Rethinking Serotonin in Depression: Toward a Modern Clinical Framework

Research has failed to demonstrate that depression is caused by a deficit in central serotonin activity. Umbrella reviews show no consistent association between serotonin markers and major depressive disorder (MDD), and routine clinical practice does not measure serotonin before treatment. Selective serotonin reuptake inhibitors (SSRIs) produce statistically significant but modest improvements over placebo in pooled analyses that include multiple antidepressant classes, with benefit concentrated in patients with severe depression and diminished in mild-to-moderate cases. SSRIs do provide meaningful relief for some patients and remain an important treatment option, particularly when access to psychological therapies is limited. Emerging mechanistic models suggest that SSRIs act less by correcting a chemical imbalance and more by reducing negative affective bias and modestly enhancing neuroplasticity, creating a window in which psychosocial and behavioral interventions can take hold. Because SSRIs are linked to common adverse effects, including sexual dysfunction, weight gain, and sleep disturbance, their routine use as a universal first-line treatment warrants re-examination. Recent international guidelines from the World Health Organization (WHO), the National Institute for Health and Care Excellence (NICE), and the American Psychiatric Association (APA) now prioritize psychological therapies, structured exercise, and combination approaches over antidepressant monotherapy for non-severe depression. This editorial proposes a pragmatic, patient-centered framework for general internists that accounts for real-world access barriers, screens for reversible contributors, offers evidence-based non-pharmacological options where feasible, and repositions SSRIs as adjuncts or facilitators rather than default interventions.