Efficacy and Safety of Histamine H3 Receptor Antagonist/Inverse Agonist Including Betahistine for Schizophrenia: A Systematic Review and Meta-Analysis

Aim: Whether histamine H3 receptor antagonists (H3R-ANTs)/inverse agonists (H3R-IAs) provides benefit for the treatment of schizophrenia remains unclear. This meta-analysis was conducted to address the above clinical question. Methods: Cognitive Function Scale's composite score (primary), seven domains of cognitive function (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, and social cognition) score, University of California San Diego Performance-Based Skills Assessment score, psychopathology scales score, discontinuation rate, and incidence of individual adverse events were among the study outcomes. The standardized mean differences (SMD) or risk ratios (RR) with 95% confidence intervals (CIs) were calculated. Results: Our meta-analysis included 11 double-blind, randomized, placebo-controlled trials (n = 754). Our study evaluated ABT-288, betahistine, betahistine+reboxetine, GSK239512, MK-0249, and pitolisant. Betahistine has an H1-receptor agonistic reaction and H3-receptor antagonistic reaction, while other drugs only have an H3-receptor antagonistic/inverse agonistic reaction. Hence, we conducted a meta-analysis for all outcomes divided by betahistine or other pooled H3R-ANTs/H3R-IAs. The study results show that betahistine outperformed placebo in the improvement of overall cognitive symptoms (SMD [95% CI] = −0.61 [−1.03, −0.18]), speed of processing (−0.44 [−0.87, −0.02]), attention/vigilance (−0.43 [−0.85, −0.01]), working memory (−0.48 [−0.90, −0.06]), verbal learning (−0.62 [−1.04, −0.19]), visual learning (−0.57 [−1.00, −0.15]), and betahistine+reboxetine was superior in the improvement of depressive symptoms (−4.04 [−5.10, −2.97]). Pitolisant outperformed placebo in depressive symptom improvement (−3.24 [−4.22, −2.26]). However, the results were derived from one betahistine, betahistine+reboxetine, or pitolisant study. Other pooled H3R-ANTs/H3R-IAs revealed risk of insomnia (RR [95% CI] = 2.18 [1.05, 4.55]). However, no differences were observed in other any outcomes between betahistine or other pooled H3R-ANTs/H3R-IAs and placebo. Conclusions: Some H3R-ANTs/H3R-IAs might provide benefit for the treatment of cognitive symptoms and depressive symptoms in individuals afflicted with schizophrenia.