Chemical Imbalance? Readers Respond

September 11, 2019

Psychiatrist Boris Vatel, MD and others respond to “Debunking the Two Chemical Imbalance Myths (Again),” by Ronald W. Pies, MD. Check out this lively exchange, with an addition from other readers.

A number of readers have weighed in on “Debunking the Two Chemical Imbalance Myths (Again),” by Ronald W. Pies, MD. The article appeared in the April 2019 issue of Psychiatric Times.




LETTER I, byBoris Vatel, MD

In his article, Dr Pies criticizes the position of anti-psychiatrists who question the rationale of telling patients that emotional problems are due to a chemical imbalance when it is known known all along that a chemical imbalance theory is bogus. Dr Pies says that these critics cite no credible evidence that psychiatrists describe emotional problems in this way. However, that there are no studies of how many psychiatrists actually use that explanation does not mean that this is not what often happens in reality. In fact, the “chemical imbalance” theory may be the best approximate explanation a psychiatrist can give a patient as a reason for using an antidepressant in the first place. If these medications were synthesized with restoration of serotonin activity in mind and if we find them useful in clinical practice, is it wrong to invoke the “chemical imbalance” theory when discussing them with patients? SSRIs and other medications may work or fail to work for reasons other than restoration of optimal neurotransmitter function but the alternative to using the “chemical balance” explanation in clinical work with patients is admitting that we don’t really know how they work. Whether such an explanation, for all its honesty, is a therapeutic communication to a patient in distress is a good question.

Dr Pies points out in his article that an explanatory theory which combines brain volume loss, dysregulation of glial-neuronal interaction, abnormal hypothalamic-pituitary-adrenal function, and inflammatory activation cannot be reduced to chemical imbalances. I would challenge any practicing clinical psychiatrist to explain this model satisfactorily to himself, much less to a patient with mental illness, as a way of avoiding the term “chemical imbalance” which gives Dr Pies so much trouble. The fact is that psychiatrists in general practice are and have been for decades in a precarious position of having at their disposal imperfect tools for addressing a problem which they cannot adequately describe either to themselves or to those who suffer from it. This inability to clearly explain what has caused the “disease” and what the rationale is for using such-and-such drug for it is precisely the weakness which the anti-psychiatry movement preys upon. Rather than admitting that we do not have a unified theory of mental illness, that research on the biology of mental illness is comprehensible mostly to those well-versed in neurogenetics, microbiology, and neuro-science, and that our medications work often enough to be used and fail or cause harm often enough to be avoided we hide behind terms such as “the bio-psycho-socio-cultural model” which sound important but can mean anything at all. Perhaps if as a field psychiatry did not pretend to a knowledge it does not possess the anti-psychiatry movement would have fewer arguments at its disposal. In the meanwhile, as a face-saving measure, there is little reason to denigrate the “chemical imbalance” hypothesis – it sounds as good as anything else we have by way of explanation to our patients.

Reply by Ronald W. Pies, MD>

Reply by Ronald W. Pies, MD:

Before responding to my friend and colleague, Dr Vatel, I’d like to offer a bit of historical perspective. With respect to understanding the “causes” of most diseases, it is only in very recent times (the past century or so) that physicians have been able to do this-and there are still many diseases in general medicine and neurology whose causes or etiology remain unknown or unclear; eg, we still do not know the etiology of Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) or even of Alzheimer’s Disease. Equally, it is only in recent decades that we have discovered the mechanism of action (MOA) of many drugs that we have prescribed for generations. For example, physicians have prescribed aspirin for over a century, but its MOA was not discovered until 1971, through the work of John Vane.

As physicians, we should not be ashamed to admit that we don’t know, or fully understand, the causes of a particular disease or illness, or how a class of medication works. After all, the chief function of medical practice, in my view, is not didactic, but humanitarian; i.e., to relieve suffering and incapacity, as the psychologist and philosopher, Derek Bolton, argues in a recent interview. Dr Bolton rightly notes that, “The domain of healthcare [is]...a response to personal distress and disability.”

Thus, when a patient comes to us with, say, a severe major depressive episode, we can justifiably reassure the patient that we can help relieve her suffering and reduce her incapacity, through both somatic and psychosocial treatments-including the use of antidepressants. We need not understand the precise etiology of major depression, or the precise MOA of antidepressants, in order to take this therapeutic stance. That said, I think we understand more about mood disorders, including major depression, than Dr Vatel’s letter would suggest-and I will say the same with respect to how antidepressants are likely to “work” [see below, point 2].

For now, it’s important to distinguish claims regarding the etiology of depression from claims regarding the MOA of antidepressants. Anti-psychiatry critics typically confuse or conflate these issues. Thus, when they (wrongly) accuse psychiatry of espousing a “chemical imbalance theory” of mental illness in general, they seem to be referring to the etiology of these illnesses. At other times, they seem to be arguing that we have misled patients re: the MOA of antidepressants (i.e., by telling patients that the drugs correct a “chemical imbalance”). But these are two separate issues. One might not know the precise etiology of major depression but still present a provisional formulation of how antidepressants may “work.”

In contrast to Dr Vatel’s position, I think we can do better than telling patients that antidepressants (or other psychotropics) correct a “chemical imbalance.” We simply don’t know the normal or optimal “balance” of serotonin, norepinephrine, dopamine, GABA, glutamate, and the more than 100 neurotransmitters that may affect mood and cognition. Put another way: we have no validated neurochemical “baseline” by which to gauge a “chemical imbalance.”

There is no shame in acknowledging that-it’s just a fact, and we should not pretend otherwise. But it must also be emphasized that this knowledge gap does not negate the likelihood that these chemicals are, indeed, involved in mood regulation-which is why the “chemical imbalance” explanation is not a “lie,” as anti-psychiatry voices insist, but a misleading and unhelpful oversimplification.

Now to address a few of Dr Vatel’s specific points:

  • “...the “chemical imbalance” theory may be the best approximate explanation a psychiatrist can give a patient as a reason for using an antidepressant in the first place.”

  • I see the matter very differently. The best reason to justify prescribing an antidepressant (assuming we have made the correct diagnosis) is that we know antidepressants can help mitigate the suffering and incapacity of major depression. As for providing the patient with an “explanation”, see point 2.

  • “...the alternative to using the “chemical balance” explanation in clinical work with patients is admitting that we don’t really know how [antidepressants] work.”

  • I see this “either/or” conundrum as a false choice. Assuming the patient even asks us how an antidepressant “works”-and, in over 25 years as a mood disorder specialist, few patients of mine ever did-we can justifiably tell the patient this: “We don’t know exactly how antidepressants work, but we have good evidence that they boost levels of a protein called BDNF, which helps brain cells grow, mature, and communicate with one another.”* This is not an air-tight, comprehensive, and definitive explanation, but it’s reasonably accurate and far better than invoking the “chemical imbalance” trope.

  • “...we [psychiatrists] hide behind terms such as “the bio-psycho-socio-cultural model” which sound important but can mean anything at all. Perhaps if, as a field, psychiatry did not pretend to... knowledge it does not possess, the anti-psychiatry movement would have fewer arguments at its disposal.”

First, I’d like to clarify what I mean by “anti-psychiatry.” As I stated in my article [online version, footnote 1], “There are many responsible critics of psychiatric nosology and praxis who are not “anti-psychiatry”...When I use the term “anti-psychiatry”...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.” I do not believe that the anti-psychiatry movement, so defined, is motivated by reasonable, epistemological arguments re: what psychiatrists claim they “know”; rather, anti-psychiatry seems driven by a visceral hatred of virtually everything psychiatry stands for, from diagnosis, to treatment, to the very character of psychiatrists themselves. This conclusion is based on nearly 40 years of encountering anti-psychiatry in its many vitriolic forms and forums.

Regarding the “bio-psycho-sociocultural model,” [BPSCM]: with respect, I don’t agree with the characterization in Dr Vatel’s letter; ie, that psychiatry as a profession “hides” behind that term. It is true that the term itself can have a wide range of meanings and applications, but it goes too far to claim that the BPSCM can “mean anything at all.” It is essentially an elaboration of Dr George Engel’s (and Dr John Romano’s) biopsychosocial model, which “...systematically considers biological, psychological, and social factors and their complex interactions in understanding health, illness, and health care delivery.” Application of the model requires that the physician “...decide which aspects of biological, psychological, and social domains are most important to understanding and promoting the patient’s health.” While the Engel-Romano model is far from perfect, and has been justifiably criticized by several prominent psychiatrists [9], it does not seek to “hide” psychiatry’s lack of a unified theory of mental illness; rather, it acknowledges the complexity of human health and disease, and heuristically encourages the clinician to explore the three main components of the model on a case-by-case basis.

In closing, I would like to thank Dr Vatel for a stimulating exchange of views, and for taking the time to comment on my article.

*See for a comprehensive review of BDNF and its role in depression and antidepressant mechanism of action; i.e., “...current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an essential determinant of antidepressant efficacy.”



LETTER II, by Willa Goodfellow

In Chemical Imbalance? A Reader Responds Dr Boris Vatel and Dr Ronald Pies debate the value of telling patients that depression is caused by a chemical imbalance. Here is my response to Dr Vatel:

Dr Vatel writes, “SSRIs and other medications may work or fail to work for reasons other than restoration of optimal neurotransmitter function but the alternative to using the “chemical balance” explanation in clinical work with patients is admitting that we don’t really know how they work. Whether such an explanation, for all its honesty, is a therapeutic communication to a patient in distress is a good question.

This patient wants to answer that good question. Yes, admitting you don’t know something is a therapeutic communication. It is an excellent communication.

1. We walk into your office suspicious. It’s a toss-up whom we trust less, psychiatrists or the companies that sell the drugs that psychiatrists prescribe. You have to earn our trust. You don’t do that by telling us things that you know are misleading.
2. You’ll get caught. Google “chemical imbalance.” We do. When I did, the ads tried to sell the “chemical imbalance.” No surprise there. But the real links tipped me off that the phrase is “controversial,” “over-simplified,” “debunked,” “outdated,” and that it “leads the public to believe we are dangerous.” That was all on the first page of search results. None of these were “anti-psychiatry” sites. The third link was to this debate between two psychiatrists on the advisability of telling patients something that you know is misleading.
3. We are not as stupid as you treat us. See #2.
4. You cannot get from your assurance that meds will fix this chemical imbalance to all the other strategies that would make a difference if used in conjunction with the meds, exercise, diet, mindfulness, therapy, art, nature. It takes hard work to recover from depression. The chemical imbalance explanation tells us that all we have to do is pop a pill. And, sure, we’ll buy it once, because wouldn’t it be nice if it were true. But you set us up for failure when you oversimplify.
5. And then when the meds don’t work, we know you lied. You can dance around this language, but that will be our conclusion.

So consider,

6. The truth builds trust. “I don’t know how they work, but 40% of the people who take this med get better” is a perfectly believable and trustworthy statement. Over in oncology, your peers have patients who grasp at much thinner straws.

7. Maybe you should tell us that you don’t know what causes depression, simply because it is true.

Willa Goodfellow is a mental health journalist, blogger at, and author of Prozac Monologues: What If It’s More Than Depression? to be published in 2020 by She Writes Press.



LETTER III, by Arthur L. Smith III, MD

I always read Dr. Pies' articles/essays with great interest, as he combines science and philosophy quite nicely. To his point, I have been against the "chemical imbalance" model and trope since Prozac first appeared, but when the "thought leaders" of our field became pundits (and Presidents of the APA) of a chemical-only model during this era, I grew disillusioned.  I believe Dr. Pies misses some of the forest for the wind blowing through it, and I ask two questions re the wind:

1)  What percent of American psychiatrists practice medication-management only?  (last I saw it was 75%)
2) What is the definition of treatment-resistant depression?  (I believe it is still touted as failure of two or more antidepressants - hardly a non-chemical-only model)

These are the winds that still blow a song of "chemical imbalance" or chemical-only psychiatry.

Arthur L. Smith III, MD
Atlanta, GA

Reply by Ronald W. Pies, MD:

Hi, Dr. Smith,
Thanks for taking the time to write, and for the appreciative comment on my writing. You are raising some important points regarding psychiatry’s theory and practice, and their implications for the so-called chemical imbalance theory. (I am glad that we are in agreement re: the drawbacks of this term!).
With regard to your specific questions:

1)  What percent of American psychiatrists practice medication-management only? (last I saw it was 75%)
This figure seems much too high, based on the data I have found, albeit from some years ago. The "75%" implies that only 25% of psychiatrists use psychotherapy as a treatment modality. However, a study by Mojtabai and Olfson from 2008 found that while, indeed, there has been a steep decline in the number of psychiatrists who provided psychotherapy to all of their patients (from 19.1% in 1996 - 1997 to 10.8% in 2004 – 2005), the study also found that most psychiatrists (59.4%) continue to provide psychotherapy to at least some of their patients [Mojtabai R, Olfson M. National trends in psychotherapy by office-based psychiatrists. Arch Gen Psychiatry]

Also, Reif et al found that about two-thirds of cases in a managed care psychiatric practice receive some type of psychotherapy, and 30% of psychiatrist visits involved provision of both psychotherapy and medication, on the part of the psychiatrist [Reif S, Horgan C, Torres M, Merrick E, economic Grand Rounds: Types of Practitioners and Outpatient Visits in a Private Managed Behavioral Health PlanPsychiatric Services].

Similarly, a 2012 survey of psychiatrists found that 48% said that they used psychotherapy and 89% said that they used pharmacotherapy – either in combination or as monotherapy [Percentage of Psychiatrists Doing Psychotherapy Dwindles]. But if you have more recent data supporting the 75% figure, I would welcome seeing the study. In any case, I don't believe these unfortunate trends toward declining psychotherapy are being driven by a "theory" of mental illness; but rather, by economic forces that result in disincentives for psychiatrists to provide psychotherapy.

2) What is the definition of treatment-resistant depression? (I believe it is still touted as failure of two or more antidepressants-hardly a non-chemical-only model)

You are right, Dr. Smith, that, "Definitions of TRD focus predominantly on failures of pharmacotherapy and physical treatments, with only modest consideration given to outcomes following psychological therapies and social interventions; perhaps because these [somatic treaments] can be more reliably quantified." [See: Is treatment-resistant depression a useful concept?].  However, I don't believe this reflects psychiatry’s predominant model or theory of depression. For example, a 2001 paper by Thase et al, Management of treatment-resistant depression: psychotherapeutic perspectives, Journal of Clinical Psychiatry, states that,

"Treatment-resistant depression is a heterogeneous condition that occurs within a psychosocial milieu. The impact of prior pharmacologic interventions may have been adversely affected by a poor therapeutic alliance, low social support, life stress, or chronic adversity and cognitive or personality factors such as neuroticism or pessimism."

In short, I still believe that the “biopsychosocial model” is the predominant paradigm in psychiatry, but that this has been greatly undermined by economic and other non-theoretical factors, in recent decades. I hope these responses help clarify my position, and again, I thank you for writing.

This article was originally published on August 21, 2019, and has since been updated. -Ed.