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The serotonin hypothesis of depression is unsupported by a rigorous literature review, declares a new article from Dr. Joanna Moncrieff and colleagues. Their review has generated a plethora of news headlines and received extensive academic attention as well. In response to criticisms, the authors expressed concern that psychiatrists—many of whom have expressed broad agreement with their conclusions—are shrugging off their findings. So, let’s have a look.
Hi! Jim Phelps here for the Psychopharmacology Institute. The main concern behind this review is that the general public widely believes that depression has been convincingly demonstrated to be the result of low serotonin or other chemical abnormalities. This belief influences decisions about whether to take or continue an antidepressant medication. It might discourage people from attempting to discontinue treatment, and it fosters pessimism about psychotherapy and the self-management of mood. According to their follow-up responses and other publications about their article, Dr. Moncrieff and colleagues clearly want to hear more than “Yeah, that’s fair; that’s a problem.”
I’ll close this Quick Take by offering some concrete steps I think they’d like to see, but let’s look at the structure of their review first. Using standard, rigorous, and transparent search methods, they looked for studies that compared depressed and control subjects in 5 ways. They say 6, but I’ve lumped 1. One, measuring serotonin directly. Two, quantifying 5-HT1A autoreceptors. Three, quantifying serotonin transporter concentrations and activity. Four, results of tryptophan depletion-induced depression. And lastly, serotonin transporter gene variants and their interaction with stress. In each of these domains, the authors examined whether available evidence supports a serotonin hypothesis of depression. For example, take serotonin levels and depression. You can’t easily measure serotonin itself because it’s very rapidly degraded. So, the standard measure of serotonergic activity in the central nervous system is to measure concentrations of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), sampled in cerebrospinal fluid.
Moncrieff et al. report that in 2 meta-analyses of 19 studies, no relationship between 5-HIAA levels and depression was found. As to research on tryptophan depletion, remember that a sudden and substantial drop in serum serotonin levels can be induced with an amino acid drink that’s lacking in the amino acid precursor for serotonin, tryptophan.
A 2006 meta-analysis of 28 placebo-controlled studies found that “significant effects on mood were only observed in studies with recovered depressed patients.” In other words, studies of tryptophan depletion in healthy volunteers show no effect on mood, but among patients with a history of major depression, a return of depression symptoms is observed after drinking the tryptophan-depleting mix. This intriguing response is almost dismissed in Moncrieff et al.’s review. They called it a minor finding and emphasized instead the consistent lack of effect in healthy volunteers.
Oops. Hear that? I’m quibbling, and I could quibble more but quibbling usually inflames discussions, and I’ve suggested at the blog, Mad in America—the same forum where Moncrieff and Horowitz wrote their response to critics—that inflaming public discussions about psychiatry can do harm as well as good. In this case, I think it’s inflammatory to suggest that psychiatry is clinging to a complete fallacy.
Instead, let’s throw a little water on the fire, not simply by agreeing with Moncrieff et al.’s main concern but by looking at concrete changes that would address it. First, when describing treatment options during shared decision making with patients, we should avoid conveying the impression that treating depression is simply a matter of correcting chemical imbalances with pills. We should aggressively look for opportunities to suggest that our primary care colleagues do likewise. And in public presentations, we should avoid propagating the serotonin hypothesis or the more general chemical imbalance characterization of depression in favor of emphasizing the complex interplay of mind and brain in mood disorders.
Secondly, we should promote the use of evidence-based psychotherapies, especially in primary care, which is easier than you might think. Several basic mindfulness courses, albeit less studied, are also free online. Most research finds that these online resources are nearly as good as seeing a therapist if they’re accompanied by some support—such as yours, for example. If a well-trained therapist is available and affordable, all the better. Unfortunately uncommon, isn’t it?
So, I’ll offer this conclusion. When psychotherapy is as easily accessed as an antidepressant prescription and when shared decision making includes a clear description of the risks of antidepressant withdrawal, then focusing on a single neurotransmitter won’t be so relevant. And I understand why Dr. Moncrieff and her colleagues felt it necessary to put tremendous effort into their review and getting it widespread attention.
Abstract
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-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. 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-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, 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.
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Reference
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.
Related References
- Moncrieff, J. and Horowitz, M. Response to criticism of our serotonin paper. Mad In America, July 28, 2022. https://www.madinamerica.com/2022/07/response-criticism-serotonin-paper/
