Let’s say that a close friend or family member, Caitlin, takes you aside and asks you, in strict confidence, if she can “get some advice about my depression.” At age twenty-six, Caitlin has had three serious bouts of depression in the last two years, leaving her largely unable to function for weeks at a time. A self-employed web designer, she has managed to eke out a living working largely from home, where she lives with a “very understanding” female roommate who essentially acts as Caitlin’s caretaker during her depressive bouts. During these periods, Caitlin’s appetite is poor; her sleep is interrupted by early morning (4 a.m.) awakening; her concentration is markedly impaired; and, at times, she has fleeting thoughts of “just ending it all.” Caitlin asks you, “Do you think I have some kind of chemical imbalance?”
You, of course, want to be helpful to Caitlin, but you are not a mental health professional. In order to frame your response to Caitlin, you want to utilize the most accurate understanding of depression, according to the majority of psychiatrists and neuroscientists. So – which of the following two statements would you say most accurately reflects the current view of psychiatrists and other mental health professionals?
A. Depression and other mood disorders are caused by a chemical imbalance in the brain, and are best treated with antidepressants that restore the brain’s normal chemical balance.
B. Depression and other mood disorders are probably caused by a complex interaction of genetic, neurochemical, and psychosocial factors, and are best treated using a holistic, “biopsychosocial” approach.
If you chose B, you’re already quite knowledgeable about mood disorders and how psychiatrists and neuroscientists now understand these conditions. But if you chose A, don’t feel bad – you are far from alone. Unfortunately, many people in the United States have come to believe – incorrectly – that psychiatrists see mental illness in general and mood disorders in particular as largely due to a “chemical imbalance in the brain.” This notion has come to be called “the chemical imbalance theory” (CIT) of mental illness.
As we’ll see, clinical depression and other major psychiatric illnesses are most likely caused neither by chemical factors alone; nor by a simple “imbalance” in brain chemistry – nor was there ever a full-fledged “chemical imbalance theory” among psychiatrists, as in choice A.
But the so-called chemical imbalance theory didn’t come out of nowhere. It is worth considering from what circumstances the CIT arose, and why the “theory” gained so much traction among the general public. What narrative or “origin story” of mental illness did the CIT replace, and to what extent did the psychiatric community adopt it? And finally, how does that community view the CIT and its treatment implications today?
The Origins of the Chemical Imbalance Theory
If we want to be good medical historians, we can say that the CIT had its origins in ancient Greece, among physicians in the school of Hippocrates (ca. 460 BCE-370 BCE, often called, “the Father of Medicine”). As historian Noga Arikha explains, Hippocrates – and later, the Roman physician, Galen – believed that we are all born with varying amounts of four “humors” or fluids in our bodies: black bile, yellow bile, phlegm and blood. In simplest terms, too much black bile made you melancholic (depressed); too much yellow bile (choler) made you choleric (irritable); too much phlegm made you phlegmatic (slow and stolid); and too much blood made you sanguine (confidently optimistic).
There you have the earliest formulation of the “chemical imbalance theory” of mood disorders. But if we now jump over two millennia to the 1960s, we find that a sort of humoral hypothesis of mood disorders was slowly developing. And, yes: the difference between a hypothesis and a theory is very important in the history and philosophy of science. A hypothesis is essentially an educated guess, based on preliminary evidence. A theory is a kind of evidentiary web, composed of well-founded, interlinked hypotheses. Put another way, a theory is “a substantiated explanation for an occurrence.” A hypothesis is merely a stepping-stone along the path to a fully developed theory.
What was the hypothesis that developed in the 1960s, in connection with mood and depression? Essentially, it held that clinical depression was associated with – note: not caused by! – abnormalities in two (or more) brain chemicals, called biogenic amines; specifically, the neurotransmitters norepinephrine and serotonin. (Chemically, norepinephrine is a catecholamine, whereas serotonin is an indoleamine.) This biogenic amine hypothesis – sometimes called the catecholamine hypothesis – was developed largely by Dr. Joseph J. Schildkraut and Dr. Seymour S. Kety, along with Dr. Arvid Carlsson. Their hypothesis was based mostly on animal, not human studies. (Roughly at the same time, a kind of parallel hypothesis was developing, linking schizophrenia with abnormalities in another neurotransmitter, dopamine.) Here, in brief, is what Schildkraut and others proposed:
The catecholamine hypothesis of affective [mood] disorders” proposes that some, if not all, depressions are associated with an absolute or relative decrease in catecholamines, particularly norepinephrine, available at central adrenergic receptor sites. Elation, conversely, may be associated with an excess of such amines.
Despite the careful use of the words, “hypothesis” and “associated,” it’s not hard to see how this proposal came to be misunderstood as a causal theory of depression, if not all mental illness. But there was no concerted attempt by Schildkraut and Kety to promote a causal or etiological theory of mental illness in general, based solely on abnormalities in biogenic amines. Indeed, they acknowledged the possibility that catecholamine abnormalities may be the effect or result of depression, rather than a primary cause of depression. In 1967, they wrote:
It should be emphasized…that the demonstration of…[a catecholamine] abnormality would not necessarily imply a genetic or constitutional, rather than an environmental or psychological, etiology of depression…it is equally conceivable that early experiences of the infant or child may cause enduring biochemical changes and that these may predispose some individuals to depressions in adulthood…[and] any comprehensive formulation of the physiology of affective state will have to include many other concomitant biochemical, physiological, and psychological factors.
In so writing, Schildkraut and Kety actually laid the groundwork for what was later to be called – by Dr. George Engel – the “biopsychosocial model” of mental illness (see choice B, above). Furthermore, they were keenly aware of the difficulties in translating animal studies of biogenic amines into human disease states. Thus, in 1965, Dr Schildkraut stated that, “A rigorous extrapolation from pharmacological studies to [human] pathophysiology clearly cannot be made.
And while my comments are limited mainly to psychiatry in the US, there were also psychiatrists in the U.K. who acknowledged that depression probably had a multifactorial etiology. For example, as early as 1969, the late British psychiatrist, Dr. Alec Coppen (1923-2019) wrote that while
Biochemical changes are of primary etiological importance [in depression and mania]… I recognize that other factors – social and psychological – are also of great importance. I think one of our tasks in the future will be to show how these environmental events can interact with the biochemistry of the nervous system to produce the syndromes of depression and mania.
In short, there was no strictly biochemical “theory” of depression or mental illness put forward by these psychiatrists – or, to my knowledge, by any prominent US psychiatrist writing in the 1960s-70s. Rather, Schildkraut and Kety advanced a heuristic hypothesis.
How did the catecholamine hypothesis morph into the CIT?
And yet, some of psychiatry’s most vitriolic critics argued that it was Psychiatry – that monolithic entity with a capital “P” – that knowingly promoted a bogus chemical imbalance “theory.” Even some physicians (who should have known better) promoted the idea that the CIT represented a kind of paradigm shift (to use historian and philosopher Thomas Kuhn’s term) in the field of psychiatry. Thus, in 2011, in the New York Review of Books, Marcia Angell, MD wrote:
The shift from “talk therapy” to drugs as the dominant mode of treatment coincides with the emergence over the past four decades of the theory that mental illness is caused primarily by chemical imbalances in the brain that can be corrected by specific drugs
Note Angell’s use of the words, “theory,” “mental illness” (in general); and “caused by” – in contrast to what Schildkraut and Kety had hypothesized. A few months after Angell’s highly-publicized piece appeared, I wrote, in Psychiatric Times, that I had never heard a knowledgeable, well-trained psychiatrist endorse the notion that “all mental disorders are due to a chemical imbalance.” I referred to the CIT as “a kind of urban legend- – never a theory seriously propounded by well-informed psychiatrists.”
Predictably, I got a tidal wave of angry push-back from various anti-psychiatry bloggers, who argued that I was “re-writing history” by letting Psychiatry (capital “P”) off the hook. My critics were even more incensed when I doubled down on my claim, in two subsequent articles, published in 2014 and 2019.
The claim that the CIT was endorsed and (mendaciously) promoted by psychiatrists is based mainly on retrospective, anecdotal reports, rather than on contemporaneous written records of what patients were told by psychiatrists. Hence, the charge of “re-writing” history is dubious on its face. That said, I have little doubt that many psychiatrists, in the ‘80s, ‘90s, and early 2000s, used some version of the phrase, “chemical imbalance” in their meetings with patients. Some may have placed that phrase in a valid “biopsychosocial” context; others may not have done so. And, yes, during that period, a dozen or so prominent psychiatrists promoted some version of the CIT in their public pronouncements.
On the one hand, even if done with good intentions, such comments by psychiatrists inadvertently contributed to an inaccurate understanding of depression and other psychiatric illnesses. Alas, for many in the general public, “mental disorder” became nearly synonymous with “chemical imbalance.” Even cultural icons like the New Yorker picked up on the notion.
On the other hand, the vast majority of antidepressant prescriptions in the US are written by primary care physicians, not psychiatrists. It’s almost impossible to know how, in the 1980s and ‘90s, primary care providers explained the nature and etiology of depression to their patients. I suspect – but can’t prove – that for the average, harried primary care provider, explaining depression as a “chemical imbalance” was a tempting time saver, during those fifteen minute appointments. Nonetheless, we psychiatrists (myself included) should have done more to inform our colleagues in primary care that the CIT was a simplistic and misleading canard.
In any event, it seems clear that many people in the US and elsewhere came to believe that mental illness was due, entirely or largely, to some sort of “chemical imbalance in the brain.” But in my view, the most powerful force fueling this belief was not what psychiatrists said or did; but rather, the huge wave of “direct-to-consumer” advertising that pharmaceutical companies heavily financed, during the 1980s and 90s.
Was there ever a broad consensus among psychiatrists that the CIT was correct?
The short answer to this question is no. But we need to keep in mind that psychiatry in the US is not a monolithic entity (capital “P” Psychiatry). On the contrary, it is a rather motley collection of over 30,000 individuals and numerous sub-specialties, with a wide range of opinions on virtually any topic. (The old joke is not inaccurate: “Two psychiatrists, three opinions.”)
As noted above, some US psychiatrists were skeptical from the get-go that psychiatric illness in general, and mood disorders in particular, could be explained solely in terms of a “chemical imbalance.” In the US, there was never a broad, professional consensus supporting the CIT. Let’s look, for example, at one of the most influential books by an American psychiatrist written in the mid-1980s: Dr. Nancy Andreasen’s 1984 book, The Broken Brain. This work was widely considered the herald of “the biological revolution in psychiatry” – which was actually the subtitle of her book. Using the best scientific data available from the early ‘80s, Andreasen wrote this book for the general public. Her goal was to set forth what psychiatrists and neuroscientists knew – or thought they knew – about severe depression, schizophrenia, and other serious psychiatric illnesses.
To be sure, Andreasen uses the phrase “chemical imbalances” in a few instances. For example, she notes that people with schizophrenia “may have chemical imbalances in their brains – in particular, excessive transmission in the dopamine system.” Similarly, she alludes to “some type of chemical imbalance [that] might be causing the symptoms of depression.”
But note Andreasen’s careful use of the words “may” and “might.” Also, even if some type of chemical imbalance might cause certain symptoms of depression, like low energy or poor concentration, it does not follow that depression itself is caused by such imbalances. Ever the good scientist and scholar, Andreasen was cautious and measured in her statements. Indeed, The Broken Brain was no brief for a purely biological or neurochemical theory of mental illness. Throughout the book, Andreasen allowed for the role of psychosocial and environmental factors in the genesis of psychiatric illness. For example, she writes,
An inherited lack of emotional resilience may be the predisposing factor – the necessary but not sufficient cause – in the development of affective [mood] disorders. This resilience could be programmed in the brain in its neurotransmitter systems, such as the norepinephrine and serotonin systems…[but] the environmental or social factors that trigger the development of affective illness may be either physical or psychological…social factors can include acute stresses, such as a loss or accident…sometimes a series of very small stresses may have a cumulative effect…especially if the person is already predisposed to develop depressive symptoms.
Andreasen’s comprehensive framework is close to the current consensus view within American psychiatry, and aligns very closely with Dr. George Engel’s “Biopsychosocial Model.” This model was developed in the late 1970s and has functioned as the “backbone” of academic psychiatry in the US for over forty years. Andreasen and Engel were also entirely consistent with this 1978 statement from the American Psychiatric Association, approved at the highest level by the APA’s 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.
To be sure, another statement from the APA in 2003 emphasized the neurobiological basis of serious psychiatric illnesses, but did not propound a simplistic chemical imbalance theory. Specifically, the statement said that,
Serious neurobiological disorders such as schizophrenia reveal reproducible abnormalities of brain structure (such as ventricular enlargement) and function. Compelling evidence exists that disorders including schizophrenia, bipolar disorder, and autism to name a few have a strong genetic component…Ultimately… mental disorders will likely be proven to represent disorders of intercellular communication; or of disrupted neural circuitry.
In the same year as that statement appeared (2003), we have a chapter on mood disorders in the American Psychiatric Publishing Textbook of Clinical Psychiatry. In ten pages of text, the etiology of mood disorders is discussed in classic “bio-psycho-social” terms [see below]. No “chemical imbalance theory” is presented. Indeed, these psychiatrist authors actually dealt the biogenic amine hypothesis a serious blow:
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.
In short: neurobiology, yes; chemical imbalance theory, no. The latter might indeed be called, “The Theory that Never Was.”
What were the prevailing models of psychopathology before the CIT?
To oversimplify considerably, there were three principal “models” or paradigms of psychopathology, prior to – but partially overlapping with – the so-called “biological revolution” in psychiatry. You are almost certainly familiar with the psychoanalytic model, pioneered by Sigmund Freud, and predominant in clinical psychiatry in the period of roughly 1935-1965, reaching its zenith in the US in the 1950s and early 1960s. In essence, the psychoanalytic model explained psychopathology as a consequence of unconscious and unresolved conflicts, such as Freud’s famous “Oedipal Complex.” Somewhat later – roughly 1955-1975 – psychologist Dr. Albert Ellis; and later, psychiatrist Dr. Aaron T. Beck, developed a cognitive-behavioral model of psychopathology. In essence, this is “based on the psychological construct that individuals’ interpretations of situations influence their reaction (emotional, behavioral, physiological), more so than the situation itself.”
The third model or paradigm – the “Biopsychosocial Model” (BPSM) discussed earlier – soon became, and arguably remains, the “paradigm in chief” in American academic psychiatry.
What is the most current model or explanation of clinically significant psychiatric illness?
Ironically, the current dominant paradigm in psychiatry – and the best available theory of psychopathology – is almost identical to the official statement from the American Psychiatric Association in 1978:
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.
The difference between 1978 and 2022 is that we now know much more about the ways in which biological, psychological, and social factors interact to produce serious psychiatric illnesses like schizophrenia, bipolar disorder and major depressive disorder. A thorough discussion of this interaction would require much more space – maybe even a whole book! Accordingly, one paradigmatic example will have to suffice.
Let’s take major depressive disorder (MDD) as an example, with the caveat that MDD is really a motley collection of signs and symptoms, and arguably a collection of disease states that may differ in terms of etiology. (The same is almost certainly the case with schizophrenia.) Let’s return to Caitlin, who has had three serious bouts of depression in the last two years, leaving her largely unable to function for weeks at a time. Her history is certainly consistent with recurrent bouts of MDD.
We can posit that Caitlin’s family history – especially among her first-degree relatives – is “positive” for clinical depression. Although that may reflect environmental and social factors that are, so to speak, “handed down” within the family, there are almost certainly genetic factors involved. While there are no specific genes known to cause MDD, there is good evidence for a significant genetic component in MDD.
Now, genes are the segments of our DNA that synthesize various proteins, including nerve growth factors. There is growing evidence that a particular nerve growth factor (BDNF) maintains the survivability of serotoninergic neurons, and serotoninergic transmission, in turn, exerts a strong influence on this nerve growth factor’s expression. You can see already that the chemistry of the brain is linked with protein synthesis, which in turn depends on gene function. At the same time, “…stressful events during one’s life are the strongest factors that can initiate depression onset…” and stress, in turn, can affect the body’s production of various hormones, like cortisol. Depressed patients frequently show abnormally elevated cortisol levels in response to stress, and cortisol elevation is, in turn, associated with acute and severe depression. So, we already have genetic, biochemical and stress-related factors in the mix. If we now add in a person’s psychological habits, cognitions, and dispositions – for example, people who tend to “catastrophize” over even minor problems – we have the makings of the Biopsychosocial Model of psychopathology. Clearly, this is not your father’s “chemical imbalance theory”!
And while the treatment of major depression is beyond the scope of the present review, we should note that “talk therapy”, medication, or the combination of the two are often effective treatments for clinically severe depression. Most evidence suggests that the combination of the two is more effective than either treatment alone. Many other effective modalities of treatment, including Transcranial Magnetic Stimulation and ketamine, are also part of our armamentarium.
Further Thoughts on the CIT and Society
The CIT was never a bona fide theory; nor ever the official position of American psychiatry; nor the predominant model in academic psychiatry during the past 40 years. And yet – the myth of the CIT persists. I once likened the CIT to the legend of Count Dracula, who is destined to live on forever unless someone drives a stake through his heart!
Perhaps there are cultural and societal forces that keep this bogus notion alive, despite evidence to the contrary. Here I am reminded of Gresham’s Law, which posits that money of lower intrinsic value will circulate more freely than money of higher intrinsic value – i.e., “bad money drives out good money.” Perhaps simplistic notions are better at surviving in the marketplace of ideas than more complex ones – like bumper stickers beating out thoughtful essays. Then, of course, there is the benighted state of science education in the US, which leaves the public ill-equipped to sort out scientific truths from urban legends like the CIT.
At long last, it’s time to move beyond the myth of the chemical imbalance, and to see psychiatry for what it is today: a medical discipline whose core paradigm addresses psyche and soma, motives and molecules, in a holistic manner.
Ronald W. Pies, MD, is a psychiatrist, medical ethicist, and writer, who holds faculty positions at SUNY Upstate Medical University and Tufts University School of Medicine. He is also Editor-in-Chief Emeritus (2007-2010) of Psychiatric Times.
