Parkinson Disease: Phenomenology and Treatment of the Most Common Psychiatric Symptoms
By Leora L. Borek, MD |
March 1, 2008
Dr Borek is director of the Neurohealth Alzheimer's Disease and Memory Disorders Center, and is staff psychiatrist at Butler Hospital, Warren Alpert Medical School of Brown University, in Providence, RI. She reports that she has no conflicts of interest concerning the subject matter of this article.
Patients with dementia often lack insight into their psychosis and, as a result, may become agitated, in which case treatment is required. Delusions occur in 5% to 10% of patients who have PD,26 and they often develop in the setting of hallucinations. All types of delusions occur with relatively equal frequency.27
Managing psychosis in PD is often complex and challenging, in part because antipsychotic medication can adversely affect motor function while dopamine(Drug information on dopamine)rgic medication used to treat PD can worsen psychosis. Typical antipsychotics often worsen parkinsonism. Among atypical antipsychotics, clozapine(Drug information on clozapine) and quetiapine(Drug information on quetiapine) are the only agents reported to be free of motor adverse effects. Two multicenter, double-blind, placebo-controlled trials found that the most effective antipsychotic dosage of clozapine was only 6.75 mg at bedtime,28,29 a dose lower than that administered in the psychiatric population. The potential adverse effect of agranulocytosis is not dose-related and, thus, requires the same white blood cell count monitoring rules as for higher doses. This limits the use of clozapine, and it is generally not used as a first choice antipsychotic in patients with PD.
Quetiapine is widely used to treat psychosis in PD on the basis of positive open-label findings and its ease of use compared with clozapine. However, 2 recent double-blind, placebo-controlled trials found no significant antipsychotic benefit.30,31
The other atypical antipsychotics have had negative effects on motor function in patients with PD. Risperidone(Drug information on risperidone) has not been adequately tested but has been reported to cause worsening of parkinsonism even at low doses.32 Three double-blind, placebo-controlled trials found that olanzapine(Drug information on olanzapine) caused a significant worsening of motor function and did not improve psychosis.33,34
Data on ziprasidone(Drug information on ziprasidone) are conflicting; the largest of these studies (N = 43) did not reveal worsening of motor skills on ziprasidone,35 but other reports describe significant motor decline in some patients.36,37 Although aripiprazole(Drug information on aripiprazole) is considered to be a partial dopamine agonist, it has been reported to cause motor worsening, even at a dosage of less than 5 mg/d, as well as worsened psychosis.38 The AAN Practice Parameter report recommended that clozapine and quetiapine, but not olanzapine, be considered for treatment of psychosis in PD.10
The cholinesterase inhibitor, rivastigmine(Drug information on rivastigmine), is effective in reducing hallucinations and delusions in PD patients with dementia.39 Because the onset of the antipsychotic effect of cholinesterase inhibitors can take several weeks, neuroleptics may be required initially to control symptoms.
When evaluating a patient with PD who is psychotic, clinicians should rule out delirium and exclude infections, metabolic disturbances, and psychoactive medications as contributing causes for the psychosis. Anticholinergic medication should be eliminated first, followed by amatadine, monoamine oxidase inhibitors, dopamine agonists, catechol-O-methyltransferase inhibitors, and then reduction in l-dopa dosage. If a reduction in medications is not possible because of risk of worsened motor function, low-dosage quetiapine (12.5 to 25 mg at bedtime) should be initiated and titrated upward as tolerated. If this is not effective, then clozapine should be introduced (6.25 or 12.5 mg at bedtime). Cholinesterase inhibitors should be implemented in patients with comorbid dementia.
A recent systematic review found that 24% to 31% of patients with PD had dementia.40 Advanced age, hallucinations, and greater motor disease severity correlated with an increased risk for dementia.41 PD dementia is characterized as a subcortical dementia in which executive function, attention, psychomotor speed, visuospatial skills, and delayed recall are disrupted. In contrast to Alzheimer disease (AD), a cortical dementia, recognition memory and language often remain intact. PD dementia is often difficult to distinguish clinically from dementia with Lewy bodies (DLB), a dementing illness characterized by parkinsonism, visual hallucinations, and fluctuating cognition. Many researchers believe PD dementia and DLB are on the same continuum based on their similar clinical and pathological features.42 However, current criteria dictate that PD dementia should be diagnosed in patients with idiopathic PD in whom dementia develops later, whereas DLB should be diagnosed in patients whose cognitive impairment occurs concurrently or before the onset of parkinsonism.42
Dementia in PD has been associated with acetylcholine depletion43 and pathological changes of AD (amyloid plaques and neurofibrillary tangles).44 More recently, it has been reported that the degree of Lewy body pathology (Lewy bodies and Lewy neurites) correlated better with PD dementia than with AD pathology.45
Because dementia is a significant predictor of nursing home placement,46 it is important for clinicians to identify and treat PD dementia as early as possible. Routine questioning about the patient's ability to be independent in activities of daily living, such as driving and managing finances, can assess for status of cognition. Neuropsychological testing often identifies early cognitive deficits in PD that may not be apparent in a clinical interview. Screening tools for dementia have not yet been validated in the PD population.
Of the cholinesterase inhibitors that are FDA-approved for AD (tacrine, donepezil(Drug information on donepezil), rivastigmine, and galantamine(Drug information on galantamine)), only rivastigmine is approved for PD dementia. The approval was based on a large double-blind, placebo-controlled 24-week trial of PD patients with dementia who demonstrated a significant improvement when given rivastigmine compared with placebo.39 This effect was maintained at week 48 in a treatment extension study.47 Although rivastigmine is the only FDA-approved medication for the treatment of PD dementia, other cholinesterase inhibitors may be effective as well. Two double-blind, placebo-controlled trials found do- nepezil to be beneficial for PD patients with dementia.48,49
Overall, the treatment effects of riv-astigmine and donepezil on cognition in PD are small and probably similar to the effects seen in AD. The AAN Practice Parameter report recommends that both rivastigmine and donepezil be considered for the treatment of dementia in PD.20
PD is increasingly being recognized as a neuropsychiatric disease with significant behavioral symptoms. It is important for psychiatrists and neurologists to collaborate in treating patients with PD because management of PD is optimal when the psychiatric and cognitive aspects are considered along with the motor deficits. When treating the behavioral symptoms of PD, psychiatrists should be familiar with potential motor adverse effects of medication. Early recognition of the psychiatric disturbances of PD can reduce morbidity and improve the quality of life of patients with PD.
- Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med. 2004;351:2509-2518.
- Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease. N Engl J Med. 1999;340:757-763.
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