Treatment of Psychotic Symptoms in Alzheimer’s Disease

By Michael T. Lin, MD, PhD

Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College

SYNOPSIS: In a meta-analysis of several large treatment trials of patients with Alzheimer’s disease, Parkinson’s disease, and dementia with Lewy bodies, cholinesterase inhibitors demonstrated a small but statistically significant benefit in reducing psychotic symptoms.

SOURCE: d’Angremont E, Begemann MJ, van Laar T, Sommer IE. Cholinesterase inhibitors for treatment of psychotic symptoms in Alzheimer disease and Parkinson disease: A meta-analysis. JAMA Neurol 2023;Jun 6:e231835. doi: 10.1001/jamaneurol.2023.1835. [Online ahead of print].

Psychotic symptoms (hallucinations and delusions) are common in neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB). These symptoms increase the disease burden for both patients and caregivers. There are no Food and Drug Administration-approved medications for management of psychosis in elderly subjects with dementia, although brexpiprazole recently was approved for agitation in AD.¹ Benzodiazepines, antiepileptics, and antipsychotics frequently are used off-label for neuropsychiatric symptoms in dementia, but they are associated with severe adverse effects and increased mortality.

Previous trials have suggested that cholinesterase inhibitors (ChEIs; donepezil, galantamine, rivastigmine) may improve psychotic symptoms, but most randomized clinical trials only assessed neuropsychiatric symptoms as a secondary measure, and psychosis generally was lumped together with other neuropsychiatric symptoms, such as apathy, aggression, and depression. Thus, class I evidence supporting ChEIs for psychotic symptoms in neurodegenerative diseases is lacking.

Accordingly, d’Angremont and colleagues performed a meta-analysis of English language, placebo-controlled randomized clinical trials in AD, PD, or DLB, including at least one ChEI treatment arm and at least one validated neuropsychiatric outcome measure with a subscore for psychotic symptoms. They identified 34 such trials and were able to obtain individual participant raw data from the original authors for 12 trials in AD and five trials in PD. Individual participant data were not obtained for DLB trials. The most used outcome measure was the Neuropsychiatric Inventory (NPI), a scale with 12 subdomains, including delusions and hallucinations. Individually, most trials showed a nonsignificant trend favoring ChEIs.

In aggregate, the meta-analysis showed statistically significant reductions in psychotic symptoms with ChEI treatment, but the effect sizes (standardized mean difference, 95% confidence interval [CI]) were small. In AD, ChEIs reduced delusions (-0.08; 95% CI, -0.14 to -0.03; P = 0.006) and hallucinations (-0.09; 95% CI, -0.14 to -0.04; P = 0.003). In PD, ChEIs also reduced delusions (-0.14; 95% CI, -0.26 to -0.01; P = 0.04) and hallucinations (-0.08; 95% CI, -0.13 to -0.03; P = 0.01). There also was a significant interaction between the treatment outcome of total neuropsychiatric score and baseline Mini-Mental State Examination (MMSE) score, with more severe disease/cognitive decline associated with a larger effect size. Specifically, with each 10-point decrease in MMSE score, the effect size increased by 0.3 in AD and by 0.2 in PD, in favor of ChEI treatment.

COMMENTARY

A strength of this study was obtaining individual-level patient data in 6,649 subjects; the major limitation is the small effect size. Potential methodologic reasons for the small effect size include the fact that NPI is a crude tool. A more specialized scale, such as the Questionnaire for Psychotic Experiences, could more optimally assess psychotic symptoms. Also, the included trials were focused primarily on cognition and did not specifically enroll patients with psychotic symptoms.

Many patients did not report psychotic symptoms and could not experience any treatment results. However, the real reason for the small effect size most likely is biologic. Psychotic symptoms likely are not only the result of cholinergic deficiency but caused by neurotransmitter defects in general. Neurodegenerative diseases also are associated with widespread, extensive changes affecting perception, cognition, and sleep, among other factors.

Another limitation in practice is that psychotic symptoms typically occur later in neurodegenerative diseases, and ChEIs will already have been initiated earlier for their approved cognitive indication. Still, if ChEIs have not already been initiated, the results noted earlier suggest they should be the first pharmacologic agents tried when psychotic symptoms develop in AD or PD. They are relatively well tolerated, and they may even reduce mortality.^2,3

REFERENCES

1. Food and Drug Administration. FDA approves first drug to treat agitation symptoms associated with dementia due to Alzheimer’s disease. Published May 11, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-agitation-symptoms-associated-dementia-due-alzheimers-disease
2. Xu H, Garcia-Ptacek S, Jonsson L, et al. Long-term effects of cholinesterase inhibitors on cognitive decline and mortality. Neurology 2021;96:e2220-e2230.
3. Zuin M, Cherubini A, Volpato S, et al. Acetyl-cholinesterase-inhibitors slow cognitive decline and decrease overall mortality in older patients with dementia. Sci Rep 2022;12:12214.