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Efficacy and Safety of Lamotrigine as Add-On Treatment to Lithium in Bipolar Depression: A Multicenter, Double-Blind, Placebo-Controlled Trial
Marc L. M. van der Loos, M.D.; Paul G. H. Mulder, Ph.D.; Erwin G. Th. M. Hartong, M.D., Ph.D.; Marc B. J. Blom, M.D.; Anton C. Vergouwen, M.D., Ph.D.; Herman J. U. E. M. de Keyzer, M.D.; Peter J. H. Notten, M.D.; Marijke L. Luteijn, M.D.; Manuela A. Timmermans, M.Sc.; Eduard Vieta, M.D., Ph.D.; and Willem A. Nolen, M.D., Ph.D., for the LamLit Study Group
Objective: Lamotrigine is one of the pharmacologic options for the treatment of bipolar depression but has only been studied as monotherapy. This study compared the acute effects of lamotrigine and placebo as add-on therapy to ongoing treatment with lithium in patients with bipolar depression.
Method: Outpatients (N=124) aged 18 years and older with a DSM-IV bipolar I or II disorder and a major depressive episode (Montgomery-Asberg Depression Rating Scale [MADRS] score 18 and Clinical Global Impressions-Bipolar Version [CGI-BP] severity of depression score ≥4) while receiving lithium treatment (0.6 - 1.2 mmol/L) were randomly assigned to 8 weeks of double-blind treatment with lamotrigine (titrated to 200 mg/d) or placebo. The primary outcome measure was mean change from baseline in total score on the MADRS at week 8. Secondary outcome measures were response (defined as a reduction of ≥50% on the MADRS and/or change of depression score on the CGI-BP of "much improved" or "very much improved" compared to baseline) and switch to mania or hypomania (defined as a CGI-BP severity of mania score of at least mildly ill at any visit). Patients were included in the study between August 2002 (Spain started in October 2003) and May 2005.
Results: Endpoint mean change from baseline MADRS total score was -15.38 (SE=1.32) points for lamotrigine and -11.03 (SE = 1.36) points for placebo (t = -2.29, df =104, p =.024). Significantly more patients responded to lamotrigine than to placebo on the MADRS (51.6% vs. 31.7%, p =.030), but not on the CGI-BP change of depression (64.1% vs. 49.2%, p =.105). Switch to mania or hypomania occurred in 5 patients (7.8%) receiving lamotrigine and 2 patients (3.3%) receiving placebo (p =.441).
Conclusion: Lamotrigine was found effective and safe as add-on treatment to lithium in the acute treatment of bipolar depression.
Trial Registration: clinicaltrials.gov Identifier: NCT00224510
(J Clin Psychiatry 2009;70(2):223-231. Online Ahead of Print December 30, 2008. doi:10.4088/JCP.08m04152)
Received Feb. 22, 2008; accepted May 14, 2008. From the Department of Psychiatry, Isala Klinieken, location Sophia, Zwolle (Dr. van der Loos); the Department of Epidemiology & Biostatistics, Erasmus University Medical Center, Rotterdam (Dr. Mulder); the Department of Psychiatry, Canisius-Wilhelmina Hospital, Nijmegen (Dr. Hartong); Parnassia Psychiatric Institute, The Hague (Dr. Blom); the Department of Psychiatry, St. Lucas Andreas Hospital, Amsterdam (Dr. Vergouwen); Group Practice: Biological Psychiatry and Psychotherapy, Retranchement (Dr. de Keyzer); the Department of Psychiatry, St. Elisabeth Hospital, Tilburg (Dr. Notten); the Department of Psychiatry, Albert Schweitzer Hospital, Dordrecht (Dr. Luteijn); Clinical Operations, GlaxoSmithKline, Zeist (Ms. Timmermans); Bipolar Disorders Program, Department of Psychiatry, University Medical Center Groningen, University of Groningen (Dr. Nolen), the Netherlands; and Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBER-SAM, Catalonia, Spain (Dr. Vieta).
The study was supported by GlaxoSmithKline, Zeist, and the Isala Klinieken, Zwolle, the Netherlands. GlaxoSmithKline provided lamotrigine and placebo as well as the randomization list. Study monitoring was performed by GlaxoSmithKline Netherlands and GlaxoSmithKline Spain. The Isala Klinieken received a grant from GlaxoSmithKline for the coordination of the study by Dr. van der Loos. The Department of Epidemiology & Biostatistics of Erasmus University Medical Center was compensated by GlaxoSmithKline for the contribution of Dr. Mulder to this article.
This study was first presented in part at the 5th European Stanley Conference of Bipolar Disorder; October 57, 2006; Barcelona, Spain.
Author contributions, study investigators, acknowledgments, and financial disclosure appear at the end of this article.
Corresponding author and reprints: Marc L. M. van der Loos, M.D., Isala Klinieken, Lokatie Sophia, Department of Psychiatry, Dr. van Heesweg 2, Postbus 10400, 8000 GK Zwolle, the Netherlands (e-mail: email@example.com).