Episode 235: The Serotonin Hypothesis: Controversies and Nuance with Awais Aftab, MD
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Article Authors: Awais Aftab, MD, David Puder, MD
Article review team: Joanie Burns, DNP, APRN, PMHNP-BC, Erica Vega, MD
None of the presenters or review team have any conflict of interest.
On today’s podcast, I interviewed Awais Aftab, MD is a psychiatrist in Cleveland, OH, and a Clinical Assistant Professor of Psychiatry at Case Western Reserve University. His academic, educational, and public-facing work focuses on conceptual and critical issues in psychiatry. His first book, “Conversations in Critical Psychiatry,” (2024) is an edited volume of interviews published by Oxford University Press. He writes online on his Substack newsletter Psychiatry at the Margins. I would also recommend following him on X.
Introduction To The Serotonin Hypothesis And Controversies
There has been a recent surge in interest around the serotonin hypothesis of depression, the mechanisms of antidepressant action, and the efficacy of antidepressants. Meta-analyses and critical reviews (e.g., Moncrieff et al., 2023) have challenged the long-held assumption that depression is caused by a serotonin deficiency. While many researchers had already moved beyond this simplistic model years ago, its persistence in public discourse and pharmaceutical marketing made the critique particularly impactful. This notion became entrenched partly through pharmaceutical marketing in the 1990s. Given the popularity of the "chemical imbalance" narrative, these scientific debates have reignited public and academic debates about whether current treatments are based on flawed assumptions. Independently, there is a growing sentiment that antidepressants are being over-prescribed and there is increasing concern around historically-neglected adverse effects such as antidepressant withdrawal and sexual dysfunction (Aftab, 2024). Non-pharmacological interventions such as psychotherapy and lifestyle changes (see prior episodes on diet and exercise: 009, 010, 018, 059, 096, 131, 142, 163, 165, 179, 187, 230) are typically underutilized. Interest in newer treatments such as ketamine, psychedelics, and newer protocols of transcranial magnetic stimulation (TMS) has highlighted the limitations of first-line antidepressants. High-profile articles, books, and social media discussions have contributed to widespread public interest. These issues have become enmeshed with political developments and culture wars. In this context, clarity on what scientific literature says about serotonin abnormalities in depression, involvement of serotonergic pathways in regulation of mood and behavior, therapeutic mechanisms of antidepressants, and efficacy of antidepressants is essential.
What Is The “Serotonin Hypothesis”?
Discussions on the serotonin hypothesis quickly become confusing because there is no precise articulation of what the serotonin hypothesis of depression is or what the nature of the relationship between various aspects of the serotonergic system and various aspects of depression is supposed to be. As a result, it is not evident that disproving some versions of the serotonin hypothesis means that “serotonin has nothing to do with depression.”
Here is an incomplete list of the ways in which we might understand the relationship between depression and serotonin:
Depression is caused by low levels of serotonin in the brain or low serotonergic activity
Depression, generally or in some subset of patients, involves alterations of the serotonin signaling system (e.g. in the distribution or sensitivity of certain sorts of serotonin receptors)
The serotonergic system mechanistically links depressive symptoms and neurobiological dysfunctions in other aspects of brain functioning (e.g. neurogenesis or neuroplasticity)
The serotonin system is generally involved in the regulation of mood and temperament, and there may be no specific abnormality in the serotonin system in depression, by and large, but it still provides us a target for intervention with serotonergic antidepressants.
In addition, we can also talk about whether this involvement of serotonin is considered the central or primary cause of depression or whether it exists as one causal element in a more complex causal web.
We’ve known for decades that the “serotonin deficiency” version of this hypothesis is not supported by evidence. Many researchers have believed that some alterations exist in the serotonin system, and some preliminary research findings did suggest that, but nothing conclusive has emerged that commands a strong consensus.
The significance of monoamine depletion remains to be dispelled.
In 2007, a meta-analysis by Ruhé and colleagues, published in Molecular Psychiatry, reported that acute tryptophan depletion produces depressed mood in healthy individuals with a family history of depression [Hedges’ g (95% CI) −0.56 (−1.00 to −0.13)] and in patients with depression in remission [Hedges’ g of -1.90 (-3.02 to -0.78) for individuals not on antidepressants at the time of study, and Hedges’ g of -0.49 (-0.89 to -0.10) for those on antidepressants].
A 2015 meta-analysis by Kambeitz and Howes indicated that serotonin transporter availability in depressed patients is reduced in key regions of the limbic system. Fifty (n=27 in vivo and n=25 post mortem) studies including 877 patients with depression (mean age: 42.9 years) and 968 healthy controls (mean age: 42.7 years). In vivo neuroimaging studies indicated reduced serotonin transporter binding in the striatum (g=-0.39, p=0.01), the amygdala (g=-0.37, p=0.01) and the brainstem (g=-0.31, p=0.01), including the midbrain (g=-0.27, p=0.02), but no significant alteration in the thalamus or the hippocampus. The post mortem findings were not statistically significant.
And in October 2022, after the Moncrieff and colleagues (2023) paper was published online ahead of print in July 2022, Erritzoe and colleagues (2023) published the first direct assessment of serotonin release capacity in people with depression reported a reduction in serotonin release capacity in patients experiencing a major depressive episode. 17 antidepressant-free patients with major depressive episode and 20 healthy controls underwent 90-minute dynamic [11C]Cimbi-36 PET. Following d-amphetamine administration, a change in frontal nondisplaceable binding potential (BPND), a measure of serotonin release capacity, was significantly lower in individuals with major depressive episode than the HC group (HC: 15% ± 14% vs. MDE: 6.5% ± 20%, p = .041). (It’s a small study, and the difference between groups is not that striking; thus, these findings should be interpreted cautiously and considered preliminary.)
The end result is that the presence and nature of alteration of the serotonergic system in depression, a heterogenous syndrome, are open scientific problems. Depression is a highly heterogenous and multifactorial condition, and involves a range of neurophysiological, psychological, and sociopolitical factors. Given the heterogeneity of depression, it is highly unlikely that such abnormalities of serotonin, even if they exist, will be present in most individuals with depression.
Aside from the question of serotonin alteration or dysfunction, the involvement of the serotonin system in the general regulation of mood and emotions is backed by a large body of literature from animals as well as humans (e.g., Roberts et al., 2020 and Salvan et al., 2023). Serotonin’s effects on impulsivity and negative biases are supported by convergent evidence from various studies, and appear to be related to the SSRI hypothesized effects on emotional information processing.
Antidepressants, including SSRIs, show a consistent and large effect in forced swim test in rodents. The swim test involves the scoring of active (swimming and climbing) or passive (immobility) behavior when rodents are forced to swim in a cylinder from which there is no escape (Slattery & Cryan, 2012). Reduction in passive behavior has traditionally been interpreted as an antidepressant-like effect, however, others have argued that the rodent forced swim test measures stress-coping strategy, not depression-like behavior (Commons et al., 2017). (However, animal models like the FST have significant limitations in translating directly to human depression, given the complexity and variability of depressive symptoms and underlying biology in humans.) Regardless of the behavioral interpretation of FST, it is a demonstration of the behavioral effects of serotonergic transmission. In a 2018 meta-analysis of mouse FST, fluoxetine had an effect size of 1.99 compared to the control solution (p < 0.001) (Kara et al., 2018).
Using population-level brain imaging from the Human Connectome Project (HCP), Salvan et al. (2023) identified two distinct patterns in serotonin receptor network connectivity. The first pattern correlated with impulsivity (acting impatiently or without thinking), antisocial behaviors, and aggression; the second related to negatively biased reward processing (viewing rewards as less valuable), depression, and panic symptoms. These results replicate the established division of the effects of serotonin modulation on human behavior postulated by influential theories of serotonin function.
Colwell and colleagues used a selective serotonin releasing agent, fenfluramine, which directly elevates synaptic serotonin levels, to investigate its effects on behaviors traditionally associated with serotonin function. The study (n=53 participants) demonstrated through computational modeling that increased serotonin reduced sensitivity specifically to aversive outcomes (Cohen's d = -0.57, p = 0.04), influencing how participants responded to negative feedback during reinforcement learning tasks. Additionally, increased serotonin enhanced behavioral inhibition by promoting more cautious decision-making, particularly reducing impulsivity during aversive emotional interference (e.g., fearful faces) (Cohen’s d = 1.28, p < 0.0001). (Colwell et al,, 2024). These results suggest serotonin's role in reducing impulsivity and moderating negative emotional reactivity, possibly by dampening the exaggerated negative biases seen in anxiety or depression.
Even if there is no dysfunction of serotonin in depression, the link between serotonergic mechanisms and aspects of mood/behavior allows for the possibility of effective intervention. There is nothing wrong with kidneys in chronic heart failure, but we can use diuresis as a treatment; there is nothing wrong with prostaglandin pathways in infections, but we can act on them to treat fever; etc. Serotonergic pathways appear to be mechanistically involved in regulation of mood and emotions. There may not necessarily be anything “wrong,” “dysfunctional,” or “imbalanced” in these pathways (except in an indirect sense (Aftab, 2023)) — they may be working just fine — but if they are involved in how mood/emotions are regulated, they can be intervened on to produce desired effects.
Moncrieff’s 2023 Umbrella Review Focused on Serotonin Association, Not Antidepressant Efficacy
The current iteration of public and scientific debate around the serotonin hypothesis has revolved around a 2023 Umbrella Review by Moncrieff and colleagues.
This has been particularly controversial because the review was quickly used by the authors to publicly state that this challenges the idea that antidepressant medications are effective (since there is no “serotonin imbalance” to fix) and that depression cannot be considered to be a medical condition. Additionally, the authors stated that any potential benefits of antidepressants are attributable to a general blunting effect rather than specific actions on serotonin. These claims went far and beyond the questions addressed in the review.
They aimed to synthesize and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research.
Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded.
17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review.
Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002).
One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869).
Two meta-analyses of overlapping studies examining the 5-HT1A receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas.
One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75).
Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression.
The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.
Moncrieff and colleagues stated that some evidence was also consistent with the possibility that long-term antidepressant use reduces serotonin concentration.
Academic Critique Of Moncrieff’s Paper: Methodological Misrepresentation And Inappropriate Extrapolation
The review led to a fierce set of responses from the psychiatric community. The most important among them is a commentary by Jauhar and colleagues (2023), in Molecular Psychiatry, authored by 35 distinguished scientists, a who’s who of psychiatric and psychopharmacological research, aptly titled, “A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression.”
Jauhar and colleagues (2023) point out serious issues with the methodology of the umbrella review, identify compromising errors in methodological misrepresentation, and dispute the validity of the conclusions.
They argue that multiple methodological choices (such as choosing not to synthesize the results of individual meta-analyses because they included overlapping studies, exclusion of important primary studies relevant to the serotonin-depression link, assessing quality of evidence using a “modified” version of GRADE introduced in a post-hoc protocol amendment, etc.) biased the conclusions of the review.
The confounding effects of antidepressants were only considered if the results were positive. Jauhar and colleagues counter: “It is unclear why confounding of effects of antidepressants would not apply to all studies, i.e. not just where positive outcomes were seen: antidepressants are as likely to confound studies with negative results…” (Jauhar et al., 2023, p. 3150).
Aside from noting the exclusion of an important clinical and molecular imaging study of tryptophan depletion, Jauhar and colleagues also dispute the Moncrieff and colleagues’ interpretation of a meta-analysis of tryptophan depletion (Ruhé et al., 2007). The meta-analysis actually showed a large effect size of tryptophan depletion on mood in depressed people not taking antidepressants.
A more accurate interpretation is that tryptophan depletion studies suggest a role for 5-HT in people vulnerable to depression and in those remitted on SSRI treatment. In contrast, by citing a series of individual negative studies in healthy participants, the authors give the impression tryptophan depletion has no effect (Jauhar et al., 2023, p. 3150).
Several studies of circulating tryptophan concentrations were excluded from the umbrella review. L-tryptophan plasma concentrations have been shown to be decreased in major depression in small studies, including in unmedicated individuals.
Important molecular imaging evidence was misinterpreted. Moncrieff and colleagues stated that reduced binding of serotonin 1A receptors suggests increased levels of synaptic serotonin, but reduced binding can also be because of decreased receptor density or affinity. Jauhar and colleagues appear to have mistakenly assumed that serotonin 1A receptors are exclusively presynaptic autoreceptors, but most serotonin 1A receptors are post-synaptic heteroreceptors. Diminished availability of serotonin 1A receptors in unmedicated depression is consistent with lowered serotonin transmission, and Jauhar and colleagues say that this is a replicated finding in people who were not on antidepressants.
Moncrieff and colleagues stated that there is a lack of consistency in the brain areas in which serotonin transporter binding has been reported. Jauhar and colleagues argue that in serotonin transporter binding studies, a number of brain regions have actually been consistently implicated.
Moncrieff and colleagues attributed the results of serotonin transporter binding studies in meta-analyses to prior antidepressant treatment, but this ignores the fact that reduced serotonin transporter findings have also been reported in drug-naive populations, and they missed the fact that 149 out of 364 people in an included meta-analysis were drug naive.
A small study, published by Erriztoe and colleagues in 2023, employing a relatively direct assessment of serotonin release capacity, the first study of its kind, provided preliminary evidence of reduced serotonin release capacity in individuals with depression, which shows that this is still an active area of scientific inquiry and any closure is premature.
The serotonergic system continues to be an important mechanism implicated in the effects of traditional antidepressants as well as psychedelics.
To summarise, the methodology is inconsistent with an umbrella review, with substantial bias created by the authors’ chosen quality criteria, selective reporting, and interpretation of results. There is an underappreciation of the complexities of neuroscience and neuropsychopharmacology, and it is therefore impossible for the reader to draw valid or reliable conclusions. A more accurate, constructive conclusion would be that acute tryptophan depletion and decreased plasma tryptophan in depression indicate a role for 5-HT in those vulnerable to or suffering from depression, and that molecular imaging suggests the system is perturbed. The proven efficacy of SSRIs in a proportion of people with depression lends credibility to this position (Jauhar et al., 2023, Conclusion).
Concerns about methodology and interpretation are noted in some other commentaries as well. Bartova and colleagues (2023) write:
Since [Moncrieff et al.’s] deduction is based on selected literature covering serotonin exclusively, and hence, addressing only a part of the complex understanding of depression, we argue that the authors’ conclusion, that the serotonin theory cannot be empirically substantiated, cannot be derived from the present work. A meta-analysis revealing spatial-temporal dynamics of the serotonergic neurotransmission in depression underlines the fact that serotonin represents a crucial but dynamic neurobiological underpinning of depression… (Bartova et al., 2023, para 2).
The reference cited is a meta-analysis (Gryglewski et al., 2014) of molecular imaging of serotonin transporters in major depression which revealed reductions in serotonin transporter in midbrain and amygdala. Bartova and colleagues emphasize the complex etiology of depression of which the serotonin system is a part, and say, “… the serotonin theory of depression has been substantially extended and partly modified regarding neuroplastic mechanisms rather than not empirically substantiated as suggested by the authors.”
Jacobsen (2023) comments in a response statement: “Moncrieff et al. appears unfamiliar with serotonin biology and pharmacology. The review contains factual errors, makes conclusions serotonin neurobiology may not support, and quotes the cited literature in a selective manner” (Jacobsen, 2023). Jacobsen goes on to list “the most obvious errors” pertaining to tryptophan depletion and serotonin receptor studies.
In their response to comments, Moncrieff and colleagues (2023) begin by noting that critics appear to be advancing a confusing picture of the serotonin hypothesis both long discarded and still supported, which shows Moncrieff and colleagues’ remarkable lack of appreciation of the complexity of the issues at hand, the different ways in which the serotonergic system appears to be relevant to depression, and that there is no simple, well-defined serotonin hypothesis (à la serotonin deficiency) being defended here. Moncrieff and colleagues defend their methodology and the interpretation of results, but they fail to acknowledge the significance of tryptophan and serotonin receptor studies and other limitations pointed out by critics. They also continue to promote skepticism about antidepressant efficacy and push speculative ideas about antidepressant benefits being accounted for by effects such as emotional blunting, a hypothesis they consider to be more plausible than the entire scientific literature on neurotransmitters, neuroplasticity, inflammation, or neural networks!
Their response highlights that the umbrella review findings, even if accepted at face value, acquire scientific significance only in the broader context of a universe of critical beliefs that lack widespread scientific support, beliefs including a general dismissal of the neurobiology of depression, skepticism about antidepressant efficacy, and adoption of the “drug centered model.”
It is essential to emphasize that the popularized "chemical imbalance" narrative—often simplistically communicated in patient education—never fully reflected the complexity understood by neuroscientists. Depression involves multiple neurotransmitter systems (dopamine, norepinephrine, GABA, glutamate) interacting dynamically. Thus, disproving a simplistic serotonin deficiency does not invalidate serotonin’s role altogether.
The Real Goal Of The Umbrella Review Was To Shift Public Narratives Around Antidepressants
In retrospect, it seems clear that the goal of the Moncrieff and colleagues paper was not really scientific. Rather than seek to explicate the complicated role that the serotonergic system plays in depression, it appears to me that the authors were far more interested in refuting the popular “chemical imbalance” idea that exists in the public imagination. In order to effectively do so, and to generate provocative headlines, they needed a clean and simple conclusion with a critical hit on the serotonin-depression link. There was no room for intricacies, as that would have been a rhetorical impediment. The task of answering scientific questions by acknowledging complexities is quite different from the task of generating a public narrative with rhetorical appeal. Moncrieff and colleagues tried to hit two birds with one stone, and steamrolled over crucial scientific details in the process. Trying to score points in the psychiatric culture wars using scientific reviews is a recipe for bad science.
The validity of the "chemical imbalance" narrative has historically had little correlation with scientific findings regarding the serotonin system. Based on existing evidence from tryptophan and serotonin receptor binding studies, it does seem possible that alterations of the serotonin system play a role in depression, but the role of serotonin must be conceptualized within a whole network of other causal factors that range from molecular to cultural. None of this justifies characterizing depression as primarily a “chemical imbalance” (which is misleading at best, outright false at worst) or as fundamentally a problem of serotonin. Alterations in the serotonin system may be present in depression; however, the concept of a chemical imbalance, as commonly perceived by the public, lacks strong scientific support. Such a position may not generate headlines, but it does far more justice to the body of scientific evidence.
What do we know about how antidepressants work, especially in relationship to the serotonin system?
Individuals in states of depression and anxiety often show a negativity bias in processing emotionally significant information, and they can be “stuck” in a negative cognitive and emotional state such that their usual mental flexibility is lost. People with depression and anxiety are more likely to interpret neutral or ambiguous facial expressions as negative, such as assuming someone looks sad. They also tend to focus more on negative information and remember it more easily. Additionally, they don’t respond as positively to rewards, have less motivation to seek them out, and are more sensitive to punishment. Individuals not only view the world and themselves negatively but also find it difficult to benefit from positive experiences around them. Depressed people often struggle with cognitive and emotional flexibility and are limited in their ability to switch between emotions and experience a range of emotions.
Shifts in Emotional Information Processing
The cognitive neuropsychological hypothesis (Godlewska & Harmer, 2020) suggests that antidepressants lead to early positive changes in emotional processing that predict later clinical improvements. Studies on healthy volunteers who take antidepressants show a shift in emotional processing tasks, such as recognizing emotions in facial expressions, within days, sometimes even after a single dose. Similar effects have subsequently been reproduced in individuals with depression and are also supported by animal studies. SSRIs seem to primarily affect the processing of negative emotions, while norepinephrine reuptake inhibitors have a better impact on how participants respond to positive or rewarding stimuli.
An important aspect of this hypothesis is that while a positive shift in emotional processing is crucial, it is not necessarily sufficient on its own. The interaction between changes in emotional processing and the environment is vital to improvement. Social interactions allowing individuals to relearn positive emotional associations play a key role. Patients in more positive environments and with stronger social supports are more likely to benefit from these early emotional changes.
In a recent study (Colwell et al., 2024) in which serotonin was directly increased in brain synapses without using SSRIs, people became less sensitive to negative outcomes with more serotonin, and their self-control improved during decision-making. That is, an increase in synaptic serotonin decreases reinforcement sensitivity to loss outcomes and enhances behavioral inhibition and impulse control.
Cognitive Flexibility and Neuroplasticity
Shine and colleagues (2022) hypothesize the role of serotonin as allowing for a switch between modes of “cognitive automaticity” and “cognitive flux.” If a person becomes overly reliant on recurrent, well-established behavioral patterns—behaviors that are increasingly stereotyped and inflexible (such as depressive ruminations and compulsive behaviors)—this could be conceptualized as a state of “cognitive constipation.” Increasing serotonergic activity in such a situation allows for a switch to more flexible modes of cognitive processing. [A patient of mine once described his improvement on an antidepressant as, “It is as if I mentally feel more malleable, better able to identify and move away from unhelpful thinking patterns.”]
Mechanisms of this cognitive flexibility appear to be related to both serotonergic enhancement as well as neuroplasticity. Antidepressants appear to facilitate two key processes: rapid changes in emotional processing along with molecular cascades that promote long-term neuroplasticity (Page et al., 2024). There is a decent body of literature supporting the idea that antidepressants promote neurotropic signaling, particularly by increasing brain-derived neurotrophic factor (BDNF) and activating the receptor TrkB, which enhances synapse formation and maintenance. The outcome can resemble the flexible state seen in early brain development. Studies in rodents show that environmental interventions alone don’t induce functional changes, but when combined with antidepressants, they can reverse maladaptive behaviors like aggression. Similarly, in humans, antidepressants seem to create a “window of plasticity” that allows environmental factors, such as positive experiences or psychotherapy, to reshape neural activity (Page et al., 2024).
Effects on Neuroticism
SSRIs appear to reduce neuroticism (Soskin et al., 2012), a personality trait characterized by emotional instability, negative emotions, and a heightened sensitivity to stress. Neuroticism is closely linked to vulnerability to depression and anxiety, and a reduction in neuroticism appears to be a mediator of antidepressant response (Quilty et al., 2008).
The effects of neuroticism are well illustrated by Tang and colleagues in a 2009 placebo-controlled trial (n=240) that investigated the effects of an SSRI (paroxetine) on personality traits in patients with major depression. The study compared patients receiving paroxetine, a placebo, or cognitive therapy to examine whether SSRIs specifically influence these personality traits beyond simply improving depressive symptoms.
Patients who took paroxetine experienced significantly greater changes in neuroticism and extraversion compared to those who received a placebo. These personality changes were observed even after accounting for improvements in depression. Patients taking paroxetine showed much larger reductions in neuroticism (6.8 times greater) and increases in extraversion (3.5 times greater) than those on placebo, even when matched for similar depression improvements. While placebo patients experienced substantial reductions in depression, they showed minimal changes in neuroticism and extraversion. Cognitive therapy also led to notable changes in personality traits, particularly neuroticism, though the effect was less distinct once depression improvement was controlled for. In addition, a reduction in neuroticism during SSRI treatment was linked to lower relapse rates among those who responded to paroxetine, but this was not observed among those who responded to cognitive therapy.
This suggests that SSRIs have a specific pharmacological effect on neuroticism, and the effect on neuroticism contributes directly to acute and prophylactic therapeutic effects in treating depression.
Antidepressant effects on neuroticism may be linked to findings from animal models that antidepressants confer “resilience” against stress. In animal models, for example, chronic antidepressant administration can protect against the cognitive and emotional disturbances that result from chronic, unpredictable stress (Bondi et al., 2008).
Controversy Around The Efficacy Of Antidepressants
Antidepressants outperform placebo in randomized clinical trials in a manner that is statistically significant (that is, the results are unlikely to have occurred by chance alone). This was confirmed in one of the largest meta-analysis ever conducted, that included 522 clinical trials and 116K subjects: “In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline and 1·37 (1·16–1·63) for reboxetine” (Cipriani et al., 2018a, Findings). This finding has been consistently demonstrated in multiple meta-analyses and is widely accepted as robust. There is broad consensus that antidepressants exhibit statistically significant superiority over placebo.
The problem, however, is that the average difference between improvement in depressive symptoms — as measured by the most commonly used rating scale Hamilton Depression Rating Scale (HDRS) — is 2 points, or an effect size of 0.3 which is considered small. In a recent analysis of trials in the FDA database (baseline mean HDRS-17 score of 23; subjects had at least moderate severity depression on HDRS), HDRS score improved by 8 points on average in the placebo group vs 9.8 points in the antidepressant group. HDRS-17 total score ranges from 0 to 52. A difference of 2 points is not very meaningful at face-value (Stone et al., 2022).
This is the heart of the controversy: if antidepressants are clinically effective, why only a 2 point difference from placebo? How could a 2 point difference be indicative of anything but lack of clinically significant efficacy?
There are several non-mutually exclusive ways of responding to this:
An average different of 2 points obscures variation in treatment response and there are subgroups that display a substantial difference from placebo.
HDRS total score is an inappropriate measure of antidepressant efficacy; it may be sufficient to demonstrate a statistical separation from placebo, but does not appropriately quantify the magnitude of benefit.
Despite appearances, a 2 point HDRS average difference from placebo is indeed clinically meaningful.
#1. Different trajectories of response
Traditionally, this argument has been made using “response rates” (50% reduction in symptom severity) and “remission rates” (near complete resolution of depressive symptoms). The average response to placebo in meta-analyses is around 35% compared to about 50% for antidepressants (Cipriani et al., 2018b). While clinicians find thinking in terms of response and remission rates to be more clinically meaningful than average HDRS score (for good reasons), critics have objected to such binary categorizations as arbitrary and artificially inflating efficacy. There is an argument to be made in favor of response and remission rates, but I will not dwell on that here.
Fortunately, differences in response to antidepressants can also be demonstrated without appeal to arbitrary thresholds of response rate and remission rate.
Thase and colleagues (2011) used a special statistical model to demonstrate that patient subgroups of those benefiting or not benefiting from treatment could be identified, and that about 20% of patients benefited from escitalopram but not from placebo treatment (which corresponds to a number needed to treat [NNT] of 5).
In the Stone and colleagues (2022) analysis of antidepressant trials in the FDA database, 3 trajectories of response patterns were found, with average HDRS-17 score reductions of 16.0 (large response), 8.9 (nonspecific response), and 1.7 points (minimal response). Compared to placebo, antidepressant treatment was more likely to show large responses (24.5% v 9.6%) and less likely to show minimal responses (12.2% v 21.5%). Most responses (60-70%), however, were in the non-specific category, without a prominent difference between antidepressant and placebo. The NNT for large response for antidepressant vs placebo was 6.7. (There is a case to be made that this may be an underestimate based on differences among antidepressants in the database and because of inclusion of trials with pediatric patients.)
A medication that demonstrates a large response in 25% of patients (vs 10% of those in the placebo group) and reduces the likelihood of a minimal response is by no means a medication with “marginal efficacy” and with therapeutic effects that are “clinically meaningless.” This constitutes a clear signal of efficacy in a subset of patients that is otherwise obscured by a small average difference. The NNT of 6-7 also falls well within the respectable range when it comes to treatments in general medicine. Anyone who thinks that this constitutes marginal efficacy lacks a sense of perspective of what treatment efficacy generally looks like in medicine and clinical psychology.
The efficacy certainly leaves much to be desired. It is not as high as we would like it to be. It can be nonetheless be described as, in words of Peter Kramer, “ordinarily well.” It is also notable that this is efficacy data for a single trial of antidepressant. In clinical practice, it often takes 2 or 3 trials to find an antidepressant that the patient finds to be efficacious and tolerable, and the success rates are correspondingly higher in clinical practice.
#2. HDRS total score is not the right measure
Another response to the dilemma of “2 point HDRS difference from placebo” is to point out the limitations of using HDRS-17 for the purpose of evaluating antidepressant efficacy. The 17 items included in the scale represent an idiosyncratic mix. There is, for example, only one item about depressed mood, but three items about insomnia. It also includes symptoms peripherally related to depression, such as hypochondriasis, sexual symptoms, and gastrointestinal symptoms. The inclusion of sexual and gastrointestinal symptoms is particularly problematic because these are also recognized side effects of antidepressant medications, so the scale poorly discriminates between depressive symptoms and medication side effects. Furthermore, each item is given equal weight and the validity of adding these items into a single meaningful score is questioned by many.
A study by Hieronymus and colleagues (2016) provides an obvious example of the dilemma of relying on HDRS scores, as demonstrated in their patient-level post-hoc analyses of antidepressant effects on individual items of HDRS, in particular the depressed mood item. Table 3, from the article, shows an average effect size of 0.27 for HDRS total score, but 0.40 for the depressed mood item. It is also interesting to see the pattern of response among different items — there are many that change poorly. Again, emphasizing the inability of total score to illuminate the magnitude of antidepressant efficacy.
Furthermore, they also note that the depressed mood item more consistently separates active treatment from placebo at week 6:
While 18 out of 32 comparisons [56%] failed to separate active drug from placebo at week 6 with respect to reduction in HDRS-17-sum, only 3 out of 32 comparisons [9%] were negative when depressed mood was used as an effect parameter (P<0.001). The observation that 29 out of 32 comparisons detected an antidepressant signal from the tested SSRI suggests the effect of these drugs to be more consistent across trials than previously assumed (Hieronymus et al., 2016, Discussion).
Considerations, such as these, may be related to the fact that in the PANDA study in primary care patients, while the differences in the depression rating scales (PHQ-9 and BDI-II) were unimpressive (not statistically significant for PHQ-9 and only statistically significant for BDI-II at 12 weeks), a crude 1-item measure of “Feeling better (self-rated improvement)” showed prominent separation: 59% felt better with antidepressant at 12 weeks compared to 42% with placebo (Lewis et al., 2019).
#3. A 2-point average difference from placebo is nonetheless meaningful
There are different ways of supporting this point. The first relates to what we have discussed in #1 — averages can obscure subgroup differences.
A second way is to compare it to the effect of other standard treatments. In the case of depression, psychotherapy provides a meaningful comparison. A number of trials have compared antidepressant treatment to short-term manualized psychotherapy (usually CBT) and the results are pretty clear across multiple trials: both antidepressant and short-term manualized psychotherapy have equal effects on depression rating scales, and the combination of both is superior to individual treatment. This is best illustrated in a meta-analysis by Cuijpers and colleagues (2020). As a consequence, a firm commitment to the view that antidepressants are only marginally effective necessitates the acceptance that short-term manualized psychotherapy, which represents the majority of randomized controlled trial evidence for psychotherapy, is also only marginally effective in the acute treatment of depression. (There is some data to suggest that psychotherapy and combination of psychotherapy and antidepressant have more sustained long-term effects than antidepressant alone.)
A relevant comparison can be drawn with treatments in general medicine. A key reference in this context is a study by Leucht and colleagues (2012), which demonstrates that the effect size of antidepressants, relative to placebo, is comparable to that of other established medical treatments.
A third category of response makes the point that a 2-point difference from placebo group is different from a 2-point difference from no treatment. Treatment in the placebo group is not simply a dummy pill, but also involves extensive weekly evaluations with a host of built in psychosocial support and, at times, financial compensation. The improvement seen in the placebo group is likely a mixture of natural history, regression to the mean, expectancy effects, and therapeutic effects of indirect psychosocial support.
This points to a problem with the additivity of antidepressant and “placebo” effects. A robust discussion of this aspect is highlighted by Peter Kramer in Ordinarily Well. Kramer uses the example of vodka vs placebo tonic water to make the point. If we see “4 points” of intoxication/incoordination on an imaginary scale with consumption of vodka, vs “2 points” of intoxication/incoordination with placebo tonic water, the “real” effect of vodka is not vodka minus placebo. We have subtracted too much because effects of alcohol and expectancy are not additive. Vodka + placebo/expectancy (4 points + 2 points) does not equal 6 points; it is still 4 points.
In the case of depression, the antidepressant and psychotherapy effects are not additive. “[T]he common outcome in psychiatric research is, two and two do not equal four,” Kramer further elaborates:
Placebo and antidepressant effects are unlikely to be additive. Much of what medication accomplishes, it achieves on its own…. In antidepressant trials, almost certainly, full additivity does not apply—and yet our calculations, including ones for effect sizes, assume it. Virtually every formal estimate of antidepressant efficacy arises from a premise, the right to subtract, that is unproven and likely wrong. Our estimates of drug efficacy run too low (Kramer, 2017, p. 112 ).
The additivity assumption is also noted by Kirsch and colleagues (2022), who are otherwise skeptical of antidepressant efficacy: “If antidepressant drug effects and antidepressant placebo effects are not additive… then antidepressant drugs have substantial pharmacologic effects that are duplicated or masked by placebo” (Kirsch et al., 2022)
According to Kramer, this is precisely what is going on, and leads us to a certain uncomfortable conclusion:
We cannot count on additivity. This uncertainty presents a challenge for evidence-based psychiatry: Our controlled trials, conventionally analyzed, may not reflect reality. Despite our use of randomization, they are likely subject to a consistent confound, arising from a technical bias against antidepressants. We know that antidepressants work. We cannot say how well (Kramer, 2017, p 113. )
Antidepressant Efficacy and Depression Severity
Some early analyses such as by Khan and colleagues (2005) have reported the effect size of antidepressants increases with the severity of depression, such that when considering placebo vs. antidepressant effect, for the severe group there is a difference of roughly 8.3 points on HAM-D, but the overall response to antidepressant is 16.5 in this category. This is a very significant decrease in depressive symptoms.
However, subsequent analyses have re-assessed these estimates and the resulting picture is more complex.
Rabinowitz and colleagues (2016), for example, reported in their analyses of RCTs (n=10,737) that there was no significant interaction between baseline depression severity and antidepressant response (placebo vs active treatment) when using patient-level data, and a significant relationship emerged only when using trial-level data [Patient-level data is more accurate]. The drug-placebo mean difference (HDRS) was 2.04 for low baseline severity, 1.82 for medium, and 2.41 for high.
Furukawa and colleagues (2018) examined individual participant data meta-analysis of RCTs for second-generation antidepressants from Japan, and found that interaction between baseline severity and treatment was not statistically significant (coefficient = −0.04, 95% confidence interval: −0.16 to 0.08, P = 0.49). "We may expect as much benefit from antidepressant treatments for mild, moderate or severe major depression."
Hieronymus and colleagues (2019) conducted item-based patient-level, post-hoc analysis and showed that there is no relationship between baseline severity and antidepressant response as far as core symptoms of depression are concerned, but more peripheral symptoms on HDRS-17 show a more pronounced response to treatment as baseline severity increases.
Note. Reprinted from “Influence of baseline severity on the effects of SSRIs in depression: An item-based, patient-level post-hoc analysis”, by Hieronymus et al., 2019, The Lancet Psychiatry, 6(9), 745–752, Figure 2.
Note. Reprinted from “Influence of baseline severity on the effects of SSRIs in depression: An item-based, patient-level post-hoc analysis”, by Hieronymus et al., 2019, The Lancet Psychiatry, 6(9), 745–752, Figure 4.
And finally, in an individual participant data analysis of FDA trials by Stone and colleagues (2022):
When baseline severity was used as the only covariate, improvement with drug and placebo increased with greater baseline severity. The advantage of drug over placebo increased with baseline severity by 0.09 points (95% confidence interval 0.06 to 0.12) for every one point increase in severity. The estimated difference between drug and placebo at a baseline severity of 16 points (5th centile) was 1.1 points, increasing to 2.5 points at a baseline severity of 29.6 points (95th centile) (Stone et al., 2022, p. 3)
.
From discussion:
Previous analyses of the relation between baseline severity and the efficacy of antidepressants found null to moderate (slope about 0.3) effects, and these effects might be attributable to instrument behavior rather than patient experience. We found that the effect of baseline severity was statistically significant (P<0.001) but small (slope about 0.1) (Stone et al., 2022, p. 6 ).
Therefore, it appears that the effect of antidepressants on core symptoms of depression compared to placebo is generally similar across different levels of severity, but improvements in peripheral symptoms, such as insomnia, is more pronounced at higher severity. Antidepressants are effective in cases of mild depression as well, however, given their side-effect profiles (such as gastrointestinal effects, sexual dysfunction, weight gain, and antidepressant withdrawal), the risk-benefit ratio is more favorable if mild depression is preferentially treated with psychosocial and lifestyle interventions. This is the position taken by depression practice guidelines by NICE and RANZCP as well (see also Malhi et al., 2022 for a comparison of guidelines from the UK and Australia/New Zealand, which demonstrate significant convergence in recommendations).
Note. Reprinted from “The management of depression: The evidence speaks for itself”, by Malhi et al., 2023, The British Journal of Psychiatry, 222(3), 97–99, Figure 1.
Conclusion
In conclusion, the controversies surrounding the serotonin hypothesis underscore the importance of approaching depression through a nuanced and multidimensional framework. As explored throughout this paper, simplistic narratives, such as the “chemical imbalance” idea, though widely communicated to the public, have never accurately reflected the complex realities uncovered by neuroscientific and clinical research. Depression involves dynamic interactions among multiple neurotransmitter systems—not just serotonin, but dopamine, norepinephrine, glutamate, and GABA—as well as broader neurobiological factors such as neuroplasticity, stress-response dysregulation, inflammation, genetic predispositions, and psychological influences including cognitive biases and personality traits.
Critically examining Moncrieff and colleagues' (2023) umbrella review revealed significant methodological limitations and interpretative overreach, demonstrating that disproving an overly simplistic serotonin-deficiency hypothesis neither invalidates serotonin’s important role nor diminishes the relevance of antidepressants that act upon serotonergic mechanisms. Effective treatment, as discussed extensively in prior episodes of PsychiatryPodcast.com, integrates pharmacological interventions within a broader biopsychosocial context—encompassing psychotherapy, lifestyle modifications, diet, exercise, meaningful relationships, and supportive environmental factors.
Additionally, drawing upon the concept of reflective functioning (the capacity to reflect upon, understand, and interpret complex mental states in oneself and others), clinicians can move beyond oversimplified explanations and instead engage in deeper, more nuanced dialogues with patients about their depression. As clinicians and researchers, we aspire to help our patients deepen their understanding beyond the popularized but misleading “depression equals low serotonin” narrative, and toward a more holistic perspective where they value not only medication but also therapy, nutrition, exercise, and sustained lifestyle changes. Yet, this message—that meaningful improvement is not a quick fix—is less seductive. It highlights that lasting change involves deeper psychotherapy, altering daily routines, making intentional dietary choices, and maintaining consistent physical activity.
Just as patients may sometimes enter lower states of reflective function, idealizing or devaluing their early attachment figures and losing sight of relational complexities, we as healthcare providers can also find ourselves drawn to simplified, rigid narratives—idealizing certain treatments or prematurely dismissing others, especially under conditions of short visits, clinical fatigue, or burnout. Maintaining our own reflective function, along with the humility and curiosity it fosters, is essential to navigating the inherent complexity of depression and providing genuinely patient-centered care. Indeed, after years of weekly therapy—sometimes hundreds of hours spent with one patient—the deeper, more personal meanings and origins of their depression finally come to light, reinforcing that complexity, patience, and reflective understanding must remain central to our approach.
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