Research Updates in Psychiatry

Debunking the Two `Chemical Imbalance’ Myths, Again

Moving Toward a Bio-Psycho-Sociocultural Model of Major Depression

“A little learning is a dangerous thing.”—Alexander Pope

Like the legendary Count Dracula, who could be killed only by driving a stake through his heart, some myths seem almost immortal. For more than eight years, I have tried to drive a stake through the heart of two myths regarding the so-called “chemical imbalance theory”1-3—but with only limited success, as a recent piece in the New Yorker brought home to me.4

And, yes: there are really two myths to debunk. The first holds that mental illnesses (psychiatric disorders) in general are caused by “a chemical imbalance” in the brain—the so-called “chemical imbalance theory” (CIT).

The second myth holds that “Psychiatry” as a profession endorsed the first myth, deliberately and knowingly “lying” to countless, unsuspecting patients.

Depending on which anti-psychiatry group, blogger, or website you investigate [see footnote 1], you will find a number of corollaries to Myth #2, eg, “Psychiatrists lied to patients in order to justify giving them medication,” or, “Psychiatrists were corrupted by Big Pharma, and stood to make a lot of money by promoting the chemical imbalance theory.”

Rebuttals of these claims are almost always dismissed as “Psychiatry defending its guild interests” (as if the purveyors of anti-psychiatry animus have no self-serving motives).

Ironically, anti-psychiatry groups are quite right in heaping scorn on the “chemical imbalance theory” of mental illness, but not for the reasons they usually give. (I hasten to add that debunking the CIT is not to deny that biological factors play an important role in serious mental illness, including but not limited to major depression, bipolar disorder, and schizophrenia—see below).

The fact is, there could never have been a scientifically based “chemical imbalance theory” of mental illness, because a genuine theory requires an integrated network of well-supported, interlinked hypotheses. And yes, the frequently ignored distinction between a theory and a hypothesis is crucial. It is the key to understanding why claims by antipsychiatry bloggers regarding the CIT nearly always crash and burn.

The “Theory” That Never Was

Scientifically speaking, there never was a network of validated hypotheses capable of sustaining a full-blown, global “chemical imbalance theory” of mental illness in general. Moreover—and here we come back to Myth #2—psychiatry as a profession and medical specialty never endorsed such a bogus “theory,” when judged by its professional organizations; its peer-reviewed publications; its standard textbooks5 or its official pronouncements.

Furthermore, the whole notion of some looming, monolithic “Psychiatry” is absurd on its face, as my colleague, Dr. George Dawson,6 has cogently argued.

To be sure: what many psychiatrists in the 1980s and 1990s did promote was some version of the biogenic amine (or catecholamine) hypothesis of mood disorders, focusing mainly on the neurotransmitters norepinephrine and serotonin. (Schizophrenia was conventionally explained by the now outdated “dopamine hypothesis”).

And, in truth, the significance of serotonin was considerably over-emphasized—owing to what Roger S. McIntyre, MD has facetiously called, “Psychiatry’s High School Crush.”7

Furthermore, the “SSRIs” were accorded a rock-star status as effective antidepressants that they did not deserve. Most troubling from the standpoint of misleading the general public, pharmaceutical companies heavily promoted the “chemical imbalance” trope in their direct-to-consumer advertising.8

But to be clear: there was no concerted attempt by “Psychiatry” as a profession to promote a causal or etiological theory of mental illness in general, based solely on “chemical imbalances.” Nor did the originators of the biogenic amine hypothesis—psychiatrists Joseph J. Schildkraut and Seymour S. Kety—promote such a view in the 1960s.9

Indeed, in 1965, Dr Schildkraut9 stated, “A rigorous extrapolation from pharmacological studies to pathophysiology clearly cannot be made. Clinical studies relevant to the catecholamine hypothesis are limited and the findings are inconclusive. It is not possible, therefore, to confirm definitively or to reject the catecholamine hypothesis on the basis of data currently available.”9

The closest thing we have to an “official” position on the etiology of psychiatric disorders is this 1978 statement from the American Psychiatric Association, which was approved (at the highest level) by the APA Board of Trustees:

“Psychiatric disorders result from the complex interaction of physical, psychological, and social factors and treatment may be directed toward any or all three of these areas.”10

Critics of my thesis are inordinately fond of citing a dozen or so statements by various psychiatric luminaries—yes, including two former APA presidents—that do, indeed, invoke the phrase, “chemical imbalance.”

By cherry-picking quotes of this nature, anti-psychiatry groups and bloggers believe they have demonstrated that “Psychiatry” (with a capital “P”) has defended a bogus chemical imbalance theory. These critics are simply wrong. Decontextualized quotes from a dozen—or even a hundred—famous psychiatrists do not represent an official professional consensus, much less the views of more than 30,000 US psychiatrists. (If you extend the old joke about “Two psychiatrists, three opinions” to the actual number of psychiatrists out there, you can see the absurdity of the monolithic “Psychiatry” notion.6).

Moreover, most of the quotes or statements usually cited by psychiatry’s critics use the term “chemical imbalance” in the specific context of antidepressants and their putative mechanism of action; for example, here is a quote from 2004:

“Patients with neurotransmitter dysregulation may have an imbalance of serotonin and norepinephrine . . . Antidepressant medications that act as dual serotonin-norepinephrine reuptake inhibitors [SNRIs] . . . may aid in correcting the imbalance of serotonin and norepinephrine neurotransmission in the brain.”11

Here, the writer was hypothesizing a mechanism of action by which SNRIs may be helpful for patients experiencing depression in the context of pain. He was certainly not propounding a causal “chemical imbalance theory” of depression, much less of psychiatric disorders in general.

Note, as well, the careful use of the word “may.” Yes: with 20-20 hindsight, the “imbalance” claim has proved inaccurate and simplistic—but was not demonstrably false or mendacious when stated in 2004. (Even today, we simply do not have the sophisticated technology to verify or falsify, in real time, putative neurotransmitter “imbalances” in the human brain, during a patient’s depressive bout). And, indeed, with the benefit of further research, we now believe that the likely mechanisms of action of antidepressants are much more complicated than merely altering levels of neurotransmitters.12

Psychiatrists Themselves Questioned the CIT

By the early 2000s, psychiatrists themselves were poking holes in the chemical imbalance trope and raising serious questions about the entire catecholamine hypothesis. Antipsychiatry critics should read over the chapter on “Mood Disorders” in the 4th edition (2003) of The American Psychiatric Publishing Textbook of Clinical Psychiatry.13

In 10 pages of text, the etiology of mood disorders is discussed in classic “bio-psycho-social” terms. No “chemical imbalance theory” is presented. As for the catecholamine hypothesis, the text notes, “Additional experience has not confirmed the monoamine depletion hypothesis…[for example] depletion of serotonin can aggravate depression that has been in remission, but it does not predictably cause depression…”13(p479)

And let’s be clear on another point: by whatever biological mechanisms, the clinical reality is that antidepressants are effective in many patients with severe, acute major depression.14,15

Toward a Bio-Psycho-Sociocultural Model of Major Depression

Far from asserting a “chemical imbalance theory” of mental illness, academic psychiatry—for at least the past 30 years—has advocated a “bio-psycho-social” model of mental illness, as originally proposed by Dr George Engel, and as reflected in the 1978 APA statement quoted above.16,17

This position has been quite consistent. Furthermore, the most recent American Psychiatric Association’s formulation of depression (reviewed by Ranna Parekh, MD, January, 2017) states that, “Several factors can play a role in depression,” and lists the following18:

Biochemistry: Differences in certain chemicals in the brain may contribute to symptoms of depression. [Note the very qualified wording, “may contribute”—no causal theory is advanced]

Genetics: Depression can run in families. For example, if one identical twin has depression, the other has a 70% chance of having the illness sometime in life.

Personality: People with low self-esteem, who are easily overwhelmed by stress, or who are generally pessimistic appear to be more likely to experience depression.

Environmental factors: Continuous exposure to violence, neglect, abuse, or poverty may make some people more vulnerable to depression. [While Engel’s biopsychosocial (BPS) model has been roundly criticized,19 there is certainly no sense in which the BPS model amounts to a “chemical imbalance theory” of mental illness. (Nor, for that matter, have the recent DSMs asserted any such notion).

Moreover, within the biological component of the BPS model, new research is pointing to a variety of biological alterations in major depressive disorder (MDD) and bipolar disorder (BD) that have little direct connection with “chemical imbalances.”

For example, Miller and colleagues20 have summarized the data linking MDD with inflammation. Indeed, though still preliminary, there is evidence that some anti‐inflammatory agents can improve antidepressant treatment effects.21

There is also growing evidence that various nerve growth factors, such as brain-derived neurotrophic factor (BDNF) are involved in both the etiology of depression and the mechanism of action of some antidepressants.22 The rapid antidepressant effect of ketamine has also raised the possibility that the NMDA receptor, and possibly, the opioid system, are involved in the biology of depression.23

One important caveat, however: the DSM-5 construct of MDD is so broad and elastic, it almost certainly encompasses a multitude of underlying disease entities. As Dr Joel Paris24 has noted, “MDD is a highly heterogeneous category, leading to problems in classification and in specificity of treatment.”

In the area of bipolar disorder, Maletic and Raison25 have elegantly described a “unified field theory” of BD, in which loss of brain volume in mood-regulating brain regions; dysregulation of glial-neuronal interaction; and abnormal hypothalamic-pituitary-adrenal function are all interlinked with inflammatory activation. Again, there is no way in which such a sophisticated model can be reduced to “chemical imbalances” as psychiatry’s critics repeatedly claim.

It is thus abundantly clear that biological factors are an important component of severe mood disorders. However, in recent years, psychiatrists have become increasingly interested in the environmental and sociocultural risk factors for depression.

For example, the risk of postpartum depression is increased in the presence of a poor marital relationship; stressful life events; a negative attitude towards pregnancy; and lack of social support.26

A recent study has also shown that early life stress, such as childhood maltreatment, has a detrimental effect on brain structure, which increases the risk of unfavorable disease course in major depression.27

Race and ethnicity are also possible risk factors for major depression. For example, Bailey and colleagues28 found that “While minority populations are less likely to suffer from acute episodes of MDD than Caucasians, they are more likely to suffer from prolonged, chronic, and severely debilitating depression with heavy consequences on their level of daily functioning.”


In the 1980s and 1990s, and beyond, pharmaceutical companies heavily promoted something resembling a “chemical imbalance theory” of mood disorders directly to consumers—or, at least, used the “chemical imbalance” trope to explain how antidepressants supposedly work.8

Even in recent years, as psychologist Dr. John Grohol has pointed out, some non-professional websites have provided misleading graphics that reinforce the “chemical imbalance” trope.29 It is not surprising that the “Theory that Never Was” has taken hold in the minds of so many in the general public.

While some prominent psychiatrists have used the term “chemical imbalance” in their public comments about antidepressants—and possibly in their clinical practices [see footnote 2]—there was never a unified, concerted effort within American psychiatry to promote a “chemical imbalance theory” of mental illness in general.

The original catecholamine hypothesis of mood disorders was carefully qualified by its originators in the 1960s and has been recognized as significantly flawed and inadequate by US psychiatrists since at least 200313—and probably much earlier.

The hypothesis has since been modified and corrected to reflect more complex biological mechanisms in major mood disorders. These disorders are best understood using a bio-psycho-sociocultural model, which has been the mainstay of academic psychiatry for more than 30 years.

As with many other neuropsychiatric diseases, including Alzheimer’s disease, the precise causes of major mood disorders are still unknown. Almost certainly, there is a plethora of causal processes involved, depending on the diagnostic criteria and subtype of the illness (similar to the subtyping of anemia).

Fortunately, we have effective pharmacologic and psychosocial treatments for mood disorders. As for the bogus “chemical imbalance theory” and its misattribution to the profession of psychiatry: it is time to drive the stake into its misbegotten heart. We must now focus on providing our mood-disordered patients greater access to holistic, comprehensive psychiatric care.

The author reports no conflict of interest concerning the subject matter of this article.

Acknowledgement: My thanks to Dr. George Dawson for commenting on an earlier draft of this piece.

Footnote 1: The term “antipsychiatry” has a variety of meanings, as my colleague, Dr. Nassir Ghaemi, and I discuss in detail elsewhere.30 There are many responsible critics of psychiatric nosology and praxis who are not “anti-psychiatry”—several of whom are themselves prominent psychiatrists. When I use the term “anti-psychiatry” here, I am referring to persons or organizations that deny the fundamental legitimacy of psychiatry as a medical specialty; and who consistently impute malign motives and mendacious practices to psychiatrists [for more, see Reference 31].

Footnote 2: Anti-psychiatry bloggers often respond to my position by asking, “If psychiatrists knew all along that the “chemical imbalance theory” was bogus, why did they continue to tell patients that their emotional problems were due to a “chemical imbalance” that would be corrected by medication?” Characteristically, these critics cite no credible evidence that psychiatrists as a group so misled their patients. Almost always, their “evidence” consists of anecdotal claims, such as, “I’ve had dozens of patients tell me that they were given the ‘chemical imbalance’ explanation by their psychiatrist!”

Like Dr. Dawson,5 I have never seen any evidence that the psychiatrists in question were contacted or interviewed to present their side of the story, to review their chart notes for what was actually communicated, etc.

Sometimes, critics cite a study by Frances and colleagues,32 finding that among 237 psychology students, 46% had heard the “chemical imbalance” explanation from a physician. Even if valid, this study hardly implicates psychiatrists in a massive campaign of misinformation. Indeed, it is noteworthy that the overwhelming majority of antidepressant prescriptions in the US are written by primary care physicians—relatively few depressed patients in this country ever receive an evaluation by a psychiatrist.

In fact, “Primary care providers prescribe 79% of antidepressant medications and see 60% of people being treated for depression in the United States.”33 We simply have no reliable data on how often the “chemical imbalance” trope was communicated to patients, either in primary care or in psychiatry.

Nor do we know how nuanced the psychiatrists’ communications were. There is a big difference between telling a patient, “Your depression is due to a chemical imbalance and this medication will correct it;” and saying, “We believe depression may be caused by a combination of biochemical abnormalities in the brain, psychological factors, and environmental stresses. This antidepressant may help address the biological issues, while ‘talk therapy’ can be helpful for the other issues.”

In my nearly 40 years in the profession, I have heard hundreds of psychiatrists articulate some version of the latter view. I have not heard a single one voice the former.


1. Pies RW. Psychiatry’s new brain-mind and the legend of “chemical imbalance.” Psychiatric Times. July 11, 2011. Accessed April 30, 2019.

2. Pies RW. Doctor, is my mood disorder due to a chemical imbalance? PsychCentral. Accessed April 30, 2019.

3. Pies RW. Nuances, narratives, and the “Chemical Imbalance” debate. Psychiatric Times. April 11, 2014. Accessed April 30, 2019.

4. Aviv R: The challenge of going off psychiatric drugs. The New Yorker. April 1, 2019. Accessed April 30, 2019.

[Note: I am quoted without context or source in this piece. The source of the quote is:

5. Dawson G. Tweet dated March 21, 2019. Accessed April 30, 2019.

6. Dawson G. Real Psychiatry. Accessed April 30, 2019.

7. Pies RW. How psychiatry got over its high school crush. Psychiatric Times. November 3, 2015. Accessed April 30, 2019.

8. Lacasse JR. Consumer advertising of psychiatric medications biases the public against non-pharmacological treatment. Ethical Hum Psychol Psychiatry. 2005 Fall-Winter;7(3):175-179.

9. Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry. 1965;122:509-522.

10. American Psychiatric Association. Position statement on active treatment. Am J Psychiatry. 1979;136:753. Accessed April 30, 2019.

11. Trivedi MH. The link between depression and physical symptoms. Prim Care Companion J Clin Psychiatry. 2004;6(Suppl 1):12-16.

12. Lee BH, Kim YK. The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Investig. 2010;7:231–235.

13. Dubovsky SL, Davies R, Dubovsky AN: Mood Disorders. In: Hales RE, Yudofsky SC. American Psychiatric Publishing Textbook of Clinical Psychiatry, 4th ed. Washington DC: American Psychiatric Publishing;2003.

14. Pies RW. Antidepressants: Conundrums and Complexities of Efficacy Studies. J Clin Psychopharmacol. 2016;36:1-4.

15. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391:1357–1366.

16. Smith RC. The Biopsychosocial Revolution: Interviewing and Provider-patient Relationships Becoming Key Issues for Primary Care. J Gen Intern Med. 2002;17:309–310.

17. Pies RW. Comments on “cyclical swings” by Professor Hannah Decker: The underappreciated “solid center” of psychiatry. Hist Psychol. 2016;19:60-5.

18. American Psychiatric Association. What is depression? Accessed April 30, 2019.

19. Ghaemi SN: The rise and fall of the biopsychosocial model. Br J Psychiatry. 2009;195:3-4.

20. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65;732–741.

21. Köhler-Forsberg O, N Lydholm C, Hjorthøj C, et al. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand. 2019;139:404-419.

22. Hashimoto K.  Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci. 2010;64:341-357.

23. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175:1205-1215.

24. Paris J. The mistreatment of major depressive disorder. Can J Psychiatry. 2014;59:148–151.

25. Maletic V, Raison C. Integrated neurobiology of bipolar disorder. Front Psychiatry. 2014;5:98.

26. Norhayati MN, Hazlina NH, Asrenee AR, et al. Magnitude and risk factors for postpartum symptoms: a literature review. J Affect Disord. 2015;175:34-52.

27. Opel N, Redlich R, Dohm K, et al. Mediation of the influence of childhood maltreatment on depression relapse by cortical structure: a 2-year longitudinal observational study. Lancet Psychiatry. 2019;6,318-26. Accessed April 30, 2019.

28. Bailey RK, Mokonogho J, Kumar A. Racial and ethnic differences in depression: current perspectives. Neuropsychiatr Dis Treat. 2019;15:603–609.

29. Grohol JM. The problem with Google’s health knowledge graphs. Psych Central. Accessed April 30, 2019.

30. Pies RW, Thommi S, Ghaemi SN. Getting it from both sides: foundational and antifoundational critiques of psychiatry. Psychiatric Times. July 2, 2011. Accessed April 30, 2019.

31. Schramme T. The legacy of antipsychiatry. In: Schramme T, Thome J, eds. Philosophy and Psychiatry. Berlin: de Gruyter; 2004:94-119.

32. Frances CM, Lysaker PH, Robinson RP. The “chemical imbalance” explanation for depression: Origins, lay endorsement, and clinical implications. Prof Psychol Res Pr. 2007;38:411-420.

33. Barkil-Oteo A. Collaborative care for depression in primary care: how psychiatry could “troubleshoot” current treatments and practices. Yale J Biol Med. 2013;86:139–146.


Debunking the Two `Chemical Imbalance’ Myths, Again

This article originally appeared in:

Psychiatric Times

It is reprinted here with permission.

Ronald Pies, MD

Dr. Pies is Professor Emeritus of Psychiatry and Lecturer on Bioethics and Humanities, SUNY Upstate Medical University; Clinical Professor of Psychiatry, Tufts University School of Medicine; and Editor-in-Chief Emeritus of Psychiatric Times (2007-2010).


APA Reference
Pies, R. (2019). Debunking the Two `Chemical Imbalance’ Myths, Again. Psych Central. Retrieved on October 27, 2020, from


Scientifically Reviewed
Last updated: 1 May 2019
Last reviewed: By John M. Grohol, Psy.D. on 1 May 2019
Published on All rights reserved.