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Original Investigation
June 26, 2023

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

Author Affiliations
  • 1Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, Groningen, the Netherlands
  • 2Department of Neurology, University Medical Center Groningen, Groningen, the Netherlands
  • 3Department of Psychiatry, University Medical Center Groningen, Groningen, the Netherlands
JAMA Neurol. 2023;80(8):813-823. doi:10.1001/jamaneurol.2023.1835
Key Points

Question  Are cholinesterase inhibitors (ChEIs) associated with improvement of individual neuropsychiatric symptoms, specifically delusions and hallucinations, in Alzheimer disease and Parkinson disease?

Findings  This individual patient data meta-analysis examined the results of treatment with ChEIs in 6649 patients from 17 randomized clinical trials. The findings suggest that ChEI therapy significantly ameliorates delusions and hallucinations in Alzheimer disease and Parkinson disease.

Meaning  Treatment with ChEIs may be considered in people with neurodegenerative disorders and psychotic symptoms.


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.

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