Depression and the ‘chemical imbalance’
Psychiatry’s largest involvement in the field of mental health, depression, is based on the theory of there being a ‘chemical imbalance in the brain.’ Simply, the whole idea was that depression was due to certain chemicals being in short supply in the brain and if you could rectify that, then the patient would no longer be depressed.
For the last 30 years or so this theory has been the mainstay of one of the largest pharmaceutical marketing campaigns ever. Billions were spent on it and more billions were made by pharmaceutical companies and psychiatry.
Despite hundreds, if not thousands of contributions from psychiatrists in support of the theory, some leading voices in the field deny there ever was a theory and the public have been misled. It was all somehow pharmaceutical marketing at fault.
Nonetheless, what it does provide us with is a study in psychiatry as a pharma marketing tool.
The theory that never existed – just an ‘urban legend’
In response to criticism of the theory, there are psychiatrists who have been stating that there never was a psychiatric theory where depression was caused solely by a chemical imbalance in the brain.
“In truth, the “chemical imbalance” notion was always a kind of urban legend – never a theory seriously propounded by well-informed psychiatrists.”
Dr Ronald Pies
One of these is Dr Ronald Pies, Professor Emeritus of Psychiatry and Lecturer on Bioethics and Humanities, SUNY Upstate Medical University and Clinical Professor of Psychiatry, Tufts University School of Medicine. Dr Pies in his essay “Psychiatry’s New Brain-Mind and the Legend of the “Chemical Imbalance” states:
“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”… “And, yes-the “chemical imbalance” image has been vigorously promoted by some pharmaceutical companies, often to the detriment of our patients’ understanding. In truth, the “chemical imbalance” notion was always a kind of urban legend- – never a theory seriously propounded by well-informed psychiatrists.”
Dr Ronald Pies. 1 2
Where did this “theory” really come from?
Hypothesis suggested by psychiatrists
The idea of chemical imbalance has been attributed to a psychiatrist by the name of Joseph J. Schildkraut, formerly of the Harvard Medical School. Schildkraut published a paper called “The catecholamine hypothesis of affective disorders: a review of supporting evidence.” in 1965. 3 4
Catecholamines are hormones produced by the adrenal glands which can produce various reactions in the body. Schildkraut hypothesized that these hormones could directly address depression in human beings. He was however careful to point out:
“Clinical studies relevant to the catecholamime 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.”
Joseph J. Schildkraut. 5
This was further expanded upon by psychiatrist Alec Coppen who published a paper “The Biochemistry of Affective Disorders” in 1967. It stated:
“A biochemical aetiology implies that there are certain biochemical changes in the brain which need to be restored to normal before the patient’s clinical condition will improve. This does not deny that psychological and environmental events may precipitate and maintain the biochemical events which in turn lead to the affective disorder.”
A Coppen. The Biochemistry of Affective Disorders. 6
While Coppen was also careful to note caveats of ‘psychological and environmental events may precipitate and maintain the biochemical events,’ it is he who was responsible for putting forward selective serotonin reuptake inhibitors – SSRIs (simply, a drug type that affects the available supply of catecholamine hormones in the brain – serotonin being one of them) as a drug of choice in handling depression. 7
Enter pharma and marketing
In 1970 Eli Lilly developed an SSRI, fluoxetine. While tried as a drug to treat several other conditions, the work of Schildkraut and Coppen was known to Eli Lilly and it eventually was established for use as an antidepressant and was marketed as Prozac in 1987. By 2001 Pozac had made over $21 billion in sales, annually producing $2.4 billion and one of the biggest selling drugs ever. 8 9 10
…pharma marketing moved into high gear (by 2004 pharmaceutical companies were spending $1.5 billion promoting SSRIs). The ‘chemical imbalance theory’ then featured heavily.
Over time other pharmaceutical companies brought forward other SSRIs for depression and pharma marketing moved into high gear (by 2004 pharmaceutical companies were spending $1.5 billion promoting SSRIs). The ‘chemical imbalance theory’ featured heavily. 11
The following examples of pharmaceutical marketing statements are taken from a paper: Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature PLoS Med. 2005. by Jonathan Leo & Jeffrey R. Lacasse: 12
Fluoxetine: “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®.”
Citalopram: “Celexa helps to restore the brain’s chemical balance by increasing the supply of a chemical messenger in the brain called serotonin. Although the brain chemistry of depression is not fully understood, there does exist a growing body of evidence to support the view that people with depression have an imbalance of the brain’s neurotransmitters.”
Sertraline: “While the cause is unknown, depression may be related to an imbalance of natural chemicals between nerve cells in the brain. Prescription Zoloft works to correct this imbalance. You just shouldn’t have to feel this way anymore.”
And of course statements from the pharma marketing campaigns began to appear in the media, notably quoting psychiatry’s support of the theory
“In the New York Times (12/31/06), Michael Kimmelman wrote about the life and work of Joseph Schildkraut, one of the founders of the chemical theory of depression. The Times reporter stated, “A groundbreaking paper that he published in 1965 suggested that naturally-occurring chemical imbalances in the brain must account for mood swings, which pharmaceuticals could correct, a hypothesis that proved to be right.”
“In the Vancouver Sun (2/24/07), an article quoted several psychiatrists on the subject of mental illness, one of whom makes this statement about the antidepressants: “they seek to correct chemical imbalances in the brain usually caused by a genetic predisposition to them.”
Jonathan Leo & Jeffrey R. Lacasse The Media and the Chemical Imbalance Theory of Depression. 13
Psychiatry gets on the gravy train
Four of the most infamous ‘ghostwriting’ case studies, where psychiatrists would just sign off on papers actually written by pharma employees, involved antidepressants.
With the pharmaceutical company’s marketing campaigns in place, psychiatrists played their part as a marketing tool.
Psychiatrists were and are appearing on highly paid pharmaceuticals ‘advisory boards’ and ‘speaker bureaus’. (In looking for examples, from 1987 – Prozac release – forward, searching Google Scholar for terms “speakers bureau” and “depression” returns 13,900 results and examples aplenty. For the same time period, the search terms “advisory board,” “depression” and “remuneration” return 3,600 results.) 14
Four of the most infamous ‘ghostwriting‘ case studies, where psychiatrists would just sign off on papers actually written by pharma employees, involved antidepressants. 15
Psychiatrists (and doctors) made fortunes prescribing anti-depressants and the most significant endorsement of the ‘chemical imbalance theory’ occurred at the patient consultation level. No longer was there a need to examine social, environmental factors or even the person, just prescribe a pill.
“For the psychiatry profession, the theory was a major driving force behind the rise of biological psychiatrists within the profession, and moved the profession from one involved in talking to patients about everyday problems, to a profession that was treating their patients’ organic diseases—just as the internists were treating diabetics suffering from insulin shortages, the psychiatrists were now treating depressed patients suffering from serotonin shortages. Depression was no longer seen as just a natural response to stress, there was now an underlying biological factor which was the cause of the depression.”
Jonathan Leo & Jeffrey R. Lacasse The Media and the Chemical Imbalance Theory of Depression. 16
The theory wears thin
Whether the theory exists or not for psychiatry, it is still alive and well as an ‘urban legend’ but indeed it is starting to wear thin.
Treatment-Resistant Depression
So you have more than half of major depressive disorder patients not responding to ‘chemical imbalance’ drugs at all or responding to something else – placebo
It got even tougher for the ‘chemical imbalance’ theory when it was found that one-third of all patients said to have major depressive disorder did not respond to antidepressants. 17
This is a very, very significant figure if you also consider that trials of antidepressants were finding placebo results as high as 35% to 40%. 18
So you have more than half of major depressive disorder patients not responding to ‘chemical imbalance’ drugs at all or responding to something else – placebo.
SSRI trials and Placebo
“But analyses of the published data and the unpublished data that were hidden by drug companies reveals that most (if not all) of the benefits are due to the placebo effect.”
Irving Kirsch
The ‘chemical imbalance’ theory took a blow in 1998 when Irving Kirsh of the Harvard Medical School and other researchers used Freedom of Information requests to obtain antidepressant clinical trials never published by pharmaceutical companies, but used as part of drug approvals by the FDA.
“Antidepressants are supposed to work by fixing a chemical imbalance, specifically, a lack of serotonin in the brain. Indeed, their supposed effectiveness is the primary evidence for the chemical imbalance theory. But analyses of the published data and the unpublished data that were hidden by drug companies reveals that most (if not all) of the benefits are due to the placebo effect. Some antidepressants increase serotonin levels, some decrease it, and some have no effect at all on serotonin.”
Kirsch I. Antidepressants and the Placebo Effect. 19
Conclusion
“At this point in history, in my view, psychiatry has been almost completely bought out by the drug companies…No longer do we seek to understand whole persons in their social contexts rather we are there to realign our patients’ neurotransmitters.”
Loren Mosher, 1998
Does the inexorable depression juggernaut move on taking all, including psychiatry, before it?
It is true that statements have been made by individual psychiatrists over a number of years that the ‘chemical imbalance theory’ didn’t exist. Their voices however were lost in the ‘hurricanes’ of the marketing campaigns of the pharmaceutical industry.
Is it true that psychiatry was somehow the victim and had been overridden by pharma? If so, then it speaks poorly indeed of the technical integrity of the subject and the ability of its leaders to maintain it. And just perhaps there was never a more eager victim.
No, possibly the clearest statement of the situation was given by Loren Mosher the former chief of the Center for Studies of Schizophrenia at the National Institute of Mental Health. Dr Mosher in frustration, resigned from the American Psychiatric Association (APA) in 1998 saying:
“This is not a group for me. At this point in history, in my view, psychiatry has been almost completely bought out by the drug companies…No longer do we seek to understand whole persons in their social contexts rather we are there to realign our patients’ neurotransmitters.”
Loren Mosher. 20
Further references:
3. Psychiatry’s lack of science masked by pharmaceuticals
4. ‘Mental health’ is defined and controlled by profit-driven commercial interests
- Ronald W Pies. Psychiatry’s New Brain-Mind and the Legend of the “Chemical Imbalance.” Psychiatric Times. 2011.
- Ronald W. Pies Debunking the Two Chemical Imbalance Myths, Again Psychiatric Times. 2019.
- Benjamin Anga, Mark Horowitz, Joanna Moncrief. Is the chemical imbalance an ‘urban legend’? An exploration of the status of the serotonin theory of depression in the scientific literature Elsevier 2022.
- Joseph J. Schildkraut. “The catecholamine hypothesis of affective disorders: a review of supporting evidence.” Psychiatry Online. 2006.
- Joseph J. Schildkraut. “The catecholamine hypothesis of affective disorders: a review of supporting evidence.” Psychiatry Online. 2006.
- A Coppen. The Biochemistry of Affective Disorders. 1967 The British journal of psychiatry.
- Bruno Müller-Oerlinghausen and Mohammed T. Abou-Saleh. Alec J. Coppen—A pioneering psychiatrist who discovered the pivotal role of serotonin in the pathogenesis of depression as well as the antisuicidal effect of lithium. Int J Bipolar Disord. 2019.
- David Healy Let them eat Prozac’ – Introduction
- Alec Coppen: Biological Psychiatry in Britain. David Healy’s Interview. Adapted from The Psychopharmacologists, Volume I. Interviews by David Healy. Altman. An Imprint of Chapman and Hall; 1996.
- CN. Bethany McLean A Bitter Pill Prozac made Eli Lilly. Then along came a feisty generic maker called Barr Labs. Their battle gives new meaning to the term ‘drug war.’ 2001.
- Jonathan Leo & Jeffrey R. Lacasse Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature PLoS Med. 2005
- Jonathan Leo & Jeffrey R. Lacasse Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature PLoS Med. 2005
- Jonathan Leo & Jeffrey R. Lacasse The Media and the Chemical Imbalance Theory of Depression. Society volume 45, pages35–45 (2008)
- Troyen A. Brennan, David J. Rothman, Linda Blank; David Blumenthal, Susan C. Chimonas, Jordan J. Cohen, Janlori Goldman, Jerome P. Kassirer, Harry Kimball, James Naughton and Neil Smelser. Health Industry Practices That Create Conflicts of Interest. JAMA, January 25, 2006—Vol 295, No. 4.
- Leemon McHenry Of Sophists and Spin-Doctors: Industry-Sponsored Ghostwriting and the Crisis of Academic Medicine. Mens Sana Monogr. 2010 Jan-Dec; 8(1): 129–145.
- Jonathan Leo & Jeffrey R. Lacasse The Media and the Chemical Imbalance Theory of Depression. Society volume 45, pages35–45 (2008)
- V Popova, E J. Daly, M Trivedi, K Cooper, R Lane, P Lim, C Mazzucco, D Hough, M E Thase, R C Shelton, P Molero, E Vieta, M Bajbouj, H Manji, W C Drevets, J B. Singh. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study 2019. American Journal of Psychiatry.
- Furukawa TA, Cipriani A, Atkinson LZ, Leucht S, Ogawa Y, Takeshima N, Hayasaka Y, Chaimani A, Salanti G. Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies. Lancet Psychiatry. 2016 Nov;3(11):1059-1066.
- Kirsch I. Antidepressants and the Placebo Effect. Z Psychol. 2014;222(3):128-134.
- Jonathan Leo & Jeffrey R. Lacasse The Media and the Chemical Imbalance Theory of Depression. Society volume 45, pages35–45 (2008)