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The Serotonin Basis of Depression: Unraveling the Neurochemical Web

Written By: Dr. Joao L. de Quevedo, MD, PhD

Depression, a pervasive and debilitating mental health disorder, has long been a subject of scientific inquiry. Among the myriad factors contributing to its complex etiology, serotonin, a neurotransmitter, has emerged as a central player in the neurochemical landscape of depression. This essay delves into the serotonin basis of depression, exploring the intricate interplay between neurotransmitter dynamics, neural circuits, and the profound impact on mood regulation.

Serotonin, often dubbed the “feel-good” neurotransmitter, is intricately involved in the regulation of mood, appetite, and sleep. It is primarily produced in the neurons of the raphe nuclei in the brainstem and is subsequently released into various brain regions. The serotonin hypothesis posits that an imbalance or dysfunction in serotonin neurotransmission contributes significantly to the development and maintenance of depressive disorders.

The cornerstone of this hypothesis lies in the serotonin transporter (SERT), a protein responsible for the reuptake of serotonin from the synaptic cleft back into the presynaptic neuron. Research has shown that alterations in SERT function can lead to impaired serotonin reuptake, resulting in decreased serotonin availability in the synaptic cleft. This deficiency disrupts normal communication between neurons and compromises mood regulation.

The serotonin basis of depression is further underscored by the effectiveness of selective serotonin reuptake inhibitors (SSRIs), a class of antidepressant medications. SSRIs work by blocking the reuptake of serotonin, thereby increasing its concentration in the synaptic cleft. This elevation in serotonin levels is thought to alleviate depressive symptoms by enhancing neurotransmission and restoring balance within neural circuits.

Moreover, the serotonin system is intricately linked with other neurotransmitter systems, such as norepinephrine and dopamine, forming a complex network known as the monoamine hypothesis. Dysregulation in any of these systems can contribute to depressive symptoms. The serotonin basis of depression thus extends beyond serotonin alone, emphasizing the need for a holistic understanding of the intricate neurochemical interactions underlying this multifaceted disorder.

While the serotonin hypothesis provides valuable insights into the neurobiology of depression, it is crucial to recognize the inherent complexity of this disorder. Depression is a heterogeneous condition with various contributing factors, including genetic predisposition, environmental stressors, and alterations in neural circuitry. Serotonin dysfunction may be a critical piece of the puzzle, but it does not represent the entirety of the depressive landscape.

In conclusion, the serotonin basis of depression offers a compelling framework for understanding the neurochemical underpinnings of this pervasive mental health disorder. The intricate dance of serotonin within the neural circuits highlights its pivotal role in mood regulation. However, a comprehensive understanding of depression requires consideration of the myriad factors that contribute to its development. As research advances, unraveling the serotonin basis of depression will undoubtedly continue to shed light on novel therapeutic approaches and enhance our ability to alleviate the burden of this widespread affliction.

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Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature

• Jeffrey R Lacasse,

* To whom correspondence should be addressed. E-mail: [email protected]

• Jeffrey R Lacasse, 
• Jonathan Leo

Published: November 8, 2005

• https://doi.org/10.1371/journal.pmed.0020392
• Reader Comments

Citation: Lacasse JR, Leo J (2005) Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature. PLoS Med 2(12): e392. https://doi.org/10.1371/journal.pmed.0020392

Copyright: © 2005 Lacasse and Leo. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Competing interests: The authors declare that no competing interests exist and that they received no funding for this work.

Abbreviations: DTCA, direct-to-consumer advertising; FDA, Food and Drug Administration; SSRI, selective serotonin reuptake inhibitor

In the United States, selective serotonin reuptake inhibitor (SSRI) antidepressants are advertised directly to consumers [ 1 ]. These highly successful direct-to-consumer advertising (DTCA) campaigns have largely revolved around the claim that SSRIs correct a chemical imbalance caused by a lack of serotonin (see Tables 1 and 2 ). For instance, sertraline (Zoloft) was the sixth best-selling medication in the US in 2004, with over $3 billion in sales [ 2 ] likely due, at least in part, to the widely disseminated advertising campaign starring Zoloft's miserably depressed ovoid creature. Research has demonstrated that class-wide SSRI advertising has expanded the size of the antidepressant market [ 3 ], and SSRIs are now among the best-selling drugs in medical practice [ 2 ].

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Given the multifactorial nature of depression and anxiety, and the ambiguities inherent in psychiatric diagnosis and treatment, some have questioned whether the mass provision of SSRIs is the result of an over-medicalized society. These sentiments were voiced by Lord Warner, United Kingdom Health Minister, at a recent hearing: “…I have some concerns that sometimes we do, as a society, wish to put labels on things which are just part and parcel of the human condition”[ 4 ]. He went on to say, “Particularly in the area of depression we did ask the National Institute for Clinical Excellence [an independent health organisation that provides national guidance on treatment and prevention] to look into this particular area and their guideline on depression did advise non-pharmacological treatment for mild depression” [ 4 ]. Sentiments such as Lord Warner's, about over-medicalization, are exactly what some pharmaceutical companies have sought to overcome with their advertising campaigns. For example, Pfizer's television advertisement for the antidepressant sertraline (Zoloft) stated that depression is a serious medical condition that may be due to a chemical imbalance, and that “Zoloft works to correct this imbalance” [ 5 ]. Other SSRI advertising campaigns have also claimed that depression is linked with an imbalance of the neurotransmitter serotonin, and that SSRIs can correct this imbalance (see Table 2 ). The pertinent question is: are the claims made in SSRI advertising congruent with the scientific evidence?

The Serotonin Hypothesis

In 1965, Joseph Schildkraut put forth the hypothesis that depression was associated with low levels of norepinephrine [ 6 ], and later researchers theorized that serotonin was the neurotransmitter of interest [ 7 ]. In subsequent years, there were numerous attempts to identify reproducible neurochemical alterations in the nervous systems of patients diagnosed with depression. For instance, researchers compared levels of serotonin metabolites in the cerebrospinal fluid of clinically depressed suicidal patients to controls, but the primary literature is mixed and plagued with methodological difficulties such as very small sample sizes and uncontrolled confounding variables. In a recent review of these studies, the chairman of the German Medical Board and colleagues stated, “Reported associations of subgroups of suicidal behavior (e.g. violent suicide attempts) with low CSF–5HIAA [serotonin] concentrations are likely to represent somewhat premature translations of findings from studies that have flaws in methodology” [ 8 ]. Attempts were also made to induce depression by depleting serotonin levels, but these experiments reaped no consistent results [ 9 ]. Likewise, researchers found that huge increases in brain serotonin, arrived at by administering high-dose L-tryptophan, were ineffective at relieving depression [ 10 ].

https://doi.org/10.1371/journal.pmed.0020392.g001

Contemporary neuroscience research has failed to confirm any serotonergic lesion in any mental disorder, and has in fact provided significant counterevidence to the explanation of a simple neurotransmitter deficiency. Modern neuroscience has instead shown that the brain is vastly complex and poorly understood [ 11 ]. While neuroscience is a rapidly advancing field, to propose that researchers can objectively identify a “chemical imbalance” at the molecular level is not compatible with the extant science. In fact, there is no scientifically established ideal “chemical balance” of serotonin, let alone an identifiable pathological imbalance. To equate the impressive recent achievements of neuroscience with support for the serotonin hypothesis is a mistake.

With direct proof of serotonin deficiency in any mental disorder lacking, the claimed efficacy of SSRIs is often cited as indirect support for the serotonin hypothesis. Yet, this ex juvantibus line of reasoning (i.e., reasoning “backwards” to make assumptions about disease causation based on the response of the disease to a treatment ) is logically problematic—the fact that aspirin cures headaches does not prove that headaches are due to low levels of aspirin in the brain. Serotonin researchers from the US National Institute of Mental Health Laboratory of Clinical Science clearly state, “[T]he demonstrated efficacy of selective serotonin reuptake inhibitors…cannot be used as primary evidence for serotonergic dysfunction in the pathophysiology of these disorders” [ 12 ].

Reasoning backwards, from SSRI efficacy to presumed serotonin deficiency, is thus highly contested. The validity of this reasoning becomes even more unlikely when one considers recent studies that even call into question the very efficacy of the SSRIs. Irving Kirsch and colleagues, using the Freedom of Information Act, gained access to all clinical trials of antidepressants submitted to the Food and Drug Administration (FDA) by the pharmaceutical companies for medication approval. When the published and unpublished trials were pooled, the placebo duplicated about 80% of the antidepressant response [ 13 ]; 57% of these pharmaceutical company–funded trials failed to show a statistically significant difference between antidepressant and inert placebo [ 14 ]. A recent Cochrane review suggests that these results are inflated as compared to trials that use an active placebo [ 15 ]. This modest efficacy and extremely high rate of placebo response are not seen in the treatment of well-studied imbalances such as insulin deficiency, and casts doubt on the serotonin hypothesis.

Also problematic for the serotonin hypothesis is the growing body of research comparing SSRIs to interventions that do not target serotonin specifically. For instance, a Cochrane systematic review found no major difference in efficacy between SSRIs and tricyclic antidepressants [ 16 ]. In addition, in randomized controlled trials, buproprion [ 17 ] and reboxetine [ 18 ] were just as effective as the SSRIs in the treatment of depression, yet neither affects serotonin to any significant degree. St. John's Wort [ 19 ] and placebo [ 20 ] have outperformed SSRIs in recent randomized controlled trials. Exercise was found to be as effective as the SSRI sertraline in a randomized controlled trial [ 21 ]. The research and development activities of pharmaceutical companies also illustrate a diminishing role for serotonergic intervention—Eli Lilly, the company that produced fluoxetine (Prozac), recently released duloxetine, an antidepressant designed to impact norepinephrine as well as serotonin. The evidence presented above thus seems incompatible with a specific serotonergic lesion in depression.

Although SSRIs are considered “antidepressants,” they are FDA-approved treatments for eight separate psychiatric diagnoses, ranging from social anxiety disorder to obsessive-compulsive disorder to premenstrual dysphoric disorder. Some consumer advertisements (such as the Zoloft and Paxil Web sites) promote the serotonin hypothesis, not just for depression, but also for some of these other diagnostic categories [ 22 , 23 ]. Thus, for the serotonin hypothesis to be correct as currently presented, serotonin regulation would need to be the cause (and remedy) of each of these disorders [ 24 ]. This is improbable, and no one has yet proposed a cogent theory explaining how a singular putative neurochemical abnormality could result in so many wildly differing behavioral manifestations.

In short, there exists no rigorous corroboration of the serotonin theory, and a significant body of contradictory evidence. Far from being a radical line of thought, doubts about the serotonin hypothesis are well acknowledged by many researchers, including frank statements from prominent psychiatrists, some of whom are even enthusiastic proponents of SSRI medications (see Table 1 ).

However, in addition to what these authors say about serotonin, it is also important to look at what is not said in the scientific literature. To our knowledge, there is not a single peer-reviewed article that can be accurately cited to directly support claims of serotonin deficiency in any mental disorder, while there are many articles that present counterevidence. Furthermore, the Diagnostic and Statistical Manual of Mental Disorders (DSM) , which is published by the American Psychiatric Association and contains the definitions of all psychiatric diagnoses, does not list serotonin as a cause of any mental disorder. The American Psychiatric Press Textbook of Clinical Psychiatry addresses serotonin deficiency as an unconfirmed hypothesis, stating, “Additional experience has not confirmed the monoamine depletion hypothesis” [ 25 ].

Consumer Advertisements of Antidepressants

Contrary to what many people believe, the FDA does not require preapproval of advertisements. Instead, the FDA monitors the advertisements once they are in print or on the air [ 26 ]. Misleading content is frequently found in various DTCA campaigns [ 27 ]; hence, it is valuable to compare SSRI advertisements to the scientific evidence reviewed above. These SSRI ads are widely promulgated; hundreds of millions of dollars have been spent disseminating these advertisements, and one study found that over 70% of surveyed patients reported exposure to antidepressant DTCA [ 28 ].

The Role of the FDA

In the US, the FDA monitors and regulates DTCA. The FDA requires that advertisements “cannot be false or misleading” and “must present information that is not inconsistent with the product label” [ 27 ]. Pharmaceutical companies that disseminate advertising incompatible with these requirements can receive warning letters and can be sanctioned. The Irish equivalent of the FDA, the Irish Medical Board, recently banned GlaxoSmithKline from claiming that paroxetine corrects a chemical imbalance even in their patient information leaflets [ 29 ]. Should the FDA take similar action against consumer advertisements of SSRIs?

As just one example, the prescribing information for paroxetine, which is typical of the SSRI-class drugs, states, “The efficacy of paroxetine in the treatment of major depressive disorder, social anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder (PD), generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin. Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets” [ 30 ].

In other words, the mechanism of action of paroxetine has not been definitively established, and remains unconfirmed and presumptive (the prescribing information states that the efficacy of the drug “is presumed to be linked to potentiation of serotonergic activity” ([ 30 ], our italics added). Although there is evidence that paroxetine inhibits the reuptake of serotonin, the significance of this phenomenon in the amelioration of psychiatric symptoms is unknown, and continually debated [ 12 , 31 ]. Most importantly, the prescribing information does not mention a serotonin deficiency in those administered paroxetine, nor does it claim that paroxetine corrects an imbalance of serotonin. In contrast, the consumer advertisements for paroxetine present claims that are not found in this FDA-approved product labeling.

In order to determine whether these advertisements actually comply with FDA regulations, it is useful to consult the Code of Federal Regulations under which DTCA is regulated. The regulations state that an advertisement may be cited as false or misleading if it “[c]ontains claims concerning the mechanism or site of drug action that are not generally regarded as established by scientific evidence by experts qualified by scientific training and experience without disclosing that the claims are not established and the limitations of the supporting evidence…” ([ 32 ], our emphasis added]).

Stating that depression may be due to a serotonin deficiency is seemingly allowed, but, as stated in the regulations, only if the limitations of the supporting evidence are provided. In our examination of SSRI advertisements, we did not locate a single advertisement that presented any such information. Instead, the serotonin hypothesis is typically presented as a collective scientific belief, as in the Zoloft advertisement, which states that regarding depression, “Scientists believe that it could be linked with an imbalance of a chemical in the brain called serotonin” [ 33 ]. Consumers viewing such advertisements remain uninformed regarding the limitations of the serotonin hypothesis (reviewed above).

According to federal regulations, advertisements are also proscribed from including content that “contains favorable information or opinions about a drug previously regarded as valid but which have been rendered invalid by contrary and more credible recent information” [ 32 ].

This means that a disconnect between the evolving peer-reviewed literature and advertisements is not permitted. Regarding SSRIs, there is a growing body of medical literature casting doubt on the serotonin hypothesis, and this body is not reflected in the consumer advertisements. In particular, many SSRI advertisements continue to claim that the mechanism of action of SSRIs is that of correcting a chemical imbalance, such as a paroxetine advertisement, which states, “With continued treatment, Paxil can help restore the balance of serotonin…” [ 22 ]. Yet, as previously mentioned, there is no such thing as a scientifically established correct “balance” of serotonin. The take-home message for consumers viewing SSRI advertisements is probably that SSRIs work by normalizing neurotransmitters that have gone awry. This was a hopeful notion 30 years ago, but is not an accurate reflection of present-day scientific evidence.

The FDA has sent ten warning letters to antidepressant manufacturers since 1997 [ 34–43 ], but has never cited a pharmaceutical company for the issues covered here. The reasons for their inaction are unclear but seem to result from a deliberate decision at some level of the FDA, rather than an oversight. Since 2002, the first author (JRL) has repeatedly contacted the FDA regarding these issues. The only substantive response was an E-mail received from a regulatory reviewer at the FDA: “Your concern regarding direct-to-consumer advertising raises an interesting issue regarding the validity of reductionistic statements. These statements are used in an attempt to describe the putative mechanisms of neurotransmitter action(s) to the fraction of the public that functions at no higher than a 6th grade reading level” (personal communication, 2002 April 11).

It is curious that these advertisements are rationalized as being appropriate for those with poor reading skills. If the issues surrounding antidepressants are too complex to explain accurately to the general public, one wonders why it is imperative that DTCA of antidepressants be permitted at all. However, contrary to what the FDA seems to be implying, truth and simplicity are not mutually exclusive. Consider the medical textbook, Essential Psychopharmacology , which states, “So far, there is no clear and convincing evidence that monoamine deficiency accounts for depression; that is, there is no ‘real’ monoamine deficit” [ 44 ]. Like the pharmaceutical company advertisements, this explanation is very easy to understand, yet it paints a very different picture about the serotonin hypothesis.

The impact of the widespread promotion of the serotonin hypothesis should not be underestimated. Antidepressant advertisements are ubiquitous in American media, and there is emerging evidence that these advertisements have the potential to confound the doctor–patient relationship. A recent study by Kravitz et al. found that pseudopatients (actors who were trained to behave as patients) presenting with symptoms of adjustment disorder (a condition for which antidepressants are not usually prescribed) were frequently prescribed paroxetine (Paxil) by their physicians if they inquired specifically about Paxil [ 45 ]; such enquiries from actual patients could be prompted by DTCA [ 45 ].

What remains unmeasured, though, is how many patients seek help from their doctor because antidepressant advertisements have convinced them that they are suffering from a serotonin deficiency. These advertisements present a seductive concept, and the fact that patients are now presenting with a self-described “chemical imbalance” [ 46 ] shows that the DTCA is having its intended effect: the medical marketplace is being shaped in a way that is advantageous to the pharmaceutical companies. Recently, it has been alleged that the FDA is more responsive to the concerns of the pharmaceutical industry than to their mission of protecting US consumers, and that enforcement efforts are being relaxed [ 47 ]. Patients who are convinced they are suffering from a neurotransmitter defect are likely to request a prescription for antidepressants, and may be skeptical of physicians who suggest other interventions, such as cognitive-behavioral therapy [ 48 ], evidence-based or not. Like other vulnerable populations, anxious and depressed patients “are probably more susceptible to the controlling influence of advertisements” [ 49 ].

In 1998, at the dawn of consumer advertising of SSRIs, Professor Emeritus of Neuroscience Elliot Valenstein summarized the scientific data by concluding, “What physicians and the public are reading about mental illness is by no means a neutral reflection of all the information that is available” [ 50 ]. The current state of affairs has only confirmed the veracity of this conclusion. The incongruence between the scientific literature and the claims made in FDA-regulated SSRI advertisements is remarkable, and possibly unparalleled.

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Is the Serotonin Theory of Depression Dead?

The complicated history of the serotonin hypothesis.

Posted August 11, 2022 | Reviewed by Hara Estroff Marano

• What Is Depression?
• Find a therapist to overcome depression
• Research has shown that depression is not simply caused by low monoamines such as serotonin, dopamine, and norepinephrine in the brain.
• Scientific understanding of depression has grown to include genetic factors, stress responses, and other brain changes.
• While depression treatment should include psychotherapy and lifestyle changes, antidepressants may still have an important role in recovery.

Recently, Moncrieff and colleagues published a review of the evidence for the serotonin theory of depression , concluding that there was “no consistent evidence of there being an association between serotonin and depression,” which was shocking news to the general public .

Many news organizations commented on this “long-held theory” being debunked. Some critics touted the paper as evidence that psychiatric treatments are a sham . One politician even cited the paper to suggest, in a baseless and confusing argument, that somehow antidepressants were responsible for mass shootings . Here, we hope to clarify what we know about serotonin and depression.

The serotonin hypothesis is a version of the “monoamine hypothesis of depression.” Monoamines are a group of chemicals that act as neurotransmitters in the brain and include serotonin, dopamine , and norepinephrine. As early as the 1950s, psychiatrists thought these chemicals might be important for mood regulation based on the serendipitous discovery that some drugs were effective for treating depression and all of them seemed to work by increasing the levels of monoamines in the brain. There were other clues, such as certain drugs that lowered monoamine levels seemed to make some people depressed.

For a time, it seemed there was a biological explanation for depression. However, it did not take long for people to see cracks in this theory. Most antidepressants take weeks to work even though they increase brain monoamine levels only a few hours after ingestion. Furthermore, even though there was an occasional positive finding, studies looking at how levels of monoamines in the brain correlate with symptoms of depression were inconclusive (before modern neuroimaging, these studies were notoriously difficult to do).

The results suggested a much more complex process . As early as 1965, Harvard psychiatrist Joseph Schildkraut summarized the theory and supporting data. He concluded, much like Professor Moncrieff half a century later, that “it is not possible…to confirm…or to reject” the hypothesis .

So why did it persist, even if experts knew it was, if not wholly wrong, at least inadequate? Like many imperfect explanations, it survived because it had utility for modeling the role of monoamine chemicals in the brain, especially for drug development. After all, the first antidepressants all worked by increasing the level of monoamines in the brain. Although effective, they were not targeted and had many side effects.

Researchers then began concentrating on a specific monoamine, serotonin, as a target for drugs. What followed was a revolution in antidepressant treatment. Fluoxetine (Prozac) was the first SSRI, or serotonin reuptake inhibitor introduced in the US. Approved in 1987, it was an almost immediate success, and a flurry of other serotonergic drugs followed. Even today, nearly all drug treatments for depression target one or more monoamines, and serotonin is usually one of those.

Even if most mental health experts understood that the monoamine hypothesis was inadequate, it became one way to explain to patients what might be causing depression. It was not uncommon for doctors to tell patients that they had a “chemical imbalance.” This biological explanation was perceived less stigmatizing for most patients, who tended to blame themselves for something outside their control.

As Dr. Montcrieff fairly points out in a blog discussing her study, “even if leading psychiatrists were beginning to doubt the [serotonin hypothesis]…no one told the public.” Many of us thought, “what is the harm.” Even if not exactly true, the point of the explanation is well intended: that depression is a biological disease, not a moral failing or, in some other way, the patient’s fault .

Although the monoamine theory spurred drug discovery and integrated a biological element into our understanding of mood disorders, it may have also limited it. Most antidepressants for the last several decades were “me too” drugs that differed little from their predecessors. The success of the monoamine approach, along with the expense of drug development, may have made pharmaceutical companies reluctant to explore new approaches to depression. It may also have dissuaded patients and their doctors from pursuing other proven approaches to depression, such as psychotherapy , exercise, and a healthy diet .

Professor Moncrieff and her coauthors are doing a service in getting the news out. However, we caution against misrepresentations of the report as a way to conclude that medications have no role in mental health treatment.

Since the monoamine theory emerged in the 1950s, thousands of scientists have added to knowledge about depression and its treatment. The whole puzzle isn't solved yet, but we know a lot. Most modern theories take an integrative approach, meaning that many things cause depression, all working (or not working) together. The “perfect storm” of depression includes genetic vulnerabilities that put people at risk, epigenetic responses to stress , and changes in certain vulnerable parts of the brain that, yes, include the serotonin system.

Is there still a role for antidepressants? Depending on the person, antidepressants are not always needed. However, for many patients, they can be lifesaving, especially those with severe depression. Our understanding of how they work continues to evolve. For example, one mechanism thought to underly the efficacy of antidepressants is their ability to either directly or indirectly lead to an increase in brain-derived neurotrophic factor (BDNF), which is involved in the growth, maturation, and survival of neurons . New research also suggests that some antidepressants may work better for individuals of specific age, sex , medical history, and symptoms .

As our scientific knowledge grows, so should our communication to those directly affected. We believe that the serotonin theory isn’t dead; it just has grown up a lot.

About the Authors

Robert J Boland, MD is the Chief of Staff and a Senior Vice President at The Menninger Clinic. He is also vice chair of the Menninger Department of Psychiatry and Behavioral Science at Baylor College of Medicine and the Brown Foundation Endowed Chair in Psychiatry at Baylor. He is also the co-host of the Menninger Clinic’s Mind Dive Podcast , which examines dilemmas faced by mental health professionals.

Kelly Truong MD is a staff psychiatrist at The Menninger Clinic and an assistant professor at Baylor College of Medicine. She specializes in addiction psychiatry, psychodynamic psychotherapy, and addiction psychopharmacology . She is a member of the American Academy of Addiction Psychiatry, American Psychoanalytic Association and the Houston Psychoanalytic Society.

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Boku, S., Nakagawa, S., Toda, H., & Hishimoto, A. (2018). Neural basis of major depressive disorder: Beyond monoamine hypothesis. Psychiatry and Clinical Neurosciences, 72(1), 3–12. https://doi.org/10.1111/pcn.12604

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How to take the news that depression has not been shown to be caused by a chemical imbalance. (2022, July 24). Joanna Moncrieff. https://joannamoncrieff.com/2022/07/24/how-to-take-the-news-that-depres…

Moncrieff, J., Cooper, R. E., Stockmann, T., Amendola, S., Hengartner, M. P., & Horowitz, M. A. (2022). The serotonin theory of depression: A systematic umbrella review of the evidence. Molecular Psychiatry, 1–14. https://doi.org/10.1038/s41380-022-01661-0

Schildkraut, J. J. (1965). The catecholamine hypothesis of affective disorders: a review of supporting evidence. The American Journal of Psychiatry, 122(5), 509–522. https://doi.org/10.1176/ajp.122.5.509

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The serotonin theory of depression: a systematic umbrella review of the evidence

Affiliations.

• 1 Division of Psychiatry, University College London, London, UK. [email protected].
• 2 Research and Development Department, Goodmayes Hospital, North East London NHS Foundation Trust, Essex, UK. [email protected].
• 3 Faculty of Education, Health and Human Sciences, University of Greenwich, London, UK.
• 4 Psychiatry-UK, Cornwall, UK.
• 5 Department of Dynamic and Clinical Psychology, and Health Studies, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy.
• 6 Department of Applied Psychology, Zurich University of Applied Sciences, Zurich, Switzerland.
• 7 Division of Psychiatry, University College London, London, UK.
• 8 Research and Development Department, Goodmayes Hospital, North East London NHS Foundation Trust, Essex, UK.
• PMID: 35854107
• PMCID: PMC10618090
• DOI: 10.1038/s41380-022-01661-0

The serotonin hypothesis of depression is still influential. We aimed to synthesise 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. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. 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-HT 1A 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. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 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. Quality of reviews was variable with some genetic studies of high quality. 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-HT 1A 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, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. 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. No systematic review of tryptophan depletion studies has been performed since 2007. 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. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.

© 2022. The Author(s).

Publication types

• Meta-Analysis
• Systematic Review
• Antidepressive Agents
• Depression* / genetics
• Hydroxyindoleacetic Acid
• Receptor, Serotonin, 5-HT1A / genetics
• Serotonin Plasma Membrane Transport Proteins / genetics
• Receptor, Serotonin, 5-HT1A
• Serotonin Plasma Membrane Transport Proteins

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Study claims to find first direct evidence of a link between low serotonin and depression

Exclusive: Results add to debate over decreased serotonin response and depression

Scientists claim to have found the first direct evidence that people with depression have a reduced capacity for releasing serotonin in the brain.

The findings from a brain-imaging study reignite a debate within psychiatry over the so-called serotonin hypothesis of depression and challenge the conclusions of an influential review published in July that found “no clear evidence” that low serotonin levels are responsible. The latest work, led by scientists at Imperial College London, suggested that people with depression have a decreased serotonin response.

“This is the first direct evidence that the release of serotonin is blunted in the brains of people with depression,” said Prof Oliver Howes, a consultant psychiatrist based at Imperial College and King’s College London, and a co-author. “People have been debating this question for 60 years, but it’s all been based on indirect measures. So this is a really important step.”

The serotonin hypothesis arose from evidence from postmortem brains and blood samples that suggested a serotonin deficit could be involved in depression. The theory provides a plausible biological mechanism for how the main class of antidepressant drugs, selective serotonin reuptake inhibitors (SSRIs), are effective, and is why the brain chemical is sometimes referred to as a “happy hormone”.

However, there is not yet conclusive evidence that serotonin abnormalities are the underlying cause of depression and resolving this question is seen as crucial to providing better treatments. The latest paper adds weight to the view that serotonin plays a role and demonstrates a new brain imaging technique that could pave the way to a better understanding of why SSRI drugs fail to help an estimated 10% to 30% of patients.

“It’s the closest anyone has been able to get so far,” said Howes. “It’s hard to measure these transmitters in the brains of living people. We can’t put a pipette in there and take a sample. This is the closest we’re likely to come.”

The study, published in the journal Biological Psychiatry , involved seventeen patients with major depressive disorder or depression linked to Parkinson’s disease and 20 healthy volunteers. The participants were given a PET scan that uses a radioactive tracer to reveal how much serotonin was binding to certain receptors in the brain. They were then given a dose of amphetamine, which stimulates serotonin release, and scanned again. A reduced serotonin response was seen in the depressed patients, the researchers found.

Prof Catherine Harmer, of the University of Oxford, who was not involved in the work, described it as an important finding. “It’s really noteworthy that they found evidence for lower serotonin release,” she said. Harmer said that few in the field would now argue that all depression was a result of low serotonin, but that the findings were “very much in line with the idea that serotonin may play an important role”.

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Others were more sceptical. Eiko Fried, a clinical psychologist at the University of Leiden, questioned whether the results were statistically robust. “The conclusions the authors draw is not proportional to the evidence presented,” he said. “The statistical analyses are inconsistent and do not … establish ‘clear evidence’ for the serotonin theory of depression.”

Joanna Moncrieff, professor of psychiatry at University College London who led the review that concluded there is no evidence that chemical imbalances in the brain cause depression , said the latest paper would not cause her to revise this view. She pointed to the size of the study and the fact that it still measured a proxy for serotonin as shortcomings. “This study does not provide convincing evidence that a serotonin abnormality is the cause or mechanism underlying depression, or one of the causes or mechanisms,” she said.

Howes said the findings would need to be replicated and then further studies would be needed to determine whether any serotonin differences cause depression or arise from the condition. “It’s important because whilst current treatments do help a lot of people they don’t work for everyone,” he said. “For large numbers of people the first treatment doesn’t work and some people can’t find any treatment that helps.”

The headline and subheading of this article were amended on 10 November 2022. This was to make it clear that the study claims to have found the first direct evidence of a link between low serotonin and depression, but more work will be needed on this subject.

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Is the serotonin hypothesis/theory of depression still relevant? Methodological reflections motivated by a recently published umbrella review

Hans-jürgen möller.

Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Nussbaumstr. 7, 80336 Munich, Germany

Peter Falkai

Associated data.

Not applicable.

The serotonin hypothesis of depression was first proposed in 1967, when the first antidepressants were being developed. It was subsequently refined, but for a long time it was criticized as being too one-sided. Later, the hypothesis was replaced by complex neurobiological theories, e.g., the chemical imbalance theory, which included additional neurotransmitters [ 1 ]. Consequently, the critical findings of the recently published umbrella review by Joanna Moncrieff and colleagues [ 2 ], which claim to falsify the serotonin hypothesis, come as no surprise. The publication of these findings is a good reason to carefully examine the content and methodologies of research on this topic and the basic problems associated with falsifying hypotheses and theories. However, for reasons of space, this editorial will discuss only a few of the main methodological aspects.

The umbrella review by Moncrieff et al. summarizes the results of all systematic reviews and meta-analyses on the serotonin hypothesis of depression and subdivides the hypothesis into six areas: serotonin and the 5-hydroxyindoleacetic acid (HIAA) level in body fluids, serotonin receptor activity, serotonin transporter activity, results of tryptophan depletion studies, serotonin transporter gene levels, and the interaction between the serotonin transporter gene and stress. The areas address the main serotonin theory but not all aspects of it. They make the complexity of the topic clear, in particular the fact that the serotonin theory comprises a bundle of related individual hypotheses. Thus, from the perspective of scientific theory, the authors have to confirm or falsify not a single hypothesis but a whole group of hypotheses held together by a complex theory. Testing and perhaps refuting such a complex theory is much more demanding than testing/refuting a single hypothesis.

The umbrella review includes only data from patients and no findings from animal experiments. The exclusion of animal studies limits the scope of the study considerably and is difficult to reconcile with the demands of testing a complex neurobiological theory.

In evidence-based medicine, meta-analyses and systematic reviews are considered to represent the highest evidence level. However, the inherent problems of these methodological approaches are often not adequately considered [ 3 ] and are also not discussed by Moncrieff et al. The main methodological problem of meta-analyses and thus also of the umbrella review is the question of how to decide which studies to include and which to exclude. Systems of formalistic rules exist for selecting studies, but content-related criticisms about study selection are frequently expressed by people with knowledge of the topic (e.g. clinical psychopharmacologists and neuroscientists). One wonders why from among the 360 studies identified by the PRISMA search process as being theoretically relevant, the systematic umbrella review included only 17 in its final evaluation/description. The respective flow diagram gives only a rough idea of the reasons why studies were excluded.

As is the case in many systematic reviews and meta-analyses, the content-related problems of the individual included studies are not discussed. However, these problems should be reviewed critically. It only makes sense to include studies that were well planned and implemented not only with respect to the formal aspects considered by systematic reviews and meta-analyses, but also with respect to their content. Whether and how this latter aspect was assessed remains unclear in the umbrella review because the authors do not discuss it in detail. Therefore, one must assume that such a detailed evaluation was performed not by the authors of the umbrella review but by the authors of the original meta-analyses. However, that was probably not the case in most of the meta-analyses because when selecting empirical studies for inclusion in such analyses, researchers normally check only formal aspects. The aspects that should actually be considered when evaluating studies were presented by Riederer [ 4 ], among others, by using the example of studies related to serotonin/tryptophan and include the following: problems in determining serotonin in plasma HIAA in cerebrospinal fluid; the fact that plasma serotonin does not reflect the serotonin concentration in the brain because serotonin is metabolized at the blood–brain barrier; consideration of the suboccipital/lumbar HIAA gradient when performing a lumbar puncture; and the temporal difference between tryptophan depletion and the effects of serotonin metabolism on the brain.

In addition to systematic reviews and meta-analyses on the serotonin hypothesis, the umbrella review includes several large studies and a large genetic study based on UK-wide data; the former studies summarize data from individual studies without using the strict approach of a systematic review. The authors state that including these studies was the best way to comprehensively portray the evidence. However, this approach is unusual for an umbrella review and methodologically questionable. Although umbrella reviews typically consider previous meta-analyses/systematic review of primary studies and umbrella reviews of meta-analyses/systematic reviews (also termed “meta-umbrella reviews”) separately, Moncrieff et al. summarized these different types of studies together. This approach means that a comparison of effect sizes is potentially unreliable. In addition, the selection criteria for the primary studies are unclear, which opens the door to uncontrolled selection biases: Some primary studies appear to have been included at the expense of others.

The tryptophan-related studies can be used as an example of how problematic the presentation by Moncrieff et al. is in terms of study selection [ 5 ]. Moncrieff et al. included one meta-analysis, one systematic review, and ten recent studies involving healthy volunteers, but they did not include a clinical and molecular imaging study that showed an effect in people with major depressive disorder [ 6 ]. They also omitted several studies included in two meta-analyses that evaluated circulating concentrations of tryptophan, a substance that directly influences central serotonin [ 7 , 8 ].

The umbrella review also contains a number of material errors and misinterpretations, e.g., concerning imaging data on both 5-HT 1A receptor and serotonin transporter protein (SERT) binding [ 5 ]. For example, the statement by Moncrieff et al. [ 2 ] that 5HT 1A receptors are known as autoreceptors mistakenly assumes that 5HT 1A receptors are exclusively pre-synaptic autoreceptors, whereas most of these receptors are post-synaptic 5-HT 1A heteroreceptors. Reduced availability of post-synaptic 5-HT 1A receptors in unmedicated depression would be consistent with decreased 5-HT neurotransmission.

Overall, the included studies in the various relevant areas produced hardly any evidence for the serotonin theory, and at the most, they found weak connections that support only a few aspects of it. Therefore, the authors conclude from their results that their evaluation cannot confirm the serotonin theory of depression. Even though the authors discuss some of the methodological problems of the individual studies and meta-analyses and the reason for the negative results, they believe that their overall result falsifies the serotonin hypothesis, in particular because they consider the umbrella review approach, which summarizes all available reviews and meta-analyses, as the highest level of evidence synthesis.

Even if one initially accepts the result of the umbrella review by Moncrieff et al. [ 2 ], the broad non-confirmation of various sub-hypotheses of the serotonin theory of depression does not mean that the theory is completely false and, consequently, that a neurobiological explanation of depression is refuted. As in other areas of medicine, the serotonin theory has been expanded through various new basic research findings, e.g., neurogenesis and synaptogenesis, neuronal networks, neuroendocrinology, neuroinflammation, and genetics, independent of the serotonergic system, so these aspects must be included in the etiopathological reflections on the cause of the complex disease depression or its subgroups [ 1 ]. Consequently, the studies on the serotonergic system included in the umbrella review represent only part of the complex neurobiological understanding of depression. The serotonin theory can definitely continue to be scientifically relevant as a partial aspect of the theoretical concept of depression and as part of more complex concepts.

Of relevance in this context is the work of the famous science theorist Thomas S. Kuhn, who showed in his studies on the history of science [ 9 ] that in contrast to the falsification theory from the equally famous science theorist Karl Popper—whom we are in no way questioning here—most complex theories, unlike simple hypotheses, cannot be refuted by falsification. Instead, people lose interest in them because of paradigm shifts in the sense that a younger generation of researchers becomes interested in other theories or because highly complex theories characterized by more advanced technologies gain the upper hand. However, until that happens, the theories can retain a certain usefulness for research, even if they are insufficiently proven. These considerations help one understand why, despite being criticized, the serotonin theory is still relevant as an explanation of depression. Depression is characterized neurobiologically by an imbalance of a complex dynamic system involving genetic, epigenetic, environmental, and stress vulnerabilities, and this imbalance initiates a cascade of neurobiological alterations in and beyond serotonergic functioning. All integrally related pathways interact multi-directionally throughout the various phases of depression [ 1 ].

Moncrieff et al. do not limit their argumentation to their critical conclusion about the validity of the serotonin theory of depression. Instead, with the following sentence in the Discussion section they go far beyond the empirical results of their study by drawing conclusions about the use of antidepressant treatment: “The idea that depression is the result of a chemical imbalance also influences decisions about whether to take or continue antidepressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs” (2, p. 11). This treatment-related conclusion is highly problematic and cannot be directly inferred from the result of the umbrella review. Furthermore, the efficacy of antidepressant treatment, including serotonergic antidepressants, is well supported by the evidence [ 10 ]. In principle, we can view the efficacy of antidepressants independently from the validity of the serotonin theory of depression and simply interpret the serotonin mechanism as a favorable mechanism for achieving antidepressant effects, not as a theory of causality of depression. Interestingly, Moncrieff et al. do not cite studies that prove the efficacy of antidepressants; as far as the serotonergic antidepressants are concerned, such studies could well be discussed as providing ex juvantibus support for the serotonin theory.

The conclusion drawn by Moncrieff et al. [ 2 ] that the usefulness of antidepressant treatment should be questioned—a conclusion that is in line with the position that Joanna Moncrieff has frequently published, especially in the lay press—can have severe negative consequences for the treatment adherence of people with depression. The question we need to ask is whether the results of their umbrella review are strong enough, as far as the methodology and content of the review are concerned, that they allow such a far-reaching conclusion to be drawn or whether this conclusion rather reflects the authors’ own bias.

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• Correspondence
• Published: 16 June 2023

Reply to: “The serotonin theory of depression: a systematic umbrella review of the evidence” published by Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA in Molecular Psychiatry (2022 Jul 20. doi: 10.1038/s41380-022-01661-0)

• Lucie Bartova   ORCID: orcid.org/0000-0002-1769-8025 1 , 2 ,
• Rupert Lanzenberger   ORCID: orcid.org/0000-0003-4641-9539 1 , 2 ,
• Dan Rujescu   ORCID: orcid.org/0000-0002-1432-313X 1 , 2 &
• Siegfried Kasper   ORCID: orcid.org/0000-0001-8278-191X 1 , 2 , 3  

Molecular Psychiatry volume  28 ,  pages 3153–3154 ( 2023 ) Cite this article

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The serotonin theory of depression focusing primarily on the serotonergic neurotransmission, that was originally introduced by the English psychiatrist Alec Coppen in 1967 [ 1 ], has been increasingly amplified by groundbreaking insights on neurobiological mechanisms involving further crucial monoaminergic, glutamatergic, GABAergic and other systems [ 2 , 3 ]. According to the current state of evidence-based knowledge, depression represents a dysbalanced dynamic system involving genetic, epigenetic, environmental and stress vulnerabilities initiating a cascade of neurobiological alterations in and beyond the serotonergic functioning [ 4 , 5 , 6 , 7 ]. These alterations are reflected by impaired neurotransmission, attenuated neuroplasticity and neurogenesis, dysfunctional neural circuitries, hypothalamic pituitary axis (HPA) abnormalities, increased inflammation and vascular changes, whereby monoamines including serotonin, norepinephrine and dopamine, as well as glutamate, GABA, glucocorticoids, inflammatory cytokines and neurotrophic factors including the brain-derived neurotrophic factor seem to be essential mediators [ 8 ]. It is noteworthy that all these pathways have been shown to be integrally related and are thought to interact multi-directionally throughout different phases of depression [ 9 , 10 ]. Interacting as nodes in a matrix they are crucial in the development of depressive symptoms, in the heterogenous clinical manifestation of depression as well as its course and, importantly, antidepressant treatment, and must be hence included in the etiopathological and therapeutic considerations of this frequent and burdensome disease [ 4 , 7 , 11 , 12 ].

The systematic umbrella review of the evidence on the serotonin theory of depression, that was published by Moncrieff et al. very recently, focused on studies investigating serotonergic mechanisms [ 13 ]. Accordingly, the authors concluded that there is no consistent international evidence of an association between serotonin and depression, and consequently no convincing evidence of a biochemical basis of depression [ 13 ]. Since this deduction is based on selected literature covering serotonin exclusively, and hence, addressing only a part of the complex understanding of depression [ 4 ], 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 [ 10 ], and that the methods applied in some previous studies may have not been sensitive enough to measure fluctuations in neuronal activity to be able to answer the question.

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Bartova, L., Lanzenberger, R., Rujescu, D. et al. Reply to: “The serotonin theory of depression: a systematic umbrella review of the evidence” published by Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA in Molecular Psychiatry (2022 Jul 20. doi: 10.1038/s41380-022-01661-0). Mol Psychiatry 28 , 3153–3154 (2023). https://doi.org/10.1038/s41380-023-02093-0

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