Up to 30% of patients with schizophrenia continue to manifest residual moderate to severe positive symptoms, despite two or more adequate trials of antipsychotic drugs, excluding clozapine. Such patients may be considered treatment resistant. This definition of treatment resistance identifies only a subset of those with 'poor outcome' schizophrenia, a much broader concept based on a variety of deficits which persist despite treatment. The latter group of patients includes many with severe cognitive impairment or negative symptoms, or both, but are spared persistent moderate to severe positive symptoms. Identification of clinical predictors of treatment resistance defined on the basis of positive symptoms is of great value in directing pharmacotherapy and other special treatment programs required to control psychotic symptoms, because clozapine is effective in most of these patients while other drug treatments are not. We consider here two factors - duration of untreated psychosis (DUP) and poor premorbid adjustment (PPA) - as potential predictors of treatment resistance, particularly in first-episode patients. Longer DUP has been associated with diminished response of positive symptoms to antipsychotic drug treatment in first-episode patients. The evidence for DUP as a causal factor or correlate of treatment resistance as defined above, either beginning with the first episode or its development during the course of long-term treatment after an initial positive response to pharmacotherapy, will be reviewed. We conclude that the available evidence relating DUP and treatment resistance is not as strong as many have concluded. Nevertheless, it is important to initiate treatment with antipsychotic drugs as soon as possible after their emergence in first-episode patients. PPA has also been reported to predict resistance to antipsychotic drug treatment. Two studies which define treatment resistance according to the definition used here suggest that poorer PPA may increase the risk of treatment resistance, but more evidence is needed.
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