An international research agenda for clozapine-resistant schizophrenia.

Treatment-resistant symptoms occur in about a third of patients with schizophrenia and are associated with a substantial reduction in their quality of life. The development of new treatment options for clozapine-resistant schizophrenia constitutes a crucial, unmet need in psychiatry. Additionally, an overview of past and possible future research avenues to optimise the early detection, diagnosis, and management of clozapine-resistant schizophrenia is unavailable. In this Health Policy, we discuss the ongoing challenges associated with clozapine-resistant schizophrenia faced by patients and health-care providers worldwide to improve the understanding of this condition. We then revisit several clozapine guidelines, the diagnostic tests and treatment options for clozapine-resistant schizophrenia, and currently applied research approaches in clozapine-resistant schizophrenia. We also suggest methodologies and targets for future research, divided into innovative nosology-oriented field trials (eg, examining dimensional symptom staging), translational approaches (eg, genetics), epidemiological research (eg, real-world studies), and interventional studies (eg, non-traditional trial designs incorporating lived experiences and caregivers' perspectives). Finally, we note that low-income and middle-income countries are under-represented in studies on clozapine-resistant schizophrenia and propose an agenda to guide multinational research on the cause and treatment of clozapine-resistant schizophrenia. We hope that this research agenda will empower better global representation of patients living with clozapine-resistant schizophrenia and ultimately improve their functional outcomes and quality of life.
Competing Interests: Declaration of interests JL has received honoraria from Otsuka, Janssen, Lundbeck, and Sumitomo Pharmaceuticals. CUC has been a consultant or advisor to, or has received honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen (Johnson & Johnson), Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He has provided expert testimony for Janssen and Otsuka. He has served on a data safety monitoring board for Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He has received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma, and Quantic. ROC has received research funding (awarded to his institution) from Roche and Alkermes, is a consultant to Saladax Biomedical, and is a speaker for Clinical Care Options. ST has received speaker honoraria from Otsuka, Mochida, Takeda, Meiji, Eisai, Sumitomo, Viatris, and Teijin. JT has participated in research projects funded by grants from Janssen-Cilag and Eli Lilly awarded to his institution. He also reports personal fees from Eli Lilly, Evidera, Janssen-Cilag, Lundbeck, Mediuutiset, Otsuka, Sidera, and Suvovion; and he is a consultant to HLS Therapeutics, Orion, and WebMed Global. AH is co-editor of the German Association for Psychiatry, Psychotherapy and Psychosomatics schizophrenia treatment guidelines and first author of the World Federation of Societies of Biological Psychiatry schizophrenia treatment guidelines. He has been on the advisory boards and has received speaker fees from Janssen, Lundbeck, and Otsuka. EW has been on the advisory boards of Recordati. JMG-D is funded by a grant from Ministerio de Ciencia y Tecnología (Colombia), and has been a consultant for, received honoraria from, or been on the speakers or advisory boards of Janssen, Eurofarma, Servier, Sanofi, Lilly, and Pfizer. DSh is an expert advisor to the National Institute for Health and Care Excellence (NICE) centre for guidelines; the views expressed in this Health Policy are the authors' and not those of NICE. All other authors declare no competing interests.
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