Neuropsychiatric Symptoms in Parkinson’s Disease

FREQUENCY AND IMPACT

Parkinson’s disease (PD) is the second most common chronic neurodegenerative condition and is diagnosed by characteristic motor features. However, PD may be preceded and is very frequently accompanied by a wide range of cognitive and neuropsychiatric features. A variety of neuropsychiatric symptoms including depression, anxiety, apathy, hallucinations and impulse control disorders, occur in up to 60% of PD patients [1]. In cross sectional studies, the most prevalent and well-studied NPS in specialty care settings are anxiety (40%–50%) [2, 3], depression (20%–40%), dementia (20%–30%) and psychosis (15%–30%)[1, 5]. NPS have a significant impact on patients and their caregivers, as well as on the health care system [6]. However they are under-recognized and undertreated overall [7] due to patient related factors (e.g. incomplete understanding of mental health problems), access to care issues and lack of interest and knowledge among clinicians [7, 8]. Here we present an overview of clinical presentation, diagnostic and management strategies for NPS.

DIAGNOSTICS – SPECTRUM OF NEUROPSYCHIATRIC SYMPTOMS

A complex clinical picture of PD is present throughout the disease course. Various motor and non-motor symptoms are not only different between PD patients but are also changing along the course of the disease progression in each patient. The neurodegenerative change of PD and its pharmacological management are involved in this clinical heterogeneity. Progressive spread of Lewy body neuropathology from subcortical to cortical structures is reflected clinically in different disease stages and can be also recognized in distinct disease subtypes. Therefore, and due to the overlap between NPS and motor (for example slowness of movement and masked face) features of PD, it might sometimes be more difficult to identify and rate severity of distinct NPS.

When diagnosing NPS several diagnostic approaches are important. In daily clinical practice an unstructured interview on NPS would commonly be used. However, we recommend use of one of the several well established and easy to use rating scales (observer-based, carer-based, or self-report) evaluating a spectrum of NPS (i.e. Neuropsychiatric Inventory-NPI, Non-Motor Symptom Scale (NMSS), Unified Parkinson’s Disease Rating Scale (UPDRS). Rating scales may serve as a tool for NPS screening, as an additional diagnostic measure, as a NPS severity scale or as a tool for measuring a symptom change with time.

Underlying mechanism for development of NPS is multifactorial. Different neuropathological changes might be reflected in presentation of different NPS. There are also several contributory non-specific biological and psychosocial mechanism involved in expression of NPS. Furthermore the association of PD therapy and NPS is well known. Commonly used clinical rating scales and pharmacological treatment for most prevalent NPSs are summarized in the Table 1.

DEPRESSION

Extensive research in the field of depression in last years has provided major advances in characterization of depression, a very frequent accompaniment of PD. The frequency of depressive symptoms vary according to population and symptom definition, but clinically relevant symptoms may occur in 20–30% of patients. Possible risk factors for depression in PD have been identified: female sex, personal and family history of depression, early onset of PD, “atypical” parkinsonism, and psychiatric comorbidity (worse cognition, psychosis, anxiety, apathy, fatigue and insomnia). Although depressive symptoms are common in all disease stages, the frequency tends to be higher in more advanced PD and in patients with dementia. Depression is regarded as a putative risk factor for cognitive decline [9, 10], however several other studies failed to show association of depression with subsequent rate of cognitive decline [11–14]. Depression can be under-or over-diagnosed due to symptom overlap with motor characteristics of PD, apathy and dementia. A data driven approach has been used to explore heterogeneity in depressive and anxiety related symptoms in patients with PD. This resulted in a four class, empirically defined subgroups; class 1: “anxious depressed” with marked prevalence of female sex, subjectivetension, general anxiety, greater disability, longer disease duration and younger onset, class 2: “depressed or “apathetic depressed” with high levels of cognitive impairment, class 3: “anxious” with a profile similar to generalized anxiety disorder and the largest group of class 4: ‘psychologically healthy’ older patients with a high proportion of males, later age at onset, shorter disease duration, lower levels of motor symptoms, disability and medication [15].

Depression likely results from a complex interaction of psychological and neurobiological factors. NPS in PD have been associated with imbalances in the catecholaminergic and serotonergic neurotransmitter systems, as well as additional up-regulatory effects in the dopaminergic system that can arise with medication. Throughout the limbic circuitry, conversely hyper-and hypo-dopaminergic levels are known to contribute to positive (i.e. impulsivity) and negative (i.e. depression, apathy) [16] clinical presentation.

A Movement Disorders Society task force reviewed and made recommendations for the use of depression rating scales in PD, including clinical interviews such as MADRS and HDS, and questionnaires such as GDS and HADS [17]. In addition an NINDS/NIMH work group suggested provisional diagnostic criteria for depression in PD [18]. In the advanced stage of the disease with dementia, the informant based scales like NPI and the Cornell Scale for Depression in Dementia (CSDD) were recommended and reported to have adequate properties also in PD [19]. Exploratory analyses of functional imaging using [11C] RTI-32 PET, an in vivo marker of both dopamine and noradrenaline transporter binding, revealed that the severity of anxiety in the PD patients was inversely correlated with the [11C] RTI-32 binding in several regions of the limbic system including the anterior cingulate cortex, the thalamus, the amygdala and the ventral striatum and apathy was inversely correlated with [11C] RTI-32 binding in the ventral striatum. These results suggest that depression and anxiety in Parkinson’s disease might be associated with a specific loss of dopamine and noradrenaline innervation in the limbic system [20].

ANXIETY

Anxiety disorders are more common in PD patients than in general population, in primary care clinics or in patients with other chronic medical conditions, where prevalence rates vary between 5 and 11% [21]. Anxiety in PD is associated with increased subjective motor symptoms [22], more severe gait problems [23]dykinesias [23], freezing [24], motor response fluctuations [22] and a decrease in health related quality of life [25]. In a large PD cohort, 34% of patients met a diagnosis of one type of anxiety disorder, with generalised anxiety disorder being most common, followed by panic attacks and phobias [19]. Panic attacks commonly present with symptoms such as increased heart rate, chest pain, dizziness, shortness of breath, sweating, concern over “ losing control” or “going mad” and may lead to fear over their consequences and avoidance behaviour [26]. A strong link between anxiety and symptoms of depression was reported in two large series [27, 28], but unlike many other NPS, anxiety was found to be less common in PDD compared to PD [29]. Anxiety is also common in patients with motor fluctuations and may be the presenting feature of non-motor fluctuations. Beck Anxiety Inventory (BAI), Hospital Anxiety and Depression Scale (HA) and Neuropsychiatric Inventory (NPI) are most common clinical ratings scales for anxiety.

Studies have shown that depression and anxiety are among the strongest predictors of poor quality of life in PD. Their detrimental impact on wellbeing and functional ability was rated greater than the one from motor symptoms, even in the most advanced stages of thePD [30].

PSYCHOSIS

Psychotic symptoms are common, and if minor symptoms are included may affect up to 60% PD patients [29, 31]. Due to high prevalence and characteristics, the psychosis in PD is a challenging clinical problem because it has been found to increase caregiver stress and it is the main risk for nursing home placement [32].

Psychosis in PD usually present with one of the following symptoms: illusions (misinterpretation of existing stimuli), hallucinations and/or delusional symptoms.

Delusions in PD tend to be paranoid in nature but are relatively rare. Misidentification syndromes, including Capgras, are more common.

Visual hallucinations are the most common psychotic feature in PD, and are sometimes accompanied by olfactory and auditory hallucinations [33]. Complex visual hallucinations, often of animals and people are the most typical manifestation [34] but other visuperceptual disturbances can occur, including illusionary experiences, sensations of movement in the periphery (passage hallucinations) and sensations of presence (extracampine or “social” hallucination) [35]. Psychosis can manifest across all the disease spectrum of PD, even in the earliest stages of the disease [36], although typically it occurs in later in the diseasecourse [37].

Screening for psychosis should occur at all stages of PD as part of a broad non-motor assessment. It is important to take into account the known risk factors for visual hallucinations: disease duration [38, 39], disease severity, ocular disorders [40], late onset of PD [37], depression [41] and REM sleep behaviour disorder [42]. The occurrence of visual hallucinations in PD may be a harbinger of subsequent cognitive decline, or it may lead to more rapid decline in the pre-existent cognitive impairment [43]. Then again cognitive decline may be an important risk for visual hallucinations [36]. Notably even non-demented PD patients with hallucinations tend to have poor sustained attention, worse visuo-spatial function and more executive dysfunction, compared to those without hallucinations. Cognitive function may be important in interpretation of visual stimuli.

The role of dopamine replacement therapy in the aetiology of psychosis in PD remains unclear. While dopamine agonists seem to be associated with an increased risk for visual hallucinations [31], it is noteworthy that patients with dementia with Lewy bodies can experience similar visual hallucinations without exposure to dopamine replacement therapy. Moreover there are observations that anticholinergics can exacerbate visual hallucinations [33] and cholinesterase inhibitors can improve them. These observations make pure dopamine based explanation for PD psychosis unlikely and suggest other neurotransmitter systems may also play a role [44].

APATHY

Apathy is characterised by reduced interest and participation in normal purposeful behaviour, lack of initiative with problems in initiation or sustaining an activity to completion, lack of concern or indifference and flattening of affect [45]. The prevalence of apathy is not clear as it varies depending on the assessment procedure, study population, and has been reported to be 16.5 to 40% [46]. The relationship between apathy and depression, anxiety or severity of motor symptoms is not confirmed [45, 47], half of patients with apathy do not suffer from concomitant depression or cognitive impairment, confirming its status as a separate clinical syndrome in PD [46]. Apathy in the treatment-naive patients with early-stage PD, was shown to be associated with more severe motor symptoms and a worse cognitive status. After adjustment for these factors, apathy appeared to be a relatively isolated, independent symptom because the only other associated non-motor symptoms were fatigue and anhedonia [48].

Recent study showed that apathy in in non-depressed, non-demented patients might be a predictor of future cognitive decline and dementia in PD [49]. The pervasiveness of apathy in PD warrants research into its treatment, although different underlying pathophysiological mechanisms may require different treatment strategies. It has been suggested that apathy in PD results from dopaminergic depletion [50]. Research in patients before and after deep brain stimulation also suggests that apathy in patients post-surgery is related to dopamine withdrawal [51]. Several different assessment instruments (Apathy Scale; Apathy Evaluation Scale; Lille Apathy Rating Scale, Neuropsychiatric inventory), sources, and cutoff points used may be an important source of heterogeneity.

IMPULSE CONTROL DISORDERS

Many studies have reported a high rate of impulsive compulsive disorders (ICD) in patients with PD. The manifestation of ICD with compulsive gambling, buying, sexual behaviour and eating is increasingly recognised as common and clinically significant disorder in PD. It is suggested that these disorders are arising from aberrant or excessive dopamine receptor stimulation, with reported prevalence rate of 35.9 to 60% [49]. These rates are much higher than those reported for individual disorders by Evans et al.[52]. The rates of ICDs are higher in young and male patients receiving dopaminergic agents, especially direct D2/D3 dopamine agonists, resolution of ICDs is reported with reduction or discontinuation of therapy [52].

SUICIDAL BEHAVIOUR

Suicidal behaviour includes suicidal ideations, suicidal gestures, attempted suicide and completed suicide. Studies on suicidal behaviour in PD are scarce. The suicide rate among patients with PD is reportedly lower than expected [53] despite the relatively higher prevalence of depression [54]. Suicide is supposedly associated with depression, other psychiatric conditions [55] and a number of unrelated demographic factors. As well, impulse control disorder in PD patients undergoing subthalamic nucleus (STN) deep brain stimulation (DBS) [56, 57] has been a well-recognized suicide risk factor. Following DBS, especially of STN, suicides have been documented and stipulated to be connected to postoperative depression due to psychosocial changes and reduced dopaminergic stimulation after therapy withdrawal [57].

NON-MOTOR FLUCTUATIONS

Motor and non-motor fluctuations are common in advanced PD. The majority of patients with motor fluctuations also experience some degree of non-motor fluctuations. Non-motor fluctuations may often be very disturbing for the patient and carers and would typically present as a mix of psychiatric (anxiety, fatigue, dysphoria) and cognitive (slowness of thinking, confusion, poor concentration, word finding problems, impairment of memory) symptoms [58, 59]. Recent large muticenter, open label, comparative study showed a robust improvement in motor symptoms, motor complications, quality-of-life, and some non-motor symptoms in patients with advanced PD, treated with either subcutaneous apomorphine infusion or intrajejunal levodopa infusion [60]. Fatigue is one of the key non-motor symptoms of PD and commonly reported bothersome symptom associated with the off state. Its prevalence reaches up to 50% even in early PD [61]. Study on health related quality of life showed that presence of anxiety, depression, pain and fatigue had a negative impact measured by Parkinson’s disease Questionnaire-8 [62].

TREATMENT

The treatment of NPS in PD is complicated by the overlap with motor and non-motor symptoms of PD, anti PD medication side effects, frequent comorbidity with other NPS and an increased vulnerability to the side effects of certain psychotropic drugs [63]. Primarily management of NPS in PD includes measures for the correct diagnosis and evaluation of severity and profile. In this process NPS caused by drugs, physical disease and stressors should be excluded and other brain diseases presenting with NPS (DLB, AD, schizofrenia) should be excluded.

General approach in management of NPS should include: removal of contributing factors, modification of dopaminergic therapy, provision of NPS information on coping and other psychological strategies. If the NPS remain and are troublesome despite these measures, symptomatic drug treatment for the specific syndrome should be considered. Regular monitoring of treatment response, dose adjustments and recording of possible adverse effects are milestones of a successful treatment in patients with PD and NPS.

Multidisciplinary rehabilitation (speech therapy, physiotherapy, social services need assessment, psychotherapy, relaxation techniques, dietary counselling and advice for caregivers) with wide array of possible approaches for motor and non-motor symptoms is indispensable throughout the disease course of PD.

Randomized trails in patients with depression and PD have reported improvement of symptoms with nortriptyline [64], venlafaxine and paroxetine [65], also supported by meta-analyses [66]. There is some evidence suggesting that cognitive behaviour therapy (CBT) is effective for depression in PD [67], with improvement of executive functioning as an independent predictor of treatment effect [68]. However recent evidence based review determined that repetitive transcranial magnetic stimulation, electroconvulsive therapy, MAOIs and newer antidepressants like atomoxetine and nefazodone have insufficient evidence for efficacy for treatment of depression inPD [69].

There have been no controlled anxiety treatment studies in PD, but antidepressant treatments studies have reported secondary benefit for anxiety symptoms [26]. CBT may be relieving for anxiety in PD too [70]. When anxiety episode present as a part of “off” state, adjustments of PD medication may be first attempt to reduce the duration and severity of these episodes. Many patients benefit from small doses of benzodiazepines, but the dose and duration should be limited due to the many risks associated with these drugs in the elderly.

A significant treatment paradox is present with psychosis in PD as the dopamine needed to improve the motor function has been implicated in increasing the frequency of and severity of hallucinations and delusions and the medications most often used to treat these psychotic symptoms block dopamine and cause parkinsonism [31].

Practically, removal of antiparkinsonian medication may help to ameliorate psychotic symptoms, particularly in earlier stages of the disease, and a specific order of withdrawal has been suggested beginning with anticholinergic agents, through to dopamineagonists/COMT inhibitors and then finally, if required levodopa [71].

All typical and most atypical antipsychotics are contraindicated in PD because they worsen motor function and carry a higher risk for adverse events including cognitive decline, confusion, drowsiness and in some cases an increased risk of mortality [72]. Quetiapine and clozapine are exceptions in that they do not appear to appreciably worsen motor function. However only clozapine (doses 12.5–100 mg/d) has been adequately tested to demonstrate improvement in hallucinations without worsening of motor function [73, 74].

There is a small risk for agranulocytosis, and more commonly orthostatic hypotension, confusion and somnolence during treatment with clozapine.

Cholinesterase inhibitors in particular rivastigmine [75] may be an alternative first line treatment option in psychosis in people with dementia as these agents can improve cognition, function and NPS. Although there is no systematic evidence that they reduce psychotic symptoms, there is anecdotal evidence, and also suggestions that cholinesterase inhibitors can reduce the risk for emerging visual hallucinations [75]. Other drugs like, memantine (NMDA antagonist) and ondanserton (5-HT3 antagonist) have also been considered for treatment of PS psychosis, but the overall therapeutic effect remains inconclusive [76, 77].

A recent randomized placebo controlled phase 3 trail with pimavanserin a selective serotonin 5-HT2A inverse agonist without dopaminergic, adrenergic, histaminergic, or muscarinic affinity reported significantly reduced psychotic symptoms in patients with moderate to severe PD [78].

The evidence for treatment of apathy is lacking. Apathy in PD may benefit from dopamine agonist use. Among other treatment options, anticholinergic, antidepressants and non-pharmacological treatment strategies such as cognitive training and exercise have been suggested. A recent small randomized controlled trail showed that rivastigmine improved apathy in patients with PD, without depression and cognitive impairment [79]. There is a class II evidence of the efficacy of the dopamine agonist piribedil in the treatment apathy in PD [80]. Treatment of apathy could improve patient quality of life, reduce caregiver burden, alleviate disability by increasing motivation for self-care, and reduce cognitive impairment [47].

CONCLUSION

NPS are common, important, frequently under-diagnosed and therefore undertreated non-motor symptoms of PD. General management strategies are crucial for good clinical practice and important for the improvement of patient’s wellbeing. The limited evidence for efficiency of standard psychotropic medications, the overlap between NPS and PD symptoms and increased vulnerability to side effects suggests the need for further studies in PD and selected NPS.

CONFLICT OF INTEREST STATEMENT

The authors have no conflict of interest to report.