Antipsychotic drugs are the mainstay in the treatment of schizophrenia. However, one-third of patients do not show adequate improvement in positive symptoms with non-clozapine antipsychotics. Additionally, approximately half of them show poor response to clozapine, electroconvulsive therapy, or other augmentation strategies. However, the development of novel treatment for these conditions is difficult due to the complex and heterogenous pathophysiology of treatment-resistant schizophrenia (TRS). Therefore, this review provides key findings, potential treatments, and a roadmap for future research in this area. First, we review the neurobiological pathophysiology of TRS, particularly the dopaminergic, glutamatergic, and GABAergic pathways. Next, the limitations of existing and promising treatments are presented. Specifically, this article focuses on the therapeutic potential of neuromodulation, including electroconvulsive therapy, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Finally, we propose multivariate analyses that integrate various perspectives of the pathogenesis, such as dopaminergic dysfunction and excitatory/inhibitory imbalance, thereby elucidating the heterogeneity of TRS that could not be obtained by conventional statistics. These analyses can in turn lead to a precision medicine approach with closed-loop neuromodulation targeting the detected pathophysiology of TRS.
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MW, ST, YH, DS, HK, EP, KO, FC, TK, PG, MM, GR, DJM, and AGG have no actual or potential conflicts of interest. YN has received a Grant-in-Aid for Scientific Research (B) (21H02813) from the Japan Society for the Promotion of Science (JSPS), research grants from Japan Agency for Medical Research and Development (AMED), investigator-initiated clinical study grants from TEIJIN PHARMA LIMITED (Tokyo, Japan) and Inter Reha Co., Ltd. (Tokyo, Japan) YN also receives research grants from Japan Health Foundation, Meiji Yasuda Mental Health Foundation, Mitsui Life Social Welfare Foundation, Takeda Science Foundation, SENSHIN Medical Research Foundation, Health Science Center Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Taiju Life Social Welfare Foundation, and Daiichi Sankyo Scholarship Donation Program. YN has received speaker’s honoraria from Dainippon-Sumitomo Pharma, MOCHIDA PHARMACEUTICAL CO., LTD. (Tokyo, Japan), and Yoshito-miyakuhin Corporation within the past 3 years. YN also receives equipment-in-kind support for an investigator-initiated study from Magventure Inc. (Farum, Denmark), Inter Reha Co., Ltd., BrainBox Ltd. (Cardiff, United Kingdom), and Miyuki Giken Co., Ltd. Y.I. has received fellowship grants from Canadian Institute of Health Research (CIHR), research support from Japan Society for the Promotion of Science, SENSHIN Medical Research Foundation, Japanese Society of Clinical Neuropsychopharmacology, Inokashira Hospital Grants for psychiatry research, manuscript fees from Dainippon-Sumitomo Pharma, and speaker’s fees from Eli Lilly, Meiji-Seika Pharma, Mochida Pharmaceutical, Yoshitomi Yakuhin within the past 3 years. KY has received manuscript fees from Sumitomo Dainippon Pharma, fellowship grants from the Japan Research Foundation for Clinical Pharmacology, and Azrieli Adult eurodevelopmental Center Postdoctoral Fellowship and Discovery Fund Postdoctoral Fellowship at CAMH, and consultant fees from Signant Health and VeraSci within the past 3 years. HT has received fellowship from the Japanese Society of Clinical Neuropsychopharmacology and the Canadian Institutes of Health Research, a research grant from Eli Lilly, and manuscript fees from Dainippon-Sumitomo Pharma, Otsuka Pharmaceutical, Wiley Japan and Yoshitomi Yakuhin. YH has received grants from JSPS KAKENHI (JP21H02851, JP19H03579, JP18K07604 and JP19H03579), the Fund for the Promotion of Joint International Research (Fostering Joint International Research B: JP20KK0193) from the JSPS, AMED (JP20dm0207069 and GAJJ020620 [JP19dm0107124h0004]), Takeda Science Foundation, Brain Science Foundation, UBE Industries Foundation and SIRS Research Fund Award from the Schizophrenia International Research Society. SK has received grants from JSPS KAKENHI (19H03579, 20KK0193 & 21H02851), AMED (JP21dm0307004 & JP21dm0207069), Japan Science and Technology Agency (JST) Moonshot R&D Grant Number JPMJMS2021 and The Naito Foundation. SK has received speaker’s honoraria from Siemens Healthineers and Janssen Pharmaceutical. DS has received grants from JSPS KAKENHI (18K15509, 19H03579, and 20KK0193), the SENSHIN Medical Research Foundation, and the HOKURIKU BANK Grant-in-Aid for Young Scientists. FU has received fellowship grants from Discovery Fund, Nakatani Foundation, and the Canadian Institutes of Health Research (CIHR); manuscript fees from Dainippon-Sumitomo Pharma; and consultant fees from VeraSci, and Uchiyama Underwriting within the past 3 years. TS has received manuscript or speaker’s fees from Astellas, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, Elsevier Japan, Janssen Pharmaceuticals, Kyowa Yakuhin, Lundbeck, Meiji-Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Nihon Medi-Physics, Novartis, Otsuka. Pharmaceutical, Shionogi, Shire, Tsumura, Wiley Japan, and Yoshitomi Yakuhin, and research grants from Dainippon-Sumitomo Pharma, Eisai, Mochida Pharmaceutical, Meiji-Seika Pharma and Shionogi. HU has received grants from Eisai, Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, Daiichi Sankyo Company, Mochida Pharmaceutical, and Meiji-Seika Pharma; speaker’s honoraria from Otsuka Pharmaceutical, Dainippon-Sumitomo Pharma, Eisai, and Meiji-Seika Pharma; and advisory panel payments from Dainippon-Sumitomo Pharma within the past 3 years. MM has received speaker’s honoraria from Byer Pharmaceutical, Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, Fuji Film RI Pharma, Hisamitsu Pharmaceutical, Janssen Pharmaceutical, Kyowa Pharmaceutical, Mochida Pharmaceutical, MSD, Mylan EPD, Nihon Medi-physics, Nippon Chemipher, Novartis Pharma, Ono Yakuhin, Otsuka Pharmaceutical, Pfizer, Santen Pharmaceutical, Shire Japan, Takeda Yakuhin, Tsumura, and Yoshitomi Yakuhin within the past 3 years. Also, he received grants from Daiichi Sankyo, Eisai, Pfizer, Shionogi, Takeda, Tanabe Mitsubishi and Tsumura within the past 3 years outside the submitted work. DJM was funded by the Canadian Institutes of Health Research (CIHR) and holds the Joanne Murphy Chair at CAMH. AAG has received funds from Lundbeck, Pfizer, Otsuka, Lilly, Roche, Asubio, Abbott, Autofony, Janssen, Alkermes, Newron, Takeda, Concert, SynAgile and Minerva. SN has received grants from Japan Society for the Promotion of Science (18H02755, 22H03002), Japan Agency for Medical Research and development (AMED), Japan Research Foundation for Clinical Pharmacology, Naito Foundation, Takeda Science Foundation, Watanabe Foundation, Uehara Memorial Foundation, and Daiichi Sankyo Scholarship Donation Program within the past 3 years. SN has also received research support, manuscript fees or speaker’s honoraria from Dainippon-Sumitomo Pharma, Meiji-Seika Pharma, Otsuka Pharmaceutical, Shionogi, and Yoshitomi Yakuhin within the past 3 years.
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Wada, M., Noda, Y., Iwata, Y. et al. Dopaminergic dysfunction and excitatory/inhibitory imbalance in treatment-resistant schizophrenia and novel neuromodulatory treatment. Mol Psychiatry 27, 2950–2967 (2022). https://doi.org/10.1038/s41380-022-01572-0
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