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Defining treatment resistance among schizophrenia patients is problematic since most patients experience persistent morbidity over the course of their illness and full remissions are infrequent. In addition, the level of response to antipsychotic medication is not an immutable feature of the patient's illness that is present at its onset; rather, it can change over the course of the illness (usually unidirectionally with patients becoming less responsive to treatment) and is determined by various modifying factors. Although treatment resistance may be an enduring feature of a patient, present at illness onset and throughout, more commonly it develops over the course of patients' illnesses. Evidence from both retrospective and prospective studies suggests that a longer duration of untreated psychosis in the early stage of schizophrenia is associated with a longer time to remission and a lower level of recovery, a greater likelihood of relapse and a worse overall outcome. The pattern of deterioration observed is analogous to a well replicated neurobiologic phenomenon, termed behavioral sensitization. In sensitized animals a pathologic behavioral process emerges whereby the response to a pharmacologic or stress challenge is progressively increased in proportion to the number of pretreatments. Thus, endogenous neurochemical sensitization resulting from the inability to regulate presynaptic dopamine release in the limbic striatum may be a useful way to conceptualize the continuum of response-refractoriness that is clearly evident in schizophrenia patients. Most importantly, early detection, intervention and optimal maintenance treatment may improve the long term course of schizophrenia.