Managing the Psychiatric Manifestations of Parkinson Disease: An Update

Parkinson disease (PD) is a progressive neurodegenerative disorder affecting 1% of people 65 years and older.¹ The core symptoms include the motor manifestations of tremor, bradykinesia, and rigidity. Asymmetric onset and response to dopamine(Drug information on dopamine)rgic therapy are typical of idiopathic PD compared with other causes of parkinsonism. As the disease progresses, postural instability, motor fluctuations, and dyskinesias develop, and treatments become less effective.

Dementia and psychosis occur frequently in advanced PD. Not only does psychosis severely limit therapeutic options for motor symptoms but it also becomes a highly disabling symptom. Increasingly, nonmotor aspects of PD are recognized as important causes of morbidity and mortality, which is consistent with evidence of disease pathology beyond the dopaminergic neurons of the substantia nigra. In this article, we review the overall clinical course of PD and the major psychiatric manifestations associated with the illness.

There are several choices for the initial treatment of early PD. Dopamine agonists delay the onset of motor fluctuations and dyskinesia; compared with levodopa(Drug information on levodopa), however, they are less effective for reducing motor signs; they are more expensive; and they cause more severe and more frequent adverse effects, including nausea, vomiting, somnolence, confusion, peripheral edema, orthostatic hypotension, and hallucinations.^2-4 As a result, levodopa is preferred in older patients and in those with comorbidities. Compared with immediate-release preparations, controlled-release forms of carbidopa/levodopa may be inconsistently absorbed, which may lead to dose failures and evening dyskinesias.⁵

The non-ergot-derived agonists ropinirole(Drug information on ropinirole) and pramipexole(Drug information on pramipexole) are preferred, because ergot-derived agonists are associated with an increased risk of cardiac valve damage^6,7 and retroperitoneal fibrosis. Recently, rotigotine has been approved as a 24-hour patch for use in early PD. Table 1 summarizes available pharmacotherapy for PD.

Patients with more advanced PD develop several motor complications. Loss of response to levodopa leads to wearing-off between doses, motor fluctuations (ie, on-off phenomena), and dyskinesias. Reducing off time is achieved by more frequent dosing of levodopa formulations and adding supportive medications such as dopamine agonists, monoamine oxidase type B inhibitors, and catechol-O-methyltransferase (COMT) inhibitors. (COMT inhibitors are only effective in combination with levodopa and should not be used as monotherapy.)

Usually, dyskinesias are directly related to peak-dose dopamine therapy and may be difficult to treat without exacerbating rigidity and bradykinesia. Management of troublesome dyskinesias involves decreasing the levodopa dose and/or adding longer-acting dopamine agonists and COMT inhibitors. Amantadine(Drug information on amantadine) may also be effective in reducing dyskinesias.⁸

Cognitively intact patients who become medically refractory after a good initial response to levodopa may be candidates for bilateral deep brain stimulation of the subthalamic nucleus or globus pallidus interna.^9,10 Deep brain stimulation reduces motor signs, motor fluctuations, off time, and dyskinesias^8,11 but is not as effective at treating postural instability, freezing, and falls. Some studies suggest that deep brain stimulation of the pedunculopontine nucleus may be effective in treating these symptoms, but those results require replication.^12,13

Deep brain stimulation is generally well tolerated in properly selected patients. Most studies report no changes in mood or cognition, or only transient perioperative effects.¹⁴ Other studies have documented persistent decreased verbal fluency and positive affect as well as increased irritability, although there was no effect on overall quality of life.^15,16 Subthalamic nucleus stimulation may be more effective for reducing motor symptoms and lowering levodopa dosing but possibly at the expense of adverse effects on mood and cognition. Stimulation of globus pallidus interna may be more effective for treating dyskinesias and may not be associated with neuropsychiatric adverse effects.¹⁶ Further research is under way to better define the risks and benefits of each treatment.

Clinically significant depressive symptoms affect an estimated 40% to 50% of patients with PD during the course of their illness; such symptoms are associated with increased disability¹⁷ as well as impaired quality of life.¹⁸ The cause of depression in PD remains uncertain, but it appears to be related to the underlying neurodegenerative process. Imaging and autopsy data suggest that structural and neurochemical changes are similar to those seen in non-PD depression.^19,20 Multiple nuclei that degenerate in PD, such as the substantia nigra, ventral tegmental area, and locus ceruleus, are implicated in depression. Finally, certain clinical PD phenotypes appear to correlate with depression; for example, depression is more common in the akinetic-rigid form of PD than in the tremor-predominant phenotype.²⁰

Diagnosing depression in a patient with PD can be complex, particularly because it is unclear whether the available diagnostic categories for unipolar depression are appropriate for PD. Depression may be underdiagnosed when symptoms are attributed to somatic symptoms of PD, and patients with PD may be apathetic and socially withdrawn without being depressed. Minor depression is more common in patients with PD than in those with major depression.¹⁸ Also, the symptom palette may be different from that of major depression, including more anxiety and pessimism with less guilt and self-reproach.²⁰ Evaluation for depression should ideally occur when the patient is "on," because patients with PD can experience dysphoria, anxiety, or frank panic attacks during "off" periods of motor fluctuations.

Evidence is limited regarding pharmacotherapy for depression in patients with PD, and most available data are from small trials of varying quality. Consequently, in a 2006 practice parameter, the American Academy of Neurology chose to recommend only amitriptyline(Drug information on amitriptyline). However, given their anticholinergic adverse effects, tricyclics can be problematic in the elderly. This problem is magnified in patients with PD, because orthostasis and cognitive impairment are often present. As a result, an SSRI is prescribed for most patients with depression. The data on SSRIs and heterocyclics for depression in patients with PD are summarized in Table 2.

Emerging evidence suggests that pramipexole may have potential antidepressant effects, presumably because of its effect on D₃ receptors. In an observational cohort of 657 patients with PD, Lemke and colleagues²¹ noted a significant reduction in depression and anhedonia during treatment with pramipexole. In a prospective, randomized, single-blind study of pramipexole and pergolide(Drug information on pergolide), Rektorová and colleagues²² discovered an antidepressant effect for pramipexole but not for pergolide. Pramipexole has also been shown to be effective in bipolar depression in preliminary controlled trials.²³ This evidence suggests that the antidepressant response in patients with PD is not simply due to improvement in motor functioning.

No controlled trials are available regarding other therapies, such as psychotherapy, electroconvulsive therapy, or transcranial magnetic stimulation.