view/its-time-for-us-to-realize-we-are-all-on-the-same-side

3:  Morehead D.  The History of Psychiatry—A History of Failure? Psychiatric Times. April 19, 2022  https://www.psychiatrictimes.com/view/the-history-of-psychiatry-a-history-of-failure

4:  Morehead D.  Is There a Cure for Ignorance? The Shocking Truth About Psychiatric Treatment.  Psychiatric Times. June 27, 2022  https://www.psychiatrictimes.com/view/is-there-a-cure-for-ignorance-the-shocking-truth-about-psychiatric-treatment

5:  Pies RW.  Debunking the Two Chemical Imbalance Myths, Again.  Psychiatric Times. August 1, 2019  https://www.psychiatrictimes.com/view/debunking-two-chemical-imbalance-myths-again

6:  Pies RW. Nuances, narratives, and the “chemical imbalance” debate. Psychiatric Times. April 1, 2014.  https://www.psychiatrictimes.com/view/nuances-narratives-and-chemical-imbalance-debate

7:  Pies RW.   Psychiatry’s New Brain-Mind and the Legend of the “Chemical Imbalance”.  Psychiatric Times.  July 11, 2011 https://www.psychiatrictimes.com/view/psychiatrys-new-brain-mind-and-legend-chemical-imbalance

8:  Pies RW.  Doctor, Is My Mood Disorder Due to a Chemical Imbalance? Psychiatric Times.  August 12, 2011  https://www.psychiatrictimes.com/view/doctor-my-mood-disorder-due-chemical-imbalance

9:  Ruffalo, M. L., & Pies, R. W. (2018, August 19). The reality of mental illness: Responding to the criticisms of antipsychiatry. Psychology Today. https://psychologytoday.com/us/blog/freud-fluoxetine/201808/the-reality-mental-illness…

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.

 

 

 

 

Saturday, May 25, 2019

Chemical Imbalance As Advertising Meme




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 volumes over 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."

https://www.rcpsych.ac.uk/mental-health/problems-disorders/schizoaffective-disorder

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:

Monday, May 20, 2019

The Non-Existent Chemical Imbalance Theory





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 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 GABAreceptor 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 Î±-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  GABAreceptor 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 GABAreceptor 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 signalling.  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.





Wednesday, May 2, 2012

A Consciousness Based Model


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.

George Dawson, MD, DFAPA

1: Moncrieff J, Cohen D.  How do psychiatric drugs work?  BMJ. 2009 May 29;338:b1963.

2: Andreasen NC. DSM and the death of phenomenology in america: an example of unintended consequences. Schizophr Bull. 2007 Jan;33(1):108-12. Epub 2006 Dec 7.