Diana K. Orsini

Major depressive disorder (MDD) and treatment‐resistant depression (TRD) remain leading causes of disability, providing the impetus for receptor‐level treatment strategies beyond monoamine reuptake. The serotonin 5‐HT2B receptor (5‐HT2BR) is uniquely positioned at the interface of central‐antidepressant mechanisms and peripheral cardiac risks. Herein, we reviewed preclinical, translational and clinical literature identified via PubMed and OVID (MEDLINE, Embase, AMED, PsychINFO) databases from inception to September 2025, supplemented by manual searches. Evidence converges that peripheral 5‐HT2BR agonism is mechanistically linked to valvular heart disease (VHD) through mitogenic/profibrotic signaling in valve tissue, consistent with historical signals for anorectic agents (e.g., fenfluramine) and ergot‐derived dopamine agonists, with supportive but limited data for 3,4‐methylenedioxymethamphetamine (MDMA). Classical serotonergic psychedelics bind 5‐HT2BRs; therefore, while contemporary dosing regimens are intermittent, cumulative exposure risks remain insufficiently characterized. Conversely, central 5‐HT2BR signaling appears bidirectional wherein astrocytic 5‐HT2BR activation under sustained serotonergic tone may support metabolic and plasticity programs, whereas neuronal 5‐T2BR antagonism can normalize mesolimbic dopamine output and enhance medial prefrontal glutamatergic activity. Clinically, several approved antidepressant adjuncts (e.g., aripiprazole, brexpiprazole, cariprazine) display 5‐HT2BR antagonism or inverse agonism and improve depressive symptoms without observed valvular signals in trials. The 5‐HT2BR represents a tractable augmentation target for TRD provided that peripheral agonism is rigorously avoided. Consistent with evolving scientific and regulatory safety frameworks, we propose advancing centrally selective, periphery‐sparing 5‐HT2BR antagonists into biomarker‐anchored early cardiac monitoring and preclinical exclusion of valve‐cell 5‐HT2BR agonism. This framework integrates central efficacy with defined safety boundaries, guiding development of mechanistically informed antidepressant therapies.

1. Major depressive disorder (MDD) is a leading cause of disability worldwide, affecting over 300 million individuals globally and contributing to more than 800,000 deaths by suicide annually [1]. ...