Dopaminergic dysfunction and excitatory/inhibitory imbalance in treatment-resistant schizophrenia and novel neuromodulatory treatment

Masataka Wada, Yoshihiro Noda, Yusuke Iwata, Sakiko Tsugawa, Kazunari Yoshida, Hideaki Tani, Yoji Hirano, Shinsuke Koike, Daiki Sasabayashi, Haruyuki Katayama, Eric Plitman, Kazutaka Ohi, Fumihiko Ueno, Fernando Caravaggio, Teruki Koizumi, Philip Gerretsen, Takefumi Suzuki, Hiroyuki Uchida, Daniel J. Müller, Masaru MimuraGary Remington, Anthony A. Grace, Ariel Graff-Guerrero, Shinichiro Nakajima

Research output: Contribution to journalReview articlepeer-review

27 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2950-2967
Number of pages18
JournalMolecular Psychiatry
Issue number7
Publication statusPublished - Jul 2022

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Molecular Biology


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