Targeting the serotonin 1B receptor for the treatment of depression and anxiety.

Abstract

Introduction: Depressive and anxiety disorders impose a substantial public health burden, yet current serotonergic therapies are limited by delayed onset, modest remission rates, and adverse side effects. Here we put forward the serotonin 1B receptor (5-HT1BR) as an important therapeutic target for mood related pathology.

Areas covered: We synthesize converging evidence from human and preclinical studies that link 5-HT1BR expression and function to affective phenotypes. Importantly, agonists and the p11 dependent surface trafficking pathway produce antidepressant like effects. Additionally, recent work demonstrates that 5-HT1BR signaling is required for the sustained pro-hedonic and anxiolytic actions of psilocybin. Mechanistically, 5-HT1BR modulates corticolimbic synaptic plasticity and regulates neurotransmitter release from both serotonergic and non-serotonergic terminals, positioning it to reshape dysfunctional neural circuitry. FDA-approved drugs that have 5-HT1BR agonist activity show favorable safety profiles, but there is limited clinical data from brain-penetrant selective ligands.

Expert opinion: We propose prioritized research avenues: PET-based occupancy biomarkers, clinical trials with 5-HT1BR agonists, and exploration of sex and stress dependent effects. Additionally, in the recent drive to study and develop novel psychedelic-related compounds, it is important to consider 5-HT1BR activation. Collectively, preclinical evidence supports 5-HT1BR as a tractable, high-impact target poised to contribute to antidepressant strategies.