The SSRIs’ mechanism of action is no index of safety and efficacy.
Imagine that you, as a physician, just saw a headline splashed all over the internet, reading, “Depression Probably Not Caused by Excessive Black Bile,” followed by a long discourse on how an imbalance in the 4 bodily humors is not responsible for mood disorders. You might scratch your head and wonder why anyone would bother to refute the Galenic-medieval humoral theory.
As senior academic psychiatrists and psychopharmacologists, we reacted with similar puzzlement to a recent umbrella review and follow-up article by researchers in the United Kingdom.1,2 The review, published in Molecular Psychiatry (henceforth, “the review”) argued that there is “no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations” and that, “the serotonin theory of depression is not empirically substantiated.”
The follow-up article by 2 of the review’s authors was titled, “Depression is probably not caused by a chemical imbalance in the brain – new study.”2 The article went well beyond the data of the original review, claiming (inaccurately, in our view) that, “antidepressants appear to have a generalized emotion-numbing effect”; that it is “impossible to say that taking SSRI antidepressants is worthwhile”; and that “it is not clear that [SSRIs] do more good than harm.”2
We suspect that the review authors sincerely believed they were publishing something extraordinarily newsworthy or controversial. The credulous popular media certainly thought so; and, predictably, antipsychiatry groups were quick to pounce on the UK group’s findings. Headlines all over the internet trumpeted variations of, “Study says depression not caused by chemical imbalance, raising questions about antidepressants…”3 Press coverage of the review quickly morphed from discussion of serotonin into doubts about the value, efficacy, and safety of antidepressants, with many in the general public voicing alarm or heaping scorn on psychiatry,4 with a few notable exceptions.5
Such public consternation was completely understandable. In our view, the credulous, media-driven narrative generated by the Molecular Psychiatry review and the authors’ follow-up article amounts to well-worn rhetoric—and the review itself is little more than old wine in new bottles. Furthermore, we find at least 7 serious problems with the UK group’s claims. In brief:
1. As we have shown in several articles, there has never been a causally based, “chemical imbalance theory” or a “serotonin theory” of depression espoused by academic psychiatrists; psychopharmacologists; standard psychiatric textbooks; or professional psychiatric organizations, at least in the US.
2. Psychiatrists have known for decades that the etiology of depression and other mood disorders is extremely complicated and cannot be explained solely in terms of a single neurotransmitter.
3. The review by the UK group sampled a very small portion of a much larger universe of serotonin-related hypotheses and their applicability to psychiatric disorders and their treatment.
4. The report’s findings were not news, in that at least 4 previous reviews of the serotonin (5-HT) hypothesis (1954-2017) found that the total evidence was inconclusive or inconsistent.
5. The brain contains dozens of neurotransmitters, and hypotheses regarding the etiology of depression have extended far beyond serotonin—indeed, far beyond biogenic amines—to many other potential biological causes and risk factors. In some cases, layered models integrating several hypotheses have been developed.
6. Many effective drugs used in general medicine, neurology, and oncology act through unknown or multiple mechanisms, and this is not an indictment of the drugs or those who prescribe them.
7. The precise mechanism of action of SSRIs is irrelevant to the safety and efficacy of these agents in the treatment of major depressive disorder. While there is legitimate debate over the efficacy of long-term antidepressant use, the UK group’s review contributes no new information in that regard.
We now elaborate on each of these points:
1. Despite claims to the contrary,6 there has never been a full-blown theory of depression proposed by a monolithic entity called “psychiatry,” asserting that depression is directly caused by abnormal levels of 1 or more neurotransmitters.7,8 In fact, there are numerous quotations from psychiatrists and researchers dating back to the 1960s about why that is not likely. For example, as pioneering psychiatrist Joseph Schildkraut and neuroscientist Seymour Kety put it in 19679:
“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.”
Indeed, a detailed review by one of us (GD) found no references to a “chemical imbalance theory” of mental illness in any standard psychopharmacology textbook or peer-reviewed psychopharmacology literature over the past 30 years. The conflation of monoaminergic, catecholaminergic, or indoleaminergic hypotheses of depression with a so-called chemical imbalance theory of mood disorders is inaccurate.
2. Psychiatrists have known for decades that the etiology of depression and other mood disorders cannot be explained solely in terms of 1 neurotransmitter—whether serotonin, norepinephrine, or some other biogenic amine. For more than 40 years, the operative paradigm in academic psychiatry has been the biopsychosocial model10—which, ironically, was articulated in rudimentary form by Schildkraut and Kety themselves, in the very passage quoted previously. Furthermore, in the period of 1990-2010, psychiatrists and neuroscientists proposed at least 17 other hypotheses regarding depression, with 8 additional ideas since then.11
3. The complexity of serotonergic systems and signaling in the brain is not captured in the Moncrieff et al review. Detailed recent reviews suggest that the early serotonin studies did not capture the complexity of the 5-HT system and should be viewed as merely preliminary sampling of a very small part of the universe of serotonin-related hypotheses. Recent work in this area reveals that although serotonin systems are now much better characterized, additional work needs to be done.12 Moncrieff et al’s claim that psychiatric research on serotonin has yielded no useful information—and that this whole area of research should be brought to a close—does not accurately reflect the current scientific research program.
On the contrary, more recent integrated theories incorporating 5-HT systems with other depression hypotheses are under active development. Several research groups are using multi-omics approaches, in which the data sets are multiple omes, such as the genome, the proteome, and the transcriptome. Approaches that examine serotonin and its metabolites have been used by some research groups to predict antidepressant response and have been internally replicated.13 A recent review of 50 studies of the metabolomics of major depression concluded that several metabolites are altered in major depression, including kynurenine—a tryptophan metabolite thought to be a key mediator of psychiatric illness that interfaces with the immune and mood systems.14
4. The Moncrief et al review was hardly news to psychiatrists.15 As shown in the Table,9,15-17 at least 4 investigations of the 5-HT hypothesis found inconclusive or inconsistent evidence. The most recent review (2017) concluded that additional evidence was needed to support the model and resolve inconsistencies. These authors also proposed several new 5-HT receptor-based hypotheses.15
5. The brain contains about 50 to 100 neurotransmitters.18 Hypotheses regarding depression have extended far beyond serotonin—indeed, far beyond biogenic amines. The Molecular Psychiatry review is focused narrowly on serotonin and does not address other small molecule or neuropeptide neurotransmitters that may figure in antidepressant action.19 Furthermore, the review does not address effective nonserotonergic antidepressants like bupropion,20 or antidepressants like vortioxetine, which have very complex serotonergic effects.21
6. In the area of drug development, there has been an active debate about whether a specific mechanism of action and/or drug target is necessary for an approved medication. Many medications like aspirin, acetaminophen, and digoxin were used for decades before a putative mechanism was identified. One of us (GD) recently reviewed the package inserts of drugs that were FDA-approved as disease-modifying drugs for multiple sclerosis.22 There have been 18 approved drugs since 1993. The mechanism of action listed for 17 of the 18 medications is unknown.
The trade-offs of searching for a mechanism of action or drug target—as opposed to phenotypic screening for drug effects—have been discussed by Davis, who point out that disease complexity is important in considering mechanism of action and drug target identification, especially in complex central nervous system diseases.23 In any case, the precise mechanism of action of SSRIs cannot be determined from the data in this recent review.
7. The techniques described in the Moncrieff review were not designed to determine antidepressant efficacy, which is determined by randomized controlled clinical trials. Thus, no conclusions can be drawn from their review regarding antidepressant efficacy, or the “good versus harm” associated with antidepressant treatment.
Although the topic is beyond the scope of this commentary, there is convincing evidence that most antidepressants are safe and at least modestly effective in the acute treatment of moderate-to-severe major depressive episodes.24-26
Clinical Approach to Depression
As several neuroscientists and researchers pointed out in response to this recent review, the role of serotonin in mood disorders is by no means settled science, and there may well be some role for this neurotransmitter in some types of depression, which is almost certainly a heterogeneous group of disorders.27 That heterogeneity complicates efforts to identify consistent biomarkers of psychiatric illnesses, including major depressive disorder.
Although there have been some critiques of this recent review, psychiatrist and researcher Michael Bloomfield, MD, states the issues well27:
“I don’t think I’ve met any serious scientists or psychiatrists who think that all [cases] of depression are caused by a simple chemical imbalance in serotonin. What remains possible is that for some people with certain types of depression… changes in the serotonin system may be contributing to their symptoms. The problem with this review [by Moncrieff et al] is that…it has lumped together depression as if it is a single disorder, which from a biological perspective does not make any sense.”
Most importantly, the review by Moncrieff et al does not in any way impugn the overall safety and effectiveness of serotonergic antidepressants in the acute treatment of moderate-to-severe major depression. That said, we believe that antidepressant treatment should be undertaken conservatively; monitored closely; and regarded as only one component of a comprehensive, biopsychosocial approach to depression, generally including talk therapy. As such, patients should be educated regarding all 3 components of mood disorders—biological, psychological, and sociocultural.
Compared with treatment of an acute major depressive episode, long-term use of antidepressants (eg, over several years) presents a more complicated picture with a thinner evidence base, and merits a careful risk/benefit discussion with patients.28 Similarly, particular care must be taken in discontinuing long-term antidepressant use.29
Finally, the risk/benefit discussion concerning antidepressants (and other biological treatments in psychiatry) should be approached in the same way as the physician would approach any other serious medical intervention.
Depression is a complex, heterogeneous disorder with biological, psychological, and sociocultural determinants and risk factors. Very few—if any—US psychopharmacologists and academic psychiatrists have ever endorsed a sweeping chemical imbalance theory of mood disorders. Historically, psychiatrists have never explained clinical depression solely in terms of reduced serotonin or any specific neurotransmitter. As with SSRIs, many drugs in clinical medicine work through unknown or multiple mechanisms, and this does not affect their safety, efficacy, or approval for medical use. There is ample evidence from placebo-controlled studies that serotonergic antidepressants are safe and effective in the treatment of acute major depressive episodes. If serotonergic agents are not helpful, antidepressants from other classes (eg, noradrenergic/dopaminergic agents) may be considered.
Finally, we hope that patients and clinicians are not deterred from the use of antidepressants by the UK review, or the mere fact that SSRIs’ mechanism of action is complex and not completely understood.
Dr Pies is professor emeritus of psychiatry and a lecturer on bioethics and humanities at SUNY Upstate Medical University in Syracuse, New York; a clinical professor of psychiatry at Tufts University School of Medicine in Boston, Massachusetts; and editor in chief emeritus of Psychiatric Times™ (2007-2010). He is the author of several books. A collection of his works can be found on Amazon. Dr Dawson is recently retired from clinical practice and is a free-lance writer and researcher on psychiatric topics. He writes the Real Psychiatry Blog.
Acknowledgments: The authors thank John J. Miller, MD; Heidi Anne Duerr, MPH; and Cynthia M.A. Geppert, MD, for encouraging this contribution.
1. Moncrieff J, Cooper RE, Stockmann T, et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry. 2022 Jul 20. Online ahead of print.
2. Moncrieff J, Horowitz M. Depression is probably not caused by a chemical imbalance in the brain – new study. The Conversation. July 21, 2022. Accessed August 2, 2022. https://theconversation.com/depression-is-probably-not-caused-by-a-chemical-imbalance-in-the-brain-new-study-186672
3. Collins LM. Study says depression not caused by chemical imbalance, raising questions about antidepressants. Deseret News.July 21, 2022. Accessed August 2, 2022. https://www.deseret.com/2022/7/21/23272690/depression-not-caused-by-chemical-imbalance-study-serotonin-brain-stress-anxiety-antidepressants
4. McIntosh AM, Lewis C. Depression: low serotonin may not be the cause – but antidepressants still work. The Conversation. July 22, 2022. Accessed August 2, 2022. https://theconversation.com/depression-low-serotonin-may-not-be-the-cause-but-antidepressants-still-work-187477
5. Yasgur BS. No evidence low serotonin causes depression? Medscape.July 22, 2022. Accessed August 2, 2022. https://www.medscape.com/viewarticle/977753?src=wnl_tp10_daily_220730_MSCPEDIT&uac=430527SG&impID=4478009
6. Ang B, Horowitz M, Moncrieff, J. Is the chemical imbalance an ‘urban legend’? An exploration of the status of the serotonin theory of depression in the academic literature. SSM - Mental Health. 2022;2(100098).
7. Pies RW. Debunking the two chemical imbalance myths, again. Psychiatric Times. 2019;36(8).
8. Pies R. The myth of the chemical imbalance. RETURN. March 17, 2022. Accessed August 2, 2022. https://return.life/2022/03/17/the-myth-of-the-chemical-imbalance/
9. Schildkraut JJ, Kety SS. Biogenic amines and emotion. Science. 1967;156(3771):21-37.
10. Pies RW. Comments on “cyclical swings” by Professor Hannah Decker: the underappreciated “solid center” of psychiatry. Hist Psychol. 2016;19(1):60-65.
11. Dawson G, Pies RW. An ‘urban legend’ remains an ‘urban legend.’ SSM - Mental Health. 2022;2(100133).
12. Marin P, Bècamel C, Chaumont-Dubel S, et al. Classification and signaling characteristics of 5-HT receptors: toward a concept of 5-HT receptosomes. In: Müller CP, Cunningham KA, eds. Handbook of the Behavioral Neurobiology of Serotonin. Academic Press; 2020:91-120.
13. Joyce JB, Grant CW, Liu D, et al. Multi-omics driven predictions of response to acute phase combination antidepressant therapy: a machine learning approach with cross-trial replication. Transl Psychiatry. 2021;11(1):513.
14. Savitz J. The kynurenine pathway: a finger in every pie. Mol Psychiatry. 2020;25(1):131-147.
15. Carhart-Harris RL, Nutt DJ. Serotonin and brain function: a tale of two receptors. J Psychopharmacol. 2017;31(9):1091-1120.
16. Woolley DW, Shaw E. A biochemical and pharmacological suggestion about certain mental disorders. Proc Natl Acad Sci U S A. 1954;40(4):228-231.
17. Murphy DL, Campbell IC, Costa JL. The brain serotonergic system in the affective disorders. Prog Neuropsychopharmacol. 1978;2(1):5-31.
18. Snyder SH, Ferris CD. Novel neurotransmitters and their neuropsychiatric relevance. Am J Psychiatry. 2000;157(11):1738-1751.
19. Caviedes A, Lafourcade C, Soto C, Wyneken U. BDNF/NF-κB signaling in the neurobiology of depression. Curr Pharm Des. 2017;23(21):3154-3163.
20. Thase ME, Haight BR, Richard N, et al. Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials. J Clin Psychiatry. 2005;66(8):974-981.
21. Rege S. A focus on vortioxetine—mechanism of action and efficacy. Psychscenehub. July 7, 2012. Accessed August 2, 2022. https://psychscenehub.com/psychinsights/vortioxetine-mechanism-of-action-2
22. Dawson G. Disease modifying—or something else. Real Psychiatry. July 13, 2022. Accessed August 2, 2022. https://real-psychiatry.blogspot.com/2022/07/disease-modifying-or-something-else.html
23. Davis RL. Mechanism of action and target identification: a matter of timing in drug discovery. iScience. 2020;23(9):101487.
24. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357-1366.
25. Pies RW. Antidepressants: conundrums and complexities of efficacy studies. J Clin Psychopharmacol. 2016;36(1):1-4.
26. Vöhringer PA, Ghaemi SN. Solving the antidepressant efficacy question: effect sizes in major depressive disorder. Clin Ther. 2011;33(12):B49-B61.
27. Expert reaction to a review paper on the ‘serotonin theory of depression’ Science Media Center. July 20, 2022.Accessed August 2, 2022. https://www.sciencemediacentre.org/expert-reaction-to-a-review-paper-on-the-serotonin-theory-of-depression/
28. Peterson A. New concerns emerge about long term antidepressant use. Wall Street Journal. August 28, 2019. Accessed August 2, 2022. https://www.wsj.com/articles/new-concerns-emerge-about-long-term-antidepressant-use-11567004771
29. Pies RW. Antidepressant discontinuation: a tale of two narratives. J Clin Psychopharmacol. 2019;39(3):185-188.
For Further Reading:
Guerreiro F, Costa LN, Carneiro BA, et al. Metabolomics of major depressive disorder: a systematic review of clinical studies. Cureus. 2022;14(3):e23009.