Beyond the serotonin deficit hypothesis: communicating a neuroplasticity framework of major depressive disorder.

Major depressive disorder (MDD) is better understood not as a serotonin deficit but as inflexibility in cognitive and emotional brain circuits that creates a persistent negativity bias. Effective treatments—including conventional antidepressants, ketamine, psychedelics, psychotherapy, and neuromodulation—work by enhancing neuroplasticity, restoring synaptic, network, and behavioral function to enable adaptive cognitive and emotional processing. The article provides accessible language and metaphors for clinicians and researchers to communicate this updated framework to patients and the public, aiming to improve understanding and trust.

Study at a glance

Abstract

The serotonin deficit hypothesis explanation for major depressive disorder (MDD) has persisted among clinicians and the general public alike despite insufficient supporting evidence. To combat rising mental health crises and eroding public trust in science and medicine, researchers and clinicians must be able to communicate to patients and the public an updated framework of MDD: one that is (1) accessible to a general audience, (2) accurately integrates current evidence about the efficacy of conventional serotonergic antidepressants with broader and deeper understandings of pathophysiology and treatment, and (3) capable of accommodating new evidence. In this article, we summarize a framework for the pathophysiology and treatment of MDD that is informed by clinical and preclinical research in psychiatry and neuroscience. First, we discuss how MDD can be understood as inflexibility in cognitive and emotional brain circuits that involves a persistent negativity bias. Second, we discuss how effective treatments for MDD enhance mechanisms of neuroplasticity-including via serotonergic interventions-to restore synaptic, network, and behavioral function in ways that facilitate adaptive cognitive and emotional processing. These treatments include typical monoaminergic antidepressants, novel antidepressants like ketamine and psychedelics, and psychotherapy and neuromodulation techniques. At the end of the article, we discuss this framework from the perspective of effective science communication and provide useful language and metaphors for researchers, clinicians, and other professionals discussing MDD with a general or patient audience.