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Background: Roughly 30% of schizophrenia patients fail to respond to at least two antipsychotic trials. Psychosis has been traditionally considered to be poorly sensitive to psychotherapy. Nevertheless, there is increasing evidence that psychological interventions could be considered in treatment-resistant psychosis (TRP). Despite the relevance of the issue and the emerging neurobiological underpinnings, no systematic reviews have been published. Here, we show a systematic review of psychotherapy interventions in TRP patients of the last 25 years. Methods: The MEDLINE/PubMed, ISI WEB of Knowledge, and Scopus databases were inquired from January 1, 1993, to August 1, 2018, for reports documenting augmentation or substitution with psychotherapy for treatment-resistant schizophrenia (TRS) and TRP patients. Quantitative data fetched by Randomized Controlled Trials (RCTs) were pooled for explorative meta-analysis. Results: Forty-two articles have been found. Cognitive behavioral therapy (CBT) was the most frequently recommended psychotherapy intervention for TRS (studies, n = 32, 76.2%), showing efficacy for general psychopathology and positive symptoms as documented by most of the studies, but with uncertain efficacy on negative symptoms. Other interventions showed similar results. The usefulness of group therapy was supported by the obtained evidence. Few studies focused on negative symptoms. Promising results were also reported for resistant early psychosis. Limitations: Measurement and publication bias due to the intrinsic limitations of the appraised original studies. Conclusions: CBT, psychosocial intervention, supportive counseling, psychodynamic psychotherapy, and other psychological interventions can be recommended for clinical practice. More studies are needed, especially for non-CBT interventions and for all psychotherapies on negative symptoms.

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