A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder

Abstract

Background: Multiple treatments for patients with major depressive disorder (MDD) have demonstrated efficacy, but up to one-third of individuals with MDD do not achieve symptomatic remission despite various interventions. Existing augmentation or combination strategies can have substantial safety concerns that may limit their application.

Method: This study investigated the antidepressant efficacy of a flexible dose of the dopamine agonist pramipexole as an adjunct to standard antidepressant treatment in an 8-week, randomized, double-blind, placebo-controlled trial conducted in a tertiary-level depression center. We randomized 60 outpatients (aged 18 to 75 years) with treatment-resistant nonpsychotic MDD (diagnosed according to DSM-IV) to either pramipexole (n = 30) or placebo (n = 30). Treatment resistance was defined as continued depression (Montgomery-Asberg Depression Rating Scale [MADRS] score ≥ 18) despite treatment with at least 1 prior antidepressant in the current depressive episode. Patients were recruited between September 2005 and April 2008. The primary outcome measure was the MADRS score.

Results: The analyses that used a mixed-effects linear regression model indicated a modest but statistically significant benefit for pramipexole (P = .038). The last-observation-carried-forward analyses indicated that 40% and 33% of patients randomized to augmentation with pramipexole achieved response (χ(2) = 1.2, P = .27) and remission (χ(2) = 0.74, P = .61), respectively, compared to 27% and 23% with placebo; however, those differences were not statistically significant. Augmentation with pramipexole was well-tolerated, with no serious adverse effects identified.

Conclusion: For patients who have failed to respond to standard antidepressant therapies, pramipexole is a safe and potentially efficacious augmentation strategy.

Trial registration: ClinicalTrials.gov identifier: NCT00231959.

Conflict of interest statement

Dr Iosifescu has been a consultant for CNS Response, Forest, Gerson Lehrman, and Pfizer; has received grant support from Aspect Medical Systems, Forest, Janssen, NARSAD, and the National Institutes of Health; and has received speaker honoraria from Eli Lilly, Forest, Pfizer, and Reed Elsevier (a company working as logistics collaborator for the Massachusetts General Hospital (MGH) Psychiatry Academy; education programs conducted by the Academy were supported through independent medical education grants from pharmaceutical companies co-supporting programs along with participant tuition). Dr Nierenberg has consulted for the American Psychiatric Association (only travel expenses were paid), Appliance Computing (Mindsite), AstraZeneca, Basilea, BrainCells, Brandeis University, Bristol-Myers Squibb, Dainippon Sumitomo/Sepracor, Eli Lilly, EpiQ, Johnson & Johnson, Labopharm, Merck, Methylation Science, Novartis, PGx Health, Shire, Schering-Plough, Takeda/Lundbeck, and Targacept; has received grant/research support through MGH from the National Institute of Mental Health (NIMH), Pamlabs, Pfizer, and Shire; has received honoraria from Belvoir Publishing, University of Texas Southwestern Dallas, Hillside Hospital, American Drug Utilization Review, American Society for Clinical Psychopharmacology, Baystate Medical Center, Columbia University, Imedex, MJ Consulting, New York State, Medscape, MBL Publishing, Physicians Postgraduate Press, State University of New York at Buffalo, University of Wisconsin, University of Pisa, American Professional Society of ADHD and Related Disorders, International Standard Bibliographic Description, and SciMed; has been a presenter for the MGH Psychiatry Academy (education programs conducted by the Academy were supported through independent medical education grants from various pharmaceutical companies). Dr Fava has received research support from Abbott, Alkermes, Aspect Medical Systems, AstraZeneca, BioResearch, BrainCells, Bristol-Myers Squibb, CeNeRx, Cephalon, Clintara, Covance, Covidien, Eli Lilly, ElMindA, EnVivo, Euthymics Bioscience, Forest, Ganeden, GlaxoSmithKline, Icon Clinical Research, i3 Innovus/Ingenix, Johnson & Johnson PRD, Lichtwer, Lorex, NARSAD, the National Center for Complementary and Alternative Medicine, the National Institute on Drug Abuse, NIMH, Novartis, Organon, Pamlab, Pfizer, Pharmavite, Photothera, Roche, RCT Logic (formerly Clinical Trials Solutions), Sanofi-Aventis, Shire, Solvay, Synthelabo, and Wyeth-Ayerst; has served as an advisor/consultant for Abbott, Affectis, Alkermes, Amarin, Aspect Medical Systems, AstraZeneca, Auspex, Bayer, Best Practice Project Management, BioMarin, Biovail, BrainCells, Bristol-Myers Squibb, CeNeRx, Cephalon, CNS Response, Compellis, Cypress, DiagnoSearch Life Sciences, Dainippon Sumitomo, Dov, Edgemont, Eisai, Eli Lilly, EnVivo, ePharmaSolutions, EPIX, Euthymics Bioscience, Fabre-Kramer, Forest, Genomind, GlaxoSmithKline, Grunenthal, i3 Innovus/Ingenix, Janssen, Jazz, Johnson & Johnson PRD, Knoll, Labopharm, Lorex, Lundbeck, MedAvante, Merck, MSI Methylation Sciences, Naurex, Neuralstem, Neuronetics, NextWave, Novartis, Nutrition 21, Orexigen, Organon, Otsuka, Pamlab, Pfizer, PharmaStar, Pharmavite, PharmoRx, Precision Human Biolaboratory, Prexa, Puretech, PsychoGenics, Psylin Neurosciences, RCT Logic (formerly Clinical Trials Solutions), Rexahn, Ridge Diagnostics, Roche, Sanofi-Aventis, Sepracor, Servier, Schering-Plough, Solvay, Somaxon, Somerset, Sunovion, Supernus, Synthelabo, Takeda, Tal Medical, Tetragenex, TransForm, Transcept, and Vanda; has received speaking and publishing honoraria from Adamed, Advanced Meeting Partners, American Psychiatric Association, American Society of Clinical Psychopharmacology, AstraZeneca, Belvoir Media Group, Boehringer-Ingelheim, Bristol-Myers Squibb, Cephalon, CME Institute/Physicians Postgraduate Press, Eli Lilly, Forest, GlaxoSmithKline, Imedex, MGH Psychiatry Academy/PRIMEDIA Healthcare, MGH Psychiatry Academy/Reed Elsevier, Novartis, Organon, Pfizer, PharmaStar, United BioSource, and Wyeth-Ayerst; holds equity in Compellis; holds a patent for Sequential Parallel Comparison Design, which is licensed by MGH to RCT Logic; has a patent application for a combination of azapirones and bupropion in major depressive disorder; has received copyright royalties for the MGH Cognitive and Physical Functioning Questionnaire, Sexual Functioning Inventory, Antidepressant Treatment Response Questionnaire, Discontinuation-Emergent Signs and Symptoms scale, and SAFER Criteria Interview diagnostic instruments; and has received publishing royalties from Lippincott Williams & Wilkins, Wolters Kluwer, and World Scientific Publishing. Dr Rush has received consulting fees from Otsuka, University of Michigan, and Brain Resource; has received speaker fees from Singapore College of Family Physicians; has received royalties from Guilford Publications and University of Texas Southwestern Medical Center; has received a travel grant from Collegium Internationale Neuro-Psychopharmacologicum; and has received research support from NIMH and Duke-NUS. Dr Perlis has received consulting fees from RID Ventures, Proteus Biomedical, and Pamlab; has served on the scientific advisory board of Genomind; and has received royalties from Concordant Rater Systems (now a Medco subsidiary). Drs Cusin and Iovieno have no personal affiliations or financial relationships with any commercial interest to disclose relative to this article.

© Copyright 2013 Physicians Postgraduate Press, Inc.

Figures

Figure 1.

Mixed-Effects Linear Regression Analysis of Montgomery-Asberg Depression Rating Scale (MADRS) Scores Over Time, by Treatment Group

Figure 2.

Flow Diagram of Study Subjects Abbreviation: ITT = intent-to-treat.