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. 2023 Jun 26;80(8):813–823. doi: 10.1001/jamaneurol.2023.1835

Cholinesterase Inhibitors for Treatment of Psychotic Symptoms in Alzheimer Disease and Parkinson Disease

A Meta-analysis

Emile d’Angremont 1,✉, Marieke J H Begemann 1, Teus van Laar 2, Iris E C Sommer 3
PMCID: PMC10294019  PMID: 37358841

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.

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.

This meta-analysis examines the use of cholinesterase inhibitors as treatment of psychotic symptoms in patients with Alzheimer disease, Parkinson disease, and dementia with Lewy bodies.

Introduction

Psychotic symptoms are a common feature in many neurodegenerative diseases, including Alzheimer disease (AD) and Lewy body disorders, such as Parkinson disease (PD) and dementia with Lewy bodies (DLB). A review of 35 studies on psychosis in AD reported a median prevalence of hallucinations of 23% and 36.5% for delusions.1 Hallucinations typically occur in the more advanced stages of AD.2 In DLB, visual hallucinations are one of the core clinical features and occur in up to 80% of patients.3 Delusions, together with hallucinations in other modalities, are reported by approximately 50% of patients with DLB.3 In PD, the reported prevalence of psychotic symptoms is 60% when including minor and nonvisual hallucinations,4 with a higher prevalence in PD-related dementia.5

Research has consistently shown that the burden of psychotic symptoms in neurodegenerative diseases is extensive, both for patients and caregivers. In PD, their presence is an independent predictor of mortality,6 nursing home placement,7 and caregiver burden.8 In DLB, psychotic symptoms, together with apathy and anxiety, predict high caregiver distress.9 The presence of psychotic symptoms in AD increases the risk for rapid cognitive and functional decline, hospital admissions, and death.10,11 Treatment of psychotic symptoms in patients with neurodegenerative disorders remains challenging as benzodiazepines, typical antipsychotics, and atypical antipsychotics are associated with severe adverse effects and increased mortality.11,12

Convergent evidence from neuroimaging and biochemistry studies showed that the development of psychosis is related to a cholinergic deficiency in AD.13 The prominent role of cholinergic deficits in the development of psychosis was also reported in PD and DLB.14,15,16 Therefore, cholinesterase inhibitors (ChEIs) could be effective treatments for psychotic symptoms in AD, PD, and DLB, with better tolerability compared with antipsychotics and benzodiazepines. Several case series, open-label trials, and post hoc analyses reported a marked improvement of delusions and hallucinations in AD, PD, and DLB after ChEI treatment.17,18,19,20 Meta-analyses reviewed evidence from randomized clinical trials (RCTs) on the use of ChEIs in AD, PD, and DLB, including the effects on neuropsychiatric symptoms.21,22,23,24 Most of the reviewed trials only assessed neuropsychiatric symptoms as a secondary outcome measure and were not powered to investigate the effect on these specific symptoms.1,11,12,17 Moreover, scores for hallucinations and delusions were generally combined with quite different psychiatric symptoms, such as apathy, aggression, and depression, as one rating for neuropsychiatric symptoms. However, the mechanism behind depression and aggression may be rather different than that for psychotic symptoms. The effect of ChEI treatment on this overall score was found to be inconsistent, with some RCTs finding efficacy and others not. As a result, class I evidence for the efficacy of ChEI treatment to ameliorate psychotic symptoms in neurodegenerative diseases is lacking.

To specifically address ChEI treatment for hallucinations and delusions, we requested the individual participant data from previous RCTs to evaluate the combined outcomes noted with use of these drugs in psychotic symptoms in a meta-analysis.

Methods

Search Strategy and Selection Criteria

The study protocol was registered in PROSPERO under record number CRD42022296953. We performed a meta-analysis on individual items of the neuropsychiatric assessment instruments as used in RCTs implementing ChEI treatment in DLB, PD, and AD. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.

A systematic search was performed in PubMed (MEDLINE), Embase, and PsychInfo, without year restrictions. The full search terms are noted in the eTable 1 in Supplement 1. Additional eligible studies were retrieved by searching the reference lists of the primary articles and relevant reviews. The search cutoff date was April 24, 2020. When we updated the search to April 21, 2022, we identified 1 additional eligible trial.25 These data were retrieved from the corresponding author.

The inclusion criteria were as follows: (1) placebo-controlled RCTs with at least 1 donepezil, rivastigmine, or galantamine treatment arm; (2) patients diagnosed with AD, PD, or DLB; (3) applying a validated neuropsychiatric or behavioral outcome measure that included a subscore for psychotic symptoms (hallucinations and/or delusions); and (4) full text available in the English language.

Outcome Measures and Data Collection

Primary outcomes were hallucinations and delusions; secondary outcomes included all other individual neuropsychiatric subdomains as well as the total (ie, summed) neuropsychiatric score. Corresponding authors and several data-sharing platforms were approached for obtaining raw scores from the neuropsychiatric rating scale of the included trials (eMethods in Supplement 1). The most used scale was the Neuropsychiatric Inventory (NPI), consisting of 12 subdomains: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, sleep, and appetite. The maximum score is 12 per domain; the score per domain is the result of multiplication of the frequency (1-4) and severity (1-3) of the symptom. The score is 0 when absent. Individual items from other scales were mapped to 1 NPI item (eTable 2 in Supplement 1). Items that did not correspond to any NPI item were included in the analysis of the total neuropsychiatric score but were discarded for the analysis of item subscores.

Data Analysis

We performed a 2-stage individual participant data (IPD) meta-analysis using R, versions 3.5.2 and 3.6.3 (R Foundation for Statistical Computing) (eMethods in Supplement 1). Bonferroni correction was applied to correct for multiple comparisons in the secondary outcome analyses including the 12 NPI subscales. Given the substantial number of study participants without psychotic symptoms, we performed a post hoc analysis for delusions and hallucinations in which we specifically included individuals who had a positive score on the concerning symptom at baseline.

Study Heterogeneity

To investigate whether studies could be combined to share a common population effect size, the Q value and I2 statistic were evaluated for each analysis. Q values higher than the degrees of freedom indicate significant between-studies variability. We considered I2 values of 25% as low, 50% as moderate, and 75% as high heterogeneity.26 Potential publication bias for total neuropsychiatric score was investigated by means of a visual inspection of the funnel plot and Egger test (P < .10; 2-tailed).

Risk of Bias Assessment

We used the Revised Cochrane risk-of-bias tool for RCTs for the quality assessment of the included studies.27 Specifically, the randomization process, blinding to the intervention, and missing outcome data were assessed for all studies. We considered a trial to have a possible risk of missing outcome data if less than 90% of the randomized participants could be used for our analysis.

Results

We identified 34 eligible studies (Figure 1). On request, raw data were obtained for 17 studies (50% of the eligible trials) including 6649 individuals, with data on sex and age available for 6123 (2293 [37.4%] men; 3830 [62.6%] women; mean [SD] age, 75.0 [8.2] years). No IPD data could be obtained for DLB, so this disease group was disregarded in our main analysis. The second-stage meta-analysis as performed on the aggregated data from 2 DLB trials can be found in eFigure 1 in Supplement 1.

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

Figure 1.

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

Five different rating scales evaluating psychotic symptoms were applied in the included studies: Behavioral Pathology in Alzheimer Disease Rating Scale (n = 2), Parkinson Psychosis Rating Scale (n = 1), Scale to Assess Positive Symptoms (n = 1), the Neuropsychiatric Inventory (NPI) (n = 12), and a questionnaire-based version of the NPI (NPI-Q) (n = 1). Mini-Mental State Examination (MMSE) scores were used to assess global cognition within each included RCT. An overview of the included studies is given in the Table.25,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46

Table. Overview of Studies Included in Meta-analysis.

Source Data supplier Disease Severity of dementiaa Intervention Duration, wk Neuropsychiatric outcome No. of participants No. of participants included in analysis Mean (SD) ageb Sex (% male)b Mean (SD) baseline neuropsychiatric outcomeb Mean (SD) baseline MMSEb
Tariot, et al28 2001 Eisai AD MMSE 5-26 Donepezil, 10 mg/d 24 NPI 208 200 85.0 (5.9) 15.5 20.2 (14.4) 14.6 (5.6)
Black, et al29 2007 Eisai AD MMSE 1-12 Donepezil, 10 mg/d 24 NPI 343 297 77.8 (7.7) 29.3 22.3 (20.2) 7.6 (3.4)
Homma, et al30 2008 Eisai AD MMSE 1-12 Donepezil, 5, 10 mg/d 24 BEHAVE-AD 290 289 78.3 (7.7) 19.7 8.0 (6.2) 7.8 (3.4)
Haig, et al31 2014 AbbVie AD MMSE 10-24 Donepezil, 10 mg/d 12 NPI 123 113 70.1 (8.3) 39.8 11.8 (11.8) 18.1 (4)
Gault, et al32 2015 AbbVie AD MMSE 10-24 Donepezil, 10 mg/d 12 NPI 136 134 72.9 (8.3) 47.0 9.8 (11.6) 19.7 (3.9)
Gault, et al33 2016 AbbVie AD MMSE 10-24 Donepezil, 10 mg/d 24 NPI 179 170 73.9 (7.5) 41.2 11.5 (11.1) 18.8 (4.2)
Gold, et al34 2010 GSK AD MMSE 10-23 Donepezil, 10 mg/d 24 NPI 235 207 72.4 (8.3) 39.6 9.9 (12.2) 19.6 (4)
Nakamura, et al35 2011 Novartis AD MMSE 10-20 Rivastigmine, 4.6, 9.5 mg/d (skin patch) 24 BEHAVE-AD 855 829 75.4 (8.1) 31.6 5.1 (5) 16.7 (2.9)
Winblad, et al36 2007 Novartis AD MMSE 10-20 Rivastigmine, 9.5, 17.4 (skin patch), 12 mg/d (capsule) 24 NPI 1190 1055 73.5 (7.9) 33.6 15.0 (14.5) 16.5 (3)
Tariot, et al37 2000 JNJ AD MMSE 10-22 Galantamine, 8, 16, 24 mg/d 21 NPI 978 948 76.8 (7.5) 36.5 11.3 (12.2) 17.9 (3.6)
Brodaty, et al38 2005 JNJ AD MMSE 10-24 Galantamine, 16, 24 mg/d 26 NPI 965 918 76.3 (7.7) 36.5 11.3 (13.1) 18.0 (4)
Rockwood, et al39 2001 JNJ AD MMSE 11-24 Galantamine, 24-32 mg/d 12 NPI 386 372 75.0 (7.5) 44.6 10.8 (13) 19.8 (3.8)
Ikeda, et al40 2005c Eisai DLB MMSE 10-26 Donepezil, 5 and 10 mg/d 12 NPId 138 138 NA NA 25.4 (9.4) NA
Mori, et al41 2012c Eisai DLB MMSE 10-26 Donepezil, 3, 5, 10 mg/d 12 NPId 135 134 NA NA 24.5 (9.8) NA
Dubois, et al42 2012 Eisai PD MMSE 10-26 Donepezil, 5, 10 mg/d 24 NPI 550 499 71.9 (7.3) NA 13.5 (11.8) 21.4 (3.5)
Emre, et al43 2004 Novartis PD MMSE 10-24 Rivastigmine, 3-12 mg/d 24 NPI 541 478 72.5 (6.9) 65.9 16.4 (14.9) 19.4 (3.8)
Mamikonyan, et al44 2015 Author PD MCI based on Winblad et al46 Rivastigmine, 9.5 mg/d 10 PPRS 28 27 NA NA 5.8 (1.2) NA
van Mierlo, et al25 2021 Author PD MMSE 26-30 Rivastigmine, 6-12 mg/d 24 SAPS 91 70 66.9 (8.2) 71.4 6.5 (5.6) 28.7 (1.3)
Grace, et al45 2009 Author PD 3MS 77-100 Galantamine, 24 mg/d 16 NPI-Q 69 43 68.4 (9) 69.8 3.3 (3.5) NA
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Abbreviations: AD, Alzheimer disease; BEHAVE-AD, Behavioral Pathology in Alzheimer Disease Rating Scale; DLB, dementia with Lewy bodies; JNJ, Johnson & Johnson; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; 3MS, Modified Mini-Mental State; NA, not applicable; NPI, Neuropsychiatric Inventory; NPI-Q, screening version of NPI; PD, Parkinson disease; PPRS, Parkinson Psychosis Rating Scale; SAPS, Scale to Assess Positive Symptoms.

a

Possible MMSE scores range from 0 to 30, with a score of 0 to 9 indicating severe; 10 to 18, moderate; and 19 to 23 mild cognitive impairment.

b

Summary statistics are based on participants included in the analyses.

c

For these studies only aggregate data were obtained.

d

This version of the NPI includes an item for fluctuation cognition instead of appetite and eating disorders.

Forest plots for treatment effects on delusions and hallucinations are shown in Figure 2. Both symptoms showed a significant effect size in the AD subgroup (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). In the PD subgroup, a significant effect size was observed for both 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). There were no between-group differences or significant heterogeneity in any of the subgroups. There were no significant differences between the ChEI types, although rivastigmine showed the largest effect size for both delusions (−0.11; 95% CI, −0.21 to −0.01; P = .03) and hallucinations (−0.10; 95% CI, −0.17 to −0.04; P = .01). Forest plots for all other items can be found in eFigure 2 in Supplement 1.

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

Figure 2.

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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 shows the results for all individual items of the NPI. In the AD subgroup, significant positive outcomes were found only for delusions and hallucinations. Moreover, we observed a negative association of ChEI treatment with appetite in the AD subgroup. Considering all individual NPI items, hallucinations were the only symptom that remained significant after Bonferroni correction. In the PD subgroup, significant results were found for elation/euphoria and apathy/indifference, in addition to delusions and hallucinations. None of these results in the PD subgroup remained significant after Bonferroni correction. Furthermore, the treatment outcomes significantly differed for the 2 disease groups for apathy/indifference and appetite: no association was seen for apathy/indifference in the AD group and appetite in the PD group.

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

Figure 3.

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

Figure 4 shows a forest plot summarizing the results of ChEI treatment for the total neuropsychiatric outcome. The effect size was nonsignificant within the AD group. We found a significant effect size in the PD subgroup on the total neuropsychiatric score (−0.18; 95% CI, −0.25 to −0.11; P = .002). We observed a between-group difference (χ21 = 15.62; P < .001).

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

Figure 4.

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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.

The PD group showed a significant interaction between the treatment effect and the baseline neuropsychiatric total score (coefficient = −0.21; 95% CI, −0.36 to −0.05; P = .02), compared with placebo. Specifically, this finding means that a 1-SD increase in baseline neuropsychiatric score increased the effect size by 0.21 in favor of ChEI treatment. This interaction was not found for any of the individual items of the neuropsychiatric outcome, nor for the AD subgroup, with high heterogeneity observed between the studies.

We also found a significant interaction between treatment outcome of total neuropsychiatric score and MMSE score at baseline for both the AD (coefficient = 0.03; 95% CI, 0.01-0.05; P = .003) and PD (coefficient = 0.02; 95% CI, 0.01-0.03; P = .008) groups. Specifically, with each 10-point decrease in baseline the MMSE score, the effect size increased by 0.3 in AD and by 0.2 in PD, in favor of ChEI treatment. This interaction remained significant for the individual items agitation/aggression, irritability/lability, and aberrant motor behavior, also after correction for multiple comparisons, but only in the AD subgroup. For delusions, the interaction was significant in the PD subgroup (coefficient = 0.03; 95% CI, 0.002-0.05; P = .04), which did not remain significant after Bonferroni correction. For both age and sex, the interaction with treatment outcome did not remain significant after Bonferroni correction. Significant heterogeneity was found for the interaction with age, specifically in the AD subgroup.

The results of the multivariate analysis were similar to those observed in the separate univariate analyses. Delusions (coefficient = −0.09; 95% CI, −0.14 to −0.03; P = .003), hallucinations (coefficient = −0.10; 95% CI, −0.15 to −0.04; P = .001), and appetite (coefficient = 0.14; 95% CI, 0.04-0.24; P = .007) showed significant results in the AD group, with only delusions and hallucinations remaining significant after correction for multiple comparisons. In the PD subgroup, results were significant for apathy (coefficient = −0.15; 95% CI, −0.29 to 0.00; P = .04) and delusions (coefficient = −0.15; 95% CI, −0.29 to −0.01; P = .04); however, neither remained significant after Bonferroni correction for multiple comparisons.

In the post hoc analysis of the AD group, a larger effect size was shown for participants who scored positive on delusions (n = 1515; −0.13; 95% CI, −0.23 to −0.03; P = .02) or hallucinations (n = 742; −0.17; 95% CI, −0.33 to −0.01; P = .04) at baseline. For the PD group, the effect size for delusions increased (n = 211; −0.39; 95% CI, −0.52 to −0.25; P = .006). However, the effect size for hallucinations in PD was no longer statistically significant (n = 449; −0.18; 95% CI, −0.37 to 0.02; P = .06).

The results of the risk-of-bias analysis are shown in eFigure 3 in Supplement 1. There were some concerns about the randomization process of 1 trial (5.3% of included trials), as some of the baseline characteristics were remarkably similar.34 Similar concerns arose about the anonymization of participants and staff of a large percentage of studies (88.2% of included trials), due to a difference in adverse effect profiles between groups that are relatable to the intervention drug. In 6 trials (35.3% of included trials), these adverse effects likely caused a relatively large group of patients to drop out, possibly resulting in an incomplete outcome data bias.

The funnel plot (eFigure 4 in Supplement 1) shows some asymmetry, especially for the studies with a relatively large effect size. However, results of the Egger test were nonsignificant (t15 = −0.57; P = .58).

Discussion

This individual participant data meta-analysis evaluated the use of ChEIs for treatment of psychotic symptoms in 5 PD trials and 12 AD trials. No individual participant data could be obtained from the DLB trials. Our analysis showed an association with improvement of delusions and hallucinations in the AD and PD subgroups. This finding may be clinically relevant, as psychotic symptoms pose an extensive threat to health and well-being for both patients and caregivers and current evidence-based treatment options for patients with neurodegenerative disorders are scarce.12

When all neuropsychiatric symptoms were evaluated, we also found significant results for elation/euphoria and apathy/indifference in the PD group. In the AD subgroup, we found a negative treatment outcome for appetite, which may limit the use of ChEIs in patients with AD who are underweight. Notably, only the association with hallucinations in AD remained significant after Bonferroni correction when considered in the context of all individual neuropsychiatric items. The observed negative association with appetite is likely related to the frequently observed gastrointestinal adverse effects of ChEIs, including nausea and vomiting. In 88.2% of the included trials, more adverse events were observed in the active treatment vs placebo group. In 35.3% of the included trials, these adverse events may have led to a dropout rate of greater than 10%. The current practice of ChEI treatment shows that most patients are now using patches, which significantly reduced the number of adverse effects.47 However, 82% of the included trials included only the oral form of ChEIs, which may have influenced the overall number of adverse events negatively.

Effect Sizes

The observed effect sizes of ChEI treatment of hallucinations and delusions were smaller than expected. Several factors might explain these findings. First, there is a methodologic factor involved, as the RCTs included in this meta-analysis were not designed to optimally assess hallucinations and delusions. For example, the NPI (used in most included studies) includes only 1 signaling question investigating whether the patient has had any hallucinatory experiences. This question is generally asked of the partner, not the patient. The more subtle hallucinatory experiences, such as sensed presence or passage hallucinations, therefore might be easily missed.48 To report psychotic symptoms in an optimal way, specialized rating scales, such as the Questionnaire for Psychotic Experiences,49 the Scale for Assessment of Positive Symptoms adjusted for PD psychosis,50 and the PD psychosis scale51 have been developed.

Second, the included trials focused on cognitive functioning and were not specifically enrolling patients with psychotic symptoms. As a result, many included patients did not report psychotic symptoms and hence could not experience any treatment results. To account for this, we performed a post hoc analysis including only individuals with delusions or hallucinations at baseline. The effect sizes increased, specifically those of delusions in PD. However, the results of hallucinations in PD were no longer statistically significant, likely due to the reduced power, because only 449 patients could be included for this analysis.

Another reason for the small effect sizes is that acetylcholine is not the only neurotransmitter involved in psychotic symptoms in neurodegenerative disorders. Although marked structural and neurophysiologic changes in the cholinergic system have been reported in patients with psychosis in PD and AD,14,15,52 research on neurochemical abnormalities has shown that the presence of psychosis in these diseases is determined by the interaction between cholinergic and serotonergic activity, rather than by cholinergic activity alone.14,53,54,55 For a long time, psychotic symptoms in PD were even regarded as a specific adverse effect of dopaminergic overstimulation, which still may be a contributing factor.55 Other factors involved in the generation of psychotic symptoms in PD and/or AD are perceptual losses (ie, loss of vision) or cognitive impairments (eg, related to a reduced attentional performance). Lack of sleep might be another contributing factor.56 This multifactorial pathogenesis of psychosis might explain the relatively small effect sizes of ChEI as monotherapy in treating psychosis.

Patient Characteristics

The small effect sizes of ChEI treatment for hallucinations and delusions may also reflect the large heterogeneity in efficacy of ChEI therapy among patients with neurodegenerative disorders. We found that ChEI treatment had larger effect sizes for neuropsychiatric symptoms in patients with more severe cognitive deficits, which supports previous data on this topic.57,58 Post hoc analyses of RCTs also reported that responders to ChEI therapy had significantly higher baseline scores of neuropsychiatric symptoms.17,18,59,60 However, in our results this appeared to be true for total neuropsychiatric outcome in patients with PD, but not for the AD subgroup, nor for any of the individual neuropsychiatric items.

Another source of heterogeneity may stem from demographic variables, such as sex and age. Healthy adults show an age-related cholinergic decline,61 suggesting that ChEI treatment might be more useful in older patients. However, no interaction effects of age or sex were seen in our data.

One retrospective study of a clinical cohort treated with ChEIs reported an association between age and cognitive response.58 In contrast, another retrospective study that included patients with AD treated with ChEIs did not note a significant difference in age between responders and nonresponders in the cognitive domain, which parallels our findings.57 Both studies did not report an association between sex and treatment response.

Clinical Practice

In AD, all 3 ChEIs investigated in this meta-analysis have received US Food and Drug Administration approval for the treatment of mild to moderate cognitive impairments, but not yet for the treatment of psychotic symptoms. Notably, the current US Food and Drug Administration approval mainly concerns patients with early-stage AD, whereas psychotic symptoms tend to develop in the more severe stages of the disease.2 In PD, only rivastigmine is currently approved for the treatment of PD-related dementia. However, use of ChEIs has been endorsed by expert opinion for the treatment of hallucinations and delusions in PD and DLB.12,62,63 Just one study has tried to show an effect of rivastigmine on minor visual hallucinations in PD.25 Because the study was terminated early, it was insufficiently powered to properly evaluate the primary outcome, being an effect on minor hallucinations. The limited data of the study favored a wait-and-see approach instead of early treatment with rivastigmine in patients with PD with minor visual hallucinations at that time. However, our data are supportive for using ChEI treatment in patients with PD and AD with psychotic symptoms and hopefully will pave the route toward a formal approvement of this indication.

Strengths and Limitations

Individual participant data could be obtained from 6649 patients, thereby minimizing the risk of bias in our meta-analysis.64 However, the study has limitations. Fifty percent of all the eligible studies retrieved by our literature search could not provide individual participant data for the individual items of the included neuropsychiatric rating scale.

In total, 5 studies could be included in the PD subgroup and 12 for the AD subgroup. For DLB, no individual patient data could be obtained, meaning no associations could be noted for this disease group. Analysis of the 2 DLB studies for which aggregate data were obtained showed large heterogeneity in this group. This may be explained by the trial of Ikeda et al,40 which had negative results due to a surprisingly large effect in the placebo group, which could not be fully explained by the authors. Very likely, the mechanism of psychosis in DLB is not substantially different from psychosis in PD, with both related to a cholinergic deficit, suggesting that we could expect a similar efficacy of ChEI treatment in DLB.65,66,67 However, this still has to be confirmed.

The various neuropsychiatric rating scales included in our analysis may differ in their sensitivity to detect psychosis and were not validated for the use of their individual items. This may have diluted the power to find statistical differences, meaning that the ESs of ChEI treatment may be greater than those reported here.

The funnel plot showed some asymmetry, especially for the studies with a relatively large SE, which may indicate some publication bias. However, the linear regression test of funnel plot asymmetry was nonsignificant.

Another potential limitation of this study is that linear regression models are not able to identify nonlinear patterns in the data. For example, the observed increased efficacy in moderate cognitive deficits might plateau or even decrease in severe cognitive deficits.68

The included trials were performed in a variety of areas around the world, including North America, Europe, Oceania, Japan, South Africa, and Russia. This may indicate increasing potential generalizability. Three AD trials included patients with an MMSE score less than 10. The PD group did not contain trials with severe dementia. Furthermore, all AD trials included a majority of women, whereas men were overrepresented in the PD trials, although these numbers are in line with the prevalence of these diseases in the general population. In addition, the mean age of the included trial participants ranged from 67 to 85 years, making the results less generalizable to patients with young-onset dementia.

Significant heterogeneity was found in the AD subgroup for the interaction between the baseline neuropsychiatric scores and the observed treatment effect. This may be explained by the limited ranges of neuropsychiatric baseline scores in patients who were included in the separate trials.

Conclusion

This meta-analysis noted an improvement with ChEI treatment of delusions and hallucinations in patients with AD and PD. Psychotic symptoms appear to significantly increase the disease burden for patients and caregivers, and alternative treatment with, for instance, antipsychotic medication has been associated with serious adverse effects. Therefore, our data may provide an extra reason to consider ChEI treatment as a first-line pharmacotherapy for psychotic symptoms in people with AD and PD.

Supplement 1.

eMethods. Detailed Methods

eTable 1. Search Terms for PubMed

eTable 2. Mapping of Items of Included Neuropsychiatric Rating Scales to Items of the Neuropsychiatric Inventory

eFigure 1. Effect of Cholinesterase Inhibitor Treatment on Psychotic Symptoms in Dementia With Lewy Bodies

eFigure 2. Forest Plots of Individual Neuropsychiatric Inventory Items

eFigure 3. Risk of Bias Analysis

eFigure 4. Funnel Plot of Included Studies for Total Neuropsychiatric Score

Click here for additional data file. (713.1KB, pdf)
Supplement 2.

Data Sharing Statement

Click here for additional data file. (14.4KB, pdf)

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eMethods. Detailed Methods

eTable 1. Search Terms for PubMed

eTable 2. Mapping of Items of Included Neuropsychiatric Rating Scales to Items of the Neuropsychiatric Inventory

eFigure 1. Effect of Cholinesterase Inhibitor Treatment on Psychotic Symptoms in Dementia With Lewy Bodies

eFigure 2. Forest Plots of Individual Neuropsychiatric Inventory Items

eFigure 3. Risk of Bias Analysis

eFigure 4. Funnel Plot of Included Studies for Total Neuropsychiatric Score

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Supplement 2.

Data Sharing Statement

Click here for additional data file. (14.4KB, pdf)

Articles from JAMA Neurology are provided here courtesy of American Medical Association

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