“...the study design has some “patient friendly” features, which aid both scientific power and ethical considerations.”

The paper is frequently cited in part because it is the first published maintenance study in bipolar disorder to employ a clinically relevant endpoint of time to intervention for worsening manic or depressive symptomatology as the primary outcome measure. Such an endpoint is consistent with the practice of frontline psychiatrists, and thus the published results are directly generalizable to the practice setting. Additionally, it provides the most compelling evidence of substantial, albeit limited maintenance efficacy in recently depressed patients for two treatments: lamotrigine and lithium.

The study employs time-to-event analysis, which is not new per se, but is often difficult for the non-researcher to interpret clearly. The choice of endpoints, the separation of analyses for efficacy for mania and for depression, adds to the clarity of the results for a broad range of professionals, as well as for well-informed lay persons. The decision to include an effectiveness analysis, which incorporates tolerability of the drugs as well as their efficacy, further makes the results relevant to the practice setting, since a drug that is highly efficacious, but poorly tolerated, is not a major advance. Finally, the study design has some "patient friendly" features, which aid both scientific power and ethical considerations. The use of a placebo is both a necessary and justifiable strategy in the development of improved treatments for serious diseases. However, no more patients than needed to obtain a clear result, and no longer exposure to an ineffective treatment for longer than necessary are both important values in study design. The study endpoint of the psychiatrist’s decision to intervene serves both values. Not only is it undesirable to keep a patient on placebo if he/she is worsening, it is equally undesirable to keep a patient on an active treatment if the same unsatisfactory clinical state is developing. The design used accomplished this. In fact, half of patients receiving placebo were dropped from the study within 12 weeks, despite the fact that the overall study was planned for 18 months. The design also allows any patient who is doing well to continue in treatment, whether the improvement is from the medication, the natural course of the illness, or the substantial benefits that come from the disease educational information and the strong staff support provided all patients.

Lamotrigine extended the time well following a depressive episode significantly longer than seen with treatment conducted as usual without medication. Lithium, the first drug recognized as a mood stabilizer, had similar overall benefits. However, the major portion of benefits differed for the two treatments. Lamotrigine, but not lithium, extended the time well without depression. Conversely, lithium, but not lamotrigine, extended the time well without mania. Although both drugs were adequately tolerated by the patients, lamotrigine was clearly better tolerated. Secondary analyses of the study also provided practical information on the safety of lamotrigine when used with other principle drugs employed in the overall management of bipolar disorders.

Dr. Joseph R. Calabrese and I were requested by the developing pharmaceutical company, Burroughs Wellcome, to advise on the possible planning of a research program for lamotrigine in 1994. The drug’s benefits on mood regulation had been observed spontaneously by patients, parents of patients, and neurologists when the drug was studied in the treatment of epilepsy. The research development since that time represents the first for a drug which started with no experience from clinician’s use of the drug in their everyday practices. The research program remained on track through one corporate buyout of the first company, and a subsequent merger with a second major pharmaceutical company.