The impact of psychiatric comorbidity on Parkinson's disease outcomes: a systematic review and meta-analysis

Background: The burden of psychiatric symptoms in Parkinson's disease includes depression, anxiety, apathy, psychosis, and impulse control disorders. However, the relationship between psychiatric comorbidities and subsequent prognosis and neurological outcomes is not yet well understood. In this systematic review and meta-analysis, in individuals with Parkinson's disease, we aimed to characterise the association between specific psychiatric comorbidities and subsequent prognosis and neurological outcomes: cognitive impairment, death, disability, disease progression, falls or fractures and care home admission. Methods: We searched MEDLINE, Embase, PsycINFO and AMED up to 13th November 2023 for longitudinal observational studies which measured disease outcomes in people with Parkinson's disease, with and without specific psychiatric comorbidities, and a minimum of two authors extracted summary data. Studies of individuals with other parkinsonian conditions and those with outcome measures that had high overlap with psychiatric symptoms were excluded to ensure face validity. For each exposure-outcome pair, a random-effects meta-analysis was conducted based on standardised mean difference, using adjusted effect sizes–where available–in preference to unadjusted effect sizes. Study quality was assessed using the Newcastle–Ottawa Scale. Between-study heterogeneity was assessed using the I2 statistic and publication bias was assessed using funnel plots. PROSPERO Study registration number: CRD42022373072. Findings: There were 55 eligible studies for inclusion in meta-analysis (n = 165,828). Data on participants’ sex was available for 164,514, of whom 99,182 (60.3%) were male and 65,460 (39.7%) female. Study quality was mostly high (84%). Significant positive associations were found between psychosis and cognitive impairment (standardised mean difference [SMD] 0.44, [95% confidence interval [CI] 0.23–0.66], I2 30.9), psychosis and disease progression (SMD 0.46, [95% CI 0.12–0.80], I2 70.3%), depression and cognitive impairment (SMD 0.37 [95% CI 0.10–0.65], I2 27.1%), depression and disease progression (SMD 0.46 [95% CI 0.18–0.74], I2 52.2), depression and disability (SMD 0.42 [95% CI 0.25–0.60], I2 7.9%), and apathy and cognitive impairment (SMD 0.60 [95% CI 0.02–1.19], I2 27.9%). Between-study heterogeneity was moderately high. Interpretation: Psychosis, depression, and apathy in Parkinson's disease are all associated with at least one adverse outcome, including cognitive impairment, disease progression and disability. Whether this relationship is causal is not clear, but the mechanisms underlying these associations require exploration. Clinicians should consider these psychiatric comorbidities to be markers of a poorer prognosis in people with Parkinson's disease. Future studies should investigate the underlying mechanisms and which treatments for these comorbidities may affect Parkinson's disease outcomes. Funding:Wellcome Trust, UKNational Institute for Health Research (NIHR),National Institute for Health Research (NIHR)Biomedical Research Centre (BRC) atSouth London and Maudsley NHS Foundation Trust and King's College London,National Institute for Health Research (NIHR)Biomedical Research Centre (BRC) atUniversity College London Hospitals NHS Foundation Trust, National Brain Appeal.