Management of Psychiatric Disorders in Patients with Parkinson's Diseases.

Parkinson's disease (PD) is a heterogeneous progressive neurodegenerative disorder, with a triad of motor symptoms with akinesia/bradykinesia, resting tremor (4-6 Hz), and rigidity. It is the second most common neurodegenerative disease after Alzheimer's disease. The overall management of PD depends on the status of symptoms, functioning of the patients, impairment, disability, and its impact on quality of life. Depression, anxiety disorders, apathy, anhedonia, psychosis, cognitive impairments, dementia, and impulse control disorders (ICDs) are the common psychiatric symptoms/disorders comorbid with PD. Depression remains the most common psychiatric disorder reported to be comorbid with PD. Several pharmacological and nonpharmacological management strategies are used for the treatment of comorbid psychiatric disorders in PD. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are used to treat depression in patients with PD. The best evidence of efficacy in PD psychosis is for clozapine and pimavanserin. The treatment for cognitive impairments in PD remains poorly researched. Rivastigmine is the only approved treatment for PD as per the Food and Drug Administration. Pramipexole, a dopamine agonist (DA), is reported to cause improvement in the symptoms of decreased willingness in apathy. The treatment approaches for different sleep disorders in PD are different. Identifying the cause, reviewing the patient's ongoing medications, and evaluating the impact of comorbid medical conditions and sleep hygiene are common to all conditions related to sleep disorders. The first approach for treating ICD symptoms is the reduction or discontinuation of DAs. The psychiatric symptoms in patients with PD are highly prevalent, and their management should be included in the basic treatment algorithm for PD. This paper summarizes common psychiatric symptoms/disorders in PD and their management approaches. Copyright:

INTRODUCTION

Parkinson’s disease (PD) is a heterogeneous progressive neurodegenerative disorder. It primarily originates from the degeneration of dopaminergic neurons present in the substantia nigra pars compacta (SNpc). Akinesia/bradykinesia, resting tremor (4–6 Hz), and rigidity are the triad of motor features and are hallmarks of the disease. The other characteristic clinical manifestations include gait (festinating) and postural abnormalities.

The classic motor symptoms of PD and the other common nonmotor clinical characteristics are elaborated in Table 1.[12]

Table 1

Clinical characteristics of Parkinson’s disease

Type of symptoms	Descriptions
Motor symptoms	Resting tremor (4–6 Hz), bradykinesia, rigidity, postural instability
	Hypomimia (“masked facies”), softer and monotone speech, dysphagia, dysarthria, sialorrhea
	Shuffling gait, decreased arm swing, festination, difficulty turning in bed, arising from chair, slowness in activities of daily living, micrographia
	Glabellar reflex, striatal deformity, scoliosis, blepharospasm, dystonia, etc.
Nonmotor symptoms	Cognitive impairments, dementia, depression, anxiety disorders, anhedonia, apathy, psychosis, ICDs, and other psychiatric disorders
	Sensory symptoms: Anosmia, ageusia (loss of taste), pain (shoulder, back), paresthesia
	Dysautonomia (urinary symptoms, constipation, orthostatic hypotension, and sexual dysfunction, seborrhea, abnormal sweating), weight loss
	Sleep disorders (insomnia, excessive daytime sleepiness, REM sleep behavior disorder, restless leg syndrome, obstructive sleep apnea, and other sleep disorders

ICDs – Impulse control disorders; REM – Rapid eye movement

NONMOTOR SYMPTOMS AND PSYCHIATRIC SYNDROMES IN PARKINSON’S DISEASE

This paper describes features and management of following common psychiatric symptoms/disorders in PD.

Depression

Anxiety

Psychosis

Cognitive impairments and dementia

Apathy

Sleep-related disorders

Impulse control disorders (ICDs).

Patients with PD have a high rate of depression. There seems to be vicious cycle between depression and PD; the presence of one increases the risk of the other. Though considered a risk factor for PD, depression is neither indicative nor predictive of progression motor symptoms in PD patients.

Anxiety is also a prevalent feature in PD and the second most common psychiatric disorder after depression.[3] Anxiety has also been reported as a predictor of PD even when smoking, caffeine intake, and anxiolytic medication had been controlled for.[4] As reported by some studies, increased frequency of anxiety disorders could be observed up to 20 years before PD onset.[5] Due to imprecision in diagnosis, overlapping of symptoms with motor, and various other reasons, anxiety symptoms/disorders are often under-recognized and even under-treated in patients with PD. Anxiety symptoms/disorders in PD patients are categorized into primary and secondary anxiety disorders. Secondary anxiety disorders include anxiety caused 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 PD.[6]

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 PD” and has implications for staging the disease development and its management. It is associated with overall poor prognosis, disease burden, and even death. The combined National Institute of Mental Health (NIMH) and National Institute of Neurological Disorders and Stroke (NINDS) workgroup provisionally described termed it as Parkinson’s disease psychosis (PDP). The NINDS-NIMH Workgroup concluded that various phenomena occurring in PDP are not just a distinct symptom class but also a continuum representing the overall progression of the PD process. This continuum or positive symptoms spectrum was called PDP, and the given diagnostic criteria included its chronology and duration of the symptoms.

Cognitive dysfunctions can be commonly seen at any disease stage of PD.[7] 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 PD. Deterioration of cognitive abilities is progressive, and the incidence and prevalence of cognitive dysfunctions increase with the progression of PD. The cognitive impairments in PD significantly affect the functioning and quality of patients’ lives and 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 (PDD) [Table 2].

Table 2

Common definitions of cognitive impairments in Parkinson’s disease

Dysfunctions	Definitions
SCD	Decline in cognitive ability which is self-perceived. However, age, sex, and education-adjusted performance on standardized cognitive tests are normal
PD-MCI	Gradual deterioration in cognitive ability is reported by either a patient with PD or a caregiver or observed by a clinician. Objective cognitive deficits on either formal neuropsychological test or on a scale of global cognitive abilities are demonstrated. These dysfunctions are causing significant impairments of functioning. PD-MCI can be classified based on number of cognitive abilities involved as single or multiple domains
PDD	Cognitive impairments with deficits in at least two out of four cognitive domains (executive functioning, attention, memory, and visuospatial abilities) significantly affecting normal functioning, which cannot be explained by impairment caused by motor and autonomic symptoms related to PD. Depending on the level of impairments in daily functioning, it can be classified as mild, moderate, or severe. Generally, dementia after at least 1 year of motor symptoms is diagnosed as PDD

SCD – Subjective cognitive decline; PD – Parkinson’s disease; MCI – Mild cognitive impairment; PDD – PD dementia

Apathy is another distinct clinical syndrome in PD 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.[8] Hence, apathy, depression, and cognitive dysfunctions need to be separately diagnosed.[9] Apathy syndrome is a separate morbid state with remarkable apathy, 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.[10]

Sleep disorders are one of the common nonmotor symptoms found in PD. Some sleep disorders in PD, such as rapid eye movement sleep behavior disorder (RBD), are seen to have a specific association with PD and may occur several years before PD. The various types of sleep disorder in PD and their clinical features, along with their prevalence, are mentioned in Table 3.[1112]

Table 3

Types of sleep disorder in Parkinson’s disease and their clinical features with their prevalence

Sleep disorder	Clinical features	Prevalence (%)
Insomnia	Difficulty in (i) initiating asleep, (ii) maintaining the sleep, and (iii) early morning awakenings	27-80
EDS	Excessive unintentional daytime sleep	13-47
RBD	Dream enactment leads to screaming, laughing, crying, talking, violent limb movements during sleep, leading to risk of injury to the patient and bed partner	22-60
RLS	Urge to keep the legs in motion, not always associated with distressing sensations. During periods of rest or inactivity the symptoms increase and by moving the legs, patients feels relieved	8-35
OSA	Loud snoring, awakening abruptly which is accompanied by excessive daytime sleepiness, choking, fragmented sleep and frequent nocturnal awakenings	20-60

EDS – Excessive daytime sleepiness; REM – Rapid eye movement; RBD – REM sleep behavior disorder; RLS – Restless legs syndrome; OSA – Obstructive sleep apnea

ICDs are also commonly observed in PD. 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.

All these psychiatric disorders in PD are related to patients’ impaired quality of life and are also associated with higher caregiver distress.[1314]

EPIDEMIOLOGY

Parkinsonism is the second most common neurodegenerative disease following Alzheimer’s disease. Over 1% of the population above the age of 55 and approximately 3% of the population over the age 70 suffer from PD. Incidence and prevalence of PD increase with advancing age. Few studies estimated 10 million people globally (i.e., approximately 0.3% of the world population) suffer from PD.[15] The nationwide epidemiological data from India are not available. The estimated prevalence in India is roughly estimated to be 10% of the global burden, i.e., 5.8 lakhs.[16] From India, the crude prevalence rates (PRs) are reported between 6 and 53/100,000. Over 60 years of age, the reported PRs were higher and were found to be 247/100,000.[17]

The PRs 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 in 22.5%.[18192022]

Anxiety symptoms or disorders are experienced by nearly 3.6%–40% of PD patients.[3] 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%).[14] Anxiety and depression are highly comorbid. They co-occur in up to 80% of patients. Apathy is observed up to 40% of PD patients.[923]

PDP is usually seen in people over 50, where the incidence and prevalence increase with age. Studies have shown that in PD patients, up to 60% will develop psychosis within 12 years of onset of PD, while in some studies, it has been reported early as 19th month of the diagnosis among 27% of the patients.[24] 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 to include are other hallucinations (auditory and tactile) and delusions.

The reported prevalence of cognitive dysfunctions in PD 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 in comparison 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 of onset of motor symptoms in dementia.[2526]

The prevalence of the common sleep disorders in PD is mentioned in Table 3. 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%).[11]

Many other nonmotor symptoms such as psychosis, cognitive impairment, and ICDs have been reported to have a strong association with RBD.[13]

ETIOPATHOGENESIS

PD is a neurodegenerative disorder referred to as synucleinopathy. The hallmark pathology includes progressive decline of dopaminergic neurons stores in the SNpc and a-synuclein protein aggregation in the form of characteristic Lewy bodies in the surviving neurons.

The motor symptoms in PD are seen when dopamine production is inadequate after a critical degree of neuronal loss and approximately 60%–80% neuronal loss has occurred. The exact causes of PD remain unclear, and how these Lewy bodies are linked to the progression of the disease is also unknown. Neuronal loss in PD can be a consequence of oxidative stress inflammation, mitochondrial dysfunction, and abnormalities in protein handling. The cause of development of these psychiatric disorders in PD patients is not clearly understood although the evidence suggests that the etiology is multifactorial for all.

Evidence suggests that the pathophysiological disease process of PD, i.e., degeneration of dopaminergic neurons, can contribute to the etiopathogenesis of depression, cognitive dysfunction, anxiety, and apathy seen in PD patients.[27] The deposition of Lewy body in amygdala and para-hippocampus and other brainstem structures is considered central to the development of PDP and sleep disorders.[28] Depleting acetylcholine and serotonin can also contribute to the etiopathogenesis of depression. Dysfunction of the habenula, impairment at the limbic system level, basal ganglia, and their connections with the orbitofrontal cortex can also contribute to depression.[327]

The anxiety can be attributed to psychosocial, medical, and neurochemical factors. Neurochemically, anxiety in PD may be linked to a depletion of dopaminergic and noradrenergic neurons in the locus coeruleus and limbic system.[29] Anxiety disorders in some patients are a “reactive” response that can be secondary to the PD diagnosis. In others, it may be secondary to the impairment and limitation due to motor symptoms. Anxiety in patients with PD may also be secondary to the anti-Parkinsonian medications (e.g., levodopa, pergolide).[8] Discrete anxiety disturbances at specific times of day (e.g., in late afternoon or early evening) are unique to PD. Such episodes have been found to have an association with fluctuations in levodopa levels and motor function, mostly occurring with the onset of “off” periods.[23] These attacks mostly manifest as panic attacks.

In PDP dysfunctions in the brainstem’s eye movement control mechanisms, cortical and subcortical motion pathways, including dorsal stream areas in the visual parietal lobe, are found to have neurobiological association with passage hallucinations.[30]

The specific dysfunctions implicated for cognitive impairments in PD are reduced dopamine uptake of the frontal lobe, cholinergic disturbance within the brainstem, and corticostriatal pathways. However, several other neuropathological abnormalities were also reported to have an important role in cognitive dysfunction in PD, such as Lewy bodies and neurites in limbic and cortical regions, neurofibrillary tangles, amyloid deposition, and cerebrovascular disease, mitochondrial dysfunction, inflammation, and abnormalities in the levels of neurotrophic factors.

Apathy can also be correlated to diminished cingulate and inferior frontal gyri volumes. Some studies have suggested apathy as a side effect of deep brain stimulation (DBS).

Poor nocturnal sleep or fragmented sleep can be due to various other PD-related symptoms, such as difficulty turning in bed due to rigidity, nocturia, and increased urinary frequency. Poor sleep quality can also be iatrogenic, and causes may include drug-induced insomnia caused by dopaminergic or anticholinergic drugs, as a consequence of “off” periods or dyskinesia due to dopaminergic drugs.[13] Other sleep disorders, such as sleep-disordered breathing and RBD, may also contribute to poor sleep quality. Sleep may also be impaired by other psychiatric symptoms such as depression, anxiety, and psychosis. Nocturnal sleep disturbances due to any of these reasons may result in excessive daytime sleepiness.[1213]

ICDs were initially reported in PD patients who were on dopamine agonist (DA) therapies. Some studies report ICDs in the general population and PD patients without DA therapies.[31] It is still under discussion whether PD biology could be a risk factor for ICDs.[32] Classically, impulsivity in PD can be secondary to neuronal dopaminergic degeneration and further manifestations of ICD due to dopamine replacement therapies.[33]

CLINICAL FEATURES

The clinical features of various psychiatric disorders in PD are as follows:

Depression

The commonly observed symptom profiles included pessimism, hopelessness, decreased motivation, anxiety, suicidal ideation without suicidal behavior, and increased health concern. The patients can present with both dysphoric (irritable) and sad moods.[3] Guilt, self-blame, and worthlessness are uncommon.[523]

Psychosis

Symptoms of PDP are mentioned in Table 4.

Table 4

Symptoms of Parkinson’s disease psychosis

Type of symptoms	Descriptions
Minor symptoms	These symptoms are not strictly required for the diagnosis but depict PD’s early stage and present in increased frequency
Illusions	A distorted perception of any object. In PD, “Pareidolia” - a specific illusion in which faces and objects are seen in formless visual stimuli, such as clouds, or in geometric visual patterns, such as wallpaper
Presence hallucinations	A feeling or vivid sensation that someone is nearby
Passage hallucinations	A feeling where an indefinite object, a person, or an animal is seen passing by
Major symptoms	These symptoms (positive symptoms) are full formed symptoms and depicts a higher stage of PD. E.g., visual hallucinations and delusions

PD – Parkinson’s disease

The presence of insight indicates early, while 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.

Cognitive dysfunction

The core feature of cognitive dysfunction in PD is 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.

Apathy

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

Impulse control disorders

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 the DSM-5. The spectrum of ICDs-RD also includes hoarding, hobbyism, punding, walkabout, and compulsive medication use (dopamine dysregulation syndrome).

RISK FACTORS

The possible risk factors for the common psychiatric disorders in Parkinson disorder patients are enumerated in Table 5.

Table 5

The possible risk factors for the various psychiatric disorders in Parkinson’s disease patients

Psychiatric disorder	Risk factors
Depression	Female gender[323]
	Older-aged PD patients[3]
	Personal or familial history of depression[23]
	Early-onset PD[23]
	“Atypical” Parkinsonism (presence of pyramidal symptoms or prominent autonomic signs or rapidly progressive disease)[23]
	Psychiatric comorbidity (e.g., impaired cognition, anxiety, apathy, psychosis, fatigue, and insomnia)[23]
	Anti-Parkinsonian medications[8]
Anxiety symptoms/disorder	Female gender
	Younger age
	Early-onset PD
	Severity of PD
	More depressive symptoms
	Worse sleep quality
	Gait dysfunction
	Postural instability
	Morning dystonia
	Higher rates of motor fluctuations
	Dyskinesia[834]
Cognitive dysfunction	Advancing age
	Longer disease duration
	Severity of motor symptoms, specifically postural and gait disturbances
	Presence of mild cognitive impairment
	Visual hallucinations, early hallucinations
	Male sex
	Smoking
	Alcohol use
	Cardiovascular and cerebrovascular disease
	PD patients with poor response to dopamine agonist
	Depression
Psychosis	Older age of onset[3536]
	Longer disease duration
	Changes in visual function (diplopia)
	Sleep disturbances (rapid eye movement sleep behavior disorder)
	Cognitive changes
	Dopaminergic medications[2435]*
ICDs related disorder	Young age
	Male sex
	Unmarried[3738]
	Dopaminergic/dopamine agonist drugs[3337] (pramipexole, ropinirole, L-dopa, amantadine, selegiline)
	Monoamine oxidase B inhibitors
	ICD-related disorder symptoms before PD
	Substance abuse
	RBD
	Depressive symptoms, anxiety, novelty-seeking[3133]
	Subthalamic nucleus deep brain stimulation*
	Personality factors*
	Cognitive decline*
	Genetic factors (SNPs and FosB overexpression)*

PD – Parkinson’s disease; REM – Rapid eye movement; RBD – REM-sleep behavior disorders; ICDs – Impulse control disorders; SNPs – Single nucleotide polymorphisms; FosB – A type of protein

MANAGEMENT

Assessment for psychiatric disorders in Parkinson’s disease patients

For screening and diagnosis of psychiatric disorders, several rating scales are available. A list of most commonly used rating scales is provided in Table 6.

Table 6

Scales used for assessment of various psychiatric disorders in Parkinson’s disease patients

Disorder	Assessment scale
Depression in PD	GDS-15*
	HADS*
	BDI
Anxiety in PD	PAS*
	BAI
	HARS
	HADS
PDP	MDS-UPDRS
	NEVH-I
	SAPS-PD
Cognitive impairments	SCOPA-COG*
	MoCA
	MMSE
Apathy	AS
	LARS
Sleep disorders	PDSS
	PSQI
	SCOPA-Sleep
	ESS
	SSS
	ISCS

GDS-15 – 15-item Geriatric depression scale; PD – Parkinson’s disease; HADS – Hospital anxiety and depression scale; BDI – Beck depression inventory; PAS – Parkinson anxiety scale; BAI – Beck anxiety inventory; HARS – Hamilton anxiety rating scale; HADS – Hospital anxiety and depression scale; MDS-UPDRS – Movement Disorder Society United PD Rating Scale; NEVH-I – North-East Visual Hallucinations Interview; SAPS-PD – Scale for assessment of positive symptoms for PD; SCOPA-COG – Scales for outcomes in Parkinson disease–cognition; MoCA – Montreal cognitive assessment; MMSE – Mini-mental state examination; AS – Apathy scale; LARS – Lille apathy rating scale; PDSS – PD Sleep Scale; PSQI – Pittsburgh sleep quality index; SCOPA-COG – Scales for Outcomes in PD Sleep; ESS – Epworth sleepiness scale; SSS – Stanford sleepiness scale; ISCS – Inappropriate sleep composite score

Depression

Owing to its high prevalence, screening for depression is recommended in PD. There are various validated tools such as the Beck depression inventory, the 15-item geriatric depression scale (GDS-15), and the hospital anxiety and depression scale (HADS), along with a clinical interview assessment of depression in PD. The most specific screening tools for depression in PD are the GDS-15 and HADS. These scales are considered more reliable for patients with physical impairments as they remain unaffected by somatic symptoms.[3]

Anxiety

Anxiety can be part of the disease process; thus, routine screening is helpful for most patients with PD. This routine screening in PD patients should be done, especially, at the initiation of the treatment, upon a change in pharmacological treatment and follow-ups. Anxiety can also appear with increasing severity of illness and may get worsened by motor fluctuations and anti-Parkinsonian drugs.[3] Anxiety in PD can be assessed using several rating scales. Nonspecific scales such as Hamilton anxiety rating scale, Beck anxiety inventory, and the HADS can be useful. Parkinson anxiety scale, a PD-specific, validated rating scale for anxiety, can be used to assess the severity of anxiety.[39]

Psychosis

Since there was no standard way to diagnose PDP and few specific clinical characteristics of PDP were also reported, in 2007, a joint workgroup from NINDS-NIMH[40] developed diagnostic criteria for PDP[24] [Table 7], and the tools used to assess the severity of PDP are mentioned Table 6.

Table 7

Diagnostic criteria for Parkinson’s disease psychosis

PDP (should meet all three criteria)
Diagnosis of PDP based on the UK brain bank criteria
≥1 PDP symptoms (illusions, false sense of presence/hallucinations/delusions)
PDP symptoms for≥1 month since PD diagnosis

PD – Parkinson’s disease; PDP – PD psychosis

Cognitive impairments

Differentiation of PDD and dementia with Lewy body (DLB) 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 quite similar clinical profile and course of illness, neuropathological findings, and treatment approaches. The cluster of clinical signs and symptoms of both DLB and PDD include progressive cognitive impairment associated with Parkinsonism, visual hallucinations, and fluctuations of attention and wakefulness. The major clinical difference between DLB and PDD is the timing of dementia in relation to Parkinsonism. Dementia occurring after at least 1 year of onset of motor symptoms, i.e., in the context of well-established idiopathic PD, denotes PDD, and the appearance of earlier cognitive impairment earlier than motor symptoms of Parkinsonism is diagnosed as DLB.

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 PDD.

Alzheimer’s disease

Multiple cognitive domains are affected. Memory, visual-spatial ability, language, and executive functions are commonly involved.

Toxic metabolic process

Metabolic dysfunction sometimes presents with the symptoms common in PDD. Clinical features and arterial blood gas analysis, laboratory analysis of blood biochemistry, electroencephalography, computed tomography or magnetic resonance imaging, etc., may help in diagnosis.

Medication toxicity

Excessive dopamine replacement using medications can cause problems in executive functioning and attention and can also trigger or worsen hallucinations or delusions. Although many medicines can be a potential offender in this regard, DAs are particularly implicated, and amantadine can cause the above problems in some patients. Carbidopa/levodopa is least troublesome in this regard, but at a sufficiently high dose, carbidopa/levodopa can also aggravate cognitive impairments and precipitate psychosis. Trihexyphenidyl, a central anticholinergic agent used to treat PD tremors, can be particularly detrimental to cognitive functioning.

The common scales used are Montreal cognitive assessment and mini-mental state examination. A specific scale developed for dementia in PD, Scales for Outcomes in PD–Cognition, can also be used.

Apathy

Apathy scale (AS)[41] is extensively used to screen and assess the severity of apathy. As the AS is based on subjective evaluation, it has limited use in patients with remarkably low spontaneity. In such patients, Lille apathy rating scale[42] can be useful.

Sleep disorders

In patients with PD, the scales used to assess and rate the severity of nocturnal sleep (sleep disturbance and insomnia) and daytime sleepiness are PD sleep scale (PDSS), Scales for Outcomes in PD Sleep (SCOPA-Sleep), Pittsburgh sleep quality index (PSQI), Epworth sleepiness scale (ESS), Stanford sleepiness scale, and inappropriate sleep, composite score (ISCS). These scales are designed to assess severity and to a lesser extent the presence of sleep disturbances. Five out of these six scales (PDSS, PSQI, SCOPA-Sleep, ESS, and ISCS) are designed to have proposed cutoff values for the presence of sleep disorder and to discriminate between good and bad sleepers.[43]

TREATMENT

The overall management of PD depends on the status of symptoms, functioning of the patients, impairment, disability, and its impact on quality of life. The medications commonly used for the treatment of PD are listed in Table 8. Common issues and behavioral, affective, and other neuropsychiatric side effects of these medications are also listed.[1]

Table 8

Medications commonly used in pharmacological treatment for Parkinson’s disease

Medication with class	Dosages	Side effects	Special comments
Dopaminergic medication
Carbidopa/levodopa	Started at 25/100 TID, dosing titrated as per symptomatic relief	Dyskinesia more common due to short half-life	Most potent medication
Pramipexole	Started at 0.125 mg TID, with gradual building the dose as per clinical response weekly, till a dose of up to 1.5-4.5 mg/daily	Fatigue and drowsiness are frequently noted. May cause Compulsive behaviors	Less potent than carbidopa/levodopa. Less potential to cause dyskinesia
Ropinirole	Started at 0.25 mg TID with gradual building the dose as per clinical response, up to 24 mg daily doses
Rotigotine	2 mg patch daily, as per clinical response increase weekly, up to 8 mg/day
COMT and MAO-B inhibitors
Entacapone (COMT inhibitor)	200 mg taken with each dose of carbidopa/levodopa		Prolong the effect of carbidopa/levodopa and also increase its side effects
Rasagiline (MAO-B inhibitors)	0.5 mg to 1 mg taken daily	Potential serotonin syndrome due to multiple drug interaction including serotonergic antidepressants
Selegiline (MAO-B inhibitors)	5 mg taken daily, if tolerated, increase the dose to 5 mg BID
Anticholinergics
Benztropine	Started at 0.5 mg BID. Build up the dose based on the response up to 2 mg TID	Dry mouth, dry eyes, cognitive impairments, urinary retention	Use with caution in elderly
Trihexyphenidyl	Started at 2 mg QD. Build the dose based on clinical response up to 2 mg TID

COMT – Catechol-O-methyl transferase; MAO-B – Monoamine oxidase aldehyde dehydrogenase B; TID – Three times a day; BID – Bis in die i.e. Two times a day; QD – Quaque die or once in a day

Various guidelines (American Psychiatric Association CPG, National Institute for Health and Care Excellence [NICE], the Spanish National Health System, and the EFNS/MDS-ES guidelines) have recommended both selective serotonin reuptake inhibitor (SSRIs) and serotonin-norepinephrine reuptake inhibitor (SNRIs) in the treatment of depression in patients with PD. Among the SSRIs, sertraline is reported as the safest drug. Among the SNRIs, venlafaxine, desvenlafaxine, and duloxetine are considered effective options.[3]

However, the SSRIs (fluoxetine, sertraline, citalopram, and fluvoxamine) may have the potential to exacerbate PD tremors in up to 5% of patients and sometimes worsen Parkinsonism.[44] Among the other side effects, few SSRIs appear to escalate the risk of pharmacological interactions (fluvoxamine, fluoxetine, and paroxetine) and dose-dependent cardiac arrhythmia (citalopram and escitalopram).[344]

Although efficacious, cautious use of tricyclic antidepressants (TCAs) is recommended due to their anticholinergic adverse effects in the PD population. Their use is mainly restricted when there is no response to the second SSRIs or SNRIs. Nortriptyline and desipramine may be the safest options considering their less anticholinergic side effects and therapeutic window than other TCAs.[344]

A multimodal antidepressant vortioxetine has high efficacy and tolerability, which may be considered a suitable option for PD patients with depression. However, studies interpreting the safety profile and benefits of vortioxetine are not available.[3]

Considering the tolerability and efficacy criteria (in the context of minimal or no increase in motor symptoms, unlike the SSRIs), other drugs considered useful for depression in PD were bupropion (norepinephrine–dopamine reuptake inhibitor), mirtazapine (noradrenergic and specific serotonergic antidepressant), and tianeptine (glutamatergic modulator). Tianeptine, unlike serotonin-reuptake inhibitor antidepressants, can be safely combined with Parkinson’s medication. Bupropion has useful properties such as lack of serotonergic activity, dopaminergic action, and the resultant low risk of Parkinsonism; hence, it may be useful medicine for PD, but it may also potentially induce psychotic symptoms.[3]

There is little evidence on agomelatine and trazodone in this context. Non-ergot dopamine receptor agonists (pramipexole, ropinirole, and rotigotine) are also considered effective for treating PD-related depression. These agents, however, can magnify the risk of ICDs and thus should be replaced by other options such as antidepressants when patients have no response to 3 mg of pramipexole and 15 mg ropinirole daily.[3]

Nonpharmacological treatment options

The data regarding recommendations of nonpharmacological treatment are insufficient. However, the various options include electroconvulsive treatment (ECT), cognitive behavior therapy (CBT), repetitive transcranial magnetic stimulation (rTMS), and DBS.

ECT may alleviate the affective disorder. Delirium is seen in a huge proportion of PD patients who have received ECT. However, it can be used for severe, treatment-refractory depression in PD and suicidal or life-threatening affective disorders.[3] ECT can also be used in patients where rapid treatment response is required and the time needed for the treatment response using medications is difficult.[8]

The stimulation therapies such as rTMS might be useful. The treatment would need to be repeated, as the treatment effect is short term.[44]

DBS, especially focused on the subthalamic nucleus (STN), can be considered useful in the short term for managing depressive symptoms. However, with time, the effect can wanes off.[8] Some studies have reported an higher risk of suicide behaviors with the use of DBS in PD.[23]

CBT is efficacious when symptoms of depression in PD are mild and when antidepressants are undesired or contraindicated.[323] According to some studies, caregiver involvement and good executive functioning predict the response of CBT in PD patients.[8] The treatment algorithm for the management of depression in PD is given in Table 9, and an overview of the treatment options available for depression in PD is given in Table 10.

Table 9

Treatment algorithm for management of depression in Parkinson’s disease

Steps	Clinical approach for management
Step 1	Once the diagnosis of depression is confirmed, review the medications being given for PD management and adjust the doses if necessary
Step 2	If the dose adjustment is not sufficient, treatment according to the severity can be considered
	In mild cases, as the first-line therapy, cognitive behavior therapy or supportive psychotherapy can be considered, if available. However, if psychotherapeutic interventions are not available, pharmacotherapy can be used considering risk-benefit ratio analysis
	In moderate cases, antidepressants or CBT can be considered. SSRIs and SNRIs are the gold standard treatments. Other options include vortioxetine, mirtazapine, bupropion, tianeptine, agomelatine, and nonergot dopamine agonists such as pramipexole and rotigotine. TCAs such as nortriptyline and desipramine are considered only if there is no response on other available medicines
	In severe and treatment-refractory cases, along with the antidepressant, add on ECT can be considered as an option

PD – Parkinson’s disease; CBT – Cognitive behavioral therapy; SSRIs – Selective serotonin reuptake inhibitors; SNRIs – Serotonin-norepinephrine reuptake inhibitors; TCAs – Tricyclic antidepressants; ECT – Electroconvulsive treatment

Table 10

Treatment options available for depression in Parkinson’s disease

Medication and its class	Efficacy and practical usefulness	Oher relevant information
SSRIs	Recommended as first line. Sertraline being the safest	Hold potential to exacerbate PD symptoms (fluoxetine, sertraline, citalopram, fluvoxamine), pharmacological interactions (fluvoxamine, fluoxetine, and paroxetine), and dose-dependent cardiac arrhythmia (citalopram and escitalopram)
SNRIs	Venlafaxine, desvenlafaxine, and duloxetine are considered safe
TCAs	Efficacious, considered if no response to the second SSRIs or SNRIs. Safest options are nortriptyline and desipramine	Used cautiously due to anticholinergic side-effects
MAO-inhibitors	No evidence yet	Cautious use with serotonergic antidepressants due to risk of serotonin syndrome
Other antidepressants (vortioxetine, bupropion, mirtazapine, tianeptine, agomelatine, trazodone)	Given the PD-specific efficacy and tolerability, these can be considered a good option. However, there are no studies available suggesting this	Bupropion may induce psychotic symptoms
Nonergot dopamine receptor agonists (ropinirole, pramipexole, and rotigotine)	May be useful	May increase the risk for impulse control disorder
ECT	Considered useful in severe cases	Delirium or confusion may be experienced afterward
rTMS	No sufficient evidence
DBS	No sufficient evidence
CBT	May be effective	Preferred in mild cases or when antidepressants cannot be given

SSRI – Selective serotonin reuptake inhibitor; SNRI – Serotonin-norepinephrine reuptake inhibitor; TCA – Tricyclic antidepressant; MAO – Monoamine oxidase; PD – Parkinson’s disease; ECT – Electroconvulsive treatment; rTMS – Repetitive transcranial magnetic stimulation; DBS – Deep brain stimulation; CBT – Cognitive behavioral therapy

Anxiety

There is a lack of conclusive data regarding the various antianxiety medications for treating anxiety disorders in people with PD. However, among the various antianxiety medications, SSRIs and SNRIs are regarded as the first line of treatment.[823] TCAs are better avoided in the elderly.

Anecdotally, benzodiazepines have been noted to be effective in treating anxiety in patients with PD. At high doses, benzodiazepines are associated with a higher risk of falls and subsequent fractures and a higher risk of cognitive impairment in the elderly population and abuse and dependence. These reasons mandate their judicious and careful use along with the lowest possible dose for the minimum possible time in the elderly.[829]

Anxiety, secondary to various causes, needs to be managed according to the underlying causes. In case of anxiety secondary to anti-Parkinsonian medications, it is vital to adjust the dose, and if the anxiety symptoms are not tolerated, replacement of the medication should be considered. Similarly, in patients with panic attacks during off periods, the aim of the treatment should be adjusting the dose of the anti-Parkinsonian medication to reduce time off, using Food and Drug Administration (FDA)-approved medications for motor fluctuations.[8]

Nonpharmacological measures such as relaxation techniques, social measures for adaptation to PD, sleep hygiene, and psychoeducation are helpful. CBT techniques that focus on anxiety-provoking maladaptive thoughts and behaviors can effectively treat anxiety attacks and situational anxiety.[45]

Parkinson’s disease psychosis

The most important aspect of management of PDP includes finding out the modifiable risk factors and managing them. Ensuring the functioning of sensory modalities such as visual and auditory should be done. Keeping the patient in low stimulations areas with adequate lighting (to avoid minor visual hallucinations), maintaining the circadian rhythm, and reassuring the patients about symptoms are a few important steps. Possibilities of delirium should be ruled out, and the role of drugs having a high propensity of causing delirium should be evaluated. Other causes such as dehydration and electrolyte imbalances should be ruled out and managed, if any.

The evidence base for successful pharmacological treatment of PDP is highly lacking. The primary objective of pharmacological treatment is to eliminate polypharmacy and optimum use of essential medications to treat PDP symptoms. Choice of medications should be based on (1) to avoid worsening of motor symptoms and cognitive impairment and (2) to decrease the hallucinations. The 2011 Movement Disorder Society, an evidence-based medicine review of treatments, suggests a high risk of worsening motor symptoms with typical antipsychotics as well as few atypical antipsychotics such as including olanzapine and risperidone. Among atypical antipsychotics, only clozapine and quetiapine are highly prescribed, but only clozapine has evidence of a needed therapeutic effect on hallucinations.[27] However, the evidence suggesting efficacy of quetiapine in treating PDP is not clear, and many studies have shown a very minimal or no benefit with quetiapine treatment. Atypical antipsychotics are advisable for patients with minimal or low cognitive impairment, while in patients with severe cognitive impairments, rivastigmine and donepezil are advisable.[2724]

A newer drug pimavanserin received FDA approval in 2016 for PDP treatment (the medicine is not easily available in India as of now) and has shown efficacy without worsening motor or cognitive symptoms. The usual dose is 34 mg once per day. The absorption is not affected by food, and there is no need of titration or dosage adjustment for sex, age, weight, ethnicity, or mild-to-moderate renal failure (CrCL >30 mL/min). It is currently contraindicated in patients with severe renal failure (CrCL <30 mL/min) or hepatic impairment, as it lacks studies in these populations. There is a risk of QTc prolongation with the molecule such as atypical antipsychotics, but recently FDA in 2018 mentioned that its benefits are significantly higher than the associated potential risks. As pimavanserin is metabolized in liver by CYP3A4, hence in case of exposure to enzyme inhibitors such as ketoconazole, dose reduction to 10 mg daily should be considered. The only limitation suggested in the literature is its cost [Table 11].

Table 11

Atypical antipsychotics with doses used in the treatment of Parkinson’s disease psychosis

Medications	Dose range
Pimavanserin (FDA approved)	34 mg/day
Clozapine (periodic blood counts are required)	6.25-50 mg/day
Quetiapine (unclear efficacy)	50-150 mg/day

FDA – Food and Drug Administration

The algorithm for the management of PDP is depicted in Figure 1.

Figure 1

The algorithm for the management of Parkinson’s disease psychosis

Cognitive dysfunctions

The treatment for cognitive impairments in PD is still remains poorly researched. As per FDA, rivastigmine is the only approved treatment for PDD. A mainstay of pharmacological treatment remains the use of cholinesterase inhibitors and memantine. Nonpharmacological treatments are also advocated for use. Cognitive training, both computerized and pen- and paper-based methods, are being used. Some studies have suggested improved working memory, executive function, and processing speed in Parkinson’s patients and even decreased the risk of developing MCI. Physical exercise in PD can improve motor symptoms as well as ameliorate cognitive dysfunctions also. Exercise interventions such as aerobics resistance training, and dance have been shown to improve neuronal proliferation and neurogenesis. However, high-quality and large-scale clinical trials validating the role of nonpharmacological interventions in cognitive impairments in PD are still awaited. The summary of treatment options is presented in Table 12.[44]

Table 12

Medications for Parkinson’s disease dementia: Summary of evidence

Medication and its class	Efficacy and practical usefulness	Dosages and administration	Other relevant information
Acetyl cholinesterase inhibitors
Rivastigmine	Efficacious, practically useful	Start with 1.5 mg BD, increase by 1.5 mg every 2–4 weeks. Maximum dose is 6 mg BD, PO	Approved by FDA for PDD
		Transdermal 4.6 mg/day×4 weeks, may be increased up to 9.5 mg/day
Donepezil	Insufficient evidence, potentially useful	5 mg/d, can be increase up to 10 mg/day after 4 weeks
Galantamine	Insufficient evidence, potentially useful	4 mg BD, can be increased to 8 mg/day after 4 weeks, maximum dose 12 mg/day
NMDA antagonists
Memantine	Insufficient evidence, potentially useful	Start with 5 mg/day, can be increased 5 mg after 1 week, the maximum dose is 10 mg BD
MAO-B inhibitors
Rasagiline	Insufficient evidence, investigational	Monotherapy - 1 mg/day
		With levodopa - 0.5 mg/day	Risk of hypertension
Selective norepinephrine reuptake inhibitors
Atomoxetine	Insufficient evidence, investigational	Start from 40 mg, usual dosages are 80 mg in adults
Nonpharmacological interventions
t-DCS	Insufficient evidence, investigational	NA
Cognitive rehabilitation	Insufficient evidence, investigational	NA

NMDA – N-methyl-D-aspartate; MAO-B – Monoamine oxidase B; t-DCS – Transcranial direct-current stimulation; NA – Not available; FDA – Food and Drug Administration; PDD – PD dementia; BD – Bis in die i.e. Two times a day; PO – Per os or by mouth

Currently, evidence-based treatment strategies for milder cognitive impairments are not available. The efficacy of existing medications in halting or slowing rates of cognitive impairments is also not established. The medications that should preferably be avoided in PDD are mentioned in Table 13.

Table 13

Medications preferably avoided in Parkinson’s disease dementia

Type of medications	Potential complications
Dopamine antagonist (D2 receptor)	It can cause drug-induced parkinsonism, may exacerbate executive dysfunction and inattention, somnolence, postural hypotension
Both typical (haloperidol, trifluoperazine, etc.) and atypical antipsychotics with high affinity for D2 receptors (risperidone, olanzapine, etc.)	May cause neuroleptic malignant syndrome, risk of increased mortality in dementia patients
Anticholinergic medications	Increases risk of cognitive dysfunctions
Both central anticholinergic medications (benztropine and trihexyphenidyl)

Apathy

There are no proven medicines for apathy. However, due to its pathophysiological association with dopamine deficiency, the effectiveness of few dopaminergic agents has been suggested. Pramipexole, a DA, is reported to cause improvement in the symptoms of decreased willingness in apathy. Amantadine hydrochloride enhances dopamine secretion and stimulates a catecholamine action, hence can be useful in apathy.[10]

A cholinesterase inhibitor (rivastigmine) also has positive randomized controlled trial results, suggesting its possible use to treat PD apathy.[44] In addition to these agents, stimulant-like (methylphenidate) and stimulant (amphetamines) medications are used clinically, and the structurally antidepressant to these stimulants, bupropion, can also be used in the treatment of PD apathy.[23]

Sleep disorders

Common points in the management of sleep disorders in PD are as follows:

Establishing the cause that involves reviewing the patient’s medications, sleep hygiene, and comorbid conditions

The patient should be advised to maintain a sleep log, including various problems encountered during sleep

A detailed general medical and neurological history and examination should be carried out.

The treat approach for different sleep disorders in PD is different as mentioned below.

Insomnia in Parkinson’s disease

The initial step is to treat the motor symptoms optimally, which are considered a major cause of physical discomfort during nocturnal sleep.[46] For this, low doses of dopamine receptor agonists in the evenings can be considered, and the judicious use of slow-release preparations is also useful.

Before starting pharmacological therapy for insomnia, relaxation techniques, sleep hygiene, and CBT should be considered.

Pharmacotherapy-earlier used benzodiazepines have almost been replaced by zopiclone and eszopiclone for the management of insomnia. The effective dose in the elderly is considered to be 3.75 mg, which can be increased up to 5 or 7.5 mg may be needed.[47] Doxepin has also been proven in patients of PD with insomnia.[48] Melatonin can be considered in patients who have not shown benefits from the newer hypnotics and doxepin.[49]

Excessive daytime sleepiness

Identifying and managing comorbidities (underlying depression, disrupted night-time sleep fatigue, and obstructive sleep apnea [OSA]) is the mainstay of managing EDS in patients with PD.

Another useful step in patients with EDS is D2-receptor agonist titration to the lowest possible dose or complete discontinuation of these agents.

Pharmacotherapy – modafinil, caffeine, and atomoxetine – can be considered an effective treatment in EDS, but the result regarding their use is conflicting.[50]

Rapid eye movement sleep behavior disorder in patients with Parkinson’s disease

In patients diagnosed with RBD, SSRIs, SNRIs, TCAs such as clomipramine, and beta-blockers such as bisoprolol should be discontinued as they can cause RBD secondary to their use.

Pharmacological treatment options include melatonin and clonazepam. Melatonin is a good first option (The usual dose ranges from 3 to 12 mg/night).[51]

Restless legs syndrome

Restless legs syndrome (RLS) can be secondary to various disorders such as iron deficiency anemia, peripheral neuropathy, myelopathy, diabetes, and uremia because of renal insufficiency. The initial step in the management of RLS is identification and evaluation of these secondary causes.

The a2 d ligands (gabapentin and pregabalin) are considered as the main stay of treatment for RLS.[51] The other option is dopaminergic medications, e.g., pramipexole, rotigotine, ropinirole, and levodopa. However, due to their side effects (pedal edema, impulsive behavior disorders, EDS, and the morning rebound phenomenon), these are less preferred nowadays.[52] The studies give mixed results for botulinum neurotoxin in RLS treatment.

Obstructive sleep apnea in patients with Parkinson’s disease

Patients with RBD have increased risk of OSA; thus, RBD should be ruled out. In the case of obese patients, weight reduction is highly advised. In severe cases of OSA, the mainstay of therapy remains the continuous positive airway pressure (CPAP), and this leads to significant improvement in quality of sleep. In the patients not compliant to CPAP therapy, sustained release formulations of levodopa before sleep can be considered an option though any specific guidelines for the dose titration are not available.[13]

Impulse control disorders

The primary approach for ICD is prevention and psychoeducation of patients and family members regarding the potential risks of different dopaminergic medications. Before starting dopaminergic medications, one should assess the cost–benefit of predisposing risk factors [Table 5] and the prescribed drugs. Apart from genetic factors, the treatment decision must consider clinical findings, such as younger age, early onset of PD, longer duration of illness (PD), history of mood disorders (depression), addictive behaviors, short-acting DA drugs, DBS, and certain cultural factors. It is also important to inform patient/family members about the dopaminergic treatment and its impact on their care giving and life. The NICE guideline suggests taking informed consent before starting DA medications.[53]

ICDs symptoms can make the treatment challenging, and it must be tailor-made according to the patient’s clinical factors, such as the severity of motor symptoms, comorbidities, and quality of life.[3354] The first step for the treatment of ICDs is either discontinuation of or reduction of DAs. However, it should be kept in mind that neuropsychiatric symptoms may continue for at least 12 weeks after drug discontinuation. However, certain cases can develop DA withdrawal syndrome, and motor symptoms can worsen if DA is reduced or withdrawn. Hence, carefully planning and individualizing the management plan is needed on a case-to-case basis.[3355] There is controversial evidence regarding use of SSRIs, atypical antipsychotics, and opioid antagonists in cases of ICDs.

Several drugs reported to be potentially efficacious in increasing GABAergic inhibition (valproate, topiramate) and new drugs used to preserve the ventral striatal DA system (zonisamide, donepezil) can be useful in the treatment of ICDs.[53]

As previously mentioned, data concerning DBS and ICD treatment are still controversial. DBS may lead to a reduction in dopaminergic requirements, hence may be efficacious. Studies suggest that STN stimulation which caused increasing reward-driven behaviors by inhibitory effect in the indirect dopaminergic pathway could decrease the risk for ICDs. However, few patients may develop transient de novo ICDs after STN DBS, and some others may develop ICDs a long time after DBS.[3353]

Nonpharmacological approaches can be effective, including CBT and patient and caregiver education.[53] Table 14 gives a brief overview of the management approach for ICDs-RD in PD.

Table 14

Management approach for impulse control disorder-related disorder in Parkinson’s disease

Address modifiable risk factors (Table)	Lower dopaminergic drugs Switch DA drugs
Manage comorbidities	E.g., SSRIs for depressive and anxiety symptoms
Nonpharmacological approach	CBT
	Patient and caregiver education
Pharmacological management (limited evidence)	Valproate, topiramate
	Clozapine, quetiapine
	Naltrexone, nalmefene
	Zonisamide, donepezil, noradrenaline reuptake inhibitor
	SSRIs

DA – Dopamine agonist; SSRIs – Selective serotonin reuptake inhibitors; CBT – Cognitive behavioral therapy

CONCLUSION

Patients with PD commonly have comorbid psychiatric disorders. Comorbid psychiatric conditions have several consequences for the patients and their caregivers, including increased distress, higher disability, poorer quality of life, and increased mortality risk. Early identification and prompt treatment of associated psychiatric conditions can help reduce several negative consequences, as mentioned earlier. Hence, it is imperative to improve the knowledge and skills of the clinicians treating such patients. Several comorbidities are under-researched, and future research needs to focus on the best strategies to manage them.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest