Cognitive improvement of acetylcholinesterase inhibitors in schizophrenia

Abstract

Background: Schizophrenia is a severe, persistent mental disorder, and a leading cause of disability worldwide. Cognitive impairments presented in schizophrenia lead to a worse prognostic, thus treatments targeted to enhance cognition in schizophrenia may be clinically relevant. Aims: The purpose of this study was to assess the efficacy of acetylcholinesterase inhibitors as add-on medication to antipsychotics on cognition in patients with schizophrenia. Methods: Search strategies were developed for Medline, Embase and Cochrane Central Register of Controlled Trials, and are current to March 2018. We included randomised controlled trials that compared antipsychotics plus acetylcholinesterase inhibitors versus antipsychotics plus placebo on prespecified cognitive domains (speed of processing, attention and working memory). Two review authors independently evaluated study eligibility, extracted data and assessed the risk of bias of included studies. We used random-effects model for meta-analyses and assessed the quality of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: We included nine randomised controlled trials. Six randomised controlled trials (n=219) presented evidence that acetylcholinesterase inhibitors improve speed of processing (standardised mean difference −0.52, 95% confidence interval (−0.79 to −0.25); p value=0.0002). However, eight randomised controlled trials (n=252) did find placebo was better than acetylcholinesterase inhibitors in the attention domain (−0.43, (−0.72 to −0.13); p value=0.005) and eight randomised controlled trials (n=273) did not find differences in the working memory (−0.14, (−0.51 to 0.24), p value=0.47). Conclusions: The current evidence is too weak to base recommendations on the use of acetylcholinesterase inhibitors as adjunctive treatments to antipsychotics to improve basic cognitive functions. We have limited confidence in the effect estimates.

Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology

“…Santos et al conducted a meta-analysis of nine RCTs in which donepezil, galantamine, rivastigmine or placebo were added to current antipsychotic medication in stable patients with schizophrenia (Santos et al, 2018). Of the three cognitive domains examined, speed of processing improved, attention worsened and working memory did not change.…”

Calbindin Deficits May Underlie Dissociable Effects of 5-HT6 and mGlu7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia

“…A diverse array of compounds, including 5-HT 6 antagonists [42,[110][111][112], an mGlu 2/3 agonist [49], NMDA receptor glycine modulatory site partial agonist [113], α4β2 and α7 nicotinic receptor agonists [114], donepezil [115], risperidone [47], and fluoxetine [116], all reverse "single-hit" isolation-induced NOD deficits. Some of these approaches are associated with clinical benefit in other psychiatric or neurodegenerative disorders but ultimately lack marked clinical benefit in schizophrenia [117][118][119]. For example, 5-HT 6 antagonists appear to improve cognition in mild to moderate Alzheimer's disease [120,121] which interestingly, and consistent with our working hypothesis, does not appear to involve calbindin deficits in CA1 [122][123][124].…”

Treating disorders across the lifespan by modulating cholinergic signaling with galantamine

“…PD and other neurological conditions have been linked to alterations in gut microbiota as very recently summarized (Santos et al., 2019). Preclinical studies have demonstrated that alterations in gut microbiota mediate motor deficits, microglia activation, and brain pathology consistent with neuroinflammation, suggesting that targeting the microbiome via probiotics may reduce neuroinflammation (Sampson et al., 2016). It is intriguing to relate these findings to regulation of the gut microbiome as a therapeutic option for altering PD brain pathology.…”