Psychiatric Adverse Events of Acetylcholinesterase Inhibitors in Alzheimer’s Disease and Parkinson’s Dementia: Systematic Review and Meta-Analysis

Abstract

Background The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia.

Objectives While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined.

Methods We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer’s dementia and Parkinson’s dementia.

Results A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29–3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33–2.82; p = 0.0006; insomnia: OR 1.55, 95% CI 1.25–1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23–2.06, p = 0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine.

Conclusions Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia.

Clinical Trial Registration The study was pre-registered on PROSPERO (CRD42021258376).