Dr Pies is Professor Emeritus of Psychiatry and Lecturer on Bioethics and Humanities, SUNY Upstate Medical University; Clinical Professor of Psychiatry, Tufts University School of Medicine; and Editor in Chief Emeritus of 

 (2007-2010). Dr Pies is the author of several books. A collection of his works can be found on

Ronald W. Pies, MD

The concept of the placebo condition has been misunderstood, and the efficacy and benefits of antidepressants and lithium have been obscured or downplayed in the media.

Imagine that you have just been diagnosed with a life-threatening form of cancer. Your doctor tells you there is no cure, but a certain type of medication produces a robust response and remission—in about 15 of 100 cases. Knowing that the medication can have some serious side effects, would you still take it? For me—and for most people I know—the answer would be, “Of course—in a New York minute!”

And yet, a recent meta-analysis finding that 

antidepressants produce a robust response

—much stronger than placebo—in about 15% of depressed patients

 was widely depicted in the media as confirmation that antidepressants are “not much better than a sugar pill” and not worth the likely adverse effects. In my view, this is a serious misinterpretation of the data, at least with respect to individuals with severe or melancholic major depression. I’ll circle back to this issue shortly.

A recent study of lithium use and suicide rates in bipolar disorder also made headlines in the blogosphere and was widely cited by critics of psychiatric medication.

 This was another meta-analysis, analyzing randomized trials published after 2000, comparing lithium and placebo versus treatment as usual in mood disorders. The pooled suicide rate was 0.2% for people randomized to lithium, and twice that (0.4%) with placebo or treatment as usual. This result was judged as “not a statistically significant difference.” There was also no significant difference in rates of all non-fatal suicidal behavior. The authors concluded, “Evidence from randomized trials is inconclusive and does not support the idea that lithium prevents suicide or suicidal behavior.” This conclusion is roughly consistent with 

 but is contradicted by numerous studies showing that lithium use in bipolar disorder is associated with a substantial reduction in suicide rates. I will circle back to Nabi et al study as well, shortly.

The Placebo Condition is Not Just a “Sugar Pill”

In my experience, few among the general public—and not even some clinicians—fully understand how clinical studies of depression utilize placebos. To put it bluntly: There has never been, and likely never will be, a clinical study that simply compares an antidepressant to a sugar pill (ie, inert agent) and does nothing else

 the placebo condition in a typical study involves

[A]ttention, support, and patient education on a weekly basis for 6–8 weeks…[during which] the patient is typically seen weekly. Each of these visits lasts approximately 60 minutes, during which the patient’s response to the double-blind treatment is assessed and recorded. These visits involve giving the patient considerable education and support, even though ‘formal‘ psychotherapy is not provided. In other words, a considerable amount of energy is spent providing the ‘placebo’ treatment, energy that may well alter the natural outcome. Certainly, ‘placebo treatment’ in such a study is not the same as no treatment.

Preskorn righty argues that rather than calling it a “placebo response,” the effect of the placebo condition really represents a response to good clinical management. The “drug-specific response” is the difference between the total response to a drug and the response to such aforementioned good clinical management (ie, the placebo condition). So, if about 65% of patients respond well when receiving an antidepressant, and about 45% would have responded to good clinical management alone (ie, the placebo condition), the drug-specific response would be about 20%.

Preskorn has calculated that the drug-specific effect of most antidepressants in clinical trials is roughly 20-30%—not tremendous, but better than the 15% found in the Stone et al study. However, a narrow fixation on these numbers misses the big clinical picture. As Preskorn noted, “Antidepressants are tremendously valuable to the patients who specifically benefit from them and who otherwise would continue to suffer from their depressive illnesses.”

Indeed, the ultimate value of antidepressant treatment cannot be judged based solely on the drug-specific response rate—we must also consider the seriousness of the illnesses we treat

is a devastating illness, and it has been designated the leading cause of disability around the world.

 Severe depression is associated not only with greatly elevated rates of suicide, but also with attentional problems; memory deficits; and broad impairment in executive functions.

Finally, it is important to point out the key differences between clinical studies and the real world of psychopharmacology. The typical clinical study examines medication effects in a large group of participants; for a short duration (6-8 weeks); and usually with administration of a single antidepressant. In clinical practice, we are concerned with a particular patient who is often treated over months or years; and often, with a variety of agents and augmentation strategies. As my colleague, 

, has commented to me, “We treat until the patient is better.”

Indeed, the 15% finding from the Stone et al study does not equate to a 15% chance that Mr Smith or Ms Jones will eventually get better in the hands of an experienced psychiatrist who is using all the pharmacological tools of treatment at our disposal. Furthermore, most studies show that 

enhances response to medication, and that the level of remission obtained by successful acute-phase pharmacotherapy can be increased by a subsequent psychotherapeutic treatment.

Even if it were the case that “only” 15 in 100 depressed patients had a robust response to antidepressant treatment, the cumulative number of acutely depressed patients greatly helped by antidepressants over months and years would warrant judicious use of these medications. But again: We should be focusing not on this number, but on the soul-killing devastation of a major depressive episode. Here is one brief description from the writer William Styron (1925-2006):

Death was now a daily presence, blowing over me in cold gusts. Mysteriously and in ways that are totally remote from normal experience, the gray drizzle of horror induced by depression takes on the quality of physical pain ...[The] despair, owing to some evil trick played upon the sick brain by the inhabiting psyche, comes to resemble the diabolical discomfort of being imprisoned in a fiercely overheated room . . . [thus] it is entirely natural that the victim begins to think ceaselessly of oblivion. . .In depression the faith in deliverance, in ultimate restoration, is absent.

The study by Nabi et al—which concluded that the evidence “does not support the idea that lithium prevents suicide or suicidal behavior”—should be taken with a large grain of lithium salt!

There are numerous studies contradicting that claim, including at least 2 not cited or analyzed in the Nabi et al review. For example, Tondo and Baldessarini

 meta-analyzed 12 randomized trials in 10 reports (with at least 1 suicide in either treatment arm) including participants with bipolar disorder (BD) and major depressive disorder (MDD).Their study found a “substantial reduction of risks of suicide and [suicide] attempts with long-term lithium treatment, particularly in depressive phases of BD and in MDD.” Risk of 

 fatality was lower with lithium than with placebo, and probably lower than with mood-altering anticonvulsants or antidepressants.

Another recent study not included by Nabi et al was a systematic review of more than 200,000 participants in a variety of study types.

 Most ecological studies (eg, examining lithium in drinking water) reported a reduction in suicide in the general population, mostly in males. Most uncontrolled and controlled open-label trials also showed a reduction in the risk of suicide with long-term 

. These authors posited “an intrinsic anti-suicidal property of lithium, independent of its efficacy as [a] mood stabilizer.”

These 2 studies pointing to lithium’s anti-suicidal effects are hardly conclusive, but their omission ought to raise some red flags regarding the Nabi et al study. This also merits further analysis of its inclusion criteria and statistical methods. For example, my colleague, 

, has pointed out that the Nabi et al meta-analysis applied an entirely arbitrary cut-off year (ie, 2000

to the studies reviewed. And yet, 3 of 4 studies showing a benefit for lithium in prevention of suicide were published before the year 2000.

Finally, a recent review of lithium concluded, “Lithium is the most effective medication in psychiatry, because it has disease-modifying, not just symptomatic, effects. It is effective not only for bipolar illness but also for prevention of suicide, episodes of unipolar depression, mood temperaments, and possibly dementia. Its many benefits need better appreciation, while lowered dosing can reduce risks.”

Antidepressants are far from ideal medications. Nevertheless, on average, they are clearly superior to placebo in at least 15 in 100 depressed patients, for whom antidepressants can greatly reduce suffering and incapacity. However, the ultimate value of antidepressant treatment must be judged in light of the devastating effects of severe depression.

The ultimate value of antidepressant treatment cannot be judged based solely on the drug-specific response rate—we must also consider the seriousness of the illnesses we treat.

Having treated hundreds of patients who have bipolar spectrum disorders with lithium, I have observed that it is well-tolerated by most patients; and its adverse effects are almost always manageable with careful adjustment of lithium blood levels. Until we have more randomized, placebo-controlled studies of lithium and suicide rates, I believe that Osser’s conclusion stands, ie, “the best recommendation at this time regarding lithium in patients with bipolar disorder who are suicidal would be to consider it a worthwhile option.”

 is Professor Emeritus of Psychiatry and Lecturer on Bioethics and Humanities, SUNY Upstate Medical University; Clinical Professor of Psychiatry, Tufts University School of Medicine; and Editor in Chief Emeritus of 

As I inch my way toward full retirement, I will be taking a few months off to work on a book project and may not be contributing as frequently on these pages.

I would like to express my deep appreciation to Dr Sheldon Preskorn for his sage guidance and many publications pertaining to this article.Thanks to Dr Dave Osser for commenting on an early draft. This article grew from many valuable discussions with my colleagues Nassir Ghaemi, MD, Alexander Lisinski, MD, Fredrik Hieronymus, PhD, George Dawson, MD, Chris Aiken, MD, Jim Phelps, MD, Marc Stone, MD, Awais Aftab, MD, Andrew Nierenberg, MD, Randall F. Moore, MD, Roger McIntyre, MD, Daniel Morehead, MD, Cathryn Lewis, PhD, John J. Miller, MD, Mark L. Ruffalo, MSW, DPsa, and many colleagues I have inadvertently left out

A special thanks also go to Mark S. Komrad, MD, Cynthia Geppert, MD, MA, MPH, MSBE, DPS, and Anne Hanson, MD, for their collegial support and contributions to 

. Thanks as well to the diligent editorial staff of 

1.Stone MB, Yaseen ZS, Miller BJ, et al. 

Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis

2. Nabi Z, Stansfeld J, Plöderl M, Wood L, Moncrieff J (2022). 

Effects of lithium on suicide and suicidal behaviour: a systematic review and meta-analysis of randomised trials

Lithium and Suicide Prevention: More Thoughts on Recent VA Study

What do the terms "drug-specific response/remission rate" and "placebo" really mean?

Depression is the leading cause of disability around the world

Sequential combination of pharmacotherapy and psychotherapy in major depressive disorder: a systematic review and meta-analysis.

Antisuicidal effects in mood disorders: are they unique to lithium? 

10. Del Matto L, Muscas M, Murru A, et al. 

Lithium and suicide prevention in mood disorders and in the general population: A systematic review

How to mislead with meta-analysis: Lithium and suicide

. Oct. 24, 2022. Accessed November 9, 2022. 

https://psychiatryletter.com/how-to-lie-with-meta-analysis-lithium-and-suicide/

Lisinski A. Hooked on hype? A critical examination of recent anti-antidepressant reporting. 

A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults

Cipriani A, Hawton K, Stockton S, Geddes JR. 

Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis

A Brief History of Lithium Treatment in Psychiatry

Articles

In the case of antidepressants, a few recent articles may make it tempting to throw the baby out with the bathwater. But on close examination, that would be a mistake on many levels...  

Antidepressants, Placebos, and Lithium—Some Parting Thoughts

Recent evidence from randomized, placebo controlled trials (1979 to 2016) has shown that, in about 15% of patients with depression, antidepressant treatment is robustly superior to placebo—contrary to the often-repeated claim that 

 are “not much better than a sugar pill.”

 It is not yet clear what clinical or biological features make this subgroup so antidepressant-responsive, although differences between drug and placebo increased significantly (P<0.001) with greater baseline severity of depression.

Perhaps if we had a better understanding of antidepressants’ mechanisms of action—and how these mechanisms interact with this drug-responsive subgroup—we would be better able to predict which patients are likely to do well on antidepressants. Unfortunately, the matter is further complicated by the marked heterogeneity of 

 (MDD), which almost certainly contains several biological subtypes.

Critics of antidepressant treatment sometimes argue that antidepressants work—to the extent that critics acknowledge they work—by “numbing” or “blunting” emotions. Thus, Moncrieff has hypothesized that “Antidepressant-induced emotional numbness may directly reduce the intensity of people’s feelings of depression.”

 Similarly, Moncrieff and Horowitz have argued that

“…antidepressants appear to have a generalized emotion-numbing effect which may influence people’s moods, although we do not know how this effect is produced or much about it…[but] if antidepressants exert their effects as placebos, or by numbing emotions, then it is not clear that they do more good than harm.”

A recent review provided a much more nuanced picture, concluding that

“Emotional blunting has been reported by many patients diagnosed with MDD, but its neuropsychological basis remains indefinite. Most patients specifically attribute this symptom to their antidepressant medication; however, some psychologists believe that emotional blunting is also a residual symptom of depression due to incomplete treatment.”

In this article, we examine 3 independent studies of antidepressant treatment in major depression and its effects on emotional numbing or blunting. The key difference between 2 of these studies and much of the critical writing about antidepressants is their use of the 

Oxford Questionnaire on the Emotional Side-effects of Antidepressants

 (OQESA or OQuESA)—arguably the “gold standard” of assessment in this area.

 (This scale is now called the Oxford Depression Questionnaire, or ODQ.)

We shall see that none of the studies support the claim that antidepressants act to reduce depression through a process of emotional blunting or “numbing.” This is not to deny the clinical importance of assessing emotional blunting in the course of antidepressant treatment, nor is it to discount in any way the patient’s felt experience during treatment.

A Randomized-Controlled Study from France

Corruble and colleagues carried out a randomized, controlled, double-blind study comparing agomelatine (25-50 mg/d, n=164) and the SSRI, escitalopram (10-20 mg/d, n=160).

 Agomelatine is an atypical antidepressant that acts as an agonist to the melatonin receptors MT1 and MT2 and an antagonist of the serotonin receptors 5HT2B and 5HT2C. It is not approved for use in the United States. [

https://www.psychiatryadvisor.com/home/depression-advisor/unique-attributes-of-agomelatine-might-renew-interest/]

The trial involved 12 weeks of active treatment, then a 12-week double-blind extension. The effects of these drugs on emotional experiences were compared in patients who completed the OQESA (agomelatine: n= 25; escitalopram: n= 20). Agomelatine and escitalopram similarly improved depressive symptoms, but emotional blunting was reported by 60% of patients taking escitalopram, versus 28% of those taking agomelatine.

At baseline before antidepressant treatment, the emotional experiences probed were extremely common and the same in both treatment groups. Of 20 OQESA items, 8 were more common in the escitalopram group and 12 in the agomelatine group. The occurrence of blunting items was associated with the depressed state measured by the Hamilton Depression Scale (HAMD) and Clinical Global Impression (CGI). Emotional blunting was significantly less prominent after 2 weeks, 12 weeks, and 24 weeks of treatment. At 24 weeks, emotional blunting was endorsed more frequently in the escitalopram group than in the agomelatine group, despite similar depression ratings in the 2 groups.

The authors concluded that “emotional blunting is prominent among patients with MDD at baseline” and hypothesized that emotional blunting “…behaves overall like a correlate of depressive symptoms.”

“The simplest explanation for our present findings is that emotional blunting is a symptom of depression not measured in conventional scales, which is incompletely treated with SSRIs as compared with agomelatine.” 

In short, the study findings provide no support for the claim that antidepressants act by a generalized emotion-numbing effect.

Two More Studies Reach Similar Conclusions

In a 16-week study of 98 patients diagnosed with MDD, Aşçibaşi et al analyzed the effects of antidepressant treatment (SSRI, n = 41; SNRI, n=40, other, n=13) on Montgomery-Åsberg Depression Rating Scale (MADRS) and OQESA scores.

 The OQESA scale was used at the 8- and 16-week visits. In brief, the study found that 

as the rate of remitted patients is increased, OQESA scores get decreased; 

and furthermore, the OQESA score of the remitted group was statistically low when compared with that of the nonremitted group at the 8- and 16-week visits. OQESA and MADRS scores were significantly correlated in all assessments. The authors opined that “…during the treatment of depression, depression-related emotional blunting symptoms and antidepressant-related emotional adverse effects may coexist”; however, “…as the severity of [the] depressive syndrome decreases, the severity of emotional adverse effects due to the antidepressants also decreases.”

These findings are not consistent with the claim that 

 reduce depressive symptoms via an emotion-numbing effect.

Finally, Peters et al analyzed data from adult outpatients with acute MDD who participated in 3 8-week randomized controlled trials.

 Trials 1 and 2 were pooled (venlafaxine, n = 378; bupropion, n = 389; placebo, n = 383), and Trial 3 (escitalopram, n = 254; bupropion, n = 260) was analyzed separately. Emotional blunting was measured with the “inability to feel” item from the MADRS. The study found that emotional responsiveness 

, on average, in all treatment groups, and that fewer than 6% of participants experienced more emotional blunting after antidepressant treatment. The authors acknowledged that this was a short-term study that cannot speak to the long-term effects of antidepressant treatment. Nonetheless, they concluded that, “The study medications did not significantly decrease emotional responsiveness, and there was no evidence that emotional blunting mediated treatment response.” Rather—and consistent with the previous 2 studies—the authors hypothesized that “In acute treatment, emotional blunting may be better conceptualized as a residual symptom than as an adverse drug effect.”

Some Important Caveats and Study Limitations

 Emotional Blunting By Antidepressants or Persistent Depression Research

 highlight the methodological advantages and limitations of the research discussed in this article. The Peters et al study has the highest-quality evidence, using completed controlled clinical trials, with a substantial number of research participants in each arm, including the placebo group.

 The study also uses the most neutral screen for emotional blunting, in that there is no suggestion of what might be the cause.

 both use the OQESA/ODQ, which was designed to measure more than emotional blunting and has a separate section to determine if the patient endorses emotional blunting to be caused by antidepressant treatment. The wording of the questions—and the fact that no other possible etiology for emotional blunting is suggested in the remainder of the questionnaire—is a potential source of bias. In this case, the participants are forced to choose antidepressants as an etiology. In effect, this is a “leading question,” and research participants may be able to guess that antidepressant induced emotional blunting is a focus of the research.

 In contrast, MADRS Item 8 captures emotional blunting but does not suggest a specific cause.

Emotional numbing or blunting is a fairly common complaint among patients taking serotonergic antidepressants and appears less common with noradrenergic/dopaminergic agents like 

 It is important to inform and educate patients about this problem and to inquire about it periodically, since emotional blunting is both distressing and associated with poor adherence to antidepressant treatment.

 However, it should not be assumed that the patient’s antidepressant is necessarily 

 of the patient’s complaint, since emotional blunting or numbing is frequently reported at baseline (prior to treatment).

Indeed, the studies reviewed here show that antidepressants did 

 significantly decrease emotional responsiveness, and that treatment response was 

 mediated by emotional blunting. More likely, emotional numbing, in most cases, is a residuum of the original depression.

How, then, do antidepressants work? Their precise mechanism of action is not fully understood, although recent studies point to the role of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), which is now regarded as “… a key player in antidepressant action.”

 Antidepressants may also have anti-inflammatory effects—potentially important, since major depression is associated with elevated biomarkers of inflammation.

 During the past 4 years, 2 antidepressants modulating the glutamate system have been approved by the US Food and Drug Administration (FDA) for the treatment of major depression.

 Evidence supporting a role for stress, GABAergic dysfunction, altered neurosteroid signaling, and HPA axis dysregulation in 

 may suggest a role, in the near future, for neuroactive steroids in the treatment of depression.

In summary, there is no credible, scientific basis for telling patients that antidepressants are acting by means of generalized emotional numbing. On the contrary, our review shows that several antidepressants are actually associated with 

 of emotional numbing during the course of treatment. That said, if emotional blunting is convincingly related to use of a serotonergic antidepressant, changing to a noradrenergic/dopaminergic agent is a viable option for many patients.

 is recently retired from clinical practice and is a freelance writer and researcher on psychiatric topics. He writes the Real Psychiatry Blog. 

 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 

(2007-2010). He is the author of several books. A collection of his works can be found on Amazon.

Dr Pies would like to thank Dr Marc Stone, Dr Randall Moore, and Prof Cathryn Lewis for their helpful email comments on aspects of this article. Thanks to Dr John J. Miller for suggestions re: mechanism of action. The views presented here are solely those of the authors. 

1. Stone MB, Yaseen ZS, Miller BJ, et al. 

Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis.

Unpacking major depressive disorder: from classification to treatment selection.

Against the stream: antidepressants are not antidepressants – an alternative approach to drug action and implications for the use of antidepressants.

4. Moncrieff J, Horowitz M. Depression is probably not caused by a chemical imbalance in the brain – new study. 

. July 20, 2022. Accessed September 22, 2022. 

https://theconversation.com/depression-is-probably-not-caused-by-a-chemical-imbalance-in-the-brain-new-study-186672

Emotional blunting in patients with major depressive disorder: a brief non-systematic review of current research.

The Oxford Questionnaire on the Emotional Side-effects of Antidepressants (OQuESA): development, validity, reliability and sensitivity to change.

7. Corruble E, de Bodinat C, Belaïdi C, Goodwin GM; agomelatine study group. 

Efficacy of agomelatine and escitalopram on depression, subjective sleep and emotional experiences in patients with major depressive disorder: a 24-wk randomized, controlled, double-blind trial.

8. Aşçibaşi K, Çökmüş FP, Dikici DS, et al. 

Evaluation of emotional adverse effects of antidepressants: a follow-up study.

Emotional blunting with bupropion and serotonin reuptake inhibitors in three randomized controlled trials for acute major depressive disorder.

11. Goodwin GM, Price J, De Bodinat C, Laredo J. 

Emotional blunting with antidepressant treatments: a survey among depressed patients.

BDNF - a key transducer of antidepressant effects.

13. Tynan RJ, Weidenhofer J, Hinwood M, et al. 

A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia.

The effect of glutamatergic modulators on extracellular glutamate: how does this information contribute to the discovery of novel antidepressants?

The novel rapid-acting neurosteroid-based antidepressant generation.

A new depression scale designed to be sensitive to change.

As patients improve with antidepressant treatment, emotional numbing decreases.

Antidepressants Do Not Work by Numbing Emotions

Imagine that you, as a physician, just saw this headline splashed all over the internet: “Depression Probably Not Caused by Excessive Black Bile.” It was 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 in 2022 would be bothering 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.

 The review, by Moncrieff et al and published in 

 (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.”

Two of the review authors published a follow-up article, “Depression is probably not caused by a chemical imbalance in the brain – new study.”

 This article’s data went well beyond those 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 selective serotonin reuptake inhibitor [SSRI] antidepressants is worthwhile”; and that “it is not clear that SSRIs do more good than harm.”

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.”

 Media 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,

Such public consternation was completely understandable. In our view, the credulous, media-driven narrative generated by the review and the 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 review’s claims (

), each of which undermine the review’s thesis, as we will elaborate.

 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

 In fact, numerous statements from psychiatrists and researchers dating back to the 1960s include reasoning on why this is not likely. For example, pioneering psychiatrist Joseph J. Schildkraut, MD, and neuroscientist Seymour S. Kety, MD, explained this idea in 1967.

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 a single neurotransmitter—whether serotonin, norepinephrine, or some other biogenic amine. For more than 40 years, the operative paradigm in academic psychiatry has been the biopsychosocial model

—which was articulated in rudimentary form by Schildkraut and Kety themselves, in the very passage quoted previously. Furthermore, in the period of 1990 to 2010, psychiatrists and neuroscientists proposed at least 17 other hypotheses regarding depression, with 8 additional ideas since then.

3. The complexity of serotonergic systems and signaling in the brain is not captured in the review. Other 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.

 The review’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—those that incorporate the significance of 5-HT systems with other depression hypotheses—are under active development. Several research groups are using multiomics 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.

 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.

Selected Reviews of the Serotonin Hypothesis in Depression

4. Information in the review was hardly news to psychiatrists. As shown in 

 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.

5. The brain contains about 50 to 100 neurotransmitters.

 Hypotheses regarding depression have extended far beyond serotonin—indeed, far beyond biogenic amines. The review is focused narrowly on serotonin and does not address other small molecule or neuropeptide neurotransmitters that may figure in antidepressant action.

 Furthermore, the review does not address effective nonserotonergic antidepressants like bupropion

 or antidepressants like vortioxetine, which have very complex serotonergic effects.

6. In the area of drug development, there has been active debate about whether a specific mechanism of action and/or drug target is necessary for a medication to be approved. 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.

Eighteen drugs have been approved since 1993, yet the mechanism of action for 17 of the 18 medications is listed as 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 points out that disease complexity is important in considering mechanism of action and drug target identification, especially in complex central nervous system diseases.

 In any case, the precise mechanism of action of SSRIs cannot be determined from the data in the review.

7. The techniques described in the review were not designed to determine antidepressant efficacy, which is determined by randomized controlled clinical trials. Thus, no conclusions can be drawn from the 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.

As several neuroscientists and researchers pointed out in response to the 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.

 That heterogeneity complicates efforts to identify consistent biomarkers of psychiatric illnesses, including major depressive disorder.

Although there have been some critiques of the review, psychiatrist and researcher Michael Bloomfield, MD, states the issues particularly well

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 the 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 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 a single 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 this merits a careful risk/benefit discussion with patients.

 Similarly, particular care must be taken in discontinuing long-term antidepressant use.

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. Many drugs in clinical medicine work through unknown or multiple mechanisms, as SSRIs do, and this does not affect their safety, efficacy, or approval for medical use. Results of placebo-controlled studies offer ample evidence 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—and perhaps most importantly—we hope that patients and clinicians are not deterred from the use of antidepressants by the review, or by the fact that SSRIs’ mechanism of action is complex and not completely understood.

 The authors thank John J. Miller, MD; Heidi Anne Duerr, MPH; and Cynthia M.A. Geppert, MD, MA, MPH, 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.

2. Moncrieff J, Horowitz M. Depression is probably not caused by a chemical imbalance in the brain – new study. 

. Updated July 21, 2022. Accessed August 2, 2022. 

3. Collins LM. Study says depression not caused by chemical imbalance, raising questions about antidepressants. 

The latest claim that antidepressants don't work: refuted. 

Ronald W. Pies, MD

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