Review article
Genetic substrates of psychosis in patients with Parkinson's disease: A critical review

https://doi.org/10.1016/j.jns.2016.03.005Get rights and content

Highlights

  • Patients with Parkinson's disease (PD) may develop several non-motor symptoms.

  • Psychosis is one of the common non-motor symptoms of PD.

  • Exact pathogenesis of emergence of psychosis in PD is not clearly understood.

  • Polymorphism of several genes have been explored in PD patients with psychosis.

  • This review analyzes the studies on genetic polymorphisms in PD patients with psychosis.

Abstract

Patients with Parkinson's disease (PD) may develop several non-motor symptoms such as psychosis, depression, cognitive impairment, autonomic disturbances and sleep disturbances. Psychosis is one of the common non-motor symptoms, which commonly manifests as visual hallucinations and minor hallucinations such as sense of passage and presence. Though long-term dopaminergic therapy, longer duration of PD and cognitive impairment have been described as risk factors for emergence of psychosis in PD, predicting psychosis in PD remains challenging. Multiple studies have explored the genetic basis of psychosis in PD by studying polymorphisms of several genes. Most of the studies have focused on apolipoprotein E polymorphism followed by polymorphisms in cholecystokinin (CCK) system, dopamine receptors and transporters, HOMER gene, serotonin, catechol-o-methyltransferase, angiotensin converting enzyme and tau. Other than the studies on polymorphisms of CCK, most of the studies have reported conflicting results regarding association with psychosis in PD. Three out of four studies on CCK polymorphism have reported significant association of − 45C > T polymorphism with the presence of hallucinations. The discrepancies in the results across the studies reviewed are possibly due to racial differences as well as differences in the patient characteristics. This review critically analyzes the published studies on genetic polymorphisms in patients with PD and psychosis.

Introduction

Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder. Bradykinesia, rigidity, tremor at rest and postural instability are the important motor features of PD [1]. In addition to the motor features, patients with PD may develop various non-motor symptoms (NMS) such as psychosis, depression, cognitive decline, autonomic dysfunctions and sleep disturbances [2], [3]. Psychosis is one of the common and debilitating NMS of PD, which commonly manifests as minor hallucinations (presence hallucination and passage hallucination) and formed visual hallucinations (VH). Though delusions and hallucinations of modalities other than visual such as auditory, tactile and gustatory are also observed in PD, they are uncommon and usually coexist with formed VH [4], [5]. Dopaminergic therapy, long duration of PD, older age of the patients and sleep disturbances have been described as risk factors for emergence of VH in PD [6], [7]. Though dopaminergic therapy is a well-known risk factor for emergence of psychosis, patients with PD who received high dose intravenous levodopa in an experimental study did not experience any VH [8]. Further, not all patients on long-term dopaminergic therapy develop psychotic symptoms, inviting the speculation that there may be other risk factors predisposing individuals with PD to develop psychosis. Hence many studies based on neuroimaging and genetic polymorphisms have been conducted to explore the risk factors other than dopaminergic medications for development of psychosis in PD. Presence of psychosis has been reported to be an independent risk factor for development of dementia, increased nursing home placements [9] and mortality [10] in patients with PD. This underscores the importance of early identification of PD patients who are at risk of developing psychosis in order to formulate therapies to prevent or to treat psychotic symptoms in PD. Genetic biomarkers for psychosis in PD are of immense importance compared to the neuroimaging and molecular biomarkers because the genetic elements are fairly stable throughout the life of a patient and are not usually affected by the duration or severity of the disease. Identification of the association of any particular genotype or genetic mutation with psychosis in PD may open up new preventive and therapeutic avenues. The purpose of this review is to analyze the previous studies based on genetic polymorphisms in PD patients with psychosis, which may provide a clue towards identifying the PD patients susceptible to psychosis during the course of their illness.

Section snippets

Search strategies and selection criteria

The relevant criteria of the preferred reporting items for systematic reviews and meta-analyses (PRISMA) were taken into consideration for this review. We searched the literature in PubMed and PsycINFO database till August 2015 for articles on genetic polymorphism in PD patients with psychotic symptoms. A broad search strategy was applied by using a number of terms and combinations, details of which are given in Table 1. A large number of studies were excluded after screening the titles,

Conclusions

Polymorphism of multiple genes has been studied to explore possible associations with psychotic symptoms in PD. Most studies were on the ApoE polymorphism followed by studies on polymorphisms of CCK gene. Of all the polymorphisms reviewed, the − 45C > T polymorphism of CCK gene was found to have association with hallucinations in 75% of the studies (3 out of 4). This makes − 45C > T polymorphism a potential target for future studies. Further confirmation of the association of − 45C > T polymorphism with

Financial disclosure/Conflict of interest

None of the authors have any financial disclosure to make or have any conflict of interest.

Source of funding

Nil.

Acknowledgement

Nil.

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