Second-Generation Antipsychotics: Looking beyond Efficacy

A few years ago, I was asked to write about “The Aim of Antipsychotic Medications: What Are They and Are They Being Achieved?”(1). I always believed that the aims of therapy with antipsychotic medications in schizophrenia are basically similar to the aims of therapy with medications used to treat long-term medical conditions that may require life-long treatment. Such aims include efficacy without adverse effects, improved subjective tolerability and quality of life, positive long-term outcomes, and cost-effectiveness. When I review data from the drug-development programs of the recently introduced second-generation antipsychotics, it is clear that the major thrust of research has been directed toward demonstrating efficacy in both the short and long terms. Obviously, efficacy and safety are the major prerequisites for approval of new medications. However, in a long-term illness like schizophrenia, which has significant impact on several aspects of behaviour and mental and emotional functioning, it is equally important to demonstrate the impact of new medications on such issues as subjective tolerability, compliance, and quality of life. The best medications have no value unless they are taken (2). Enhanced tolerability can improve medication compliance, which contributes to less-frequent relapse and less use of health resources, as well as improved quality of life. A few decades ago, research on such outcomes as subjective tolerability or quality of life was looked at as soft science—a view reflected in a certain publication bias and low priority in research funding. In addition, new medical technology such as neuroimaging and neurogenetics attracted much of the research interest, particularly among young researchers. As the late Dr Theodore Van Putten, an early pioneer of research in neuroleptic dysphoria, once lamented: “Research in neuroleptic dysphoria and subjective responses to medications, compared with neuroimaging, is not sexy anymore” (personal communication). I am sure he would be pleased to learn that the few of us who have persisted in researching these areas have already moved them to the forefront. Subjective tolerability, quality of life, and medication compliance behaviour are now all recognized as important outcomes in the long-term management of schizophrenia (3,4).