Paralleling the preclinical evidence, are there clinical data to suggest antipsychotic tolerance with continuous treatment? Work with first-episode schizophrenia has confirmed three findings related to antipsychotic treatment: (a) response to lower doses; (b) sensitivity to side effects; and (c) comparatively high response rate.[2,21] In contrast, the more chronic stages of schizophrenia are associated with higher antipsychotic doses and diminished clinical response,[22,23] keeping in mind that the chronic population is more heterogeneous and includes a larger proportion of refractory patients who may be receiving higher doses. While antipsychotic tolerance has been raised to account for a progressive decline in response,[24] nonadherence and/or illness progression are routinely endorsed as more viable explanations. That as many as 25% of individuals on depot antipsychotic therapy relapse[25] tempers the nonadherence argument, but at the same time does not rule out alternative explanations, eg, a discrete breakthrough episode vs tolerance per se. In contrast, the preclinical description of behavioral dopamine supersensitivity closely parallels the notion of "supersensitivity psychosis" and withdrawal dyskinesias reported clinically, linked to D2 upregulation as a result of ongoing antipsychotic exposure and observed in the face of drug discontinuation.[26–28]
Antipsychotic Dosing: How Much but Also How Often?
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