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Practice Changing Continuing Education

Neurology Clinics

Neuropsychiatric Aspects of Parkinson’s Disease

Parampreet Singh Kharbanda, Shivangi Sharma1, Sahil Mehta
Department of Neurology, Postgraduate Institute of Medical Education and Research, 1Department of Psychiatry, Government Medical College and Hospital,
Chandigarh, India

Abstract
Neuropsychiatric complications are an under recognized and undertreated aspect of Parkinson’s disease  (PD). A  gamut of psychiatric
disturbances can occur in PD and include depression, anxiety, psychosis, dementia, impulse control disorders, apathy, and sleep disturbances.
They substantially affect the lives of the patients and their caregivers and have negative impact on the quality of life. Optimal assessment and
treatment is the key to manage these patients.

Key words: Dementia, depression, Parkinson’s, psychiatric, psychosis

Introduction
Parkinson’s disease (PD) was first described as “shaking palsy”
by British Physician James Parkinson in 1817.[1] It is widely
accepted that PD is a multisystem disorder characterized
by degeneration of not only nigrostriatal dopaminergic
system, but also serotonergic and noradrenergic brainstem
areas and cholinergic frontal regions. The clinical features
include both the motor as well as nonmotor symptoms.
Motor symptoms include tremor, bradykinesia, rigidity, and
postural instability.[2] Various nonmotor features range from
cognitive and behavioral symptoms, autonomic dysfunction,
and sleep disturbances. [3] Because of the predominant
psychiatric comorbidities associated with PD, it is essentially
a neuropsychiatric disorder. [4] Presence of psychiatric
disturbances in patients with PD have negative effects on
the quality of life leading to excess disability, poor cognitive
and motor outcomes, increased risk of hospitalization, and
increased distress to the caregivers.[5] Psychiatric complications
are an under recognized and undertreated aspect of PD.
Classification
Neuropsychiatric complications in PD can be divided into
two types:
• Disease‑related
• Treatment‑related.
These are elaborated in Table 1.
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Depression
Depression is one of the most common psychiatric disturbances
in PD. Prevalence of depression in patients with PD is
approximately 20–40%.[6] Other psychiatric disorders such
as anxiety, psychosis, apathy, and insomnia are frequently
comorbid with PD. Presence of depression in PD is predictive
of rapid progression of motor and cognitive impairment and
portends a poor prognosis. It can also be a premotor feature of
PD presenting years before the onset of motor symptoms.[7‑9]
It has been found that female sex, patients with right‑sided
motor symptoms, or with more severe cognitive impairment
and akinetic rigid subtype compared to tremor predominant
variant have more chances of developing depression.[6,10]
Clinical features of depression may mimic those of PD.
Hypomimia, motor slowness, sleep disturbances, and fatigue
can occur even in nondepressed Parkinson’s patients. The
clinical profile of depression in patients with PD varies slightly
from patients with idiopathic depression. Parkinsonian patients
have higher rates of anxiety, dysphoria, irritability, pessimism,
suicidal ideation without suicidal behavior, and less rates of self
Address for correspondence: Dr. Sahil Mehta,
Department of Neurology, Postgraduate Institute of Medical Education and
Research, Chandigarh, India.
E‑Mail: mehtasahilpgi@gmail.com
This is an open access article distributed under the terms of the Creative Commons
Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows others to remix,
tweak, and build upon the work non‑commercially, as long as the author is credited and
the new creations are licensed under the identical terms.
For reprints contact: reprints@medknow.com

DOI:
10.4103/2349-0977.168248 How to cite this article: Kharbanda PS, Sharma S, Mehta S. Neuropsychiatric
aspects of Parkinson’s disease. Astrocyte 2015;2:25-30.

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Kharbanda, et al.: Neuropsychiatric Aspects

guilt and reproach.[11] The severity ranges from mild dysthymia Electroconvulsive therapy can also be used in severe and
to major depression. Major depression accounts for about 50% refractory depression. It temporarily improves parkinsonism
of the patients. Features of depression may fluctuate with the for a few days to weeks.[19‑21] Efficacy is similar to depressed
motor fluctuations and be present only in the off phase.[10,12] nonPD patients and is based on case reports only.
As the disease advances, the risk of developing depression
Various antidepressants used for depression are summarized
also increases.
in Table 2 with their doses and side effects.
The occurrence of depression in patients with PD is not simply
an emotional reaction to illness but has a biological basis. Parkinson’s Disease Dementia
Dysfunction of the striatothalamic frontal and basotemporal
Prevalence of dementia in patients with PD is around 30%
limbic circuits has been implicated in the pathophysiology of
with this number increasing to 80% in patients with course
depression. In addition to the deficiency of dopamine, serotonin
of more than 10 years.[22] Presence of cognitive dysfunction
and nor epinephrine also play a role in various neuropsychiatric
and dementia is associated with increased mortality, increased
manifestations including depression. [13] Disruption of
chances of hospitalization, and worse quality of life. There
dopaminergic efferents from ventral tegmental area to the
is a “12  month rule” to differentiate PD dementia  (PDD)
orbitofrontal or prefrontal cortex along with disruption of
from dementia with Lewy bodies. Presence of parkinsonism
efferents from orbitofrontal cortex to the serotonergic neurons
at least 1 year prior to the onset of dementia favors PDD.[23]
in the dorsal raphe nucleus are thought to be responsible for
Patients with certain characteristics are more prone to develop
depression in PD.
dementia. These include older age at PD onset, nontremor
Tr e a t m e n t i n v o l v e s b o t h p h a r m a c o l o g i c a l a n d predominant phenotype, longer disease duration, male sex,
nonpharmacological therapies. Psychotherapy should be presence of psychosis, greater severity of motor symptoms,
offered initially, especially in patients with less severe and presence of postural instability or gait impairment.[24‑26]
symptoms. There are no systematic clinical trials of the
Dementia in PD is classically described as sub cortical with
treatment of depression in patients with PD. However, open
dysexecutive syndrome and absence of aphasia, apraxia,
label studies have shown efficacy of both selective serotonin
and agnosia. Clinically, patients can have mild cognitive
reuptake inhibitors  (SSRIs) and tricyclic antidepressants,
impairment or frank dementia. Neuropsychological testing
despite a theoretical risk of worsening of parkinsonian
reveals impaired attention, executive and visuospatial
symptoms with SSRIs.[14‑16] Adverse effects of SSRIs include
dysfunction, and problems in retrieval. Tests of semantic
nausea, headache, tremor, sweating, and sexual dysfunction.
and phonemic fluency are impaired with inability to copy
Use of tricyclic antidepressants can lead to worsening of
intersecting pentagons.[24‑26] Patients with PDD improve on
orthostatic hypotension, constipation, urinary retention, and
recall with external cues. Cognitive impairment in PD is
cognitive problems. Dopamine agonists and selegiline have
frequently accompanied with other behavioral symptoms
also been shown to confer antidepressant properties.[17] There
such as psychosis, depression, apathy, and sleep disturbances.
is also a risk of development of serotonin syndrome with the
simultaneous use of Selegiline and SSRIs, though it is rarely Table  3 shows the differences between Alzheimer’s
encountered in the clinical practice.[18] dementia (AD) and PDD.
Degeneration of dopaminergic neurons leading to dopaminergic
Table 1: Neuropsychiatric Disturbances in PD deficiency is mainly implicated in the pathogenesis of
dementia in PD. Disruption of striatofrontal connections is
Disease‑related Treatment‑related
responsible for the predominant executive dysfunction. Other
Depression Psychosis
neurotransmitter systems such as cholinergic deficiency due
Anxiety ICD
Apathy Dopamine dysregulation syndrome
to degeneration of nucleus basalis of Meynert and loss of nor
Dementia Excessive daytime somnolence
adrenergic and serotonergic neurons are also implicated in
Sleep disorders Effect of DBS the pathogenesis of PDD. Both alpha synuclein and AD‑like
PD: Parkinson’s disease, ICD: Impulse control disorders, DBS: Deep brain pathology play an important role in PDD. Neuropathological
stimulation specimens show the presence of cortical Lewy bodies along

Table 2: Antidepressants and Their Doses and Side Effects

Drugs Dose (mg) Sedation Hypotension Sexual dysfunction Weight gain
Fluoxetine 10–80 Negative Negative Considerable Mild
Sertraline 25–100 Negative Negative Moderate Mild
Citalopram 10–60 Mild Negative Moderate Mild
Escitalopram 10–20 Mild Negative Moderate Mild
Amitryptyline 25–200 Considerable Moderate Mild Considerable
Nortryptyline 50–150 Mild Mild Negative Mild

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Kharbanda, et al.: Neuropsychiatric Aspects

Table 3: Differences Between Alzheimer’s Disease and PDD Psychosis

Characteristics Alzheimer’s disease PDD Psychosis occurs in 10% of untreated and 15–40% of treated
Common Memory impairment Motor (tremor, bradykinesia,
PD patients.[34] It usually occurs in the late stages of PD and
presentation and gait impairment) is characterized by visual hallucinations, delusions, illusions,
Psychotic Later in disease Hallucinations common and “sense of presence” hallucinations. Various risk factors that
symptoms process; hallucinations with anticholinergic and contribute to the development of psychosis include exposure
rare dopaminergic drugs to PD medications, old age, greater cognitive impairment,
Memory Earlier, global, Difficulty accessing
increasing severity and duration of PD, depression, anxiety,
decline progressive, difficulty memories
in forming memories sleep disorders, visual impairment, and polypharmacy. [34]
Speech Aphasia and paraphasia Hypophonic dysarthria Presence of psychosis is predictive of increased chances of
Gait Late after the onset of Often before the onset of hospitalization, mortality, and distress to the caregivers.
dementia dementia
Pathophysiology involves complex interaction of medication
Response to Absent Common
levodopa exposure, PD neuropathology, and other risk factors (cognitive
PDD: Parkinson’s disease dementia impairment and visual disturbances). Excessive stimulation
or hypersensitivity of mesocorticolimbic D2 D3 receptors,
with senile plaques and neurofibrillary tangles with profound cholinergic deficiency, and serotonergic and dopaminergic
loss of subcortical cholinergic neurons.[26] imbalance underlies the mechanism of development of
psychosis in patients with PD.[35]
Randomized controlled trials have shown benefits of
cholinesterase inhibitors such as donepezil and rivastigmine in Most common presentation is visual hallucinations occurring
the treatment of cognitive dysfunction. Rivastigmine has been in around 50–60% cases. Visual hallucinations are complex,
approved by the Food and Drug Administration for mild to formed, and moving. Patients often see people or animals
moderate dementia associated with PD. Memantine (N‑methyl and occur with eyes open. Hallucinations in other modalities
D‑aspartate antagonist) can also be used. Antipsychotics can such as auditory, tactile, and olfactory are rare. In the initial
be used in patients with coexisting psychosis.[27] Atypical stages when hallucinations are mild and insight is present, it is
antipsychotics clozapine and quetiapine are the most termed as benign hallucinosis. Complex formed hallucinations
effective drugs for treating psychosis in patients with PD usually occur in the context of severe cognitive impairment
without worsening of motor symptoms. Both olanzapine and with lack of insight. Delusions also occur in conjunction with
risperidone are associated with worsening of motor function. hallucinations. The most common delusions are delusions of
They are also associated with two- or three-fold increase in infidelity or delusions of phantom boarders.[34]
risk of stroke in patients with dementia. First and foremost part in the treatment of psychosis is to rule
out reversible causes of delirium. Discontinue antiparkinsonian
Anxiety drugs in the order of least efficacy: Anticholinergics, selegiline,
Prevalence of anxiety in patients with PD is around 40%.[28] amantadine, dopa‑agonist, catechol‑O‑methyltransferase
Patients can present with generalized anxiety disorder, panic inhibitors, and finally levodopa. If the psychosis still
attacks, social phobia, and anxiety disorder, not otherwise persists, then atypical antipsychotics can be used. Atypical
specified. [29] It frequently coexists with depression. [30] antipsychotics with least propensity to induce parkinsonism
Features of anxiety can occur with the onset of off periods are clozapine and quetiapine. Clozapine can be used in the
though it is not a universal phenomenon. It can also be a dose of 25–50 mg/day. Regular monitoring of blood counts
behavioral side effect of dopaminergic therapy. It is also is mandatory as it can cause agranulocytosis.[36] Quetiapine
one of the premotor feature of PD suggesting that it is not has also been found safe in clinical practice as far as risk
a psychological reaction but linked to neurochemical and of parkinsonism is concerned.[37] Cholinesterase inhibitors,
neuropathological substrates occurring in PD. Symptoms especially rivastigmine has also been found to improve
of anxiety can antedate even 20 years prior to the onset of cognition and psychosis in patients with coexistent dementia.[38]
motor features of PD.[31,32]
Nor adrenergic dysfunction plays a role in the pathophysiology Impulse Control Disorders
of anxiety in PD.[33] Other neurotransmitters such as serotonin Impulse control disorders (ICD) are defined as failure to resist
or dopamine may be involved in the pathogenesis of anxiety. an impulse, drive, or temptation to perform an act that is
There are no randomized controlled trials for the treatment of harmful to the individual or to others.[39] Prevalence of ICD is
anxiety in PD. If anxiety symptoms are part of off periods, around 15%. They can be of various types namely pathological
adjustment of PD medications can alleviate the symptoms. gambling, compulsive sexual behavior, compulsive buying,
Newer antidepressants are effective in the management. binge eating, dopamine dysregulation disorders, punding, and
Benzodiazepines should be used with caution as they can aimless wandering.[40,41] These addictive behaviors can lead
increase the propensity to falls in patients with PD. to devastating consequences such as financial loss, divorce,

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Kharbanda, et al.: Neuropsychiatric Aspects

loss of employment, and other health risks. Pathological
gambling is defined as maladaptive gambling behavior despite
deleterious consequences on familial, occupational, and
social functioning. Punding consists of an intense fascination
with repetitive handling, examining, sorting, and arranging
of objects. Dopamine dysregulation syndrome is defined
as compulsive use of high doses of dopaminergic drugs,
particularly levodopa, associated with severe behavioral
symptoms with impaired social functioning. It was previously
referred as hedonic homeostatic dysregulation. Hoarding is
defined as acquisition of and failure to discard a large number
of items with little or no objective value, which in some cases
can lead to unsafe or unsanitary living conditions.
Risk factors involve dopamine receptor agonist treatment,
previous history of ICD behaviors, personal or family history of
substance abuse, male sex, and younger age early onset PD.[40]
Eight percentage cases treated with dopamine agonists can
develop ICD percent.[41] They are seen at both higher and low
doses (used for restless leg syndrome[42]) of dopamine agonists.
On the contrary, only 1–4% of cases treated with levodopa
develop ICD and that too at higher doses  (>1000  mg/day).
Amantadine use has also been associated with ICD in PD.[43]
Pathophysiology involves supersensitivity of D3 receptors.[44]
Initial reports in the literature were due to pramipexole only
but subsequent reports suggest class effect.
Treatment involves lowering or stopping the drug. It is
usually reversible when dopamine agonists are the culprit
as levodopa is difficult to stop because of the requirement
for motor control.[45] There are no prospective randomized
trials of pharmacological treatment of ICD in PD. However,
antidepressants such as citalopram, sertraline, and atypical
antipsychotics such as clozapine and quetiapine have been
shown to be of benefit in various case reports. Deep brain
stimulation has also been considered in some cases of ICD with
PD associated with higher dosages of dopamine replacement
therapy. Improvement is related to decrease in the dose of
dopaminergic medications postoperatively.
improve sleep disturbances due to PD symptoms and can
relieve early morning dystonia.
20–50% of PD patients have sleep apnea despite normal body
mass index. Upper airway muscle dysfunction may play a role
in the development of obstructive sleep apnea. Nocturnal stridor
more commonly occurs in patients with multiple system atrophy.
Periodic leg movements of sleep are myoclonic jerks, which
occur in nonrapid eye movement  (REM) sleep. These are
associated with restless leg syndrome, which is characterized
by unpleasant or painful sensations mainly affecting legs but
can affect arms also. These unpleasant sensations are relieved
by voluntary movement.[49] Symptoms follow a circadian
pattern with onset in the evening hours when patients lie in bed
to sleep. Dopaminergic therapy shows excellent response.[50]
REM sleep behavior disorder  (RBD) involves vigorous
physical activity while sleeping and patient can cause injury
to self or others. It represents enactment of dreams and
predates the motor manifestation of PD.[51,52] Pathophysiology
involves degeneration of cholinergic pedunculopontine
nucleus and reduced striatal dopaminergic activity. No
randomized controlled trials exist for the treatment of RBD.
No pharmacological intervention is necessary if symptoms
are mild and intermittent. Clonazepam is the drug of choice
and is effective in the doses of even 0.25  mg.[53] Serotonin
antidepressants may increase risk of RBD and should be
avoided in susceptible individuals.
PD patients can suffer from drowsiness or fatigue during the
day time. It may be intrinsic to disease or a peak effect of
dopaminergic treatment. These features can be contributed
by depression also. Excessive day time somnolence is more
Table 4: Sleep Disturbances in PD
Category Specific disorders
Disorders of sleep initiation Insomnia
and maintenance Sleep fragmentation (frequent
night‑time awakenings)

Sleep Disorders Early arousal

PLMS
Sleep disorders are one of the most common nonmotor Restless leg syndrome
symptoms in PD. Prevalence ranges from 40–90%. Various Obstructive sleep apnea
sleep disorders that can occur in PD are enumerated in Parasomnias REM sleep behavior disorder
Table 4. Nocturnal vocalizations
Somnambulism
Disorders of sleep initiation and maintenance involve
Nightmares
difficulty in falling asleep, poor sleep quality, frequent
Night terrors
wakening, and early arousal. [46] Most common sleep
Excessive daytime sleepiness Medication effect
complaint of PD patient is frequent nocturnal awakening
Sudden‑onset sleep
or sleep fragmentation. Sleep disruption can occur
DBS surgery effect
due to immobility, dyskinesias, cramps, micturition, Contributory cognitive‑ Depression
pain, excessive sweating, and coexistent sleep apnea or behavioral dysfunction Anxiety
periodic limb movements of sleep.[47] Sleep fragmentation Visual hallucinations
due to recurrence of PD symptoms is more common in Dementia
Stages 1 and 2 of sleep. Treatment involves adjustment of PLMS: Periodic limb movements of sleep, REM: Rapid eye movement,
PD medication.[48] Levodopa preparation at night time can DBS: Deep brain stimulation

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Kharbanda, et al.: Neuropsychiatric Aspects
common with dopamine agonists and in patients who are
on combination therapy of dopamine agonist and levodopa.
Sudden onset of sleep or “sleep attacks” has been described
in patients on dopamine agonists. These can occur with little
or no warning and has implications for driving.[54,55] Modafinil
can be used for excessive day time somnolence.[56]
Apathy
Apathy is defined as decrease in goal directed behavior,
thinking, and mood. Prevalence in PD is around 40%.[57,58] It is
usually reported by caregivers and has to be differentiated from
depression and dementia. Apathy in PD is multidimensional
and is caused by dysfunction in the various neural circuits
that connect the prefrontal cortex with the limbic system.
Pathophysiology involves dopaminergic, cholinergic, and
noradrenergic dysfunction. Apathy in PD is classified as
emotional affective apathy, cognitive apathy, and auto‑activation
apathy.[58] Apathy has also been reported after sub thalamic
stimulation in PD. Various studies have shown improvement
of apathy with various drugs namely rivastigmine, piribedil,
methylphenidate, and some antidepressants.[58]
Impact of Deep Brain Stimulation
Impact of deep brain stimulation on nonmotor symptoms is
complex and varied. Patients can develop confusion, psychosis,
and agitation in the acute postoperative period. Worsening in
executive functions and verbal learning has been seen as the
long‑term side effect of deep brain stimulation in PD. Reports
of onset or worsening of depression, anxiety, psychosis, mania,
and emotional lability occurring after deep brain stimulation
are enormous in the literature.[59,60]
Generally, neuropsychological decline occurs in patients
with pre‑existing neuropsychological defects. There are
reports of suicidal ideation and suicidal attempt after deep
brain stimulation  (DBS). Management involves adjustment
of DBS parameters or PD drugs or psychotherapy and
pharmacotherapy.
Conclusions
A wide range of neuropsychiatric complications can occur in
PD. They substantially affect the lives of PD patients and their
caregivers. Pathophysiology involves the interplay between the
disease pathology and its treatment. Optimal assessment and
treatment is the key in managing these patients.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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Astrocyte  ¦  Apr-Jun 2015  ¦  Volume 2  ¦  Issue 1