Parkinson disease, depression, hallucinations, psychosis, suicidality, motor control, psychiatric adverse effects
The prevalence of psychiatric symptoms in patients with Parkinson disease (PD) and the fact that pharmacologic management of motor symptoms can trigger or exacerbate psychiatric symptoms leaves clinicians with a Faustian dilemma. Motor symptom management must be weighed against the potential emergence of psychiatric adverse effects.Treatment-associated depression, hallucinations, obsessive-compulsive behaviors, and mania have been documented in patients with PD. Little scientific evidence exists to provide clinical guidance on how to achieve motor control while avoiding emergence of psychiatric adverse effects or exacerbation of existing psychiatric symptoms. Recent developments in the field, however, suggest that management of psychiatric symptoms, such as psychosis and depression, is becoming more of a science than an art.The Quality Standards Subcommittee of the American Academy of Neurology (AAN) included evidence-based recommendations for the treatment of depression, hallucinations, and psychosis in its PD practice parameters published in April.1 (See also, "At a Glance: New Practice Parameters for Parkinson Disease Introduced at AAN," page 20 in the May 2006 issue of Applied Neurology.) A spate of more recent studies not included in the practice parameter review (which based its findings on literature published between 1966 and 2004) have put more emphasis on psychiatric symptoms and possible management strategies. This trend should result in better-informed patient management while research accumulates.VEXING COMPLEXITYVariability is the most frustrating aspect of psychiatric symptoms in patients with PD. Hallucinations have been associated with the use of dopaminergic therapy,2,3 but some studies have found no association between hallucinations and dopaminergic drug use.4,5 While the role of dopaminergic drugs in PD-associated hallucinations is being wrangled with, a study-reported at the recent annual meeting of the AAN, held from April 1 to 8 in San Diego-concluded that patients with PD are subject to a wide range of psychiatric sequelae but depression appears to be less common among patients receiving dopamine agonists.6Furthermore, several studies have identified depression in patients with PD as an adverse effect of subthalamic deep brain stimulation therapy (STN-DBS),7-11 but other studies have reported no change.12,13 Some studies have found that depressive symptoms decreased in the setting of STN-DBS.14,15Given these findings, it should not be surprising that the strength of the AAN's recommendations for treatment of depression and psychosis in patients with PD ranges from level C (possibly effective, ineffective, or harmful) to level B (probably effective, ineffective, or harmful). This indicates that none of the existing evidence is strong enough to warrant a level A recommendation, which requires the support of at least 2 prospective, randomized, controlled clinical trials in a representative population. Given the heterogeneity of the patient population in which psychiatric complications occur-and given the lack of definitive evidence on which to base clinical decisions-experts' advice is to treat each case individually and not to assume anything."Any decision regarding Parkinson disease treatment initiation should rely on a careful weighing of clinical need, expected treatment benefits, and the probability of complicating side effects," said Edward C. Lauterbach, MD, professor of psychiatry, neurology and radiology and chief of adult and geriatric psychiatry at Mercer University in Macon, Georgia.PSYCHOSIS AND PDFor the treatment of psychoses in patients with PD, the AAN practice parameter includes level B recommendations for clozapine and against olanzapine (Zyprexa) and a level C recommendation for quetiapine (Seroquel). The cases for clozapine and against olanzapine are persuasive, if not definitive. The clozapine recommendation was based on a randomized, double-blind, controlled trial, the findings of which were published in the New England Journal of Medicine in 1999.In the trial, 30 patients who received a low dosage (mean of 24.7 mg/d) of clozapine for 4 weeks demonstrated significantly greater improvement on 3 psychosis assessment scales than did 30 patients who received placebo.16 The recommendation against olanzapine was based on 2 studies17,18 that compared olanzapine with placebo and suggested that olanzapine led to worsening motor function and was not better than placebo in ameliorating psychotic symptoms.The subcommittee's case for quetiapine is less conclusive. The recommendation was based on a randomized, open-label comparison trial of quetiapine and clozapine published in 2002.19 In that study, Letterio Morgante, MD, and colleagues from the University of Messina, Italy, found that psychiatric improvements were similar at 12 weeks among a group of 23 patients, 11 of whom received quetiapine and 12 of whom received clozapine. Motor symptoms worsened slightly but not significantly among the patients who received quetiapine and improved slightly but significantly among the patients who received clozapine.The recommendations won't surprise most clinicians, among whom there is general consensus that clozapine is the only antipsychotic therapy supported by the literature for patients with PD. Most clinicians also note, however, that the well-known risk of agranulocytosis associated with clozapine and the frequent neutrophil-count monitoring required as a result of this risk have made alternative therapies such as quetiapine more attractive."Clozapine is the only well-documented therapy. The problem is the required drug monitoring because of a small risk of agranulocytosis. Thus, its use may be problematic for elderly, frail, or home-dwelling patients. Use of quetiapine is less well documented, but it is much used by most clinicians, including myself, as first-line therapy," said Dag Aarsland, MD, a professor of geriatric psychiatry at Stavanger University Hospital in Stavanger, Norway.In fact, since quetiapine was reviewed by the AAN subcommittee, research on quetiapine has increased, with conflicting results. Morgante and colleagues expanded their randomized, open-label comparison trial of quetiapine and clozapine to include 40 patients. They found no significant between-group differences at 12 weeks-including no significant motor changes from baseline in either group.20 But a randomized, double-blind study performed by William G. Ondo, MD, and colleagues at Baylor College of Medicine in Houston, found that 12-week outcomes for 21 patients who received quetiapine were not significantly different from those for 10 patients who received placebo.18STOP ANTICHOLINERGICSThere is also general agreement that one of the first steps in managing psychoses in patients with PD is to discontinue anticholinergic medications, which, despite their effectiveness for controlling tremor, are associated with hallucinations and other psychiatric adverse effects, particularly in elderly patients.21 On the flip side, many clinicians are encouraged by studies suggesting that cholinesterase inhibitors, often used in patients with PD for treatment of dementia, also may have antipsychotic benefits.22-26"If cognitive impairment is present and hallucinations not too badly tolerated, I would rather use a procholinergic drug such as rivastigmine [Exelon], because there is some evidence that these drugs may improve hallucinations in this setting. If the hallucinations are not well tolerated-if they are associated with anxiety or behavioral disturbances-or if they are not improved by rivastigmine, I would make haste to switch to clozapine," said Gilles Fenelon, MD, PhD, a neurologist at Henri Mondor Hospital in Creteil, France. (Fenelon noted that quetiapine is not available in France.)Many experts, including Fenelon, Aarsland, and Lauterbach, recommend adjusting antiparkinsonian medications to address hallucinations in patients with PD before prescribing an antipsychotic drug. Without conclusive evidence, however, the question of when to adjust PD therapies and when to start an antipsychotic essentially comes down to personal preference."Different clinicians handle it differently," said Daniel Weintraub, MD, assistant professor of neurology and psychiatry at the University of Pennsylvania. "Neurologists often place a high value on PD medications and may be more willing to start a psychiatric medication, but there's really not much objective evidence on which to base the decision. We don't even know to what extent the antipsychotics work in patients with Parkinson disease."To further complicate matters, recent studies suggest that antiparkinsonian drug therapy may not be the root cause of hallucinations.4,5 In one study,5 3 factors were predictive of hallucination onset: severe sleep disturbances, ocular disorders, and a high axial motor score. Ocular disorders also were found to be predictive of visual hallucinations. A recently published Japanese study27 identified visual acuity as a risk factor and suggested that ophthalmologic treatment could reduce or prevent hallucinations.DEPRESSION AND PDThe practice parameter recommendations for treatment of depression in patients with PD are, if anything, even less definitive than those for treatment of psychosis-such that the AAN's sole recommendation in this category comes with the caveats that "although the highest level of evidence is for amitriptyline, it is not necessarily the first choice for treatment of depression associated with PD," and that "absence of literature demonstrating clear efficacy of non-tricyclic antidepressants is not the same as absence of efficacy."1The subcommittee's level C recommendation of amitriptyline was based on a 2002 study from Quito, Ecuador, in which 77 patients with PD and depression randomly received either amitriptyline or fluoxetine daily for 12 months.28 The researchers found that amitriptyline was more effective in controlling depressive symptoms than fluoxetine but also reported that 15% of the patients receiving amitriptyline dropped out of the study after experiencing adverse effects; no similar attrition occurred in the fluoxetine group.Study design flaws prevented the subcommittee from drawing definitive conclusions about the effectiveness of other antidepressive drugs associated with fewer anticholinergic adverse effects than amitriptyline. For example, in one study,29 no significant difference in Beck Depression Inventory score improvement was seen between nefazodone and fluoxetine, but because of a lack of placebo control, the subcommittee was unable to determine the actual antidepressant effectiveness of either drug. Studies published in 1998 and 2003 compared placebo with citalopram (Celexa)30 and sertraline (Zoloft), respectively.31 The subcommittee found that both studies lacked the statistical power to demonstrate clinical significance.Although the subcommittee concluded that between-group differences in the severity of depression at baseline compromised results, a study by Czech researchers found that Montgomery and Asberg Depression Rating Scale scores were significantly improved in patients with PD who received pramipexole (Mirapex) for depression compared with patients who received pergolide (Permax).32 Recently, more light has been shed on this issue, however. In May 2005, findings from a European multicenter, placebo-controlled trial showed that pramipexole significantly improved symptoms of depression.33 Similar findings were reported in a more recent Italian study that compared pramipexole with sertraline. At 12 weeks, 60% of patients receiving pramipexole achieved a Hamilton Depression Rating Scale (HAM-D) score of 8 or less, compared with 27.3% of patients receiving sertraline.34Additional recent studies suggest that other agents hold promise for managing depression in patients with PD. For example, a prospective Italian study, published in January, suggested that the noradrenaline reuptake inhibitor reboxetine may be of value.35 Mean HAM-D scores improved from 16.76 to 5.85 after 4 months among 17 patients with PD and major depression.STN-DBS AND PDThe Faustian dilemma perhaps is most pronounced in regard to STN-DBS for treatment of pharmacotherapy-refractory axial motor symptoms. Accumulating evidence is linking the procedure to depression and even suicide.Several studies reported between 2001 and 2003 suggest that depression develops in 6% to 30% of patients after STN-DBS for treatment of PD.7-10 At least one study11 indicated that a pre-procedural history of depression may be a risk factor for postoperative depression, and the challenge of accurately diagnosing depression in PD patients leaves open the possibility that more cases of postoperative symptoms actually reflect subclinical preexisting disease. It is also possible, however, that depression is triggered or exacerbated by electrode positioning that deviates from optimal stimulation sites.36Of note is a large multicenter retrospective study, results of which were reported at the annual AAN meeting. It found that postoperative depression was a significant predictor of both attempted and completed suicides.37 Of 5255 patients who had received STN-DBS for PD, 22 patients (0.42%) completed and 46 patients (0.88%) attempted suicide-most (80%) within 6 months post-procedure. A preoperative history of impulse control disorders or substance abuse, preoperative suicidal ideation or suicide attempts, or postoperative apathy were predictive factors in the 46 patients who attempted suicide postoperatively. Postoperative depression was the only risk factor identified in the 22 patients who completed suicide postoperatively."Like any other life-altering surgery, there are complications that can occur," said the study's presenter Valerie Voon, MD, a staff psychiatrist at the University of Toronto. She recommended that counseling be provided to patients and their families as a preventive measure.NO GUARANTEESAll told, it seems that despite increasing interest on the part of researchers and awareness on the part of physicians, the Faustian dilemma for clinicians treating patients with PD will have no easy answers any time soon. In the interim, clinicians may need to rely on their best professional judgment in weighing the risks of psychiatric complications against the potential benefits of antiparkinsonian therapies."When treating individual patients, the absence of certain risk factors does not guarantee immunity from development of a particular psychiatric disorder," Lauterbach said. "Therefore, the best approach is to be aware of psychiatric complications for which a patient is at risk and to carefully observe for these conditions as treatment is instituted and maintained. A history of a previous psychiatric disorder is an indication to observe for its recurrence, even if the condition has not been specifically related to the particular treatment modality, because the nonspecific stressor of PD itself may serve to encourage its relapse."REFERENCES1. 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 Ameri-can Academy of Neurology. Neurology. 2006;66:996-1002.2. Factor SA, Molho ES, Podskalny GD, Brown D. Parkinson's disease: drug-induced psychiatric states. Adv Neurol. 1995;65:115-138.3. Henderson MJ, Mellers JD. Psychosis in Parkinson's disease: "between a rock and a hard place." Int Rev Psychiatry. 2000;12:319-334.4. Merims D, Shabtai H, Korczyn AD, et al. Antiparkinsonian medication is not a risk factor for the development of hallucinations in Parkinson's disease. J Neural Transm. 2004;111:1447-1453.5. de Maindreville AD, Fenelon G, Mahieux F. Hallucinations in Parkinson's disease: a follow-up study. Mov Disord. 2005;20:212-217.6. Kulisevsky J, Pagonabarraga J, Pascual-Sedano B. A multicentric cross-sectional survey of the prevalence and correlates of neuropsychiatric symptoms in a population of Parkinson's disease without dementia. Neurology. 2006;66 (suppl 2):A124.7. Benabid AL, Koudsie A, Benazzouz A, et al. Deep brain stimulation of the corpus luysi (subthalamic nucleus) and other targets in Parkinson's disease. Extension to new indications such as dystonia and epilepsy. J Neurol. 2001;248 (suppl 3):37-47.8. Ostergaard K, Sunde N, Dupont E. Effects of bilateral stimulation of the subthalamic nucleus in patients with severe Parkinson's disease and motor fluctuations. Mov Disord. 2002;17:693-700.9. Kleiner-Fisman G, Fisman DN, Sime E, et al. Long-term follow up of bilateral deep brain stimulation of the subthalamic nucleus in patients with advanced Parkinson disease. J Neurosurg. 2003;99:489-495.10. Doshi PK, Chhaya N, Bhatt MH. Depression leading to attempted suicide after bilateral subthalamic nucleus stimulation for Parkinson's disease. Mov Disord. 2002;17:1084-1085.11. Houeto JL, Mesnage V, Mallet L, et al. Behavioural disorders, Parkinson's disease and subthalamic stimulation. J Neurol Neurosurg Psychiatry. 2002;72:701-707.12. Fenelon G, Soulas T, Gurruchaga J, et al. Quality of life and psychological consequences in patients and spouses 6 months after subthalamic stimulation for Parkinson's disease. Neurology. 2006;66(suppl 2):A212.13. Simonin C, Krystkowiak P, Tir M, et al. Long-term efficacy of subthalamic nucleus stimulation in advanced Parkinson's disease: five-year follow-up. Neurology. 2006;66(suppl 2):A211.14. Daniele A, Albanese A, Contarino MF, et al. Cognitive and behavioural effects of chronic stimulation of the subthalamic nucleus in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry. 2003;74:175-182.15. Funkiewiez A, Ardouin C, Caputo E, et al. Long term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood and behavior in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2004;75:834-839.16. Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease. N Engl J Med. 1999;340:757-763.17. 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;52:438-445.18. Ondo W, Levy JK, Vuong KD, et al. Olanzapine treatment for dopaminergic hallucinations. Mov Disord. 2002;17:1031-1035.19. Morgante L, Epifanio A, Spina E, et al. Quetiapine versus clozapine: a preliminary report of comparative effects on dopaminergic psychosis in patients with Parkinson's disease. Neurol Sci. 2002;23(suppl 2):S89-S90.20. Morgante L, Epifanio A, Spina E, et al. Quetiapine and clozapine in parkinsonian patients with dopaminergic psychosis [published correction appears in Clin Neuropharmacol. 2004;27:256]. Clin Neuropharmacol. 2004;27:153-156.21. Lang AE, Blair RD. Anticholinergic drugs and amantadine in the treatment of Parkinson's disease. In: Calne DB, ed. Handbook of Experimental Pharmacology. Vol 88: Drugs for the Treatment of Parkinson's Diseases. Berlin: Springer-Verlag; 1989.22. Reading PJ, Luce AK, McKeith IG. Rivastigmine in the treatment of parkinsonian psychosis and cognitive impairment: preliminary findings from an open trial. Mov Disord. 2001;16:1171-1174.23. Bullock R, Cameron A. Rivastigmine for the treatment of dementia and visual hallucinations associated with Parkinson's disease: a case series. Curr Med Res Opin. 2002;18:258-264.24. Kurita A, Ochiai Y, Kono Y, et al. The beneficial effect of donepezil on visual hallucinations in three patients with Parkinson's disease. J Geriatr Psychiatry Neurol. 2003;16:184-188.25. Pakrasi S, Mukaetova-Ladinska EB, McKeith IG, O'Brien JT. Clinical predictors of response to acetyl cholinesterase inhibitors: experience from routine clinical use in Newcastle. Int J Geriatr Psychiatry. 2003;18:879-886.26. Aarsland D, Hutchinson M, Larsen JP. Cognitive, psychiatric and motor response to galantamine in Parkinson's disease with dementia. Int J Geriatr Psychiatry. 2003;18:937-941.27. Matsui H, Udaka F, Tamura A, et al. Impaired visual acuity as a risk factor for visual hallucinations in Parkinson's disease. J Geriatr Psychiatry Neurol. 2006;19:36-40.28. Serrano-Duenas M. A comparison between low doses of amitriptyline and low doses of fluoxetin used in the control of depression in patients suffering from Parkinson's disease. Rev Neurol. 2002;35:1010-1014.29. 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;23:509-513.30.Wermuth L, Sorensen P, Timm S, et al. Depression in idiopathic Parkinson's disease treated with citalopram. Nord J Psychiatry. 1998;52:163-169.31. Leentjens AF, Vreeling FW, Luijckx GJ, Verhey FR. SSRIs in the treatment of depression in Parkinson's disease. Int J Geriatric Psychiatry. 2003;18:552-554.32. Rektorova 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;10:399-406.33. Moller JC, Oertel WH, Koster J, et al. Long-term efficacy and safety of pramipexole in advanced Parkinson's disease: results from a European multicenter trial. Mov Disord. 2005; 20:602-610.34. Barone P, Scarzella L, Marconi R, et al. Pramipexole versus sertraline in the treatment of depression in Parkinson's disease: a national multicenter parallel-group randomized study. J Neurol. 2006 Apr 20; [Epub ahead of print].35. Pintor L, Bailles E, Valldeoriola F. Response to a 4-month treatment with reboxetine in Parkinson's disease patients with a major depressive episode. Gen Hosp Psychiatry. 2006;28:59-64.36. Okun MS, Green J, Saben R, et al. Mood changes with deep brain stimulation of STN and GPi: results of a pilot study. J Neurol Neurosurg Psychiatry. 2003;74:1584-1586.37. Voon V, Krack P, Lang A, et al. Frequency and risk factors for suicidal outcomes following subthalamic deep brain stimulation for Parkinson's disease: a multicenter retrospective study. Neurology. 2006;66(suppl 2):A195.JORDANA BIEZE FOSTER is a freelance writer in Stow, Massachusetts, and former editorial director of Applied Neurology.