Drug treatment for patients with acute mania: Understanding clinical trials and treatment success

An acute manic episode of bipolar I disorder is treated with medication as antipsychotics and mood stabilizers, to rapidly reduce manic symptom severity. Before acute manic patients can have access to this medication, the medication needs to be registered for this indication. For this registration, medication needs to be proven safe and effective in phase III clinical trials. In this thesis we tried to improve our understanding of these clinical trials in order to improve its interpretation and tried to improve treatment success in clinical practice. We found significant geographic differences in the efficacy of medication for the indication acute mania between patients in the USA versus patients in Europe and the rest of the world, which questions the extrapolation of results across geographic regions. We assessed the placebo response in these registration studies and found that a high placebo response predicts low treatment efficacy and unfortunately, that the placebo response could hardly be predicted. Furthermore, we criticized the current outcome measure ‘response rate’ and proposed the more comprehensive concept of ‘net gain analysis’. Once medication is used in clinical practice, antipsychotics are more effective in acute manic patients with poor and impaired insight in their illness than in patients with good insight. Finally we found that early non-response to antipsychotics at week one or week two predicts treatment failure at study endpoint. Therefore, we recommend to switch medication at week one or week two in case of early non-response and not to wait until week three or four