The neuropsychology of chronic severe schizophrenic patients treated with clozapine versus treatment as usual

Introduction: The cognitive effects of antipsychotic drugs represent a potential exploratory tool with which to investigate theoretical models of schizophrenia. According to the `levels of explanation' model, the manipulation of cognition of drugs, reflecting prior changes in brain physiology, should result in symptomatic change. Clozapine is superior to other antipsychotic drugs in the treatment of the symptoms of schizophrenia, but there was little support for the proposition that this was because of superior improvements in cognition. This study aimed to investigate this question in severely ill patients with major cognitive deficits. Additionally since data collection commenced (1993) cognition had become established as the most important determinant of social function in schizophrenia. The methodology of the study allowed for a prospective appraisal of this tissue. Method: This was an open naturalistic study. 26 chronic schizophrenic long stay inpatients began clozapine or stayed on treatment as usual according to clinical decision. Symptoms, cognition (rated independently) and social function were comprehensively assessed at baseline, six months, one year and two years. Results: At baseline the groups were similar on most measures. Clinical response rates in the clozapine group were consistent with the literature, and were better than expected in the treatment as usual group. There were striking improvements in symptoms and social function on clozapine which overall appeared early into the two year period. By contrast, no aspects of cognition improved significantly on clozapine, although there were some between group differences which overall occurred later in the study. Comparing clinical responders with non-responders across both groups did not change the cognitive results. Analyses suggested that gains in personal function were related to negative symptoms, not to cognition. Conclusions: The `levels of explanation' model of schizophrenia was not supported. This is discussed in terms of the alternative `domains' model, and the possible impact of symptom severity on cognition in these patients. In conclusion symptomatic relief and control should remain, at least in severely ill schizophrenic patients, the primary focus of therapeutic effort.