Common sources of disparate results and experience in clinical practice vs. results from phase 2 registration studies: lamotrigine as a prototype

Doctor Parker provides a thoughtful article dealing principally with discord between the results provided by randomized, prospective clinical trials of lamotrigine in bipolar disorder (BD), and actual experience of psychiatrists who, particularly at present, use lamotrigine in their clinical practices (1). Lamotrigine is approved for long-term maintenance treatment in BD, with predominance of efficacy for prophylaxis against depression. An intrinsic problem with Kaplan–Meier (KM) survival analytic techniques, which are uniformly applied in maintenance phase studies in psychiatry, is that they measure the occurrence of a predefined event, for example, intervention, only at two time points; baseline and endpoint. To address the limitations of KM techniques, we developed a multi-state statistical technique which allows clinical episodes to be entered multiple times and which can incorporate weightings for adverse effects and functional status. This procedure, Multistate Outcome Analysis of Treatments in Bipolar Disorder (MOAT-BD), provides statistical significance from bootstrapping estimates of the variance for the estimated times spent in each of several operationally defined clinical states, including subsyndromal states of depression or mania. Such analyses strengthen the generalizability of maintenance study results for clinical practice and recommendations, in part because they conform to the practices of clinicians, who routinely continue the treatment of patients who develop syndromal or subsyndromal symptoms. To obtain an outcome classification system that integrated symptom states as defined by MOAT with measures of drug tolerability, we utilized latent class analysis. Multistate Outcome Analysis of Treatment statistics applied to the two maintenance registration studies of lamotrigine confirmed that both active drugs increased not just total time, but time remitted relative to placebo (2). Lithium was associated with less time with manic symptoms than either placebo or (non-significantly) lamotrigine. Combining symptom and tolerability data into an integrated outcome profile suggested three specific medication effects. Lamotrigine increased the likelihood of having a good symptom outcome without sideeffects by about 50%, although even with lamotrigine, that outcome profile only occurred for about 25% of patients. Lithium also increased the likelihood of having a good symptom outcome relative to placebo, but coupled with problems of adverse effects, tolerability, and increased likelihood of having to stop the study medication. Placebo increased the likelihood of having a poor symptom outcome without adverse events. Doctor Parker is appropriately concerned about the capa