{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:18:00Z","timestamp":1791357480740,"version":"4.3.1"},"reference-count":42,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2012,10,29]],"date-time":"2012-10-29T00:00:00Z","timestamp":1351468800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bipolar Disorders"],"published-print":{"date-parts":[[2012,11]]},"abstract":"<jats:p>Kemp DE, Gao K, Fein EB, Chan PK, Conroy C, Obral S, Ganocy SJ, Calabrese JR. Lamotrigine as add\u2010on treatment to lithium and divalproex: lessons learned from a double\u2010blind, placebo\u2010controlled trial in rapid\u2010cycling bipolar disorder. \u2028Bipolar Disord 2012: 14: 780\u2013789. \u00a9 2012 John Wiley &amp; Sons A\/S.<\/jats:p><jats:p><jats:bold>Objectives:\u2002<\/jats:bold> A substantial portion of the morbidity associated with rapid\u2010cycling bipolar disorder (RCBD) stems from refractory depression. This study assessed the antidepressant effects of lamotrigine as compared with placebo when used as add\u2010on therapy for rapid\u2010cycling bipolar depression non\u2010responsive to the combination of lithium plus divalproex.<\/jats:p><jats:p><jats:bold>Methods:\u2002<\/jats:bold> During Phase 1 of this trial, hypomanic, manic, mixed, and\/or depressed outpatients (n\u2003=\u2003133) aged 18\u201365\u2003years with DSM\u2013IV RCBD type I or II were initially treated with the open combination of lithium and divalproex for up to 16\u2003weeks. During Phase 2, subjects who did not meet the criteria for stabilization (n\u2003=\u200349) (i.e., remained in or cycled into the depressed phase) were randomly assigned to double\u2010blind, adjunctive lamotrigine (n\u2003=\u200323) or adjunctive placebo (n\u2003=\u200326). The primary endpoint was the mean change in depression symptom severity from the beginning of Phase 2 to the end of Phase 2 (week 12) on the Montgomery\u2010\u00c5sberg Depression Rating Scale (MADRS) total score. Data were analyzed by analysis of covariance with last observation carried forward and a mixed\u2010models analysis.<\/jats:p><jats:p><jats:bold>Results:\u2002<\/jats:bold> During Phase 1, a high rate of study discontinuations occurred due to intolerable side effects (13\/133; 10%) and study non\u2010adherence (22\/133; 17%). Only 14% (19\/133) stabilized on the open combination of lithium and divalproex. Among the 49 (37%) patients randomized to the double\u2010blind adjunctive treatment phase, mean\u2003\u00b1\u2003standard error change from baseline on the MADRS total score was \u22128.5\u2003\u00b1\u20031.7 points for lamotrigine and \u22129.1\u2003\u00b1\u20031.5 points for placebo (p\u2003=\u2003not significant; mixed\u2010models analysis). No significant differences were observed in the rates of response, remission, or bimodal response between lamotrigine and placebo.<\/jats:p><jats:p><jats:bold>Conclusions:\u2002<\/jats:bold> The poor tolerability, lack of efficacy, and high rate of early discontinuation with the combination of lithium and divalproex suggests this regimen was ineffective for the majority of patients with RCBD. Among patients who did not stabilize on lithium and divalproex, the addition of lamotrigine was no more effective than placebo in reducing depression severity. The findings suggest an opportunity for several design modifications to enhance signal detection in future trials of RCBD. The main limitation is the small number of subjects randomized to double\u2010blind treatment.<\/jats:p>","DOI":"10.1111\/bdi.12013","type":"journal-article","created":{"date-parts":[[2012,10,29]],"date-time":"2012-10-29T18:03:40Z","timestamp":1351533820000},"page":"780-789","source":"Crossref","is-referenced-by-count":30,"title":["Lamotrigine as add\u2010on treatment to lithium and divalproex: lessons learned from a double\u2010blind, placebo\u2010controlled trial in rapid\u2010cycling bipolar disorder"],"prefix":"10.1111","volume":"14","author":[{"given":"David E","family":"Kemp","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keming","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth B","family":"Fein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip 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