Efficacy and Safety of Donepezil in Patients with Schizophrenia or Schizoaffective Disorder: Significant Placebo/Practice Effects in a 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Altered expression of central muscarinic and nicotinic acetylcholine receptors in hippocampal and cortical regions may contribute to the cognitive impairment exhibited in patients with schizophrenia. Increasing cholinergic activity through the use of a cholinesterase inhibitor (ChEI) therefore represents a possible strategy for cognitive augmentation in schizophrenia. We examined the efficacy and safety of the ChEI donepezil as cotreatment for mild to moderate cognitive impairment in schizophrenia or schizoaffective disorder in a prospective, 12-week, placebo-controlled, double-blind, parallel-group study. In total, 250 patients (18-55 years) with schizophrenia or schizoaffective disorder who were clinically stabilized on risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole, alone or in combination, were enrolled at 38 outpatient psychiatric clinics in the United States. Patients were randomized to donepezil 5 mg q.d. for 6 weeks then 10 mg q.d. for 6 weeks, or placebo administered as oral tablets. The primary outcome measure was the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) neurocognitive battery composite score. In the intent-to-treat sample (donepezil, n ¼ 121; placebo, n ¼ 124), both treatments showed improvement in the composite score from baseline to week 12. At week 12, cognitive improvement with donepezil was similar to that with placebo (last-observation-carried-forward effect size, 0.277 vs 0.411; p ¼ 0.1182) and statistically significantly inferior for the observed-cases analysis (0.257 vs 0.450; p ¼ 0.044). There was statistically significant improvement in the Positive and Negative Syndrome Assessment Scale negative symptoms score for placebo compared with donepezil, while total and positive symptom scores were similar between both treatments. Statistically significant improvements in positive symptoms score and Clinical Global Impression-Improvement for donepezil compared with placebo were noted at Week 6. Treatment-emergent adverse events (AEs) were observed for 54.5% of donepezil-and 61.3% of placebo-treated patients; most AEs were rated as mild to moderate in severity. Donepezil was safe and well-tolerated but was not effective compared with placebo as a cotreatment for the improvement of cognitive impairment in this patient population. A significant and surprisingly large placebo/practice effect was observed among placebotreated patients, and is a serious consideration in future clinical trial study designs for potential cognitive enhancing compounds in schizophrenia.

Role of the cholinesterase inhibitors in the treatment of schizophrenia

“…Likewise, most RCTs investigating ChEIs include fewer than 30 patients (only one included 245 patients; otherwise, fewer than 90 were included). However, this should not be the case with ChEIs given that the study conducted by Keefe and colleagues [25] had a sufficient sample even though they found that donepezil was less effective than was placebo. The study conducted by Buchanan and colleagues [28] was also moderately powered, but only a few post hoc analyses found significant results.…”

“…In fact, the joint academic and industry initiative known as Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) has developed guidelines and proposed the use of a cognitive battery (MCCB) addressing seven cognitive domains (speed of processing, attention/ vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition) to improve the specificity of treatments for cognitive deficits [29]. Although the study conducted by Keefe and colleagues investigating donepezil [25] was designed and initiated before the establishment of the MATRICS guidelines and the MCCB, their study was consistent with these recommendations and may be considered representative of rigorous research in this field. Although the MCCB has excellent reliability, minimal practice effects, and significant correlations with measures of functional capacity, its sensitivity to changes during pharmacological treatment has yet to be confirmed [30].…”

“…In 14 RCTs (ranges: 8 --18 weeks, 5 --10 mg/d, n = 6 --245), donepezil failed to improve the cognitive impairments of patients with schizophrenia [21,23]. Keefe et al [25] conducted a prospective 12-week RCT to investigate whether donepezil should be used to augment treatment for mild-to-moderate cognitive impairment in schizophrenia or schizoaffective disorder. This study was the first large-scale RCT among patients with schizophrenia/schizoaffective disorder to use a comprehensive neurocognitive battery to evaluate cognitive improvements of patients with stable symptoms and mildto-moderate illnesses.…”

Acetylcholinesterase inhibitors and memantine in bipolar disorder: A systematic review and best evidence synthesis of the efficacy and safety for multiple disease dimensions

“…Until now, evidence suggests use of donepezil in schizophrenia yields no effect (Keefe et al, 2008), while galantamine seems to improve some cognitive domains Lee et al, 2007;Schubert et al, 2006), particularly in combination with antipsychotics; however evidence is still weak due to the limitations of included studies (Singh et al, 2012). Similarly, a systematic review (Zdanys and Tampi, 2008) did not find conclusive results for the use of memantine in several psychiatric disorders, including depression, schizophrenia, obsessive-compulsive disorder, substance abuse, pervasive developmental disorders, and binge eating disorder.…”

Doping for Chess Performance

“…Furthermore, there exists no information on the long-term effects on cognition. In addition, the studies show that there are little differences in terms of cognitive-enhancement even compared to placebo: one study [152] even showed a better cogni tive improvement in the placebo group. In addition, many of the CE drugs are most effective only on patients characterized by the lowest baseline of cognitive performance [153][154][155][156][157], while even impairing performance of patients with high baseline cognitive function [154,[158][159][160][161].…”