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 dopaminergic 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.
Clinical Course and Treatment Options
There are several choices for the initial treatment of early PD. Dopamine agonists delay the onset of motor fluctuations and dyskinesia; compared with 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 and pramipexole are preferred, because ergot-derived agonists are associated with an increased risk of cardiac valve damage6,7 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 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 dyskinesias8,11 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.
Medical Management of PD Depression
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. 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, 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.
1. Marras C, Tanner CM. Epidemiology of Parkinson's disease. In: Watts RL, Koller WC, eds. Movement Disorders. Neurologic Principles & Practice. 2nd ed. New York: McGraw-Hill; 2004:177-195.
2. Nutt JG, Wooten GF. Clinical practice: diagnosis and initial management of Parkinson's disease. N Engl J Med. 2005;353:1021-1027.
3. Horn S, Stern MB. The comparative effects of medical therapies for Parkinson's disease. Neurology. 2004;63(7 suppl 2):S7-S12.
4. Weiner WJ. Initial treatment of Parkinson disease: levodopa or dopamine agonists. Arch Neurol. 2004;61: 1966-1969.
5. Olanow C, Watts R, Koller W. An algorithm (decision tree) for the management of Parkinson's disease. Neurology. 2001;56(11 suppl 5):1S-88S.
6. Baseman DG, O'Suilleabhain PE, Reimold SC, et al. Pergolide use in Parkinson disease is associated with cardiac valve regurgitation. Neurology. 2004;63:301-304.
7. Schade R, Andersohn F, Suissa S, et al. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med. 2007;356:29-38.
8. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2006;66:983-995.
9. Anderson VC, Burchiel KJ, Hogarth P, et al. Pallidal vs. subthalamic nucleus deep brain stimulation in Parkinson disease. Arch Neurol. 2005;62:554-560.
10. Deuschl G, Schade-Brittinger C, Krack P, et al. A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med. 2006;355:896-908.
11. Simuni T, Jaggi JL, Mulholland H, et al. Bilateral stimulation of the subthalamic nucleus in patients with Parkinson disease: a study of efficacy and safety. J Neurosurg. 2002;96:666-672.
12. Stefani A, Lozano AM, Peppe A, et al. Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson's disease. Brain. 2007; 130:1596-1607.
13. Mazzone P, Lozano A, Stanzione P, et al. Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in Parkinson's disease. Neuroreport. 2005;16:1877-1881.
14. Funkiewiez A, Ardouin C, Caputo E, et al. Long term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood, and behaviour in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2004;75:834-839.
15. Contarino MF, Daniele A, Sibilia AH, et al. Cognitive outcome 5 years after bilateral chronic stimulation of subthalamic nucleus in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry. 2007;78:248-252.
16. Voon V, Kubu C, Krack P, et al. Deep brain stimulation: Neuropsychological and neuropsychiatric issues. Mov Disord. 2006;21(suppl 14):S305-S327.
17. Weintraub D, Moberg PJ, Duda JE, et al. Effect of psychiatric and other nonmotor symptoms on disability in Parkinson's disease. J Am Geriatr Soc. 2004;52:784-788.
18. Marsh L, McDonald WM, Cummings J, Ravina B. NINDS/NIMH Work Group on Depression and Parkinson's Disease. Provisional diagnostic criteria for depression in Parkinson's disease: report of an NINDS/NIMH work group. Mov Disord. 2006;21:148-158.
19. Mayberg HS, Starkstein SE, Sadzot B, et al. Selective hypometabolism in the inferior frontal lobe in depressed patients with Parkinson's disease. Ann Neurol. 1990;28:57-64.
20. McDonald WM, Richard IH, DeLong MR. Prevalence, etiology, and treatment of depression in Parkinson's disease. Biol Psychiatry. 2003;54:363-375.
21. Lemke MR, Brecht HM, Koester J, Reichmann H. Effects of the dopamine agonist pramipexole on depression, anhedonia and motor functioning in Parkinson's disease. J Neurol Sci. 2006;248:266-270.
22. Rektorová I, Rektor I, Bares M, et al. Pramipexole and pergolide in the treatment of depression in Parkinson's disease: a national multicentre prospective randomized study. Eur J Neurol. 2003;10:399-406.
23. Goldberg J, Burdick K, Endick C. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry. 2004;161:564-566.
24. Factor SA, Feustel PJ, Friedman JH, et al. Longitudinal outcome of Parkinson's disease patients with psychosis. Neurology. 2003;60:1756-1761.
25. Ravina B, Marder K, Fernandez HH, et al. Diagnostic criteria for psychosis in Parkinson's disease: report of an NINDS, NIMH work group. Mov Disord. 2007;22:1061-1068.
26. Marsh L, Williams JR, Rocco M, et al. Psychiatric comorbidities in patients with Parkinson disease and psychosis. Neurology. 2004;63:293-300.
27. Goetz CG, Fan W, Leurgans S, et al. The malignant course of "benign hallucinations" in Parkinson disease. Arch Neurol. 2006;63:713-716.
28. The 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.
29. Miyasaki JM, Shannon K, Voon V, et al. Practice parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology. 2006;66:996-1002.
30. Dewey RB Jr, O'Suilleabhain PE. Treatment of drug-induced psychosis with quetiapine and clozapine in Parkinson's disease. Neurology. 2000;55:1753-1754.
31. Ondo WG, Levy JK, Vuong KD, et al. Olanzapine treatment for dopaminergic-induced hallucinations. Mov Disord. 2002;17:1031-1035.
32. Breier A, Sutton VK, Feldman PD, et al. Olanzapine in the treatment of dopamimetic-induced psychosis in patients with Parkinson's disease. Biol Psychiatry. 2002; 52:438-445.
33. Fernandez HH, Trieschmann ME, Friedman JH. Aripiprazole for drug-induced psychosis in Parkinson disease: preliminary experience. Clin Neuropharmacol. 2004; 27:4-5.
34. Lopez-Meza E, Ruiz-Chow A, Ramirez-Bermudez J. Aripiprazole in psychosis associated with Parkinson's disease. J Neuropsychiatry Clin Neurosci. 2005;17:421-422.
35. Friedman JH, Berman RM, Goetz CG, et al. Open-label flexible-dose pilot study to evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with Parkinson's disease. Mov Disord. 2006; 21:2078-2081.
36. Mohr E, Mendis T, Hildebrand K, De Deyn PP. Risperidone in the treatment of dopamine-induced psychosis in Parkinson's disease: an open pilot trial. Mov Disord. 2000;15:1230-1237.
37. Factor SA, Molho ES, Friedman JH. Risperidone and Parkinson's disease. Mov Disord. 2002;17:221-222.
38. Aarsland D, Zaccai J, Brayne C. A systematic review of prevalence studies of dementia in Parkinson's disease. Mov Disord. 2005;20:1255-1263.
39. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium. Neurology. 2005;65:1863-1872.
40. Aarsland D, Perry R, Brown A, et al. Neuropathology of dementia in Parkinson's disease: a prospective, community-based study. Ann Neurol. 2005;58:773-776.
41. Tandberg E, Larsen JP, Karlsen K. A community-based study of sleep disorders in patients with Parkinson's disease. Mov Disord. 1998;13:895-899.
42. Voon V, Fox SH. Medication-related impulse control and repetitive behaviors in Parkinson disease. Arch Neurol. 2007;64:1089-1096.
43. Voon V, Hassan K, Zurowski M, et al. Prevalence of repetitive and reward-seeking behaviors in Parkinson disease. Neurology. 2006;67:1254-1257.
44. Antonini A, Tesei S, Zecchinelli A, et al. Randomized study of sertraline and low-dose amitriptyline in patients with Parkinson's disease and depression: effect on quality of life. Mov Disord. 2006;21:1119-1122.
45. Leentjens AF, Vreeling FW, Luijckx GJ, Verhey FR. SSRIs in the treatment of depression in Parkinson's disease. Int J Geriatr Psychiatry. 2003;18:552-554.
46. Hauser RA, Zesiewicz TA. Sertraline for the treatment of depression in Parkinson's disease. Mov Disord. 1997;12:756-759.
47. Tesei S, Antonini A, Canesi M, et al. Tolerability of par-oxetine in Parkinson's disease: a prospective study. Mov Disord. 2000;15:986-989.
48. Menza M, Marin H, Kaufman K, et al. Citalopram treatment of depression in Parkinson's disease: the impact on anxiety, disability, and cognition. J Neuropsychiatry Clin Neurosci. 2004;16:315-319.
49. Wermuth L, Sorensen PS, Timm S, et al. Depression in idiopathic Parkinson's disease treated with citalopram: a placebo-controlled trial. Nord J Psychiatry. 1998;52: 163-169.
50. Avila A, Cardona X, Martin-Baranera M, et al. Does nefazodone improve both depression and Parkinson disease? A pilot randomized trial. J Clin Psychopharmacol. 2003;23:509-513.