GSK-239512

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.

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.

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.

Some H3R‐ANTs/H3R‐IAs might provide benefit for the treatment of cognitive symptoms and depressive symptoms in individuals afflicted with schizophrenia.

Regeneration of myelin in the central nervous system is being pursued as a potential therapeutic approach for multiple sclerosis. Several labs have reported small molecules that promote oligodendrocyte formation and remyelination in vivo. Recently, we reported that many such molecules function by inhibiting a narrow window of enzymes in the cholesterol biosynthesis pathway. Here we describe a new high-throughput screen of 1,836 bioactive molecules and a thorough re-analysis of more than 60 molecules previously identified as promoting oligodendrocyte formation from human, rat, or mouse oligodendrocyte progenitor cells. These studies highlight that an overwhelming fraction of validated screening hits, including several molecules being evaluated clinically for remyelination, inhibit cholesterol pathway enzymes like emopamil-binding protein (EBP). To rationalize these findings, we suggest a model that relies on the high druggability of sterol-metabolizing enzymes and the ability of cationic amphiphiles to mimic the transition state of EBP. These studies further establish cholesterol pathway inhibition as a dominant mechanism among screening hits that enhance human, rat, or mouse oligodendrocyte formation.