Psychosis in Parkinson’s disease (PDP) represents a common and debilitating condition that complicates Parkinson’s disease (PD), mainly in the later stages. The spectrum of psychotic symptoms are heterogeneous, ranging from minor phenomena of mild illusions, passage hallucinations and sense of presence to severe psychosis consisting of visual hallucinations (and rarely, auditory and tactile or gustatory) and paranoid delusions. PDP is associated with increased caregiver stress, poorer quality of life for patients and carers, reduced survival and risk of institutionalization with a significant burden on the healthcare system. The pathophysiology of psychosis in PD is complex and still insufficiently clarified.
1. Introduction
Parkinson’s disease (PD) is a chronic and progressive neurodegenerative movement disorder associated with progressive disability and characterized by both motor and non-motor symptoms
[1]. PD represents the second most common age-associated neurodegenerative disorder after Alzheimer’s disease (AD)
[2]. Patients experience motor features, including resting tremor, bradykinesia and muscular rigidity with postural instability, often appearing as the disease progresses
[3]. Pathologically, these symptoms are mostly attributed to the extensive degeneration of striatal dopaminergic neurons in the
substantia nigra pars compacta (SNpc) projecting to the dorsal striatum
[4], resulting in a loss of dopamine transmission throughout the brain. At the histological level, the progressive SNpc degeneration correlates with the accumulation of large intra-cytoplasmic inclusions, namely Lewy bodies (LBs) containing misfolded α-synuclein (α-syn), neurofilaments and ubiquitin
[5], although α-syn deposition occurs years before motor presentations begin. PD patients also suffer from non-motor symptoms, such as autonomic dysfunction, pain, olfactory deficits, sleep disorders, cognitive impairment and psychiatric disturbances
[6]. The underlying mechanisms of PD-related non-motor manifestations are far less clear than motor features and still very difficult to treat.
Among the different non-motor symptoms of PD, psychosis in PD (PDP) is one of the most common, complex and disabling non-motor features, with an estimated prevalence of 43–63% in later stages of the disorder
[7][8][9][7,8,9]. PDP prevalence increases with disease progression and it is associated with poorer quality of life, disability and caregiver stress, as well as accelerated cognitive decline, hospitalization or institutionalization, morbidity and mortality
[10]. Importantly, the clinical features observed in PDP have a different pattern as compared to other psychotic diseases such as schizophrenia or mood disorders associated with psychotic phenomena, so the current diagnostic criteria applied to other psychiatric illnesses may be unsatisfactory when describing the diversity of PDP
[11]. The spectrum of psychotic symptoms experienced by PD patients consist of hallucinations (mainly visual, but also auditory, tactile or gustatory) and delusions, which simplistically define psychosis. Additionally, there are also minor psychotic phenomena, which include passage hallucinations, sense of presence and illusions
[12]. Once psychotic features develop, they tend to become progressive and persistent. Although PDP has some common mechanisms to other psychotic disorders, the neurobiology is different, complex and still insufficiently known
[11]. Neuroimaging and neuropathological studies have implicated executive function and visual processing deficits in neocortex and limbic structures, with an imbalance between dopamine, acetylcholine and serotonin neurotransmission
[13]. Moreover, PDP therapeutic strategies still continue to be a challenge as dopaminergic treatment for PD motor symptoms, such as levodopa or dopaminergic agonists, exacerbates the condition
[8] and the administration of antipsychotic drugs in vivo have revealed a high rate of mortality and morbidity
[14]. Apart from exogenous factors, including dopaminergic treatment, several intrinsic factors have been associated with PDP development, including ageing, a more advanced stage of the disease, depression, cognitive impairment, female sex and REM sleep behavior disorder and daytime sleepiness
[13][15][13,15]. However, not all PD patients develop psychosis, and dopaminergic drugs only partially contribute to the PDP risk. PDP has also been observed in drug naïve PD patients
[16]. Although an increasing number of studies has investigated the relationship between several genetic factors and psychotic symptoms in PD, their role in PDP is still unclear.
2. The Genetic Landscape of Parkinson’s Disease
The vast majority of PD cases are idiopathic (also defined as sporadic or sometimes “non-genetic”) with a multifactorial etiology, whereas only approximately 5–10% are the so-called monogenic forms (sometimes called Mendelian, familial or genetic), caused by pathogenic variants in single genes inherited with Mendelian transmission pattern [17][18][18,19] (summarized in Table 1).
Table 1.
Established Parkinson’s disease-causing genes and risk factors.
Gene |
Function |
Main Types of Mutations/Variants |
Autosomal dominant |
|
|
SNCA |
Synaptic vesicle trafficking and neurotransmitter release |
Genomic multiplications (duplications, triplications) and missense mutations |
LRRK2 |
Neuronal vesicular trafficking and autophagic protein degradation |
Missense mutations |
VPS35 |
Retromer and endosomal trafficking |
Missense mutations |
Autosomal recessive |
|
|
PRKN |
Mitochondrial homeostasis |
Structural variants (genomic multiplications and deletions in exons or gene promoter), missense, nonsense, splice-site and frameshift mutations |
PINK1 |
Mitochondrial homeostasis |
Structural variants, missense, nonsense and frameshift mutations |
DJ-1 |
Mitochondrial homeostasis |
Deletions, missense and frameshift mutations |
Risk factors |
|
|
SNCA |
Synaptic vesicle trafficking and neurotransmitter release |
Polymorphic variants, often in non-coding regions |
LRRK2 |
Neuronal vesicular trafficking and autophagic protein degradation |
Polymorphic variants |
MAPT |
Microtubules assembly and stabilization |
Polymorphic variants |
GBA |
Lysosomal |
Biallelic (homozygous or compound heterozygous) mutations |
X-linked |
|
|
RAB39B |
Vesicular trafficking |
Whole gene deletion, missense, splicing and frameshift variants |