Cholinesterase Inhibitors for Treatment of Psychotic Symptoms in Alzheimer Disease and Parkinson Disease: A Meta-analysis

Abstract

Importance: Psychotic symptoms greatly increase the burden of disease for people with neurodegenerative disorders and their caregivers. Cholinesterase inhibitors (ChEIs) may be effective treatment for psychotic symptoms in these disorders. Previous trials only evaluated neuropsychiatric symptoms as a secondary and an overall outcome, potentially blurring the outcomes noted with ChEI use specifically for psychotic symptoms.

Objective: To quantitatively assess the use of ChEIs for treatment of individual neuropsychiatric symptoms, specifically hallucinations and delusions, in patients with Alzheimer disease (AD), Parkinson disease (PD), and dementia with Lewy bodies (DLB).

Data sources: A systematic search was performed in PubMed (MEDLINE), Embase, and PsychInfo, without year restrictions. Additional eligible studies were retrieved from reference lists. The final search cutoff date was April 21, 2022.

Study selection: Studies were selected if they presented the results of placebo-controlled randomized clinical trials, including at least 1 donepezil, rivastigmine, or galantamine treatment arm in patients with AD, PD, or DLB; if they applied at least 1 neuropsychiatric measure including hallucinations and/or delusions; and if a full-text version of the study was available in the English language. Study selection was performed and checked by multiple reviewers.

Data extraction and synthesis: Original research data were requested on eligible studies. A 2-stage meta-analysis was then performed, using random-effects models. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed for extracting data and assessing the data quality and validity. Data extraction was checked by a second reviewer.

Main outcomes and measures: Primary outcomes were hallucinations and delusions; secondary outcomes included all other individual neuropsychiatric subdomains as well as the total neuropsychiatric score.

Results: In total, 34 eligible randomized clinical trials were selected. Individual participant data on 6649 individuals (3830 [62.6%] women; mean [SD] age, 75.0 [8.2] years) were obtained from 17 trials (AD: n = 12; PD: n = 5; individual participant data were not available for DLB). An association with ChEI treatment was shown in the AD subgroup for delusions (-0.08; 95% CI, -0.14 to -0.03; P = .006) and hallucinations (-0.09; 95% CI, -0.14 to -0.04; P = .003) and in the PD subgroup for delusions (-0.14; 95% CI, -0.26 to -0.01; P = .04) and hallucinations (-0.08, 95% CI -0.13 to -0.03; P = .01).

Conclusions and relevance: The results of this individual participant data meta-analysis suggest that ChEI treatment improves psychotic symptoms in patients with AD and PD with small effect sizes.

Figure 1.. Study Flow Diagram of Literature Search and Included Studies and Data

IPD indicates individual participant data; RCT, randomized clinical trial.

Figure 2.. Effect Sizes of Cholinesterase Inhibitor Treatment in Delusions (A) and Hallucinations (B)

Results are separated for Alzheimer disease (AD) and Parkinson disease (PD). Square size denotes weighting. The diamonds reflect the overall effect size. SMD indicates standardized mean difference.

Figure 3.. Treatment Effect Sizes of Cholinesterase Inhibitors in Individual Neuropsychiatric Items

Results are separated for Alzheimer disease (AD) and Parkinson disease (PD). Error bars indicate the 95% CIs.

Figure 4.. Effect Sizes of Cholinesterase Inhibitor Treatment in Total Neuropsychiatric Outcome

Results are separated for Alzheimer disease (AD) and Parkinson disease (PD). Square size denotes weighting. The diamonds reflect the overall effect size. SMD indicates standardized mean difference.