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Ropinirole is a nonergoline dopamine D2–D3 receptor agonist indicated for treating Parkinson’s disease. The drug is inactivated by cytochrome P450 isoenzyme CYP1A2 in the liver, and its half-life is approximately 6 hours (1). Laboratory (2) and clinical studies (3–9) support the hypothesis of an antidepressant effect exerted by pramipexole, a dopamine D2–D3 receptor agonist. We conducted a pilot, prospective, open study of the efficacy and tolerability of ropinirole augmentation in patients with treatment-resistant depression (TRD). Materials and MethodsThe study was a 16-week, prospective, open trial conducted at the Department of Psychiatry of the University of Pisa among patients with TRD. The site of this trial is a national referring center for mood and anxiety disorders. Adult patients (aged over 18 and under 75 years) diagnosed with a major depressive episode according to DSM-IV criteria were referred to our clinic during a 3-month period and were consecutively assessed for eligibility for study entry. We included in the study patients who did not respond to at least one antidepressant treatment; this was characterized by adequate dosages and an extended period of administration (for example, sertraline 100 mg daily for 6 weeks) (10). Treatment was constant for at least 6 weeks prior to ropinirole augmentation. Table 1 reports concomitant treatments, as well as their dosage and duration prior to ropinirole add-on. We assessed patient adherence and resistance to prior antidepressant treatments prospectively in clinical interviews of both patients and relatives. We excluded patients with physical diseases that might interfere with the conduct of the study, as well as those with substance abuse, serious suicide risk, and psychotic symptoms. Blood pressure was measured at baseline, and routine blood tests performed within the 3 months prior to enrolment were screened to rule out untreated concomitant physical illnesses. The local ethical committee approved the study, and patients signed a written consent prior to study participation. Ropinirole was added to patients’ current antidepressant treatment at flexible dosages: an initial dosage of 0.25 mg daily at bedtime for the first 3 days was increased to 0.75 mg daily at the end of the first week and to a maximum of 1.5 mg daily by the second week. Dosages were then adjusted in individual cases. We used the Montgomery–Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I) scales to assess depression severity. We evaluated drug safety with the Dosage Record Treatment Emergent Symptom Scale. Evaluations were performed at baseline and after 2, 4, 8, 12, and 16 weeks. Three psychiatry residents performed baseline diagnostic and drug-resistance assessments as well as follow-up evaluations. To assess the interrater reliability for the MADRS and CGI scales, the 3 residents corated 4 live interviews with depression patients conducted by a senior psychiatrist. Kappas for diagnoses ranged between 0.85 and 0.95. The intraclass evaluation for the MADRS and CGI ranged between 0.85 and 0.95. A senior psychiatrist supervised all evaluations and diagnoses by discussing cases with the residents and meeting with the patients. We performed primary analyses by using the intent-to-treat approach, with the last observation carried forward, in patients with at least one available follow-up assessment of efficacy and tolerability. Response to treatment was defined as a 50% or greater reduction in MADRS total score from baseline and a score of 1 (“very much improved”) or 2 (“much improved”) on the CGI-I scale at the end of the study. Remission was defined as a score of 12 or less on the MADRS at endpoint. Changes in the antidepressant treatment during follow-up, characterized by antidepressant switch or combination and by the use of augmenting drugs other than ropinirole, were considered endpoints for the purpose of analysis. We evaluated the tolerability of ropinirole by analyzing the frequency of moderate and severe adverse events requiring dosage adjustment or drug discontinuation. We performed 2 post hoc analyses, using multiple regression to investigate the correlation between severity of depression (MADRS total score at baseline) and ropinirole dosage, as well as between dosage and clinical improvement (change in MADRS total score at endpoint). ResultsTen patients with TRD were consecutively enrolled. Patients had a mean age of 51 years, and 7 of 10 subjects were women. Seven patients had a diagnosis of major depressive disorder, and 3 patients had a diagnosis of bipolar II disorder (Table 1). Two patients had comorbid neurologic diseases stabilized with treatment (specifically, multiple sclerosis [patient 7] and Parkinson syndrome [patient 8]); in both cases the onset of the mood disorder was prior to the onset of the neurologic disorder. The duration of the current depressive episode ranged from 5 months to more than 2 years, and the mean number of attempted trials with antidepressants was 1.6. The median duration of stable or unmodified antidepressant treatment prior ropinirole augmentation was 7 weeks. Ropinirole was added to the current treatment with an endpoint mean (SD) dosage of 1.33 (0.4) mg daily.
In this sample of patients with TRD, overall mean scores on the MADRS decreased from 29.6 (SD 7.6) at baseline to 16.9 (SD 12.1) at endpoint (T test, t = 3.10, df 9, P < 0.02); the CGI-S score decreased from 4.6 (SD 0.84) to 2.5 (SD 1.72) (Wilcoxon Signed Rank test, z = –2.45; P < 0.02). Using the 50% or more reduction of MADRS score and the CGI-I as outcome criteria, we considered 4 of 10 patients (40%) to be responders following ropinirole augmentation (Table 1). The rate of remission according to the MADRS (total score 12 or less) was 40% at the endpoint. Overall, in our study, there was a trend to prescribe higher dosages of ropinirole to patients with more severe depression (b = 0.035, t = 2.10, P = 0.068); the correlation among dosage and clinical improvement was not significant (b = 0.177, t = 0.50, P = 0.63). Two subjects discontinued ropinirole after experiencing an adverse event—one because of dizziness plus a fainting spell (patient 6 during week 1) and one because of dizziness plus falls (patient 2 by week 5). The only patient with Parkinson syndrome in the study experienced confusion and psychomotor agitation when ropinirole was increased to 1.5 mg daily. A CT scan of the brain showed minimal cerebral vascular lesions that were most likely caused by chronic vascular disease. The patient’s confusion subsided after ropinirole was tapered. At the end of the study (week 16), only 5 of 10 patients continued to take ropinirole; the remaining patients had either poor response or adverse events that were likely caused by the drug. DiscussionIn our pilot study on TRD, ropinirole augmentation of antidepressants was associated with a significant decrease in the burden of depressive symptoms. Moreover, most subjects were able to continue ropinirole in association with selective serotonin reuptake inhibitors and (or) tricyclic antidepressants. With regard to tolerability, 2 of 10 patients had to stop taking ropinirole because they both experienced dizziness and fainting spells or falls. These adverse events are consistent with ropinirole’s side effects profile (11) and suggest the occurrence of hypotension or orthostatic hypotension (12). An alternative plausible explanation would be the occurrence of sleep attacks (13). The only patient with Parkinson syndrome experienced confusion and psychomotor agitation. Indeed, confusion has been described as a potential side effect of dopaminergic drugs in patients with organic brain diseases (14). Notably, adverse events appeared in the first period of treatment and subsided after drug discontinuation or dosage reduction. Our study has several limitations; therefore, the generalizability of our findings is limited. The small sample size, the heterogeneity of the patients (in terms of age and diagnosis), and the nonstandardized concomitant medication limit the assessment of side effects rates and responder rates. The absence of a placebo control also prevents us from assessing the degree of specificity of the reported improvements. Nevertheless, rates of response in our study (40%) appear to be higher than usual rates of placebo response (12% to 20%) in TRD, suggesting a treatment effect for ropinirole (15–17). Strengths of our study are the relatively long follow-up and the straight augmentation design without concomitant changes of antidepressant treatment. Moreover, the fact that antidepressant treatment was kept constant before ropinirole augmentation minimizes the likelihood of late-onset response to the primary treatment. Finally, the heterogeneity of the sample of depression patients increases the ecologic validity of our study. In clinical practice, patients who improve their depression symptoms but either do not tolerate standard dopaminergic augmentations or present serious drawbacks (for example, psychostimulant abuse) are potential candidates for augmentation with selective dopamine agonists such as ropinirole. References1. Kaye CM, Nicholls B. Clinical pharmacokinetics of ropinirole. Clin Pharmacokinet 2000;39:243–54. 2. Willner P. The mesolimbic dopamine system as a target for rapid antidepressant action. Int Clin Psychopharmacol 1997;12(Suppl 3):S7–S14. 3. Sporn J, Ghaemi SN, Sambur MR, Rankin MA, Recht J, Sachs GS, and others. Pramipexole augmentation in the treatment of unipolar and bipolar depression: a retrospective chart review. Ann Clin Psychiatry 2000;12:137–40. 4. Lattanzi L, Dell’Osso L, Cassano P, Pini S, Rucci P, Houck PR, and others. Pramipexole in treatment-resistant depression: a 16-week naturalistic study. Bipolar Disord 2002;4:307–14. 5. Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry 2004;161:564–6. 6. Corrigan MH, Denahan AQ, Wright CE, Ragual RJ, Evans DL. Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety 2000;11:58–65. 7. Perugi G, Toni C, Ruffolo G, Frare F, Akiskal H. Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series. Pharmacopsychiatry 2001;34:137–41. 8. Ostow M. Pramipexole for depression. Am J Psychiatry 2002;159:320–1. 9. Zarate CA Jr, Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD, and others. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry 2004;56(1):54–60. 10. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am 1996;19:179–200. 11. Brooks DJ, Abbott RJ, Lees AJ, Martignoni E, Philcox DV, Rascol O, and others. A placebo-controlled evaluation of ropinirole, a novel D2 agonist, as sole dopaminergic therapy in Parkinson’s disease. Clin Neuropharmacol 1998;21:101–7. 12. Etminan M, Gill S, Samii A. Comparison of the risk of adverse events with pramipexole and ropinirole in patients with Parkinson’s disease: a meta-analysis. Drug Saf 2003;26:439–44. 13. Etminan M, Samii A, Takkouche B, Rochon PA. Increased risk of somnolence with the new dopamine agonists in patients with Parkinson’s disease: a meta-analysis of randomised controlled trials. Drug Saf 2001;24:863–8. 14. Young BK, Camicioli R, Ganzini L. Neuropsychiatric adverse effects of antiparkinsonian drugs. Characteristics, evaluation and treatment. Drugs Aging 1997;10:367–83. 15. Nierenberg AA, Papakostas GI, Petersen T, Montoya HD, Worthington JJ 3rd, Tedlow J, and others. Lithium augmentation of nortriptyline for subjects resistant to multiple antidepressants. J Clin Psychopharmacol 2003;23(1):92–5. 16. Perez V, Soler J, Puigdemont D, Alvarez E, Artigas F. A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Grup de Recerca en Trastorns Afectius. Arch Gen Psychiatry 1999;56:375–9. 17. Maes M, Vandoolaeghe E, Desnyder R. Efficacy of treatment with trazodone in combination with pindolol or fluoxetine in major depression. J Affect Disord 1996;41:201–10. AuthorsManuscript received March 2004, revised, and accepted September 2004. Previously presented at The American College of Neuro- Psychopharmacology (ACNP) Annual Meeting; 2001 Dec 9–13; Kona (Hawaii). 1. Research Fellow, Depression Clinical and Research Program, Massachusetts General Hospital, Boston, Massachusetts. 2. Director, Women’s Inpatient Unit, Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Pisa, Italy. 3. Director, Depression Clinical and Research Program Massachusetts General Hospital, Boston, Massachusetts. 4. Resident, Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Pisa, Italy. 5. Head, Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Pisa, Italy. Address for correspondence: Dr P Cassano, Depression Clinical and Research Program, Massachusetts General Hospital, 15 Parkman Street (WACC 812) Boston, MA 02114 e-mail: pcassano@partners.org
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