We’ve had 6 or 7 decades with this paradigm, what I call the “high school crush” on serotonin.
—Roger S. McIntyre, MD1
I owe the cheeky title of this piece to Roger McIntyre, MD, Professor of Psychiatry and Pharmacology at the University of Toronto, who was interviewed at the recent American Psychiatric Association (APA) meeting in Toronto. But before providing some context for Dr McIntyre’s quip, I invite you to consider 2 claims relating to mental illness:
• Psychiatrists think that most mental illnesses are caused by a “chemical imbalance”
• Psychiatrists think that some mood disorders are associated with abnormal serotonergic neurotransmission, among other functional or structural brain abnormalities, which may or may not be the “cause” of the disorder
Since there are light years of conceptual space between these 2 claims, you might imagine, or naively hope, that psychiatry’s most strident critics would be able to distinguish claim 1 from claim 2. Alas, antipsychiatry bloggers continue to bang away at the notion that “Psychiatry” (that sinister, monolithic corporate entity) deliberately duped the public by promoting a bogus “chemical imbalance theory,” in cahoots with “Big Pharma.” Suffice it to say that this line of argumentation is itself bogus, for reasons I have reiterated at length in several venues.2,3 For example, in 2005, on a publicly available website, the APA clearly stated, “The exact causes of mental disorders are unknown . . . [but] we can say that certain inherited dispositions interact with triggering environmental factors.”4 At that time, the same APA website also indicated that “several factors can play a role in the onset of depression,” including “biochemistry” (abnormalities in brain chemicals or brain networks), genetics, personality, and environmental factors. To my knowledge, no professional psychiatric organization has ever publicly promoted a “chemical imbalance theory” of mental illness in general. (And, no, the original biogenic amine hypothesis was not a “theory”—the scientific distinction is important.5) That antipsychiatry bloggers assiduously comb the Internet and find a handful of “celebrity psychiatrist” quotes to the contrary neither surprises nor impresses me.
But there is a sense in which some of psychiatry’s critics have a point, and this brings us back to Dr McIntyre and our old friend (or “frenemy”?), serotonin. It was not hard for the general public—and, alas, some doctors—to pick up the skein of serotonin and weave an entire tapestry with it, ultimately producing the threadbare “chemical imbalance theory.” No doubt, this was abetted by drug company “illustrations” of serotonergic synapses, complete with little packets of neurotransmitters whose reuptake is inhibited by the company’s ace antidepressant.6 Even today, some non-pharma websites continue to post misleading diagrams that attribute depression to a “chemical imbalance,” as Dr John Grohol recently discovered.7
So, to be clear: in order to establish, for a particular patient, a bona fide imbalance of neurotransmitters, we would need a “God’s-eye view,” in real time, of the dozens (hundreds?) of neurotransmitters in her brain; their relative concentrations in relation to well-validated norms; and their deviations from the patient’s normal baseline. Clearly, we have no such divine insight into the brain’s chemical constituents, even though we have learned a great deal about the brain’s “circuitry” and neural networks in recent years.8
Furthermore, all this focus on serotonin—while heuristically useful in some respects—may have delayed more fruitful inquiries into the biological bases of depression. Indeed, when asked about the role of serotonin in depression, Dr McIntyre replied:
I think there’s been inertia in the field insofar as we had a paradigm based on serotonin. We’ve had 6 or 7 decades with this paradigm, what I call the “high school crush” on serotonin, and we’ve had treatments that fit into that paradigm, such as the Prozac-type drugs, the serotonin agents, etc. Although that paradigm/treatment applies to a subset of around 10% to 20% of patients remarkably well, we need to think of ways to reach other subpopulations of patients.1
I agree with Dr McIntyre. And, as I recently stated:
There is little question that the role of serotonin in depression was over-emphasized and over-marketed in the 1990s, though most psychopharmacologists understood that the neurobiology of depression was much more complicated. Indeed, the term “SSRI” is itself a misnomer, since some of these agents also affect other brain chemicals (eg, sertraline has mild effects on dopamine).9
The neurobiology of depression is, of course, far more complicated than a simple deficiency of one or more neurotransmitters. In this regard, Dr McIntyre went on to elaborate an intriguing hypothesis that links some forms of depression to immune dysfunction, inflammation, and glucose dysregulation—what he calls the “immune inflammatory metabolic model.”1 But it turns out that this model may link up with the serotonin hypothesis. Dr McIntyre notes, for example, that inflammation reduces serotonin in the brain. In principle, pharmacologic agents (eg, cytokine antagonists) that alleviate certain inflammatory conditions might amplify serotonergic function and reduce some types of depression.10 All this is just to say that, while the serotonin story has been greatly overblown, there are still reasons to retain some role for serotonin in at least a subset of persons with mood disorders.
No, this does not necessarily mean that mood disorders are caused by an imbalance of serotonin—or any other brain chemical. Over 50 years ago, the fathers of the biogenic amine hypothesis, Drs Joseph Schildkraut and Seymour Kety, recognized the complexities of sorting out psychosocial causes from biological effects—which can in turn become new causes or predispositions. They wrote:
. . . it is . . . 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 [dopamine, norepinephrine, and serotonin] alone will account for the complex phenomena of normal or pathological affect.11
1. LeBano L. Inflammation, mood disorders, and disease model convergence. Psych Congress Network (interview with Dr Roger McIntyre). http://www.psychcongress.com/article/depression-inflammation-connection-diabetes-and-disease-model-convergence-23649. Accessed September 11, 2015.
2. Pies R. Doctor, is my mood disorder due to a chemical imbalance? Psych Central. http://psychcentral.com/blog/archives/2011/08/04/doctor-is-my-mood-disorder-due-to-a-chemical-imbalance/. Accessed September 11, 2015.
3. Pies R. Nuances, narratives, and the “chemical imbalance” debate. Psychiatric Times. April 11, 2014. http://www.psychiatrictimes.com/couch-crisis/nuances-narratives-chemical.... Accessed September 11, 2015.
4. American Psychiatric Association. Let’s talk facts: what is mental illness? 2005. https://www.cpp.edu/~healthcounseling/Documents/mental-illness-b1.pdf. Accessed September 11, 2015.
5. Understanding Science: How Science Really Works. http://undsci.berkeley.edu/article/howscienceworks_19. Accessed September 11, 2015.
6. Healy D. Serotonin and depression. BMJ. April 21, 2015. http://www.bmj.com/content/350/bmj.h1771.long. Accessed September 11, 2015.
7. Grohol JM. The problem with Google’s health knowledge graphs. Psych Central. http://psychcentral.com/blog/archives/2015/08/21/the-problem-with-googles-health-knowledge-graphs/. Accessed September 11, 2015.
8. Gong Q, He Y. Depression, neuroimaging and connectomics: a selective overview. Biol Psychiatry. 2015;77:223-235.
9. Borchard T. Is the link between serotonin and depression a myth? Psych Central. http://psychcentral.com/blog/archives/2015/09/01/is-the-link-between-serotonin-and-depression-a-myth/. Accessed September 11, 2015.
10. Raison CL, Miller AH. Role of inflammation in depression: implications for phenomenology, pathophysiology and treatment. Mod Trends Pharmacopsychiatri. 2013;28:33-48.
11. Schildkraut JJ, Kety SS. Biogenic amines and emotion. Science. 1967;156:21-37.
12. Ellis A, Harper RA. A Guide to Rational Living. Los Angeles: Wilshire Book Co; 1961.
13. Compton MT, Shim RS. The Social Determinants of Mental Health. Washington, DC: American Psychiatric Association Publishing; 2015.
14. Bailey RK. Book Forum. Review of The Social Determinants of Mental Health. Am J Psychiatry. 2015;172:913-914.