Clinical features of psychiatric disorders in Parkinson’s disease

Introduction

Parkinson’s disease (PD) is the second most common chronic neurodegenerative condition in older people, especially beyond the age of 60⁽⁶⁾.

Although the definition of PD is based on the presence of motor features, these are just the “tip of the iceberg.” It is now well known that, in addition to the typical motor symptoms of PD, the clinical picture includes many non-motor symptoms, with behavior problems often being the most common⁽⁶⁾. Many non-motor symptoms have been described which include cognitive decline, psychiatric disturbances (depression, psychosis and impulse control disorders), autonomic failures (gastrointestinal, cardiovascular, urinary, sexual dysfunction, thermoregulation), sleep difficulties, and pain syndrome. In fact, it is suggested that, in advanced Parkinson’s disease, non-motor symptoms dominate the clinical picture, and are associated with severe disability, impaired quality of life, and shortened life expectancy⁽⁶⁾. Non-motor symptoms, like depressive disorders, anxiety disorders, cognitive decline, pain, fatigue, insomnia and autonomic dysfunction, are shown to be associated with poor health-related quality of life of the individuals with PD. Although non-motor symptoms greatly influence the health-related quality of life of Parkinson’s disease patients, more than 50% of existing non-motor symptoms are not identified in clinical practice. In the advanced stages of disease, non-motor symptoms are major determinants of loss of independence, caregiver strain, and nursing home placement⁽⁶⁾. Among the various non-motor symptoms, psychiatric comorbidity is quite common and disabling. In terms of etiopathogenesis, it is suggested that the non-motor symptoms have the common etiopathogenesis as that of PD, or it may be due to medications used for the management of PD or as a reaction to the physical illness and its consequences. In most cases, it is more often multifactorial in origin⁽⁶⁾.

Psychiatric syndromes in Parkinson’s disease

Depression

Patients with Parkinson’s disease have a high rate of depression. There seems to be a vicious cycle between depression and PD – the presence of one increases the risk of the other. Although considered a risk factor for Parkinson’s disease, depression is neither indicative nor predictive of progression motor symptoms in PD patients⁽¹⁾.

Depression can manifest anytime, from the premotor stage to the late stages of the disease. Risk factors of depression are represented by women, severity of motor symptoms, occurrence of motor complications or fluctuations, dosage of dopaminergic medication, cognitive decline and dementia, psychotic episodes, anxiety, and sleep disturbance⁽³⁾.

Depressive symptoms in Parkinson’s disease patients can manifest across a wide range of severity, chronicity and etiology, including major depression, dysthymia, minor depression, subsyndromal depression or depressive disorder due to PD, and adjustment disorders. Subsyndromal depression can be diagnosed for depressive symptoms that do not meet the criteria for major depression, dysthymia, or minor depression with respect to severity and symptom duration; the depressive symptoms are of short duration or are not “present most of the day, nearly every day”. For example, depressive symptoms that arise only during the off phase of motor fluctuation in PD can be classified as subsyndromal depression. Depressive disorder due to Parkinson’s disease refers to depressive symptoms which could have direct pathophysiological relevance to PD, regardless of symptom severity; it can manifest a depressive episode responsive to dopamine replacement therapy or major depressive-like episodes, even with mixed features of manic or hypomanic episodes. Adjustment disorders are a reactive depression, such as grief and demoralization, to the diagnosis of Parkinson’s disease. In the Parkinson’s disease depression, symptoms such as irritability and dysphoria are more frequent than in the major depression not related to PD, while guilt, self-blame and suicide attempts are less usual⁽³⁾.

Suicide

The prevalence of suicidal ideation is approximately 17-30% among those with Parkinson’s disease, which is two times higher than in the general population. The completion rate of suicidal attempt has been reported to be between 0.7% and 4.3%. Risk factors of suicide are represented by men, upper extremity or generalized onset of motor symptoms, depression, delusion or any comorbid psychiatric disorder, higher levodopa dosage, and deep brain stimulation (DBS) at the subthalamic nucleus. Among patients treated with DBS, suicidal behavior appears to be associated with postoperative depression and/or altered impulse regulation. Parkinson’s disease patients with complete suicide were younger and had less comorbidities, better cognition, lower UPDRS motor scores, lower Hoehn and Yahr stage, and higher use of entacapone than their counterparts⁽³⁾.

Anxiety

Anxiety is also a prevalent feature in Parkinson’s disease and the second most common psychiatric disorder. Anxiety has also been reported as a predictor of PD, even when smoking, caffeine intake, and anxiolytic medication had been controlled for. Increased frequency of anxiety disorders could be observed up to 20 years before PD onset. Anxiety symptoms/disorders are often underrecognized and even undertreated in patients with Parkinson’s disease. Anxiety symptoms/disorders in PD patients are categorized into primary and secondary anxiety disorders. Secondary anxiety disorders include anxiety secondary to the limitations and impairment caused by PD, to the presence of other psychiatric comorbidities (e.g., depression, psychosis), and to the fluctuation of motor symptoms (on/off periods), anxiety secondary to the usage of anti-Parkinsonian medications (e.g., pergolide, levodopa), and anxiety as a prodromal symptom of Parkinson’s disease⁽¹⁾.

When referring to the DSM-5 diagnostic criteria, the primary anxiety disorders are represented by generalized anxiety, which is the most frequent, followed by agoraphobia, social phobia and panic disorder. A large proportion of patients have multiple anxiety disorders. Moreover, a recurrent observation of the studies is the large proportion of patients (13.3% according to the systematic review) with significant anxiety symptoms that do not fit the usual criteria for anxiety disorders. It is considered as “not otherwise specified” (NOS) anxiety disorder. It refers to PD-specific anxiety, like phobia of falling, of driving, social phobia related to potentially embarrassing symptoms (drooling, dysarthria etc.), anxiety related to withdrawal of dopamine agonist (DA) medication or to wearing-off of medication in patients with fluctuations, panic-like disorder related to off periods, among others. The adverse effects of DA medication can also generate significant anxiety, as in patients with impulse control disorders, DA dysregulation syndrome, or hallucinations. As a consequence, anxiety disorders are probably largely underestimated in Parkinson’s disease, as triggers (predisposing and precipitating factors) are multiple⁽²⁾.

Psychosis

Symptoms of psychosis in patients with PD are characterized as a separate clinical entity, having a different clinical presentation and course than schizophrenia, acute psychosis, or other psychotic disorders. It is conceptualized as the “development of hallucinations and delusions during the clinical course of Parkinson’s disease”, and it has implications for staging the disease development and its management. It is associated with an overall poor prognosis, disease burden, and even death⁽¹⁾.

More commonly reported symptoms consist of minor phenomena such as hallucinations and visual illusions that have been reported to impact 17-72% of patients. Less commonly reported symptoms include other hallucinations (auditory and tactile) and delusions⁽¹⁾.

Hallucinations⁽⁷⁾

Visual hallucinations are the most common feature of Parkinson’s disease psychosis (PDP), in contrast to primary psychotic disorders, where auditory hallucinations are most common. Hallucinations are more frequent in dim lighting or at the end of the day. Patient’s retention of insight into these hallucinations may fluctuate over time, and may be related to the degree of concomitant cognitive impairment. In a sample of 191 PD patients without dementia to whom the Parkinson Psychosis Rating Scale (PPRS) was administered, 21.5% of the participants had psychosis. Visual hallucinations were common in this sample (13.6%). Auditory hallucinations were present in 6.8% of these patients, illusions or misidentification in 7.3%, and paranoid ideation was present in 4.7%⁽⁷⁾.

The characteristics of hallucinations in Parkinson’s disease were described in a sample of 216 PD patients. The visual hallucinations were categorized into “minor” and “formed” variants. The “formed” visual hallucinations included various content, such as of persons, familiar or unfamiliar, animals, or objects, while the “minor” hallucinations included illusions, such as of presence, or of an object’s passage. Minor hallucinations were present in 25.5% of patients; formed or “non-minor” visual hallucinations were noticed in 22.2% (isolated in 9.3%), and auditory hallucinations were present in 9.7% of patients (isolated in 2.3%)⁽⁷⁾.

Although less common than visual hallucinations, auditory hallucinations have been reported in PDP. In another study, among a sample of 121 clinical patients with Parkinson’s disease, 8% were reported to have auditory hallucinations. None had auditory hallucinations unaccompanied by visual hallucinations, and all patients with auditory hallucinations were cognitively impaired. The auditory hallucinations were non-command and non-paranoid in this sample⁽⁷⁾.

Delusions⁽⁷⁾

Erotomanic, jealous, and persecutory delusions have been reported in Parkinson’s disease, and there are case reports of Cotard syndrome (“nihilistic delusion” or self-negation) and Capgras syndrome (delusion that a friend or family member has been “replaced”) in PD patients. Delusional jealousy (Othello syndrome) was observed in 20 of 805 patients with PD (approximately 2%), with a significant association with dopamine agonist therapy and, in a small sample of five patients, it was shown to be treatable with dopamine agonist therapy reduction⁽⁷⁾.

The presence of insight indicates early progression, while the absence indicates PD progression along with delusions. Similarly, cognitive deficits along with loss of insight in psychotic symptoms indicate the progressive stage of the disease⁽¹⁾.

There are few prevalence studies, and the frequencies vary widely. The point prevalence of complex hallucinations ranges from 22% to 38%. The prevalence of minor psychotic symptoms is much more variable. The risk of developing visual hallucinations increases with age, the severity of motor and cognitive symptoms, disease duration, and medication. Moreover, visual hallucinations have been shown to be the main risk factor for nursing home placement. They increase the risk of cognitive impairment and of dementia and mortality⁽²⁾.

According to clinical experience, DA agonists may cause the onset of hallucinations, suggesting a role of the dopaminergic pathways in the occurrence of psychosis. However, the role of medication is very controversial since visual hallucinations are observed even in drug-naive patients. As suggested by a work group on psychosis in Parkinson’s disease, anti-Parkinson medication is more to consider as a modifier than a trigger of hallucinations⁽²⁾.

Cognitive dysfunctions

Cognitive dysfunctions can be commonly seen at any disease stage of Parkinson’s disease. Like depression and anxiety, these dysfunctions might precede the disease onset of PD, and can occur during the early stage or at the late stage of the disease. The deterioration of cognitive abilities is progressive, and the incidence and prevalence of cognitive dysfunctions increase with the progression of PD. The cognitive impairments in Parkinson’s disease significantly affect the functioning and quality of patients’ lives, and they are one among the high priority areas for the patients and their caregivers. The cognitive dysfunctions prevalent in PD are progressive, and may manifest as subjective cognitive decline, mild cognitive impairment (PD-MCI) or dementia⁽¹⁾.

The core feature of cognitive dysfunction in Parkinson’s disease is the executive dysfunction, and patients commonly have difficulty in cognitive flexibility. Problems in memory and attention are particularly prominent. Common symptoms include impairments in processing speed, executive functioning, and spatial working memory. Attention levels may also fluctuate, and the patient may have excessive daytime sleepiness. With the progression, visual hallucinations are common. These are usually animate, unimodal (i.e., affecting only one modality, like visual), and generally do not cause dysphoria and fear⁽¹⁾.

The differentiation between Parkinson’s disease dementia (PDD) and Lewy body dementia (LBD) is often challenging. Although they are assumed to be on a Lewy body disease spectrum, few controversies persist in their differentiation in clinical practice. Some researchers even question the need for this differentiation owing to the quite similar clinical profile and course of illness, neuropathological findings, and treatment approaches. The cluster of clinical signs and symptoms of both LBD and PDD include progressive cognitive impairment associated with Parkinsonism, visual hallucinations, and fluctuations of attention and wakefulness. The major clinical difference between LBD and PDD is represented by the timing of dementia in relation to Parkinsonism. Dementia occurring after at least one year of onset of motor symptoms (i.e., in the context of well-established idiopathic Parkinson’s disease) denotes PDD, and the appearance of earlier cognitive impairment earlier than the motor symptoms of Parkinsonism is diagnosed as dementia with Lewy bodies⁽¹⁾.

In dementia with Lewy bodies, patients commonly present with fluctuating cognitive dysfunction with visual hallucinations. Parkinsonian symptoms are also commonly present. Anxiety, depression and apathy symptoms are usually less prominent than in Parkinson’s disease dementia⁽¹⁾.

Apathy

Apathy is another distinct clinical syndrome in Parkinson’s disease, as half of the patients have standalone apathy, without depression or cognitive impairment. Apathy can be described as a marked reduction in interest and participation in normal goal-directed behavior, a lack of initiative with difficulties initiating or completing an activity, and the presence of indifference or a lack of concern. Hence, apathy, depression and cognitive dysfunctions need to be separately diagnosed. Apathy syndrome is a separate morbid state with remarkable apathy, and it occurs over an extended duration. Depression is commonly referred to as an “affective disorder”, whereas apathy is classified as a “motivational disorder” distinct from affective disorders, and emotions are flattened in apathy⁽¹⁾.

Changes in personality and mood, particularly depressive and anxiety symptoms, are common⁽¹⁾.

Criteria for clinical diagnosis of apathy⁽²⁾

Criterion A. A quantitative reduction of goal-directed activity either in behavioral, cognitive, emotional or social dimensions in comparison to the patient’s previous level of functioning in these areas. These changes may be reported by the patient themselves or by observation of others.

Criterion B. The presence of at least two of the following three dimensions for a period of at least four weeks, and present most of the time.

B1. Behavior and cognition

Loss of, or diminished goal-directed behavior or cognitive activity, as evidenced by at least one of the following:

• reduced level of activity, either at home or work, makes less effort or needs to be prompted to perform activities
• less persistence in maintaining an activity or conversation
• less interest in or reaction to news, or less interest in doing new things
• less interest in their own health and well-being or personal image⁽²⁾.

B2. Emotion

Loss of, or diminished emotion, as evidenced by at least one of the following:

• less spontaneous (self-generated) emotions regarding their own affairs
• less emotional reaction in response to positive or negative events in the environment
• less concern about the impact of their actions or feelings on the people around him/her
• less empathy to the emotions or feelings of others
• less verbal or physical reactions that reveal his/her emotional states⁽²⁾.

B3. Social interaction

Loss of, or diminished engagement in social interaction, as evidenced by at least one of the following:

• less initiative in spontaneously proposing social or leisure to family or others
• less participation in social or leisure activities suggested by people around them
• less interest in family members
• less likely to initiate a conversation, or early withdrawal from it
• less interest in getting out to meet people⁽²⁾.

Criterion C. These symptoms (A-B) cause clinically significant impairment in personal, social, occupational, or other important areas of function.

Criterion D. These symptoms (A-B) are not exclusively explained or due to physical disabilities (e.g., blindness or loss of hearing), to motor disabilities, to a diminished level of consciousness, to the direct physiological effects of a substance (e.g., drug of abuse, medication), or to major changes in the patient’s environment⁽²⁾.

Patients with apathy are, on average, older than the non-apathetic patients, have more impaired cognition in general and executive function in particular, have more severe motor symptoms, and an increased risk of comorbid depression. Apathy may be a predictive factor for dementia and cognitive decline over time⁽²⁾.

Anhedonia in Parkinson’s disease

Although anhedonia is understood as a symptom of depression in patients with Parkinson’s disease, studies suggest that it may be characteristic of PD itself which could be due to the dysfunction of the dopamine reward pathway in the mesolimbic area. Studies that have evaluated the prevalence of anhedonia have reported a range of 7% to 45.7%. With regards to the prevalence of anhedonia and depression, studies suggest a strong correlation between the two; however, in many patients, anhedonia is present in the absence of depression⁽⁶⁾. Studies also suggest an association between anhedonia and apathy. Studies are inconclusive with regard to the relationship of anhedonia with the severity of motor symptoms. Regarding the management of anhedonia, which is independent of depression, no studies have specifically evaluated the efficacy of any pharmacological agent⁽⁶⁾.

Sleep disorders

Sleep disorders are one of the common non-motor symptoms found in Parkinson’s disease. Some sleep disorders in PD, such as rapid eye movement sleep behavior disorder (RBD), are seen to have a specific association with Parkinson’s disease, and may occur several years before the onset of the disease⁽¹⁾.

The sleep-related problems in patients with PD can be broadly classified into daytime manifestations, nocturnal sleep disturbance, sleep-related movement disorders, and parasomnias. The daytime sleep manifestations include excessive daytime sleepiness (EDS)⁽⁶⁾. The nocturnal sleep disturbances include insomnia and obstructive sleep apnea. The most common sleep-related movement disorder is represented by restless leg syndrome. The common parasomnias include RBD. As with depression and anxiety disorders, sleep disorders are also reported to increase the risk of Parkinson’s disease development in the later life. A longitudinal population-based prospective study reported an increased risk of PD in patients with EDS. This risk persists after controlling for various confounders like mid-life cigarette smoking and coffee drinking, bowel movement frequency, cognitive functions, depressed mood, and insomnia⁽⁶⁾. Overall, daytime sleepiness was associated with a three-fold increase in the risk of developing Parkinson’s disease. Clinic-based studies that have looked at the risk of developing PD in patients with sleep disorder have mainly focused on RBD, and these studies suggest that, when the patients with RBD are followed over the period, 16-65% of patients develop Parkinson’s disease, and the incidence of PD increases with longer follow-up duration⁽⁶⁾.

The presence of sleep disorder – especially multiple sleep disorders – is known to predict other symptoms of PD. A cross-sectional study suggested that the presence of at least two sleep disorders predicted significantly higher more overall non-motor symptoms, higher scores on the individual measures of multiple symptoms, quality of life, fatigue, depression, and cognitive decline⁽⁶⁾.

Impulse control diseases

Impulse control diseases (ICDs) are also commonly observed in Parkinson’s disease. These are characterized by pleasurable behaviors performed repetitively, excessively and compulsively. The Diagnostic and Statistical Manual (DSM-5) placed ICDs in the chapter “Disruptive, Impulse-Control, and Conduct Disorders” as dysregulation of self-emotional and behavioral control. ICDs have recently been subclassified as ICD groups and ICD-related disorder (ICDs-RD) groups. There are three core features of ICDs and ICD-RD groups: the presence of impulsivity aspects (lack of forethought or consideration of consequences), the presence of compulsivity (repetitive behaviors with a lack of self-control), and a negative or harmful behavior pattern to oneself or to others⁽¹⁾.

All these psychiatric disorders in Parkinson’s disease are related to patients’ impaired quality of life, being also associated with higher caregiver distress⁽¹⁾.

The common manifestations of ICDs in PD include compulsive buying/shopping, pathological gambling, binge eating disorders, and hypersexuality. However, pathological gambling was shifted from the category of ICDs to the category of “Substance-Related and Addictive Disorders” in DSM-5⁽¹⁾.

Other impulsive/compulsive behaviors are associated, namely dopamine agonists (DA) dysregulation syndrome, an addiction to DA medication, particularly high-potency and short-acting drugs (e.g., subcutaneous apomorphine or dispersible formulation of levodopa). Related phenomena have also been identified as punding (repetitive, purposeless, and stereotyped behaviors), hobbyism (excessive exercise or creative activities), hoarding (acquisition and keeping of a large number of items with little or no objective value – e.g., used gloves), and walkabout^(1,2). Very often, those patients also develop hypomania which interferes with their familial and social life⁽²⁾.

Pathological gambling (PG) is defined as a persistent and recurrent problematic gambling behavior as indicated by features such as increasing amounts of money, restlessness or irritability when cutting down, failing to control the behavior, preoccupation with gambling, lying to others, and so on (at least four criteria required). However, based on neuropsychiatric and possibly pathophysiological features, PG is currently considered as a typical example of behavioral addiction and is included in the diagnostic category of “Substance-Related and Addictive Disorders”, according to DSM-5.

Hypersexuality means increasing preoccupation with sexual thought, excessive sexual needs, increased use of pornography and self-stimulatory behavior, seeking out prostitutes, engaging in exhibitionism and paraphilia.

Binge eating involves uncontrollable consumption of a large amount of food, which results in harmful gain of weight.

Compulsive buying or shopping can be defined as irresistible excessive buying that can lead to psychological consequences and financial debt⁽⁴⁾.

In addition to the ICD, there are also some ICD-rela­ted disorders (ICRDs), such as dopamine dysregulation syndrome (DDS) and punding. DDS implies repeated, unnecessary, or sometimes deleterious daily intake of dopaminergic agents far more than the dosage required for the treatment of objective motor impairment, leading to severe dyskinesia, euphoria, aggressivity, hallucination, confusion, or frank psychosis. Punding is a term that was coined originally to describe complex prolonged, purposeless, and stereotyped behavior in chronic amphetamine users. It shares similarities with addictive behavior, and it involves psychiatric symptoms relating to dopamine system⁽⁴⁾.

Besides the classic ICDs symptoms, there are many other ICDs-related behavioral problems, including reckless driving, impulsive smoking, compulsive singing, tattooing, stealing, pet killing, and zoophilia. The wide clinical spectrum of ICDs symptoms necessitates careful monitoring of behavior when patients are taking dopaminergic drugs. As the researches indicated, dopamine has been known to have a strong association with impulse control diseases⁽⁴⁾.

Epidemiology

Parkinsonism is the second most common neurodegenerative disease, following Alzheimer’s disease (AD). Over 1% of the population above the age of 55 and approximately 3% of the population over the age of 70 suffer from Parkinson’s disease. The incidence and prevalence of PD increase with the advancing age. Few studies estimated that 10 million people globally (i.e., approximately 0.3% of the world population) suffer from Parkinson’s disease⁽¹⁾.

The prevalence rates of depression in PD patients vary from 2.7% to 55.6%. Epidemiological data from some studies suggested that the frequency of major or more severe depression is 5-20%, with minor depression present in 10-30% of patients and dysthymia present in 22.5%⁽¹⁾.

Anxiety symptoms or disorders are experienced by nearly 3.6-40% of the PD patients. Among the various anxiety disorders, the most frequent one is generalized anxiety disorder (14.1%), followed by social phobia (13.8%), anxiety not otherwise specified (13.3%), and panic disorder with or without agoraphobia (6.8%). Anxiety and depression are highly comorbid. They co-occur in up to 80% of patients. Apathy is observed in up to 40% of PD patients⁽¹⁾.

Psychosis is usually seen in people over 50 years old, where the incidence and prevalence increase with age. Studies have shown that, in PD patients, up to 60% will develop psychosis within 12 years after the disease’s onset, while in some studies, it has been reported early as the 19^th month after the diagnosis among 27% of the patients⁽¹⁾.

The reported prevalence of cognitive dysfunctions in Parkinson’s disease varies widely. The reported point prevalence of dementia in PD is around 30%, and the rates are up to two to six times more common compared to healthy control populations. The overall cumulative prevalence has been reported to be as high as up to 75-80% in patients with 10-year survival after the onset of motor symptoms in dementia⁽¹⁾.

The prevalence of the common sleep disorders in Parkinson’s disease is high. A study found that nocturia was the most prevalent of the various nocturnal symptoms in PD (91.5%), and hallucinations were the least common (15%)⁽¹⁾.

Many other non-motor symptoms, such as psychosis, cognitive impairment and ICDs, have been reported to have a strong association with RBD⁽¹⁾.

The prevalence of impulse control diseases in PD patients using dopamine replacement therapy (DRT) varied from 3.5% to 43%. Dopamine receptor agonist (DA) treatment in PD is associated with 2-3.5-fold increased odds of having ICDs compared with patients without DA treatment. The estimated incidence of impulse control diseases in PD patients increases with time, especially in those on DRT. In one longitudinal study, the five-year cumulative incidence of ICDs was about 46%. A study revealed that 17.5% of the PD subjects resulted positive with ICDs before starting the treatment, indicating the need for a detailed behavioral assessment before dopaminergic therapy⁽⁴⁾.

Impulse control diseases are probably much more frequent in Parkinson’s disease than previously reported, as patients often underestimate the presence and severity of their ICD symptoms. This is in part due to the lack of insight, but also as a defense mechanism with denial and minimization of symptoms on a background of feelings of shame or guilt. Some patients with impulse control diseases may have a relative lack of empathy, and they do not perceive any stress from their aberrant behavior, despite marked concerns by family members and friends⁽⁴⁾.  

Corresponding author: Raluca Pretorian E-mail: pretorianraluca@yahoo.com

CONFLICT OF INTERESTS: none declared.                                                      

FINANCIAL SUPPORT: none declared                     

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