Clozapine is the gold standard for treatment-refractory schizophrenia (TRS), but several patients only respond partially, despite adequate use. Furthermore, several issues might limit the use of clozapine, such hematological, metabolic or other disabling side effects. These issues prompted the investigation of clozapine augmentation strategies in partial responders to clozapine, as well as alternative strategies for TRS patients who do not tolerate the drug. Therefore, this chapter focuses on the novel and promising agents or techniques that have recently emerged as adjunctive treatments, such as lamotrigine, memantine and cognitive-behavioral therapy, for partial responders to clozapine. In terms of alternative strategies for patients with TRS, this review of the evidence showed modest results for risperidone and ziprasidone, while the use of high-dose olanzapine showed more consistent results, representing a viable alternative for patients with TRS who cannot use or tolerate clozapine. Nevertheless, such augmentation or alternative strategies still remain an open field of investigation.
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