For the past several years, the eminent and scholarly Ronald Pies, MD, psychiatrist, of SUNY Upstate Medical and Tufts Universities, has labored the point that psychiatry has never endorsed the simplistic chemical imbalance theory of “mental illness”.  As various anti-psychiatry bloggers, including myself, began to accumulate a great many instances of prominent psychiatrists doing just that, Dr. Pies began digging himself in on this particular topic.  In Nuances, Narratives, and the “Chemical Imbalance” Debate (April 2014, Medscape), he wrote:

“In short, the ‘chemical imbalance theory’ was never a real theory, nor was it widely propounded by responsible practitioners in the field of psychiatry.”

And here can be found:

“I have no doubt that some patients heard the phrase ‘chemical imbalance’ from some hospital-based psychiatrists, and I agree that more could have been done by those of us with academic and research experience to ‘debunk’ this notion. But too many critics constantly claim that ‘psychiatry’ endorsed the ‘chemical imbalance theory’ when this was simply never the case – if, by ‘psychiatry’, we mean the profession as a whole.” (April 13, 2014 comment in the post The “Chemical Imbalance” Myth, by Chris Kresser, MS)

Of course, we don’t mean “the profession as a whole”, a standard that would have to embrace every single psychiatrist in the world.  We mean the great majority, including the profession’s luminaries such as Dr. Pies himself!


Last year I came across a letter to the editor in the March 1992 issue of American Journal of Psychiatry.  The letter was signed by the eminent Dr. Pies.  The letter outlined Dr. Pies’ very own chemical imbalance theory of self-injurious behavior.  I have written about this here.

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In June of 2020, Awais Aftab, MD, psychiatrist, published an interview he had conducted with Dr. Pies.  In the interview, Dr. Aftab talked to Dr. Pies about the chemical imbalance theory.  Here’s the quote:

“…I am not sure I am ready to exonerate our profession. At best, it seems like we were silent spectators, watching as this misleading idea spread like wildfire in the society (including among our patients and patient advocacy groups), doing little to nothing to correct these public misperceptions. At worst, it seems like at least some of us were participants. Ken Kendler writes in a 2019 JAMA Psychiatry commentary, ‘I would commonly see patients who would say some version of “my psychiatrist said I have a chemical imbalance in my brain.”‘  I have had a very similar experience myself. Either way, surely as a profession, we could have done a better job of educating our patients and the public?”

Dr. Pies replied:

“Yes, I agree that we – all of us – could have done a better job of counteracting the so-called ‘chemical imbalance’ trope, which, as your comments imply, was more a creature of ‘Mad Men’ than of men and women who study madness! I wish I had tackled the issue earlier than my 2011 article.”

But then he shows his true colors:

“And, yes – we often hear anecdotes concerning patients who tell their current clinician some version of, ‘My psychiatrist said I have a chemical imbalance . . .’ But where is the evidence that this is what patients were actually told? Who has contacted the patient’s psychiatrist, or reviewed his/her case notes, to see if that was really what the patient was told? To my knowledge, there has never been a study examining the ‘other side of the story’—and, to be clear: patients are not infallible recorders of what their doctors tell them.”

It is my general experience that when people over-react in this kind of way, it is because the topic to hand has “touched a nerve”.  So I developed a curiosity as to what other literary gems might be lurking in the learned doctor’s various cupboards.


In 1999, Dr. Pies published a delightful little essay in the magazine Creative Non Fiction.  The title of the piece is The Music of the Brain, the Chemistry of the Lute (Issue # 13, pp 75-83).  I am grateful to Peter Kinderman, PhD, Professor of Clinical Psychology at the University of Liverpool and former President of the BPS, for drawing this piece to my attention.

The basic idea is that the workings of the brain can be likened to the music of the lute.  Here are some fascinating quotes:

“All right, let’s be honest.  The brain is not a lute, and the six brain chemicals we will discuss are not precisely like the six strings of the lute.  But the idea I want to explore – that the chemicals of the brain may be likened to specific musical tones – is not without precedent.” (p 75)

“In brief, the brain chemicals underlying mood and behavior relate to one another in roughly the way the strings of a lute interact to produce chords – or, if the instrument is out of tune, discord.  Just as one string, when plucked, exerts a harmonic influence on its neighbors, one neurotransmitter in the brain may modify, augment, or counteract another.  Just as the lute’s strings may be out of tune, the brain’s chemistry may be out of balance.” (p 75) [Emphasis added]

“Just as the strings of a lute may be plucked too loudly or too softly, a particular neurotransmitter pathway may be overactive or underactive – spilling out too much or too little of its chemical messenger.  This can have disastrous consequences for mental health and stability, as we will see.” [Emphasis added] (p 76)

“When the dopamine string is played too softly, we feel lethargic, depressed and ‘flat’.  The chemical system that underlies our sense of pleasure and reward is activated by dopamine.  Thus, when dopamine is missing, the Beethoven symphony that once excited us now seems like so much elevator music.  The sexual partner who once aroused such passion might as well be the old filing clerk at the IRS.  Even our movements are slowed without dopamine.” (p 76-77)

This seems a little harsh on elderly IRS clerks, and in fact could be seen as a classic instance of ageism from someone who ought to know better.  Aren’t elderly filing clerks at the IRS as much entitled to romance and intimacy as anyone else?  And why has he singled out filing clerks, rather than, say, directors or even cabinet secretaries?  Is this not blatant bigotry against people of lower income?  Is this not essentially the same kind of arrogant bigotry that he displayed when he cast doubt on the credibility of psychiatric “patients” unless their statements could be verified by their psychiatrists?  Is a “patient” intrinsically less truthful than a psychiatrist?  Is it OK to dismiss an “old filing clerk at the IRS” as a paradigm of sexual irrelevancy?

But I suppose a person of Dr. Pies’ elevated rank and station can’t afford to squander his precious time pandering to the sensitivities of hard-working, under-paid elders.  If they feel slighted, or if their feelings are hurt, they can always find an honest, hard-working, and valued psychiatrist who for a meager reimbursement will fix the chemical imbalances in their brains using “safe and effective treatments” like drugs, shocks, and TMS.

“In contrast to all this, the individual with an excessively loud dopamine system may be mad or manic.  In schizophrenia, for example, we think that excessive dopamine drives hallucinations and delusions.  (On the other hand, some of the so-called negative symptoms of schizophrenia – such as apathy and social withdrawal – may be due to too little dopamine in other regions of the brain.)” [Emphasis added] (p 77)

“There is some evidence that the manic phase of manic-depressive (bipolar) illness also involves too much noise from the dopamine system;…” [Emphasis added] (p 77)

“Like dopamine, serotonin modulates mood.  When its volume is too low, people often get depressed.  By increasing the amount of serotonin between brain cells, Prozac-type medications can alleviate many cases of depression.” [ Emphasis added] (p 78)

“More surprising, though, is the connection between low serotonin and aggression.  People who tend to be impulsive, violent, or self-destructive seem to have too little serotonin in their central nervous systems – or their serotonin receptors are somehow ‘tone-deaf’ to the neurochemical signal sent out by the serotonin neurons.” [Emphasis added] (p 78)

“Some individuals who wind up with too much serotonin are prone to develop various kinds of anxiety disorders, such as obsessive-compulsive or panic disorder.” [Emphasis added] (p 78)

“All this is just to say that the chemistry of mood is complex and tightly regulated.  When the serotonin string is either too soft or too loud, too flat or too sharp, mood and behavior may suffer.” (p 78)

“Serotonin does not act independently of other neurotransmitters, of course.  When its string sounds, it actually dampens the reverberations of dopamine.  This may be part of a subtle homeostatic system in the brain, designed to keep mood and motor activity in careful balance.” (p 79) [Emphasis added]

“…excessive norepinephrine in a part of the brain called the locus ceruleus may underlie the phenomenon of ‘panic attacks’ – an instance of the fight-or-flight response gone haywire.  Some symptoms of mania and post-traumatic stress disorder may also be related to too much noise from the norepinephrine system.  On the other hand, when the norepinephrine string is muted or flat, depression may ensue.” [Emphasis added] (p 80)

“…glutamate is actually the precursor of GABA.  It seems that when neuronal activity gets too intense, the enzyme that converts glutamate to GABA is activated – suggesting that the fine counterpoint between these two contrasting strings provides the brain with a self-regulating calming mechanism.  (It is tempting to speculate that in some extraordinarily anxious persons, this enzyme system is somehow defective.)” [Emphasis added] (p 81)

“Acetylcholine also affects mood.  Too loud a tone from this string, and the individual may feel depressed; too soft, and the person may veer toward euphoria or mania.” [Emphasis added] (p 82)

“First, it is clear that certain mental illnesses are critically related to abnormalities in one or more of these six neurotransmitters.  For example, in schizophrenia, the dopamine string may be too loud in some regions of the brain, while the GABA string may be too soft.  This has very direct implications for our treatment of schizophrenia, which normally utilizes drugs that block the dopamine receptor.” (p 82)

“It is also clear that simple ‘deficit’ theories of mental illness do not do justice to the abnormal brain’s cacophony.  For example, depression is unlikely to involve simply too little serotonin or norepinephrine.  Rather, the amounts of a neurotransmitter, the sensitivity of its receptors, its effects on the gene, and its interactions with many other neurotransmitters may all determine its effects on mood.” [Emphasis added] (p 82)

“In the larger arena of temperament or character, we have reason to believe that traits such as shyness or risk-taking may be related to the state of one’s neurochemical strings.  For example, socially phobic individuals may be deficient in serotonin, while ‘risk-takers’ may have a bit too much dopamine on the brain.” (p 82)

“Finally, knowing more about the music of the brain may lead us toward ways of enhancing mood, memory, and behavior.  While human creativity can never be reduced to mere neurotransmitters, we may be able to modulate that creativity by tuning one or more of our strings up or down.  Perhaps we can even envision a whole new instrument in which not six, but a hundred strings will play in symphony.” [Emphasis added] (p 83)

This last quote is particularly troubling in that it is clearly aimed, not at a theory of “mental illness”, but rather towards general improvements in the “mood, memory, and behavior” of the human race by the ingestion of psychiatric drugs.

In this regard, it should be noted that Dr. Pies’ essay did not appear in a psychiatric journal, but rather in a literary magazine intended for a general audience.  This, I suggest, indicates that Dr. Pies was attempting to disseminate to the general public an unevidenced chemical imbalance theory.  He now describes this theory as misleading and simplistic pharma advertising, but, to the best of my information, he has never acknowledged the role that he himself played in its dissemination and promotion.


In general, when people speak or write about the chemical imbalance theory, they are usually referring to a fairly limited hypothesis, e.g. the chemical imbalance theory of depression; or the chemical imbalance theory of ADHD, etc.  But in the reportedly non-fiction piece reviewed above, Dr. Pies has sketched out a comprehensive chemical imbalance theory of a very wide range of human traits and behaviors.  These include: depression; mania; euphoria; hallucinations; delusions; apathy; social withdrawal; aggression; violence; impulsivity; self-destructiveness; anxiety; obsessions; compulsions; panic attacks; PTSD behaviors and feelings; shyness; and risk-taking.  Just twelve years later, however, (July 11, 2011), he published an article in Psychiatric Times which contained the following:

“I am not one who easily loses his temper, but I confess to experiencing markedly increased limbic activity whenever I hear someone proclaim, ‘Psychiatrists think all mental disorders are due to a chemical imbalance!’ In the past 30 years, I don’t believe I have ever heard a knowledgeable, well-trained psychiatrist make such a preposterous claim, except perhaps to mock it. On the other hand, the ‘chemical imbalance’ trope has been tossed around a great deal by opponents of psychiatry, who mendaciously attribute the phrase to psychiatrists themselves.”

H’m.  So it’s all our fault.  We “opponents of psychiatry” spread the chemical imbalance deception, and then deceitfully attributed the phrase to psychiatrists themselves.  Apparently Dr. Pies believes that some opponent of psychiatry wrote the “Music of the Brain” and submitted it to Creative Non Fiction over Dr. Pies’ signature, and that the same, or perhaps different, member of the anti-psychiatry movement perpetrated a similar ploy in the submission of the chemical imbalance theory of self-injurious behavior to the American Journal of Psychiatry.  Isn’t there a psychiatric label for these kinds of beliefs?


In 1994, Dr. Pies wrote a book titled Clinical Manual of Psychiatric Diagnosis and Treatment: a Biopsychosocial Approach, published by American Psychiatric Press, Inc., which at the time was the publishing arm of the American Psychiatric Association.  Here are some quotes from the section on Major Depression; Biological Factors:

“Most of the research in this area has focused on neurotransmitters and neurotransmitter receptors.  It seems clear that the catecholamine theory of depression as initially formulated just doesn’t explain the data; that is, major depression isn’t due simply to ‘not enough’ norepinephrine or serotonin.  Rather, depression seems to result when the overall balance of neurotransmitter quantity and function is disturbed.  It’s not necessarily that the neurochemical ‘orchestra’ is missing musicians, but rather that the musicians are playing out of tune.” (p 108) [Emphasis added]

Not much ambiguity there.  But in addition to the clear statement of chemical imbalance, there is an interesting, if minor, detail.  Dr. Pies frequently takes us ignorant anti-psychiatry yobos to task for describing the catecholamine hypothesis of depression as a theory on the grounds that it never was developed or promulgated as a fully developed theory. It was all a little bit pedantic and silly, but lo and behold, in the above quote, straight from the pen of our illustrious, condescending, and self-appointed mentor, what do we have:  a clear reference to the “catecholamine theory of depression.”  But goodness, I’m being petty:  we can let that go.

Back to Dr. Pies’ Clinical Manual:

“True, there are some data suggesting deficient norepinephrine or serotonin in the blood, urine, or CSF of depressed patients (Zis and Goodwin, 1982).  But other data suggest that overactivity of the cholinergic system may also predispose to depression; indeed, McCarley (1982) has proposed a unitary hypothesis taking into account adrenergic function, cholinergic function, and their relationship to REM sleep.  In essence, McCarley hypothesizes that depression may result from adrenergic underactivity, cholinergic overactivity, or a relative imbalance of both systems.” (p 108) [Emphasis added]

Again, not much ambiguity.  And…

“Much of the recent work in depression has focused on the role of the postsynaptic beta receptors.  It has long been known that centrally active beta-blockers (such as propranolol) can cause or exacerbate depression in susceptible individuals (Petrie et al. 1982).  It is tempting to infer that a deficiency of beta receptors – or beta-receptor hypofunction – leads to depression.” [Emphasis added] (p 109)

Now, in fairness to Dr. Pies, he also acknowledges that psychological factors may play a role in the production of depression.  But, he concludes:

“Naturally, neither this view nor the psychoanalytic ones rule out the influence of biological factors in the etiology of depression.” (p 111)

Which, naturally, strikes me as a clear endorsement of biological reductionism.

. . . . . . . . . . . . . . . .

So, Dr. Pies did promote the chemical imbalance theory, not only in his learned papers, but even in an essay aimed at the general public, and when he tells us now that “the ‘chemical imbalance theory’ was never a real theory, nor was it widely propounded by responsible practitioners in the field of psychiatry,” we must – and I say this with the most profound misgivings – draw our own conclusions.



Mad in America hosts blogs by a diverse group of writers. These posts are designed to serve as a public forum for a discussion—broadly speaking—of psychiatry and its treatments. The opinions expressed are the writers’ own.

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