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SSRIs: Surprising Science Raises Issues

A media firestorm ignited last summer when a team of researchers led by University College London psychiatrist Joanna Moncrieff and her team published a paper in the journal Molecular Psychiatry. The paper, entitled “The serotonin theory of depression: a systematic umbrella review of the evidence,” rapidly became one of the most-discussed pieces of scientific literature in the world and garnered substantial coverage in the mainstream press. The topic of the paper, depression, is a serious and widespread disorder that affects 5% of the world’s population, causing crippling symptoms such as chronic sadness, despair, and a lack of motivation [1].

Specifically, the Molecular Psychiatry paper sought to determine whether the serotonin theory of depression — which postulates that depression is caused by reduced levels of the neurotransmitter serotonin — was accurate [2]. Serotonin is a neurotransmitter that affects numerous aspects of the human brain, including perception and mood, so a link to depression seemed plausible [3,4]. Moreover, some of the most prescribed antidepressants are selective serotonin reuptake inhibitors (SSRIs). SSRIs are theorized to function in the brain by disabling serotonin transport proteins, which remove serotonin from synapses. Therefore, using SSRIs should increase serotonin availability in the synapses and thus treat depression. To evaluate the theory, Moncrieff and her team performed a meta-analysis, examining the conclusions of dozens of papers. Ultimately, the researchers determined that there was no substantial evidence of a relationship between low serotonin levels and depression [2].

These results surprised the public since they seemed to invalidate the use of SSRIs. However, many scientists were unsurprised by the findings. Although the paper’s authors allege that the serotonin theory of depression commonly appears in public and educational discourse, other experts counter that it has never been widely accepted within the scientific community [2,4,5]. Depression is an extraordinarily complex disorder that affects many regions of the brain and originates for a wide variety of reasons. Scientists have postulated many causes for depression, some physiological, some environmental, and some social. Aside from biological factors, we know that depression can occur from life events, such as after birth (known as postpartum depression) or as the result of childhood events [1]. Moreover, scientists know that serotonin is involved in a diverse array of physiological functions, and its role in our health cannot be oversimplified [3]. As a result, some researchers criticized the paper for unnecessarily disproving an already-discredited theory, but the debate is still raging. A recently published primary study performed brain scanning on depressive patients and once again implicated diminished serotonin as a factor in depression, though Moncrieff and other scientists criticized flaws like low sample size [6].

However, despite all of the disagreement, one widely accepted point was revealed: scientists do not fully understand how either depression or SSRIs work [4]. What does this mean for the millions of adults who are taking these medications? Fortunately, studies show that SSRIs are effective and on par with alternative antidepressants. Experiments with adults with moderate to severe depression show that using placebos, roughly 20-40 patients out of 100 show improved symptoms after a few weeks. In comparison, roughly 40-60 patients out of 100 improve when treated with SSRIs or other antidepressants. Furthermore, antidepressants including SSRIs can also prevent relapses. Relapses occur in about half of patients on placebos within 1-2 years, but in less than a quarter treated with medication preventatively [7]. So even though we don’t understand how SSRIs work, we know that they do work in many cases. Although the idea of taking a drug which is not fully understood may seem unpalatable, it’s important to remember that we can still establish its safety and effectiveness. Even aspirin was used for many decades before scientists discovered its mechanism of action [8]. Thus, we need to ensure that there is no stigma around SSRI usage.

One of the most critical impacts of the Molecular Psychiatry paper was challenging prevalent false beliefs about depression. Up to 80% of the public believes that depression originates from a simple “chemical imbalance” [2]. This misconception is dangerous — it promotes the false narrative that drugs are the best, and only, answer. While we should not ignore the potential benefits of SSRIs, it is vital that we prescribe them carefully, and use them in conjunction with other effective treatments [5]. For example, non-psychiatric approaches like cognitive behavioral therapy (CBT) may be even more helpful than using medication. CBT and other therapies can get at the root of problems underlying depression, helping people cope with feelings and experiences by changing the way they think [8]. Furthermore, combined psychotherapy and medication treatment were found to improve depression remission by 20% over medication alone [9]. Patients should always be encouraged to explore therapy in addition to medication and determine what treatment regimen works best for their specific needs.

Overall, the Molecular Psychiatry paper reminds us that we have a limited understanding of both SSRIs and depression itself, which is a serious challenge to formulating effective treatments. Going forward, we need more research to understand the nature of depression and how it affects our biology. It is also vital that we elucidate the impacts of both serotonin and SSRIs within our bodies. With deeper knowledge, we can increase the effectiveness of medication and other therapeutic strategies. Research will revolutionize our understanding of depression, but we must always keep an open mind about new findings.


  1. Depression. (n.d.). Retrieved October 27, 2022, from

  2. 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.

  3. Berger, M., Gray, J. A., & Roth, B. L. (2009). The expanded biology of serotonin. Annual Review of Medicine, 60(1), 355–366.

  4. Brueck, H. (2022, October 7). A psychiatry researcher who taught his students depression was caused by a “chemical imbalance” in the brain says everything he thought he knew about SSRIs is wrong. Insider.

  5. Pies, R., & Dawson, G. (2022, August 3). The serotonin fixation: Much ado about nothing new. Psychiatric Times.

  6. Devlin, H. (2022, November 5). Study claims to find first direct evidence of a link between low serotonin and depression. The Guardian.

  7. Depression: How effective are antidepressants? (2020). Institute for Quality and Efficiency in Health Care (IQWiG).

  8. What is cognitive behavioral therapy? (n.d.). American Psychological Association. Retrieved October 27, 2022, from

  9. de Jonghe, F., et al. “Combining Psychotherapy and Antidepressants in the Treatment of Depression.” Journal of Affective Disorders, vol. 64, no. 2, May 2001, pp. 217–29. ScienceDirect,

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