First Demonstration of Serotonin’s Direct Role in Depression

Emerging research implicates low serotonin in depression, after all.

Grant H Brenner
7 min readNov 5, 2022


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Over the years, the serotonin hypothesis of depression, which suggests that low or impaired serotonin neurotransmission is related to the symptoms and possible causes of depression and related psychiatric disorders, has taken many hits.

Recently, a widely publicized review paper in Nature (Moncrieff et al., 2022) found no direct evidence that serotonin is involved in the pathophysiology of depression. This led to an explosion of reports and even attacks which reverberated across the internet about the serotonin hypothesis, the long-debunked “chemical imbalance” explanation, and, to an extent, psychiatry as a field.

The uproar is understandable-depression affects an estimated 20 million US citizens and nearly 300 million worldwide, and current treatments are only partially effective. There is a growing awareness that mental health problems are epidemic-a recent survey by the American Psychiatric Association found 79 percent of people see mental health as a public health emergency.

Moreover, rates of anxiety and depression are skyrocketing, especially among younger people, suicide has become a leading cause of death, and we are more aware every day of the hazardous effect of endemic stress and trauma on mental and physical health.

Despite various studies over the years and the recognition that antidepressant and psychedelic medications [1], which improve depression, often increase serotonin levels and are associated with positive brain changes (such as increased neuronal complexity via “sprouting” and possible restoration of brain volume in areas like the hippocampus), there has been a startling lack of evidence showing a direct role for serotonin, perhaps because more sophisticated research methods have not been available.

Absence of Evidence Is Not Evidence of Absence

That is, until now. For the first time, study authors have found a clear association between altered serotonin activity and depression in a robust experimental design.



Grant H Brenner

Psychiatrist, Psychoanalyst, Entrepreneur, Writer, Speaker, Disaster Responder, Advocate, Photographer