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 this 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 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  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


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.


  1. The way I always saw the nonsense about "chemical imbalances" being used by some psychiatrists was an odd way of convincing patients that major depression is a real illness rather than some sort of moral failing like not praying enough

  2. The above commenter is correct.

    And there is a difference between the argument being officially endorsed in a textbook and being widely used in practice which it was. Things take root often without official endorsement. The critics never made the argument that it was widely pushed in textbooks but that it was widely used in practice. But anyone practicing in a hospital in the past forty years knows that the explanation was often dumbed down to make it easier for patients to understand.

    I have no idea why he is writing these wordplay apologies again at this time, this subject has already been argued to death. These patients heard what their doctor or nurse told them and they aren't lying.

    1. I don't think it has been argued to death. In fact, most psychiatrists don't argue about it at all. It is useful to argue about because the alternatives are:

      1. Just give in to the antipsychiatrists per the link in paragraph 2 of the past. Per that poster there was no distinction between textbooks and clinical practice. Antipsychiatrists attack and smear all of us and they do not discriminate. Most psychiatrists seem not to care about this - but I do.

      2. Dr. Allen's point that "some" psychiatrists use this to legitimize treatment is well taken. But does any psychiatrist really need to resort to that? The legitimacy of the field is based on the fact that people come in, they get treated, and they get better. For decades even before there was effective treatment the legitimacy on the field was based on the fact that psychiatrists were interested in treating and studying people with problems that nobody else cared about.

      3. The time constraint is another argument that I frequently hear. There is not enough time to explain current theories and even then the explanations are incomplete. Is there enough time to refer the patient to an adequate resource and have them back for a discussion? Uncertainty did not slow down my gallbladder surgeon from saying: “Your symptoms could be anything, many people don’t have classic gallbladder symptoms, and even removing your gallbladder will not necessarily lead to any improvement.” Are we to the point where surgeons can deal with uncertainty and time constraints better than psychiatrists can?

      4. If there are psychiatrists out there using this term irrespective of the motivation it is time to stop. At the minimum, a statement that the mechanism of action is unknown is better than a pseudo-sophisticated one that in the end makes no sense. If you can’t say that – why not?

      At the more optimal side of things - learn more about the proposed mechanisms.

      All of these factors are important to me.

  3. It's a specious apology by the APA apologists for a number of reasons:

    1. He reframed the criticism and attacked a straw man, because the criticism was valid
    2. It's based on an arrogant appeal to authority
    3. It's gaslighting millions of people who heard what they heard, and aren't hallucinating
    4. He then claims it's an antipsychiatry conspiracy, which is in fact an unfounded conspiracy

    So if someone in the community reports multiple instances of police brutality, then the police chief says, well that couldn't happen, because it's against our official policy manual right here, what you think? It's laughable. This is the same basic thing. It's always the argument of atrocity or human rights deniers, it didn't happen because it wasn't officially endorsed. Watergate is another example. When Scientology is accused of blackmailing people to not leave the church, they always come back with, hey, that's nowhere in our doctrine. But of course that doesn't mean it didn't happen.

    I simply do not understand why we cannot admit this was said by thousands of people we never had control of (most of it was by GPs since they are the primary prescribers), and move on. Millions of people were told their ulcers were due to stress, now we know it's due to Helicobacter. Admit the error, learn, move on. This seems pretty basic.

  4. I don't think it's mostly psychiatrists saying it. 80 percent of these meds are given by generalists in 15 minute appointments. They're simplifying and dumbing it down to keep the conveyor belt moving.

  5. "Your last two posts don't seem to be consistent with one another probably because one is an accurate probability statement and the others are rhetorical.

    I agree with the former (probability statement) and not the latter.

  6. From someone has been doing Locum tenens work exclusively over 5 years, having worked in at least 13 or 14 different sites, I can tell you first-hand, the chemical imbalance model is being sold by most of the psychiatrists I interact with!

    By the way, Dr. Dawson, you do come across as an academic, so, you can argue that point with me as you've done earlier, but, I really don't understand what you're trying to accomplish with this post at least. I think you are trying to basically deflect something?

    Hey, maybe I'm living in an alternate universe, and that's why I'm getting screwed because I've changed to my National Board of Physicians and Surgeons certification, and also desperately trying to avoid doing inpatient work, but, at the end of the day, deeds speak louder than words!

    My bet, over 50% of practicing clinical psychiatrists generally believe that most of mental health is a chemical imbalance!...

    1. Thanks for the analysis - I know I can always count on you for the bleakest.

      As far as academics goes - I can assure you that I have treated more inpatients and patients with severe mental illness (and medical problems) than 99% of psychiatrists.

      That is easy to do when psychiatrists almost universally avoid inpatient work and I did it for over 22 years.

  7. “In the last decade, neuroscience and psychiatric research has begun to unlock the brain’s secrets. We now know that mental illnesses – such as depression or schizophrenia – are not “moral weaknesses” or “imagined” but real diseases caused by abnormalities of brain structure and imbalances of chemicals in the brain.” Unlocking the Brain’s Secrets, by Richard Harding, MD, then President of the APA, in Family Circle magazine, November 20, 2001, p 62.

    “More serious depression, or depression that is quickly getting worse, should be treated with medication. Antidepressants are not “uppers” and they have no effect on normal mood. They restore brain chemistry to normal.” About Depression in Women, by Nada L. Stotland, MD, Professor, Departments of Psychiatry and Obstetrics/Gynecology, Rush Medical College Chicago, and subsequently President of the APA. Op.Cit., p 65.

    “ADHD often runs in families. Parents of ADHD youth often have ADHD themselves. The disorder is related to an inadequate supply of chemical messengers of the nerve cells in specific regions of the brain related to attention, activity, inhibitions, and mental operations.” Paying Attention to ADHD, by Timothy Wilens, MD, Associate Professor of Psychiatry at Harvard Medical School, and Psychiatrist at Massachusetts General Hospital. Op. Cit., p 65

    Two of these doctors are former APA Presidents. These are quotes from lay magazines and obviously this was a public outreach education effort.

    Most doctors, even psychiatrists, don't know the official positions of the APA. But here, you have APA authorities endorsing chemical imbalance while the APA apologists claim that no one "respectable" did. Then they demand you respect them even more after saying this.

  8. I think you are spitting hairs on the "chemical imbalance term".

    I also think that none of these statements reflects the official position of the APA.

    The closest thing to the is the statement in the DSM-5 that it identifies groups with clinical utility that are not homogeneous and for which there may not be any incontrovertible evidence of etiology (those etiologies are listed).

    Chemical imbalance is not among them.

    Sorry if that is another reference book that doesn't count to you but let me know if I missed an APA official statement about that and I will withdraw my membership if there is a shred of evidence that the APA backs that idiotic statement.

  9. I'm just saying there's a difference between nonexistent (the title of the article) and not officially endorsed. Because no police dept endorses police misconduct in the training manual doesn't mean it's a myth...and here you have several APA Presidents pushing chemical imbalance....Lieberman did too, and so did Dr. Amen, I'll have to look up the citations.

    1. Before you do that I have been remiss in not asking you and Dr. Hassman a critical question here. I think I have been crystal clear on where I stand.

      Do either of you use "chemical imbalance" as an explanation to patients either of the mechanism of action of medications or the etiology of mental illness?

    2. And if you are looking up citations might I suggest peer-reviewed, published studies that support the use of the expression or even a survey of psychiatrists and what percentage of psychiatrists use it.

      I polled psychiatrist on Twitter when I posted on this a month or two ago and not a single psychiatrist endorsed it. I estimate that at a minimum about 500 psychiatrists saw it. That was in the face of many people claiming it happened.

      I do anticipate that the antipsychiatrists who read this blog will come up with a thoroughly biased online survey to demonstrate the "proof" that this exists.

    3. No but I heard it plenty of times, every week for decades. And that's not the kind of thing that would ever be honestly published. Of course, they would not answer in the affirmative, they'd be too embarrassed. Ask 500 cops if they've ever engaged in police brutality. Same answer.

      It's not antipsychiatry. It's gaslighting to suggest that something we heard all the time never happened.

    4. Well congratulations - I can count you as 501 unless of course the police brutality analogy applies to you.

    5. I gave you the proof. Three APA Presidents endorsed the idea. I don't care what a survey says, no one is going to admit to something that is professionally embarrassing. A survey isn't a study. What about the Hawthorne effect? Did you survey the patients about what the doctor told them? I'm sure you'd get a different story.

      So when you have multiple doctors saying we have heard this for over three decades in common usage are we lying or are we hallucinating?

      You should know being trained in psychiatry to be a little more careful about invalidating people's experiences especially when they're not one off events but a pattern.

      Maybe I should watch Brian Williams (who you weren't convinced was lying) tonight so I can better learn how to tell the truth because I've been clearly lying or hallucinating about all the times patients have told me this.

    6. Again - I would refer you back to your own remark about probabilities. As a refresher - here it is again:

      "I don't think it's mostly psychiatrists saying it. 80 percent of these meds are given by generalists in 15 minute appointments. They're simplifying and dumbing it down to keep the conveyor belt moving."

      As I stated before - I agree completely with this statement that you made earlier this evening.


      See the Lacasse and Leo article...was EI Lilly (Prozac) delusional or Scientology/Mad In America double agents?

      "When you’re clinically depressed, one
      thing that can happen is the level of serotonin (a chemical in your body) may drop.
      So you may have trouble sleeping. Feel
      unusually sad or irritable. Find it hard to
      concentrate. Lose your appetite. Lack
      energy. Or have trouble feeling pleasure…to help bring serotonin levels closer
      to normal, the medicine doctors now prescribe most often is Prozac® (Eli Lilly,

      Nonexistent=NOT EVEN ONE

    8. No surprises there.

      Here is a tip for you. The whole "chemical imbalance" term is an advertising meme from Lilly's marketing of Prozac back in the early days of the National Depression Screening Day (that they happened to sponsor).

      That was the first time I heard it and the year was 1990.

  10. The APA will waste thousands of hours on subjects like this and ever worsening DSMs and do nothing about the tens of thousands of mentally ill homeless not far from the convention center in SF where they are having their annual cocktails and dinner party. Then they can feel better about themselves listening to another worthless virtue signaling lecture about stigma. Not caring at all about prestige within that org allows me to see how inept and self-serving it really is.

  11. In answer to your question, I have been preaching the biopsychosocial model since even before residency. Almost all illness, medical or mental, has multiple factors and not most of it is biological. I don't know where that request for clarification comes from, but, I'm not a hypocrite, I believe firmly that when patients approach illness from multiple perspectives, they get better!

    I come here to learn, but I think some of your post lately have been very questionable in an agenda. I don't know when you get off claiming over 500 psychiatrists had denied that illness is biochemical in primary cause.

    But, you note you are an APA member, and instinctively, i believe that does jade your perspective. I don't think healthy responsible psychiatrists committed to genuine biopsychosocial constructs can belong to the APA in 2019. Be insulted, be incredulous, be outraged, but meeting people who belong to the APA, most of them are clueless to what the APA genuinely sells as an alleged representative for psychiatry...

    1. Not seeing an answer there. It's a simple yes or not.

      As far as questionable agendas go - your agenda here is clearly to suggest for some reason that you are superior (in any number of ways) to me and many other (most?) psychiatrists. Your conclusions about me and the hundreds of colleagues that I know are consistently off the mark. The idea that you have a monopoly on the biopsychosocial model over psychiatrists that happen to belong to the APA is incredible to see in print but totally consistent with other opinions that you have posted here.

    2. Here is the intro to the Amen Clinics...there are eight of them and they see a lot of patients. They are controversial not because of the chemical imbalance theory but on their use of SPECT:

      Amen has a lot of people working for him, doctors, therapists etc. And there it is right on the front page.

      "NONEXISTENT", the adjective you used in this thread, means NOT EVEN ONE. You didn't say it was exaggerated or overblown. You said "nonexistent".

      I've showed multiple examples. Therefore, the hypothesis fails, because your theory was absolute in its declaration.

      It is arrogant and inappropriate to dismiss these observations and quotes as falsehood. Thousands of patients aren't lying about this. And most of them have never been to Scientology or heard of MIA.

      BTW I don't like MIA, but Phil Hickey destroyed the APA statement on this years ago.

    3. It seems that you don't understand the meaning of nonexistent in this post. You certainly have not addressed the content of my post in your inconsistent arguments - on the one hand agreeing that most psychiatrists don't use the term and on the other suggesting that they do. But again that is not what the post is all about.

      Let me spell it out - if you are trained in the science that all physicians are trained in - that is how you know it is NON-EXISTENT. NON-EXISTENT as in not able to exist. That is how I knew it was BS the first time I heard in the late 1980s. Maybe I am smarter than Dr. Hassman thinks. At any rate that is what this post is all about.

      I think the quotation marks on Amen's web site mean something, but the practices suggested there are not all considered scientific. The connections between dental fillings and neurotoxicity were last fashionable in the 1980s and even though research is still published I don't know of anyone who is still recommending removal. I have had patients who were told that their schizophrenia was caused by dental fillings and who had them all removed.

    4. I never said MOST psychiatrists use it I said the use was widespread. SOME do and I gave examples. Most psychiatrists do not use the term. I believe that is true. However, you claimed in your survey none did and that is definitely not true given the quotes. Psychiatrists are a small part of the system. There are social workers, psychologists, psych techs. Patients hear info from many sources. Psych techs use the theory it all the time becaue of its simplicity. So do rehab counselors. BTW, some patients LIKE the theory because of its simplicity and it helps compliance.

      So, again, SOME. SOME>nonexistent. Checkmate.

    5. "Most psychiatrists do not use the term. I believe that is true."

      We have no disagreement on this as I have stated twice before.

      I said the Twitter survey was an estimate and nobody endorsed it. Since then I have pulled Twitter analytics and a total of 1882 people saw the post. As I stated the 500 psychiatrists was an estimate - but not a single psychiatrist endorsed it.

      The specific question was whether any psychiatrist endorsed the following statement:

      "Your disease is caused by a chemical imbalance in the brain".

      That informal poll was obviously not rigorous or scientific but it agrees completely with your statement.

  12. Readers who have persisted this far may be amused by the posts this evening. I am declaring an end to the festivities unless the actual post is directly addressed here. It is clear the discussion or lack of it has gone too far afield.