Doctor, Is My Mood Disorder Due to a Chemical Imbalance?


Dear Mrs. -- You have asked me about the cause of your mood disorder, and whether it is due to a "chemical imbalance."

Ed Note: This article was originally posted on PsychCentral, available at

Dear Mrs. --–
You have asked me about the cause of your mood disorder, and whether it is due to a “chemical imbalance”. The only honest answer I can give you is, “I don’t know”-but I’ll try to explain what psychiatrists do and don’t know about the causes of so-called mental illness, and why the term “chemical imbalance” is simplistic and a bit misleading.

By the way, I don’t like the term “mental disorder”, because it makes it seem as if there’s a huge distinction between the mind and the body-and most psychiatrists don’t see it that way. I wrote about this recently, and used the term “brain-mind” to describe the unity of mind and body.1 So, for lack of a better term, I’ll just refer to “psychiatric illnesses.”

Now, this notion of the “chemical imbalance” has been much in the news lately, and a lot of misinformation has been written about it-including by some doctors who ought to know better 2. In the article I referenced, I argued that “…the “chemical imbalance” notion was always a kind of urban legend-never a theory seriously propounded by well-informed psychiatrists.”1 Some readers felt I was trying to “re-write history”, and I can understand their reaction-but I stand by my statement.

Of course, there certainly are psychiatrists, and other physicians, who have used the term “chemical imbalance” when explaining psychiatric illness to a patient, or when prescribing a medication for depression or anxiety. Why? Many patients who suffer from severe depression or anxiety or psychosis tend to blame themselves for the problem. They have often been told by family members that they are “weak-willed” or “just making excuses” when they get sick, and that they would be fine if they just picked themselves up by those proverbial bootstraps. They are often made to feel guilty for using a medication to help with their mood swings or depressive bouts.

… most psychiatrists who use this expression feel uncomfortable and a little embarrassed…

So, some doctors believe that they will help the patient feel less blameworthy by telling them, “You have a chemical imbalance causing your problem.” It’s easy to think you are doing the patient a favor by providing this kind of “explanation”, but often, this isn’t the case. Most of the time, the doctor knows that the “chemical balance” business is a vast oversimplification.

My impression is that most psychiatrists who use this expression feel uncomfortable and a little embarrassed when they do so. It’s a kind of bumper-sticker phrase that saves time, and allows the physician to write out that prescription while feeling that the patient has been “educated.” If you are thinking that this is a little lazy on the doctor’s part, you are right. But to be fair, remember that the doctor is often scrambling to see those other twenty depressed patients in her waiting room. I’m not offering this as an excuse–just an observation.

Ironically, the attempt to reduce the patient’s self-blame by blaming his brain chemistry can sometimes backfire. Some patients hear “chemical imbalance” and think, “That means I have no control over this disease!” Other patients may panic and think, “Oh, no-that means I have passed my illness on to my kids!” Both of these reactions are based on misunderstanding, but it’s often hard to undo these fears. On the other hand, there are certainly some patients who take comfort in this “chemical imbalance” slogan, and feel more hopeful that their condition can be controlled with the right kind of medication.

They are not wrong in thinking that, either, since we can get most psychiatric illnesses under better control, using medication-but this should never be the whole story. Every patient who receives medication for a psychiatric illness should be offered some form of “talk therapy”, counseling, or other kinds of support. Often, though not always, these non-medication approaches should be tried first, before medication is prescribed. But that’s another story-and I want to get back to this “chemical imbalance” albatross, and how it got hung around the neck of psychiatry. Then I’d like to explain some of our more modern ideas of what causes serious psychiatric illnesses.

Back in the mid-60s, some brilliant psychiatric researchers-notably, Joseph Schildkraut, Seymour Kety, and Arvid Carlsson– developed what became known as the “biogenic amine hypothesis” of mood disorders. Biogenic amines are brain chemicals like norepinephrine and serotonin. In simplest terms, Schildkraut, Kety, and other researchers posited that too much, or too little, of these brain chemicals was associated with abnormal mood states-for example, with mania or depression, respectively. But note two important terms here: “hypothesis” and “associated”. A hypothesis is just a  stepping-stone along the path to a fully-developed theory-it’s not a full-blown conception of how something works. And an “association” is not a “cause”. In fact, the initial formulation of Schildkraut and Kety 3 allowed for the possibility that the arrow of causality might travel the other way; that is, that depression itself might lead to changes in biogenic amines, and not the other way around. Here is what these two researchers actually had to say back in 1967. It’s pretty dense biology-speak, but please do read on:

“Although there does appear to be a fairly consistent relationship between the effects of pharmacological agents on norepinephrine metabolism and on affective state, a rigorous extrapolation from pharmacological studies to pathophysiology cannot be made. Confirmation of this [biogenic amine] hypothesis must ultimately depend upon direct demonstration of the biochemical abnormality in the naturally occurring illness. It should be emphasized, however, that the demonstration of such a biochemical abnormality would not necessarily imply a genetic or constitutional, rather than an environmental or psychological, etiology of depression.

Whereas specific genetic factors may be of importance in the etiology of some, and possibly all, depressions, 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. It is not likely that changes in the metabolism of the biogenic amines alone will account for the complex phenomena of normal or pathological affect. Whereas the effects of these amines at particular sites in the brain may be of crucial importance in the regulation of affect, any comprehensive formulation of the physiology of affective state will have to include many other concomitant biochemical, physiological, and psychological factors.”3(underline emphasis added)

Now remember, Mrs. --, these are the pioneers whose work helped lead to our modern-day medications, such as the “SSRIs” (Prozac, Paxil, Zoloft and others). And they certainly did not claim that all psychiatric illnesses-or even all mood disorders-are caused by a chemical imbalance! Even after four decades, the “holistic” understanding that Schildkraut and Kety described remains the most accurate model of psychiatric illness. In my experience over the past 30 years, the besttrained and most scientifically-informed psychiatrists have always believed this, despite claims to the contrary by some anti-psychiatry groups.4

Unfortunately, the biogenic amine hypothesis got twisted into the “chemical imbalance theory” by some pharmaceutical marketers,5 and even by some misinformed doctors. And, yes, this marketing was sometimes aided by doctors who-even if with good intentions–didn’t take the time to give their patients a more holistic understanding of psychiatric illness. To be sure, those of us in academia should have done more to correct these beliefs and practices. For example, the vast majority of antidepressants are prescribed not by psychiatrists, but by primary care physicians, and we psychiatrists have not always been the best communicators with our colleagues in primary care.

Neuroscience research has moved beyond any simple notion of a “chemical imbalance”…

All that said, what have we learned about the causes of serious psychiatric illness in the past 40 years? My answer is, “More than many in the general public, and even in the medical profession, realize.” First, though: what we don’t know, and shouldn’t claim to know, is what the proper “balance” is for any given individual’s brain chemistry. Since the late 1960s, we have discovered more than a dozen different brain chemicals that may affect thinking, mood, and behavior. While a few seem particularly important-such as norepineprhine, serotonin, dopamine, GABA, and glutamate-we have no quantitative idea of what the optimal “balance” is for any particular patient. The most we can say is that, in general, certain psychiatric illnesses probably involve abnormalities in specific brain chemicals; and that by using medications that affect these chemicals, we often find that patients are significantly improved. (It is also true that a minority of patients have adverse reactions to psychiatric medications, and we need further study of their long-term effects).6

But neuroscience research has moved beyond any simple notion of a “chemical imbalance” as the cause of psychiatric illnesses. The most sophisticated, modern theories posit that psychiatric illness is caused by a complex, often cyclical interaction of genetics, biology, psychology, environment, and social factors.7 Neuroscience has also moved beyond the notion that psychiatric medications work simply by “revving up” or toning down a couple of brain chemicals. For example, we have evidence that several antidepressants foster the growth of connections between brain cells, and we believe this is related to the beneficial effects of these medications.8 Lithium-a naturally occurring element, not really a “drug”-may help in bipolar disorder by protecting damaged brain cells and promoting their ability to communicate with each other.9

Let’s take bipolar disorder as an example of how psychiatry views “causation” these days (and we could have a similar discussion of schizophrenia or major depressive disorder). We know that a person’s genetic make-up plays a major role in bipolar disorder (BPD). So, if one of two identical twins has BPD, there is better than a 40% chance that the other twin will develop the illness, even if the twins are reared in different homes.10 But note that the figure is not 100%–so there must be other factors involved in the development of BPD, besides your genes.

Modern theories of BPD hold that abnormal genes lead to abnormal communication between various inter-linked regions of the brain-so-called “neurocircuits”-which in turn increases the likelihood of profound mood swings. There’s growing evidence that BPD may involve a sort of topdown, “failure to communicate” within the brain. Specifically, the frontal regions of the brain may not adequately dampen over-activity in the “emotional” (limbic) parts of the brain, perhaps contributing to mood swings.11

So, you ask-is it still all a matter of “biology”? Not at all-the person’s environment certainly matters. A major stressor may sometimes trigger a depressive or manic episode. And, if a child with early-onset BPD is raised in an abusive or unloving home, or is exposed to many traumas, this is likely to increase the risk of mood swings in later life12-though there is no evidence that “bad parenting” causes BPD. (At the same time, abuse or trauma in childhood may change the “wiring” of the brain permanently, and this in turn may lead to more mood swings-truly, a vicious circle).13 On the other hand, in my experience, a supportive social and family environment can improve the outcome of a family member’s BPD.

Finally-while the individual’s approach to “problem-solving” is not a likely cause of BPD-there is evidence that how the person thinks and reasons makes a difference. For example, cognitivebehavioral therapy and family-focused therapy may reduce the risk of relapse, in BPD.14 And so, with appropriate support, the person with bipolar disorder can take some control of her illness–and maybe even improve its course– by learning more adaptive ways of thinking. So, boiling it all down, Mrs.--–, I certainly can’t tell you the exact cause of your or anybody’s psychiatric illness, but it’s a lot more complicated than a “chemical imbalance”. You are a whole person–with hopes, fears, wishes, and dreams-not a brain filled with chemicals! The originators of the “biogenic amine” hypothesis understood this over forty years ago-and the best-informed psychiatrists understand it today.


Ronald Pies, MD

1. Pies R: Psychiatry’s new brain-mind and the legend of the chemical imbalance. Psychiatric
Times, July 11, 2011.
2. See, for example, M. Angell MD, in the New York Review of Books: “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…”
3. Schildkraut JJ, Kety SS. Biogenic amines and emotion. Science. 1967; 156:21-37.
4. See, eg, “The cornerstone of psychiatry’s disease model today is the theory that a brainbased, chemical imbalance causes mental illness.” (PDF)
5. Lacasse JR, Leo J. Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature. PLoS Med. 2005; 2(12): e392. doi:10.1371/journal.pmed.0020392.
6. El-Mallakh RS, Gao Y, Jeannie Roberts R. Tardive dysphoria: the role of long term antidepressant use in-inducing chronic depression. Med Hypotheses. 2011; 76:769-73.
7. Moran M: Brain, Gene Discoveries Drive New Concept of Mental Illness. Psychiatric News. June 17, 2011.
8. Castrn E, Rantamki T. The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity. Dev Neurobiol. 2010;70:289-97.
9. Machado-Vieira R, Manji HK, Zarate CA Jr. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord. 2009;11 (Suppl 2):92-109.
10. Kiesepp T, Partonen T, Haukka J et al. High concordance of bipolar I disorder in a nationwide sample of twins. Am J Psychiatry. 2004 161; 1814-21.
11. Lagopoulos J, Malhi G. Impairments in “top-down” processing in bipolar disorder: a simultaneous fMRI-GSR study. Psychiatry Res. 2011; 192:100-8.
12. MacKinnon D, Pies R. Affective instability as rapid cycling: Theoretical and clinical implications for borderline personality and bipolar spectrum disorders. Bipolar Disord. 2006;8:1–14.
13. Heim C, Newport DJ, Bonsall R, et al: Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. Am J Psychiatry. 2001;158:575-81.
14. Zaretsky AE, Rizvi S, Parikh SV. How well do psychosocial interventions work in bipolar disorder? Can J Psychiatry. 2007;52:14-21.

Recommended reading:
Kramer P: In defense of antidepressants. New York Times Sunday Review, July 9, 2011.


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