Discovery and development of lamotrigine for bipolar disorder: a story of serendipity, clinical observations, risk taking, and persistence.

This paper briefly reviews and comments on the development of lamotrigine as a treatment for bipolar disorder. The events described include astute clinical observations by epileptologists, serendipitous coupling of the drug's clinical profile to unmet need of two refractory bipolar patients by a practicing psychiatrist, risk taking on the part of an industry sponsor, and persistence on the part of a few key internal and external advocates to see development through to its conclusion, taking place against a backdrop of a disease area which, at the time of the earliest events described here, had not seen the development of any new pharmacologic treatments for decades. Fortunately for patients, since that time there has been a veritable explosion of research into treatments for bipolar disorder, both old and new, so that now patients and physicians have multiple evidence-based options for the treatment of this devastating illness. The development of lamotrigine provides one example of the importance of prescience, patience and persistence in bringing a novel idea to clinical fruition.

Continuation phase treatment with bupropion SR effectively decreases the risk for relapse of depression.

BACKGROUND: This was the first controlled continuation phase study (up to 1-year total treatment) to evaluate the safety and efficacy of bupropion SR for decreasing the risk for relapse of depression in patients who responded to bupropion SR. METHODS: Patients with recurrent major depression were treated with bupropion SR 300 mg/day during an 8-week open-label phase. Responders (based on Clinical Global Impressions Scale for Improvement of Illness scores) entered a randomized, double-blind phase where they received bupropion SR 300 mg/day or placebo for up to 44 weeks. After randomization, relapse was defined as the point at which the investigator intervened by withdrawing the patient from the study to treat depression. RESULTS: Four hundred twenty-three patients were randomized. A statistically significant difference in favor of bupropion SR over placebo was seen in the time to treatment intervention for depression when survival curves were compared (log-rank test, p =.003). Statistically significant separation between bupropion SR and placebo began at double-blind week 12 (p <.05). Adverse events in bupropion SR-treated patients accounted for 9% and 4% of discontinuations from the open-label and double-blind phases, respectively. CONCLUSIONS: Bupropion SR was shown to be effective and well tolerated in decreasing the risk for relapse of depression for up to 44 weeks.

Impact of prior nicotine replacement therapy on smoking cessation efficacy.

OBJECTIVE: To examine previous use of nicotine replacement therapy (NRT) on the smoking-cessation efficacy of bupropion sustained release (SR). METHODS: Secondary analysis of a parallel-group, randomized, double-blind, placebo-controlled study. Smokers who had, based on self-report, no previous history of NRT (N = 453) or who had used NRT at least once (N = 440) were randomized to receive placebo, bupropion SR, nicotine transdermal system (NTS), or a combination of bupropion SR and NTS. RESULTS: Bupropion SR showed similar efficacy in participants with or without previous use of NRT. CONCLUSION: Bupropion SR is effective in promoting smoking abstinence regardless of prior NRT use.

Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials.

OBJECTIVES: The efficacy of lamotrigine as maintenance treatment for bipolar disorder (BD), particularly for delaying depressive episodes, is well established, but its efficacy in the acute treatment of bipolar depression is less clear. This paper reports the results of five randomized, double-blind, placebo-controlled trials of lamotrigine monotherapy for the acute treatment of bipolar depression. METHODS: Adult subjects with bipolar I or II disorder experiencing a depressive episode were randomized to placebo or lamotrigine monotherapy (after titration, at a fixed dose of 50 mg or 200 mg daily in Study 1; a flexible dose of 100-400 mg daily in Study 2; or a fixed dose of 200 mg daily in Studies 3, 4 and 5) for 7-10 weeks. RESULTS: Lamotrigine did not differ significantly from placebo on primary efficacy endpoints [17-item Hamilton Depression Rating Scale in Studies 1 and 2; Montgomery-Asberg Depression Rating Scale (MADRS) in Studies 3, 4 and 5]. In Study 1, lamotrigine significantly separated from placebo on some secondary measures of efficacy, including the MADRS, the Clinical Global Impressions-Severity (CGI-S) and the CGI-Improvement (CGI-I), but seldom differed on secondary efficacy endpoints for the other studies. CONCLUSIONS: Lamotrigine monotherapy did not demonstrate efficacy in the acute treatment of bipolar depression in four out of five placebo-controlled clinical studies. Lamotrigine was well tolerated in the acute treatment of bipolar depression.