Pramipexole in Psychiatry: a Systematic Review of the Literature

Systematic Review of Pramipexole in Psychiatry Pramipexole in Psychiatry: A Systematic Review of the Literature Chris B. Aiken, M.D. ramipexole, a dopamine agonist approved for the Ptreatment of Parkinson’s disease and restless legs syndrome, has unique properties that offer therapeutic Objective: To assess the risks and benefits potential in psychiatry. It possesses both dopaminergic of pramipexole in psychiatric populations. and neuroprotective effects, making it a promising candi- Data Sources: A PubMed search was date for bipolar depression. Recent clinical studies have performed using the keywords pramipexole 1 and ropinirole, which identified 500 articles. earned it a place as a stage-5 treatment in the Texas and 2 Study Selection: All clinical studies in psychi- Canadian algorithms for bipolar I depression. Concur- atric populations were included in the primary rently, case reports from Parkinson’s disease clinics have review (24 articles). Studies involving other raised concerns about the potential for compulsive behav- populations were then reviewed to evaluate iors and sudden sleep attacks to arise during treatment potential risks and benefits not identified in the psychiatric studies. with the drug. To investigate these promises and perils, Data Extraction: Effect sizes were calculated the neurologic and psychiatric studies of pramipexole from controlled studies. Rates of intolerable side were systematically reviewed. effects and manic switching were estimated by pooled analysis of controlled and uncontrolled studies. METHOD Data Synthesis: Pramipexole has a large effect size (0.6–1.1) in the treatment of both bipolar and A PubMed literature search was performed using the unipolar depression with a low short-term rate of keywords pramipexole and ropinirole. Abstracts and titles manic switching in bipolar patients (1% mania, from 500 articles were reviewed to identify all clinical 5% hypomania). The pooled discontinuation studies in psychiatric populations. This yielded 24 stud- rate for all reasons was 9%. Pramipexole is neuroprotective and exerts beneficial effects ies, from which 3 randomized, placebo-controlled trials 3,4 on sleep architecture. Pramipexole is associated were identified and used to calculate Cohen effect sizes with 3 rare but serious side effects: sleep attacks, (using the Hamilton Rating Scale for Depression as the which have only occurred in Parkinson’s disease; outcome measure). compulsive behaviors and pathologic gambling, To estimate short-term rates of intolerable side effects which have occurred in Parkinson’s disease and restless legs syndrome; and psychosis, which and psychosis, data from all treated subjects in prospec- has occurred in both psychiatric and neurologic tive and retrospective studies of depression (253 subjects populations. from 8 studies)5–12 were combined. Case reports and stud- Conclusions: Pramipexole is an important ies involving Parkinson’s disease were excluded. To esti- therapeutic option for treatment-resistant bipolar mate the short-term rates of manic and hypomanic switch- and unipolar depression; further studies are war- ranted to evaluate its safety in psychiatric ing, data from all bipolar subjects in these studies were 5,7–10,12 patients. combined (85 subjects from 6 studies). (J Clin Psychiatry 2007;68:1230–1236) Lastly, to assess potential risks and benefits not identified in the psychiatric studies, a review of all clinical studies and case reports involving pramipexole and the related drug ropinirole was undertaken. Received July 10, 2006; accepted Jan. 2, 2007. From the Department of Psychiatry, Wake Forest University School of Medicine, Winston-Salem, N.C. MECHANISM OF ACTION Acknowledgments are listed at the end of this article. Dr. Aiken reports no financial affiliations or other relationships Pramipexole is a presynaptic dopamine agonist with relevant to the subject of this article. Corresponding author and reprints: Chris B. Aiken, M.D., an 8-fold preference for the D3 receptor and less affinity 13 632 Holly Ave., Winston-Salem, NC 27101 for D1, D2, and D4. The D3 receptor is densely distributed (e-mail: [email protected]). in the mesolimbic system and has been implicated in the motoric and anhedonic symptoms of depression.5 Po- tentiation of dopamine receptors within this system has J Clin Psychiatry 68:8, August 2007 12311230 Chris B. Aiken Table 1. Randomized Placebo-Controlled Trials of Pramipexole in Mood Disorders Study Condition Daily Dosea N Duration, wk Effect Size Corrigan et al, 200011 Major depression, monotherapy Fixed doses of 0.375, 174 8 d = 0.6b 1.0, and 5.0 mg Zarate et al, 20045 Bipolar II depression, 1.7 mg 21 6 d = 1.1c augmentation of mood stabilizer Goldberg et al, 200412 Bipolar I and II depression, 1.7 mg 22 6 d = 0.77d augmentation of mood stabilizer aDaily dose is expressed as a mean except where noted. b 4 Calculated from HAM-D using the t test of the differences between the 2 groups: d = t(n1 + n2)/[√df × √(n1 × n2)]; see Cohen. cCalculated from HAM-D using the difference of posttreatment means divided by the pooled standard deviation.3 dCalculated from percent change in HAM-D using the difference of posttreatment means divided by the pooled standard deviation.3 Abbreviation: HAM-D = Hamilton Rating Scale for Depression. been proposed as a final common pathway for antide- each dose increment (25%, 34%, and 58%, respectively); pressants from diverse classes, including serotonin re- dropout rates were comparably lower with fluoxetine uptake inhibitors, tricyclic antidepressants, monoamine (14%). The lowest dose of pramipexole (0.375 mg/day) oxidase inhibitors and electroconvulsive therapy.14–17 The did not separate from placebo. Outcomes were reported mesolimbic dopamine system has also been speculated as completer analysis, which limits their interpretation, to play a role in resilience to trauma by enhancing an particularly in the pramipexole 5.0-mg group in which individual’s ability to recognize rewards and persist in the high dropout rate precluded the calculation of their absence.18 p values. Pramipexole also shares with antidepressants a sup- The second trial involved bipolar II depression and pressive effect on rapid eye movement (REM) sleep. In is one of the few controlled trials to examine this popula- patients with restless legs syndrome, pramipexole in- tion exclusively.5 Most of these subjects were considered creased REM sleep latency and decreased total REM treatment resistant and half were inpatients. After an ini- sleep time.19,20 tial 6-week phase of treatment with either divalproex so- The neurotrophic effects of pramipexole are mediated dium or lithium, those whose depression did not respond by the anti-apoptotic protein bcl-2, which is believed to to the mood stabilizer were randomly assigned to receive be responsible for the neuroprotection seen with lithium augmentation with either placebo or pramipexole. Prami- and valproic acid. Preliminary data suggest that com- pexole began to separate from placebo at 3 weeks and bining pramipexole with lithium or valproic acid yields brought about a significant reduction in depression by a synergistic enhancement of bcl-2.5 week 6 with a large effect size of 1.2 to 1.4. This study involved 21 subjects, had high completion rates (90% in CLINICAL STUDIES both groups), and used intent-to-treat analysis. A third randomized controlled trial12 compared flex- Pramipexole’s antidepressant effects were first ob- ible dosing of pramipexole (mean daily dose = 1.7 mg) to served in several animal models21–23 and, later, in a series placebo as an augmentation strategy for outpatients with of uncontrolled clinical studies in which it was used as bipolar depression that was unresponsive to at least 2 an- monotherapy6 or augmentation7–10,24 in bipolar and uni- tidepressant trials. All were taking mood stabilizers and polar depression. Combined, these studies involved 156 none were taking antipsychotics. Twenty-two subjects patients treated for a mean of 30 weeks, with the longest were included; 32% had bipolar II disorder. Pramipexole follow-up recorded at 74 weeks. The weighted mean brought about significantly greater improvements in de- daily dose arrived at was 1.6 mg. pression than placebo on all measures except the primary These observations have been supported by 3 ran- outcome measure (response < 50% on Hamilton Rating domized controlled trials of pramipexole, which found Scale for Depression). Data were analyzed on an intent- moderate to large effect sizes in unipolar and bipolar to-treat basis, and 72% of subjects completed the trial. depression (Table 1). Dropout rates were higher in the placebo arm (40%) than The first trial compared 3 doses of pramipexole to in the pramipexole arm (17%). fluoxetine and placebo in 174 subjects with unipolar Three of the randomized controlled trials of pram- major depression.11 At 8 weeks, pramipexole performed ipexole in Parkinson’s disease also evaluated depressive comparably to fluoxetine and significantly better than symptoms.25–27 The drug brought about significant ben- placebo. A dose-dependent effect on depression was ob- efits, particularly for anhedonia,25,26 and these benefits served among the pramipexole groups (0.375, 1.0, and occurred independently of motoric relief.27 In a random- 5.0 mg daily), but dropout rates also increased with ized comparison trial, treatment with pramipexole 12321231 J Clin Psychiatry 68:8, August 2007 Systematic Review of Pramipexole in Psychiatry brought about significantly

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