Preclinical Evidence for Antidepressant-like Effects of Histamine H3 Receptor Modulation: A Systematic Review and Meta-Analysis

BACKGROUND: Histamine H3 receptor-targeting compounds modulate histaminergic tone and downstream monoaminergic/arousal circuits and have been proposed to exert potential antidepressant-like effects in preclinical models. METHODS: We conducted a systematic review and meta-analysis of rodent studies evaluating H3-related interventions on depression-like behavior. We screened 60 records, assessed 12 studies qualitatively (four CORE, eight sensitivity), and included nine studies in random-effects meta-analyses (REML). Primary outcomes were the forced swim test (FST) and tail suspension test (TST); effect sizes were summarized as Hedges' g (positive values indicate reduced immobility). RESULTS: In the primary ALL analysis, H3-related interventions improved FST outcomes (g = 1.40, 95% CI 0.83-1.97; k = 7) and were also associated with improved TST outcomes, albeit with substantial heterogeneity (g = 2.27, 95% CI 0.80-3.73; k = 5). CORE-only analyses were directionally consistent but less precise (FST: g = 1.11, 95% CI -0.06-2.27; k = 3; TST: g = 2.95, 95% CI 0.87-5.02; k = 2). Sucrose preference was reported in one study and indicated improvement (g = 1.61, 95% CI 0.29-2.92). CONCLUSIONS: H3-related interventions show an antidepressant-like signal in rodent FST and TST, with greater heterogeneity for TST, highlighting the need for more standardized and adequately powered preclinical studies.