Elias Wagner1, John M Kane2,3,4, Christoph U Correll2,3,4,5, Oliver Howes6, Dan Siskind7,8, William G Honer9, Jimmy Lee10,11, Peter Falkai1, Thomas Schneider-Axmann1, Alkomiet Hasan1,12. 1. Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany. 2. Department of Psychiatry, The Zucker Hillside Hospital, Glen Oaks, NY. 3. Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY. 4. Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY. 5. Department of Child and Adolescent Psychiatry, Psychosomatic Medicine and Psychotherapy, Charité Universitätsmedizin, Berlin, Germany. 6. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 7. Department of Psychiatry, School of Medicine, University of Queensland, Brisbane, Australia. 8. Mobile Intensive Rehabilitation Team, Metro South Addiction and Mental Health Service, Brisbane, Australia. 9. Department of Psychiatry, Institute of Mental Health, The University of British Columbia, Vancouver, Canada. 10. Department of Psychosis, Institute of Mental Health, Singapore. 11. Neuroscience and Mental Health, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore. 12. Department of Psychiatry and Psychosomatics of the University Augsburg, Bezirkskrankenhaus Augsburg, University of Augsburg, Augsburg, Germany.
Abstract
BACKGROUND: Evidence for the management of inadequate clinical response to clozapine in treatment-resistant schizophrenia is sparse. Accordingly, an international initiative was undertaken with the aim of developing consensus recommendations for treatment strategies for clozapine-refractory patients with schizophrenia. METHODS: We conducted an online survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group. An agreement threshold of ≥75% (responses "agree" + "strongly agree") was set to define a first-round consensus. Questions achieving agreement or disagreement proportions of >50% in the first round, were re-presented to develop second-round final consensus recommendations. RESULTS: Forty-four (first round) and 49 (second round) of 63 TRRIP members participated. Expert recommendations at ≥75% agreement included raising clozapine plasma levels to ≥350 ng/ml for refractory positive, negative, and mixed symptoms. Where plasma level-guided dose escalation was ineffective for persistent positive symptoms, waiting for a delayed response was recommended. For clozapine-refractory positive symptoms, combination with a second antipsychotic (amisulpride and oral aripiprazole) and augmentation with ECT achieved consensus. For negative symptoms, waiting for a delayed response was recommended, and as an intervention for clozapine-refractory negative symptoms, clozapine augmentation with an antidepressant reached consensus. For clozapine-refractory suicidality, augmentation with antidepressants or mood-stabilizers, and ECT met consensus criteria. For clozapine-refractory aggression, augmentation with a mood-stabilizer or antipsychotic medication achieved consensus. Generally, cognitive-behavioral therapy and psychosocial interventions reached consensus. CONCLUSIONS: Given the limited evidence from randomized trials of treatment strategies for clozapine-resistant schizophrenia (CRS), this consensus-based series of recommendations provides a framework for decision making to manage this challenging clinical situation.
BACKGROUND: Evidence for the management of inadequate clinical response to clozapine in treatment-resistant schizophrenia is sparse. Accordingly, an international initiative was undertaken with the aim of developing consensus recommendations for treatment strategies for clozapine-refractory patients with schizophrenia. METHODS: We conducted an online survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group. An agreement threshold of ≥75% (responses "agree" + "strongly agree") was set to define a first-round consensus. Questions achieving agreement or disagreement proportions of >50% in the first round, were re-presented to develop second-round final consensus recommendations. RESULTS: Forty-four (first round) and 49 (second round) of 63 TRRIP members participated. Expert recommendations at ≥75% agreement included raising clozapine plasma levels to ≥350 ng/ml for refractory positive, negative, and mixed symptoms. Where plasma level-guided dose escalation was ineffective for persistent positive symptoms, waiting for a delayed response was recommended. For clozapine-refractory positive symptoms, combination with a second antipsychotic (amisulpride and oral aripiprazole) and augmentation with ECT achieved consensus. For negative symptoms, waiting for a delayed response was recommended, and as an intervention for clozapine-refractory negative symptoms, clozapine augmentation with an antidepressant reached consensus. For clozapine-refractory suicidality, augmentation with antidepressants or mood-stabilizers, and ECT met consensus criteria. For clozapine-refractory aggression, augmentation with a mood-stabilizer or antipsychotic medication achieved consensus. Generally, cognitive-behavioral therapy and psychosocial interventions reached consensus. CONCLUSIONS: Given the limited evidence from randomized trials of treatment strategies for clozapine-resistant schizophrenia (CRS), this consensus-based series of recommendations provides a framework for decision making to manage this challenging clinical situation.
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