Efficacy of clozapine in treatment-resistant schizophrenia

The term ‘treatment-resistant schizophrenia’ is broadly used to describe people with a diagnosis of schizophrenia who do not respond adequately to antipsychotic treatment and continue to have residual symptoms and/or poor psychosocial functioning. Although treatment-resistant schizophrenia is a familiar concept, various definitions and criteria have been proposed over the years to define it as a clinical entity. These include two key concepts: an adequate trial of treatment with antipsychotic medication; and an inadequate response to it. Kane et al (1988) introduced rigorous criteria to define treatment resistance, emphasising persistence of positive symptoms despite receiving ‘adequate treatment’. This involved at least three treatment periods of 6 weeks or more with first-generation antipsychotics (FGAs) within the past 5 years at doses equivalent to 1000 mg/day of chlorpromazine. Inadequate response was measured in terms of failure to improve by at least 20% in total Brief Psychiatric Rating Scale (BPRS) score. These criteria were later revised in light of emerging evidence, and now the general consensus is that a trial of two antipsychotics including one second-generation antipsychotic (SGA) for 4–6 weeks at a dose equivalent to 400–600 mg of chlorpromazine is an ‘adequate trial’ (Conley 2001). When evaluating ‘adequate response’, effect on quality of life is now considered as important as symptom reduction (Lewis 2006).