|PRACTICE CHANGING CONTINUING EDUCATION: NEUROLOGY CLINICS
|Year : 2015 | Volume
| Issue : 1 | Page : 25-30
Neuropsychiatric aspects of Parkinson's disease
Parampreet Singh Kharbanda1, Shivangi Sharma2, Sahil Mehta1
1 Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Psychiatry, Government Medical College and Hospital, Chandigarh, India
|Date of Web Publication||26-Oct-2015|
Dr. Sahil Mehta
Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
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.
Keywords: Dementia, depression, Parkinson's, psychiatric, psychosis
|How to cite this article:|
Kharbanda PS, Sharma S, Mehta S. Neuropsychiatric aspects of Parkinson's disease. Astrocyte 2015;2:25-30
| Introduction|| |
Parkinson's disease (PD) was first described as "shaking palsy" by British Physician James Parkinson in 1817. 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. Various nonmotor features range from cognitive and behavioral symptoms, autonomic dysfunction, and sleep disturbances. Because of the predominant psychiatric comorbidities associated with PD, it is essentially a neuropsychiatric disorder. 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. Psychiatric complications are an under recognized and undertreated aspect of PD.
| Classification|| |
Neuropsychiatric complications in PD can be divided into two types:
These are elaborated in [Table 1].
| Depression|| |
Depression is one of the most common psychiatric disturbances in PD. Prevalence of depression in patients with PD is approximately 20–40%. 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.,,
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.,
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 guilt and reproach. The severity ranges from mild dysthymia to major depression. Major depression accounts for about 50% of the patients. Features of depression may fluctuate with the motor fluctuations and be present only in the off phase., As the disease advances, the risk of developing depression also increases.
The occurrence of depression in patients with PD is not simply an emotional reaction to illness but has a biological basis. Dysfunction of the striatothalamic frontal and basotemporal limbic circuits has been implicated in the pathophysiology of depression. In addition to the deficiency of dopamine, serotonin and nor epinephrine also play a role in various neuropsychiatric manifestations including depression. Disruption of dopaminergic efferents from ventral tegmental area to the orbitofrontal or prefrontal cortex along with disruption of efferents from orbitofrontal cortex to the serotonergic neurons in the dorsal raphe nucleus are thought to be responsible for depression in PD.
Treatment involves both pharmacological and nonpharmacological therapies. Psychotherapy should be offered initially, especially in patients with less severe symptoms. There are no systematic clinical trials of the treatment of depression in patients with PD. However, open label studies have shown efficacy of both selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, despite a theoretical risk of worsening of parkinsonian symptoms with SSRIs.,, Adverse effects of SSRIs include nausea, headache, tremor, sweating, and sexual dysfunction. Use of tricyclic antidepressants can lead to worsening of orthostatic hypotension, constipation, urinary retention, and cognitive problems. Dopamine agonists and selegiline have also been shown to confer antidepressant properties. There is also a risk of development of serotonin syndrome with the simultaneous use of Selegiline and SSRIs, though it is rarely encountered in the clinical practice.
Electroconvulsive therapy can also be used in severe and refractory depression. It temporarily improves Parkinsonism More Details for a few days to weeks.,, Efficacy is similar to depressed nonPD patients and is based on case reports only.
Various antidepressants used for depression are summarized in [Table 2] with their doses and side effects.
| Parkinson's Disease Dementia|| |
Prevalence of dementia in patients with PD is around 30% with this number increasing to 80% in patients with course of more than 10 years. Presence of cognitive dysfunction and dementia is associated with increased mortality, increased chances of hospitalization, and worse quality of life. There is a "12 month rule" to differentiate PD dementia (PDD) from dementia with Lewy bodies. Presence of parkinsonism at least 1 year prior to the onset of dementia favors PDD. Patients with certain characteristics are more prone to develop dementia. These include older age at PD onset, nontremor predominant phenotype, longer disease duration, male sex, presence of psychosis, greater severity of motor symptoms, and presence of postural instability or gait impairment.,,
Dementia in PD is classically described as sub cortical with dysexecutive syndrome and absence of aphasia, apraxia, and agnosia. Clinically, patients can have mild cognitive impairment or frank dementia. Neuropsychological testing reveals impaired attention, executive and visuospatial dysfunction, and problems in retrieval. Tests of semantic and phonemic fluency are impaired with inability to copy intersecting pentagons.,, Patients with PDD improve on recall with external cues. Cognitive impairment in PD is frequently accompanied with other behavioral symptoms such as psychosis, depression, apathy, and sleep disturbances.
[Table 3] shows the differences between Alzheimer's dementia (AD) and PDD.
Degeneration of dopaminergic neurons leading to dopaminergic deficiency is mainly implicated in the pathogenesis of dementia in PD. Disruption of striatofrontal connections is responsible for the predominant executive dysfunction. Other neurotransmitter systems such as cholinergic deficiency due to degeneration of nucleus basalis of Meynert and loss of nor adrenergic and serotonergic neurons are also implicated in the pathogenesis of PDD. Both alpha synuclein and AD-like pathology play an important role in PDD. Neuropathological specimens show the presence of cortical Lewy bodies along with senile plaques and neurofibrillary tangles with profound loss of subcortical cholinergic neurons.
Randomized controlled trials have shown benefits of cholinesterase inhibitors such as donepezil and rivastigmine in the treatment of cognitive dysfunction. Rivastigmine has been approved by the Food and Drug Administration for mild to moderate dementia associated with PD. Memantine (N-methyl D-aspartate antagonist) can also be used. Antipsychotics can be used in patients with coexisting psychosis. Atypical antipsychotics clozapine and quetiapine are the most effective drugs for treating psychosis in patients with PD without worsening of motor symptoms. Both olanzapine and risperidone are associated with worsening of motor function. They are also associated with two- or three-fold increase in risk of stroke in patients with dementia.
| Anxiety|| |
Prevalence of anxiety in patients with PD is around 40%. Patients can present with generalized anxiety disorder, panic attacks, social phobia, and anxiety disorder, not otherwise specified. It frequently coexists with depression. Features of anxiety can occur with the onset of off periods though it is not a universal phenomenon. It can also be a behavioral side effect of dopaminergic therapy. It is also one of the premotor feature of PD suggesting that it is not a psychological reaction but linked to neurochemical and neuropathological substrates occurring in PD. Symptoms of anxiety can antedate even 20 years prior to the onset of motor features of PD.,
Nor adrenergic dysfunction plays a role in the pathophysiology of anxiety in PD. Other neurotransmitters such as serotonin or dopamine may be involved in the pathogenesis of anxiety. There are no randomized controlled trials for the treatment of anxiety in PD. If anxiety symptoms are part of off periods, adjustment of PD medications can alleviate the symptoms. Newer antidepressants are effective in the management. Benzodiazepines should be used with caution as they can increase the propensity to falls in patients with PD.
| Psychosis|| |
Psychosis occurs in 10% of untreated and 15–40% of treated PD patients. It usually occurs in the late stages of PD and is characterized by visual hallucinations, delusions, illusions, and "sense of presence" hallucinations. Various risk factors that contribute to the development of psychosis include exposure to PD medications, old age, greater cognitive impairment, increasing severity and duration of PD, depression, anxiety, sleep disorders, visual impairment, and polypharmacy. Presence of psychosis is predictive of increased chances of hospitalization, mortality, and distress to the caregivers.
Pathophysiology involves complex interaction of medication exposure, PD neuropathology, and other risk factors (cognitive impairment and visual disturbances). Excessive stimulation or hypersensitivity of mesocorticolimbic D2 D3 receptors, cholinergic deficiency, and serotonergic and dopaminergic imbalance underlies the mechanism of development of psychosis in patients with PD.
Most common presentation is visual hallucinations occurring in around 50–60% cases. Visual hallucinations are complex, formed, and moving. Patients often see people or animals and occur with eyes open. Hallucinations in other modalities such as auditory, tactile, and olfactory are rare. In the initial stages when hallucinations are mild and insight is present, it is termed as benign hallucinosis. Complex formed hallucinations usually occur in the context of severe cognitive impairment with lack of insight. Delusions also occur in conjunction with hallucinations. The most common delusions are delusions of infidelity or delusions of phantom boarders.
First and foremost part in the treatment of psychosis is to rule out reversible causes of delirium. Discontinue antiparkinsonian drugs in the order of least efficacy: Anticholinergics, selegiline, amantadine, dopa-agonist, catechol-O-methyltransferase inhibitors, and finally levodopa. If the psychosis still persists, then atypical antipsychotics can be used. Atypical antipsychotics with least propensity to induce parkinsonism are clozapine and quetiapine. Clozapine can be used in the dose of 25–50 mg/day. Regular monitoring of blood counts is mandatory as it can cause agranulocytosis. Quetiapine has also been found safe in clinical practice as far as risk of parkinsonism is concerned. Cholinesterase inhibitors, especially rivastigmine has also been found to improve cognition and psychosis in patients with coexistent dementia.
| Impulse Control Disorders|| |
Impulse control disorders (ICD) are defined as failure to resist an impulse, drive, or temptation to perform an act that is harmful to the individual or to others. Prevalence of ICD is around 15%. They can be of various types namely pathological gambling, compulsive sexual behavior, compulsive buying, binge eating, dopamine dysregulation disorders, punding, and aimless wandering., These addictive behaviors can lead to devastating consequences such as financial loss, divorce, 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. Eight percentage cases treated with dopamine agonists can develop ICD percent. They are seen at both higher and low doses (used for restless leg syndrome ) 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. Pathophysiology involves supersensitivity of D3 receptors. 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. 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.
| Sleep Disorders|| |
Sleep disorders are one of the most common nonmotor symptoms in PD. Prevalence ranges from 40–90%. Various sleep disorders that can occur in PD are enumerated in [Table 4].
Disorders of sleep initiation and maintenance involve difficulty in falling asleep, poor sleep quality, frequent wakening, and early arousal. Most common sleep complaint of PD patient is frequent nocturnal awakening or sleep fragmentation. Sleep disruption can occur due to immobility, dyskinesias, cramps, micturition, pain, excessive sweating, and coexistent sleep apnea or periodic limb movements of sleep. Sleep fragmentation due to recurrence of PD symptoms is more common in Stages 1 and 2 of sleep. Treatment involves adjustment of PD medication. Levodopa preparation at night time can 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. Symptoms follow a circadian pattern with onset in the evening hours when patients lie in bed to sleep. Dopaminergic therapy shows excellent response.
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., 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. 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 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., Modafinil can be used for excessive day time somnolence.
| Apathy|| |
Apathy is defined as decrease in goal directed behavior, thinking, and mood. Prevalence in PD is around 40%., 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. 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.
| 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.,
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.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]