TRANSLATING RESEARCH INTO PRACTICE
Rajesh R. Tampi, MD, MS, DFAPA, DFAAGP, Column Editor
A monthly column dedicated to reviewing the literature and sharing clinical implications.
The cognitive deficits related to psychotic disorders are a significant cause of disease morbidity. Antipsychotic medications used to address the positive symptoms of psychotic illness do not address cognitive symptoms and often contribute to cognitive dysfunction. Although cognitive dysfunction often has multiple contributing factors, the association between anticholinergic burden and negative cognitive effects is well established. The degree of anticholinergic burden in patients with psychosis can vary depending on the specific antipsychotic used and any other anticholinergic medications prescribed. Numerous studies have analyzed the association between anticholinergic burden and negative cognitive effects in psychosis. This study aimed to further elucidate this association through a systematic review and meta-analysis.
The Study
Mancini V, Latreche C, Fanshawe JB, et al. Anticholinergic burden and cognitive function in psychosis: a systematic review and meta-analysis. Am J Psychiatry. 2025;182(4):349-359.
Study Funding
Swiss National Science Foundation, Wellcome Clinical Research Career Development Fellowship, National Institute for Health and Care Research (NIHR), NIHR Oxford Health Biomedical Research Centre, Maudsley Charity, the Brain & Behavior Research Foundation, the Academy of Medical Sciences, and NIHR Academic Clinical Fellowship.
Study Objectives
To evaluate the relationship between anticholinergic burden and cognitive function in psychosis.
Methodology
This systematic review and meta-analysis included observational studies and clinical trials evaluating the effect of anticholinergic burden on cognitive function in psychosis. The literature search consisted of adult individuals with a diagnosis including schizophrenia, first-episode psychosis, and psychotic mood disorders and those at clinical high or ultrahigh risk for psychosis. The included studies also satisfied one of 3 criteria for subcategorization: (1) those assessing cognitive functioning using referenced standardized tools; (2) those reporting clinical or serological measure of anticholinergic burden or those showing the results of a challenge or tapering of medications with cholinergic activity; and (3) those which provided data allowing calculation of either the correlation between anticholinergic burden and cognitive performance or the standardized mean difference in cognition between groups with differing levels of anticholinergic burden. Studies were excluded for patients with a primary diagnosis other than psychosis (eg, primary psychotic disorders), although studies that included patients with psychosis and psychiatric comorbidity were still eligible.
Study Strengths
- The review considered many studies with varying methodologies, including those measuring anticholinergic burden via clinical measures, via serological assay, and via tapering/challenging patients with anticholinergic medication.
- The review included studies that overall were without significant concern for bias or quality.
- The study conducted 4 different sensitivity analyses with consistent results for each. The study also performed meta-regressions for several variables without altering results.
Study Weaknesses
- Observational studies were primarily used, thus introducing potential bias and limiting the interpretation of causality within the results. The interventional studies included were within-subject designs that lacked control groups.
- Relatively few included studies examined serological anticholinergic activity and tapering effects, thus limiting statistical power.
- While multiple variables were accounted for in analyses, other potential confounders or factors to consider include antipsychotic generation/subgroups, severity of psychotic pathology in patients receiving anticholinergic medications, and comorbid psychopathology.
The study performed meta-regressions for various factors, including age, sex, antipsychotic dosage (chlorpromazine equivalents), and study quality. The study also performed 4 separate sensitivity analyses: (1) excluding studies in which anticholinergic burden was assessed by the dosage of anticholinergic medications rather than cumulative anticholinergic burden from all medications; (2) excluding studies that measured cognitive outcomes related to a challenge with anticholinergic medication; (3) including only studies using the Anticholinergic Cognitive Burden scale as the measure of anticholinergic burden; and (4) including only studies in which first-episode psychosis was the qualifying diagnosis.
Study Results
A total of 40 studies (5188 participants; mean age, 38.6 years; 64.5% male) were included in the analysis. Among the participants, 87.6% had a diagnosis of schizophrenia and 12.4% had a diagnosis of first-episode psychosis. All participants received antipsychotic medication, and the mean chlorpromazine-equivalent dosage was 506.5 mg daily. The studies were classified into 3 categories: 25 anticholinergic burden studies, 6 serological studies, and 9 tapering or challenge studies. Overall study quality was rated using the Newcastle-Ottawa Scale with a mean score of 6.7.
There was a negative correlation between measures of anticholinergic burden and cognitive functioning, which was statistically significant across all Measurement and Treatment Research to Improve Cognition in Schizophrenia cognitive domains. Global cognition had the strongest negative relationship (r = –0.37). Other results for cognitive domains included verbal learning (r = –0.28), processing speed (r = –0.24), working memory (r = –0.22), attention (r = –0.19), visual learning (r = –0.17), executive functions (r = –0.17), and social cognition (r = –0.12).
There was also a negative correlation between serological anticholinergic burden and cognitive functioning. This statistically significant negative correlation was found for verbal learning (r = –0.26), working memory (r = –0.19), and executive functions (r = –0.16).
Furthermore, data involving anticholinergic medication tapers were associated with cognitive improvement that was statistically significant for working memory (d = 0.94), verbal learning (d = 0.77), and executive functions (d = 0.44).
Meta-regressions showed no significant impact of age, sex, antipsychotic dose, or study quality on results. The 4 separate sensitivity analyses described above also yielded similar results.
Conclusions
This analysis demonstrated that increased anticholinergic burden is associated with worsened cognitive function across multiple domains in patients with psychosis. This association was seen with various measures of anticholinergic burden, including clinical and serological measures as well as tapering and challenging with anticholinergic medication.
Practical Applications
This correlative evidence suggests that patients with psychosis may cognitively benefit from limiting anticholinergic burden when possible.
Bottom Line
Although cognitive deficits in psychotic disorders may be influenced by multiple factors, the results from this systematic review and meta-analysis suggest that anticholinergic burden is a modifiable factor that, when addressed and limited, can improve cognition for patients with psychosis.
Dr Modi is a second-year psychiatry resident at Creighton University in Omaha, Nebraska. Dr Abbaszadeh is a first-year psychiatry resident at Creighton University. Dr Allen is a fourth-year psychiatry resident at Creighton University. Dr Dickan is a fourth-year psychiatry resident at Creighton University. Dr Schuster is a fourth-year psychiatry resident at Creighton University. Dr Mullen is an assistant professor of psychiatry at St Louis University School of Medicine in St Louis, Missouri. Dr Tampi is professor and chair of the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives Health Behavioral Health Services. He is also an adjunct professor of psychiatry at Yale School of Medicine in New Haven, Connecticut, and a member of the Psychiatric Times editorial board.
Reference
Mancini V, Latreche C, Fanshawe JB, et al. Anticholinergic burden and cognitive function in psychosis: a systematic review and meta-analysis. Am J Psychiatry. 2025;182(4):349-359.
