Abstract

Clozapine-resistant or ultra-resistant schizophrenia represents a challenge for clinicians, given the lack of recommendations in all the major treatment guidelines regarding the next steps once clozapine has failed or cannot be tolerated. The first part of this narrative review investigated the pharmacological arsenal available to the clinician to deal with cases of clozapine-resistant schizophrenia. In the present section of the analysis, the results of research that explored the efficacy and tolerability of nonpharmacological methods for this type of schizophrenia will be presented. Ongoing or upcoming clinical trials in patients with ultra-resistant schizophrenia will also be reviewed. Searching electronic databases and clinical trial archives identified seven reports on the effects of psychotherapy and 15 reports on neuromodulation techniques that aimed at ameliorating psychotic symptoms and functionality in clozapine-resistant schizophrenia. A number of six ongoing clinical trials targeting this type of schizophrenia are also presented. In conclusion, based on the data analyzed, cognitive-behavioral therapy for psychosis, cognitive-behavioral therapy, and occupational therapy benefit from moderate-quality data to support their efficacy as add-ons to clozapine in these patients. Except for electroconvulsive therapy, the evidence for other neuromodulation techniques is, at least for now, insufficient to recommend them in ultra-resistant cases. It is necessary to carry out good quality and long-term clinical studies in order to confirm the usefulness of these adjuvant treatments.  

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