Parkinson's disease (PD) is the second most common neurodegenerative disorder. Although its major manifestation is motor symptoms, resulting from the loss of dopaminergic neurons in the substantia nigra, psychiatric symptoms, such as depression, anxiety, hallucination, delusion, apathy and anhedonia, impulsive and compulsive behaviors, and cognitive dysfunction, may also manifest in most patients with PD. Given that the quality of life - and the need for institutionalization - is so highly dependent on the psychiatric well-being of patients with PD, psychiatric symptoms are of high clinical significance. We reviewed the prevalence, risk factors, pathophysiology, and treatment of psychiatric symptoms to get a better understanding of PD for improved management.

BACKGROUND:The most common psychiatric complications due to dopaminergic treatment in Parkinson's disease are visual hallucinations and impulse control disorders. Their development depends on clinical and genetic factors. METHODS:We evaluated the simultaneous effect of 16 clinical and 34 genetic variables on the occurrence of visual hallucinations and impulse control disorders. Altogether, 214 Parkinson's disease patients were enrolled. Their demographic, clinical, and genotype data were obtained. Clinical and clinical-pharmacogenetic models were built by The Least Absolute Shrinkage and Selection Operator penalized logistic regression. The predictive capacity was evaluated with the cross-validated area under the receiver operating characteristic curve (AUC). RESULTS:The clinical-pharmacogenetic index for prediction of visual hallucinations encompassed age at diagnosis (OR = 0.99), rapid eye movement (REM) sleep behavior disorder (OR = 2.27), depression (OR = 1.0002), IL6 rs1800795 (OR = 0.99), GPX1 s1050450 (OR = 1.07), COMT rs165815 (OR = 0.69), MAOB rs1799836 (OR = 0.97), DRD3 rs6280 (OR = 1.32), and BIRC5 rs8073069 (OR = 0.94). The clinical-pharmacogenetic index for prediction of impulse control disorders encompassed age at diagnosis (OR = 0.95), depression (OR = 1.75), beta-blockers (OR = 0.99), coffee consumption (OR = 0.97), NOS1 rs2682826 (OR = 1.15), SLC6A3 rs393795 (OR = 1.27), SLC22A1 rs628031 (OR = 1.19), DRD2 rs1799732 (OR = 0.88), DRD3 rs6280 (OR = 0.88), and NRG1 rs3924999 (OR = 0.96). The cross-validated AUCs of clinical and clinical-pharmacogenetic models for visual hallucinations were 0.60 and 0.59, respectively. The AUCs of clinical and clinical-pharmacogenetic models for impulse control disorders were 0.72 and 0.71, respectively. The AUCs show that the addition of selected genetic variables to the analysis does not contribute to better prediction of visual hallucinations and impulse control disorders. CONCLUSIONS:Models could be improved by a larger cohort and by addition of other types of Parkinson's disease biomarkers to the analysis.

Impulse control disorders (ICDs), including compulsive gambling, buying, sexual behaviour and eating, are not only a severe disorder that can affect the general, non-clinical population, but also a serious, increasingly recognized psychiatric complication in Parkinson's disease (PD). Previous research detected some risk factors for their occurrence in PD patients and in the general population, including impulsivity. However, impulsivity is a multidimensional construct that comprises several aspects, including reflection impulsivity and delay discounting. The present work assessed different facets of impulsivity in both PD patients and in the healthy controls (HCs) to examine whether they scored differently, and if the occurrence of ICDs in PD patients and in the HCs was predicted by different aspects of impulsivity. The results showed that ICDs in PD patients were predicted by a strong preference for immediate rewards, whereas ICDs in the HCs were predicted by a deficient reflective ability. The present findings may help clinicians in the early identification of PD patients who could develop ICDs by simply assessing their impulsivity in terms of delay discounting. Furthermore, this work contributed to identify another risk factor for ICDs in the non-clinical population.

OBJECTIVES:Impulse control disorders (ICD) are commonly associated with dopamine replacement therapy (DRT) in patients with Parkinson's disease (PD). Our aims were to estimate ICD heritability and to predict ICD by a candidate genetic multivariable panel in patients with PD. METHODS:Data from de novo patients with PD, drug-naïve and free of ICD behaviour at baseline, were obtained from the Parkinson's Progression Markers Initiative cohort. Incident ICD behaviour was defined as positive score on the Questionnaire for Impulsive-Compulsive Disorders in PD. ICD heritability was estimated by restricted maximum likelihood analysis on whole exome sequencing data. 13 candidate variants were selected from the DRD2, DRD3, DAT1, COMT, DDC, GRIN2B, ADRA2C, SERT, TPH2, HTR2A, OPRK1 and OPRM1 genes. ICD prediction was evaluated by the area under the curve (AUC) of receiver operating characteristic (ROC) curves. RESULTS:Among 276 patients with PD included in the analysis, 86% started DRT, 40% were on dopamine agonists (DA), 19% reported incident ICD behaviour during follow-up. We found heritability of this symptom to be 57%. Adding genotypes from the 13 candidate variants significantly increased ICD predictability (AUC=76%, 95% CI (70% to 83%)) compared to prediction based on clinical variables only (AUC=65%, 95% CI (58% to 73%), p=0.002). The clinical-genetic prediction model reached highest accuracy in patients initiating DA therapy (AUC=87%, 95% CI (80% to 93%)). OPRK1, HTR2A and DDC genotypes were the strongest genetic predictive factors. CONCLUSIONS:Our results show that adding a candidate genetic panel increases ICD predictability, suggesting potential for developing clinical-genetic models to identify patients with PD at increased risk of ICD development and guide DRT management.