New and old antipsychotics: what ‘effectiveness’ trials tell us

Treatment options for patients with schizophrenia are more plentiful than ever before. Despite their established efficacy in treating schizophrenia symptoms, typical or first-generation compounds are associated with high rates of troubling extrapyramidal side effects. Moreover, there is still an unmet therapeutic need for the management of negative, cognitive and affective symptoms of schizophrenia. Second-generation antipsychotics were developed with the promise of enhanced efficacy and improved tolerability relative to their first-generation predecessors. The existing clinical trials, however, have not conclusively answered the questions about the clinical advantages and the cost-effectiveness of second-generation antipsychotics, especially from the perspective of clinical practice and public health. To address these issues, clinical trials of effectiveness have been conducted in the USA and the UK. Effectiveness trials are designed to answer the question ‘Will a treatment work in real-world conditions?’, whereas the existing industry-funded trials, often called efficacy trials, answer the question ‘Will a treatment work under ideal conditions?’. Overall, effectiveness trials have shown that second-generation antipsychotics are as effective and cause fewer extrapyramidal side effects relative to first-generation drugs, but come with new metabolic side effects. A clinical advantage over all other antipsy chotics was demonstrated for clozapine, the prototype of atypical antipsychotics. The goal for the next decade will be to use the current agents more intelligently, to match patients to drugs individually, and to continue the search for more efficacious antipsychotics and new add-on drugs for cognitive and negative symptoms.