Anti-Dementia Drugs for Psychopathology and Cognitive Impairment in Schizophrenia: A Systematic Review and Meta-Analysis

Background: We conducted a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials of anti-dementia drugs plus antipsychotics for schizophrenia. Methods: Primary outcomes of efficacy and safety included improving overall symptoms (Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale scores) and all-cause discontinuation, respectively. Other outcomes included psychopathology subscales (positive, negative, general, and anxiety/depressive symptoms), cognitive function (attention/vigilance, reasoning/problem solving, social cognition, speed of processing, verbal learning, visual learning, working memory, and cognitive control/executive function), Mini-Mental State Examination scores, treatment discontinuation due to adverse events and inefficacy, and individual adverse events. We evaluated the effect size using a random effects model. Results: We identified 37 studies (n = 1574): 14 donepezil-based (n = 568), 10 galantamine-based (n = 371), 4 rivastigmine-based (n = 146), and 9 memantine-based (n = 489) studies. Pooled anti-dementia drugs plus antipsychotics treatments were superior to placebo plus antipsychotics in improving the overall symptoms (24 studies, 1069 patients: standardized mean difference = -0.34, 95% CI = -0.61 to -0.08, P = .01), negative symptoms (24 studies, 1077 patients: standardized mean difference = -0.62, 95% CI = -0.92 to -0.32, P-corrected = .00018), and Mini-Mental State Examination scores (7 studies, 225 patients: standardized mean difference = -0.79, 95% CI = -1.23 to -0.34, P = .0006). No significant differences were found between anti-dementia drugs plus antipsychotics and placebo plus antipsychotics regarding other outcomes. Conclusions: Although the results suggest that anti-dementia drugs plus antipsychotics treatment improves negative symptoms and Mini-Mental State Examination scores in schizophrenia patients, they possibly were influenced by a small-study effect and some bias. However, it was not superior to placebo plus antipsychotics in improving composite cognitive test score, which more systematically evaluates cognitive impairment than the Mini-Mental State Examination score. Overall, the anti-dementia drugs plus antipsychotics treatment was well tolerated.