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

Molecular Psychiatry volume 27, pages 2950–2967 (2022)Cite this article

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Abstract

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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Fig. 1: Summary of the estimation of the key neurobiological basis of schizophrenia based on animal and human studies.
Fig. 2: The summary of treatment targets of DBS and rTMS.
Fig. 3: The summary of future directions for research of TRS.

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Article 12 November 2020

Jo Ellen Wilson, Matthew F. Mart, … E. Wesley Ely

References

  1. Howes OD, Murray RM. Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet. 2014;383:1677–87.

    Article  PubMed  Google Scholar 

  2. Caspi A, Houts RM, Ambler A, Danese A, Elliott ML, Hariri A, et al. Longitudinal assessment of mental health disorders and comorbidities across 4 decades among participants in the dunedin birth cohort study. JAMA Netw Open. 2020;3:e203221.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Conley RR, Kelly DL. Management of treatment resistance in schizophrenia. Biol Psychiatry. 2001;50:898–911.

    Article  CAS  PubMed  Google Scholar 

  4. Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2005;2:e141.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Suzuki T, Remington G, Mulsant BH, Uchida H, Rajji TK, Graff-Guerrero A, et al. Defining treatment-resistant schizophrenia and response to antipsychotics: a review and recommendation. Psychiatry Res. 2012;197:1–6.

    Article  PubMed  Google Scholar 

  6. Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJM, Birnbaum ML, et al. Treatment-resistant schizophrenia: treatment response and resistance in psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am J Psychiatry. 2017;174:216–29.

    Article  PubMed  Google Scholar 

  7. Frydecka D, Beszłej JA, Gościmski P, Kiejna A, Misiak B. Profiling cognitive impairment in treatment-resistant schizophrenia patients. Psychiatry Res. 2016;235:133–8.

    Article  PubMed  Google Scholar 

  8. Iasevoli F, Giordano S, Balletta R, Latte G, Formato MV, Prinzivalli E, et al. Treatment resistant schizophrenia is associated with the worst community functioning among severely-ill highly-disabling psychiatric conditions and is the most relevant predictor of poorer achievements in functional milestones. Prog Neuropsychopharmacol Biol Psychiatry. 2016;65:34–48.

    Article  PubMed  Google Scholar 

  9. Kennedy JL, Altar CA, Taylor DL, Degtiar I, Hornberger JC. The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. Int Clin Psychopharmacol. 2014;29:63–76.

    Article  PubMed  Google Scholar 

  10. Ventriglio A, Gentile A, Bonfitto I, Stella E, Mari M, Steardo L, et al. Suicide in the early stage of schizophrenia. Front Psychiatry. 2016;7:116.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Taylor DM. Clozapine for treatment-resistant schizophrenia: still the gold standard? CNS Drugs. 2017;31:177–80.

    Article  PubMed  Google Scholar 

  12. Yada Y, Yoshimura B, Kishi Y. Correlation between delay in initiating clozapine and symptomatic improvement. Schizophr Res. 2015;168:585–6.

    Article  PubMed  Google Scholar 

  13. Shah P, Iwata Y, Brown EE, Kim J, Sanches M, Takeuchi H, et al. Clozapine response trajectories and predictors of non-response in treatment-resistant schizophrenia: a chart review study. Eur Arch Psychiatry Clin Neurosci. 2020;270:11–22.

    Article  PubMed  Google Scholar 

  14. Shah P, Iwata Y, Plitman E, Brown EE, Caravaggio F, Kim J, et al. The impact of delay in clozapine initiation on treatment outcomes in patients with treatment-resistant schizophrenia: A systematic review. Psychiatry Res. 2018;268:114–22.

    Article  CAS  PubMed  Google Scholar 

  15. Carbon M, Correll CU. Clinical predictors of therapeutic response to antipsychotics in schizophrenia. Dialogues Clin Neurosci. 2014;16:505–24.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Farooq S, Choudry A, Cohen D, Naeem F, Ayub M. Barriers to using clozapine in treatment-resistant schizophrenia: systematic review. BJPsych Bull. 2019;43:8–16.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Siskind D, Siskind V, Kisely S. Clozapine response rates among people with treatment-resistant schizophrenia: data from a systematic review and meta-analysis. Can J Psychiatry. 2017;62:772–7.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hietala J, Syvälahti E. Dopamine in schizophrenia. Ann Med. 1996;28:557–61.

    Article  CAS  PubMed  Google Scholar 

  19. Howes O, McCutcheon R, Stone J. Glutamate and dopamine in schizophrenia: an update for the 21st century. J Psychopharmacol. 2015;29:97–115.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry. 2012;69:776–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. McCutcheon R, Beck K, Jauhar S, Howes OD. Defining the locus of dopaminergic dysfunction in schizophrenia: a meta-analysis and test of the mesolimbic hypothesis. Schizophr Bull. 2018;44:1301–11.

    Article  PubMed  Google Scholar 

  22. Laruelle M, Abi-Dargham A, van Dyck CH, Rosenblatt W, Zea-Ponce Y, Zoghbi SS, et al. SPECT imaging of striatal dopamine release after amphetamine challenge. J Nucl Med. 1995;36:1182–90.

    CAS  PubMed  Google Scholar 

  23. Howes O, Bose S, Turkheimer F, Valli I, Egerton A, Stahl D, et al. Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study. Mol Psychiatry. 2011;16:885–6.

    Article  CAS  PubMed  Google Scholar 

  24. Kim S, Shin SH, Santangelo B, Veronese M, Kang SK, Lee JS, et al. Dopamine dysregulation in psychotic relapse after antipsychotic discontinuation: an [18F]DOPA and [11C]raclopride PET study in first-episode psychosis. Mol Psychiatry. 2020 Sep 14; Available from: https://doi.org/10.1038/s41380-020-00879-0.

  25. Yilmaz Z, Zai CC, Hwang R, Mann S, Arenovich T, Remington G, et al. Antipsychotics, dopamine D2 receptor occupancy and clinical improvement in schizophrenia: a meta-analysis. Schizophr Res. 2012;140:214–20.

    Article  PubMed  Google Scholar 

  26. Muller P, Seeman P. Brain neurotransmitter receptors after long-term haloperidol: dopamine, acetylcholine, serotonin, alpha-noradrenergic and naloxone receptors. Life Sci. 1977;21:1751–8.

    Article  CAS  PubMed  Google Scholar 

  27. Zecca L, Bellei C, Costi P, Albertini A, Monzani E, Casella L, et al. New melanic pigments in the human brain that accumulate in aging and block environmental toxic metals. Proc Natl Acad Sci USA. 2008;105:17567–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lynd-Balta E, Haber SN. The organization of midbrain projections to the striatum in the primate: sensorimotor-related striatum versus ventral striatum. Neuroscience. 1994;59:625–40.

    Article  CAS  PubMed  Google Scholar 

  29. Szabo J. Organization of the ascending striatal afferents in monkeys. J Comp Neurol. 1980;189:307–21.

    Article  CAS  PubMed  Google Scholar 

  30. Joel D, Weiner I. The connections of the dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum. Plan Perspect. 2000;451:474.

    Google Scholar 

  31. Ueno F, Iwata Y, Caravaggio F, Chavez S, Carmona ET, Kim J, et al. Neuromelanin accumulation in patients with schizophrenia: a systematic review and meta-analysis. Biol Psychiatry. 2021;89:S253.

    Article  Google Scholar 

  32. Ottong SE, Garver DL. A biomodal distribution of plasma HVA/MHPG in the psychoses. Psychiatry Res. 1997;69:97–103.

    Article  CAS  PubMed  Google Scholar 

  33. Yoshimura R, Ueda N, Shinkai K, Nakamura J. Plasma levels of homovanillic acid and the response to risperidone in first episode untreated acute schizophrenia. Int Clin Psychopharmacol. 2003;18:107–11.

    Article  PubMed  Google Scholar 

  34. Bowers MB Jr, Swigar ME, Jatlow PI, Hoffman FJ. Plasma catecholamine metabolites and treatment response at neuroleptic steady state. Biol Psychiatry. 1989;25:734–8.

    Article  PubMed  Google Scholar 

  35. Roberts RC, Roche JK, Conley RR, Lahti AC. Dopaminergic synapses in the caudate of subjects with schizophrenia: relationship to treatment response. Synapse. 2009;63:520–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jauhar S, Veronese M, Nour MM, Rogdaki M, Hathway P, Turkheimer FE, et al. Determinants of treatment response in first-episode psychosis: an 18F-DOPA PET study. Mol Psychiatry. 2019;24:1502–12.

    Article  PubMed  Google Scholar 

  37. Demjaha A, Murray RM, McGuire PK, Kapur S, Howes OD. Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. Am J Psychiatry. 2012;169:1203–10.

    Article  PubMed  Google Scholar 

  38. Kim E, Howes OD, Veronese M, Beck K, Seo S, Park JW, et al. Presynaptic dopamine capacity in patients with treatment-resistant schizophrenia taking clozapine: An [18F]DOPA PET study. Neuropsychopharmacology. 2017;42:941–50.

    Article  CAS  PubMed  Google Scholar 

  39. Egerton A, Murphy A, Donocik J, Anton A, Barker GJ, Collier T, et al. Dopamine and glutamate in antipsychotic-responsive compared with antipsychotic-nonresponsive psychosis: a multicenter positron emission tomography and magnetic resonance spectroscopy study (STRATA). Schizophr Bull. 2020 Sep 10; Available from: https://doi.org/10.1093/schbul/sbaa128.

  40. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA. 2000;97:8104–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Coppens HJ, Slooff CJ, Paans AM, Wiegman T, Vaalburg W, Korf J. High central D2-dopamine receptor occupancy as assessed with positron emission tomography in medicated but therapy-resistant schizophrenic patients. Biol Psychiatry. 1991;29:629–34.

    Article  CAS  PubMed  Google Scholar 

  42. Uchida H, Takeuchi H, Graff-Guerrero A, Suzuki T, Watanabe K, Mamo DC. Dopamine D2 receptor occupancy and clinical effects: a systematic review and pooled analysis. J Clin Psychopharmacol. 2011;31:497–502.

    Article  CAS  PubMed  Google Scholar 

  43. Graff-Guerrero A, Rajji TK, Mulsant BH, Nakajima S, Caravaggio F, Suzuki T, et al. Evaluation of antipsychotic dose reduction in late-life schizophrenia: a prospective dopamine D2/3 receptor occupancy study. JAMA Psychiatry. 2015;72:927–34.

    Article  PubMed  Google Scholar 

  44. Seeman P, Corbett R, Van Tol HH. Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors. Neuropsychopharmacology. 1997;16:93–110.

    Article  CAS  PubMed  Google Scholar 

  45. Takano A, Suhara T, Kusumi I, Takahashi Y, Asai Y, Yasuno F, et al. Time course of dopamine D2 receptor occupancy by clozapine with medium and high plasma concentrations. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:75–81.

    Article  CAS  PubMed  Google Scholar 

  46. Suhara T, Okauchi T, Sudo Y, Takano A, Kawabe K, Maeda J, et al. Clozapine can induce high dopamine D(2) receptor occupancy in vivo. Psychopharmacology. 2002;160:107–12.

    Article  CAS  PubMed  Google Scholar 

  47. Valenti O, Cifelli P, Gill KM, Grace AA. Antipsychotic drugs rapidly induce dopamine neuron depolarization block in a developmental rat model of schizophrenia. J Neurosci. 2011;31:12330–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sonnenschein SF, Grace A. Emerging therapeutic targets for schizophrenia: a framework for novel treatment strategies for psychosis. Expert Opin Ther Targets. 2021;25:15–26.

    Article  PubMed  Google Scholar 

  49. White FJ, Wang RY. Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons. Science 1983;221:1054–7.

    Article  CAS  PubMed  Google Scholar 

  50. Potkin SG, Kane JM, Correll CU, Lindenmayer J-P, Agid O, Marder SR, et al. The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research. NPJ Schizophr. 2020;6:1.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Samaha A-N, Seeman P, Stewart J, Rajabi H, Kapur S. “Breakthrough” dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci. 2007;27:2979–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chouinard G, Samaha A-N, Chouinard V-A, Peretti C-S, Kanahara N, Takase M, et al. Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy. Psychother Psychosom. 2017;86:189–219.

    Article  PubMed  Google Scholar 

  53. Kimura H, Kanahara N, Komatsu N, Ishige M, Muneoka K, Yoshimura M, et al. A prospective comparative study of risperidone long-acting injectable for treatment-resistant schizophrenia with dopamine supersensitivity psychosis. Schizophr Res. 2014;155:52–8.

    Article  PubMed  Google Scholar 

  54. Servonnet A, Uchida H, Samaha A-N. Continuous versus extended antipsychotic dosing in schizophrenia: Less is more. Behav Brain Res. 2021;401:113076.

    Article  CAS  PubMed  Google Scholar 

  55. Rubio JM, Taipale H, Correll CU, Tanskanen A, Kane JM, Tiihonen J. Psychosis breakthrough on antipsychotic maintenance: results from a nationwide study. Psychol Med. 2020;50:1356–67.

    Article  PubMed  Google Scholar 

  56. Gao W-J, Yang S-S, Mack NR, Chamberlin LA. Aberrant maturation and connectivity of prefrontal cortex in schizophrenia—contribution of NMDA receptor development and hypofunction. Mol Psychiatry. 2022;27:731–43.

  57. Merritt K, McGuire PK, Egerton A, 1H-MRS in Schizophrenia Investigators, Aleman A, Block W, et al. Association of age, antipsychotic medication, and symptom severity in schizophrenia with proton magnetic resonance spectroscopy brain glutamate level: a mega-analysis of individual participant-level data. JAMA Psychiatry [Internet]. 2021 Apr 21; Available from: https://doi.org/10.1001/jamapsychiatry.2021.0380.

  58. Nakahara T, Tsugawa S, Noda Y, Ueno F, Honda S, Kinjo M, et al. Glutamatergic and GABAergic metabolite levels in schizophrenia-spectrum disorders: a meta-analysis of 1H-magnetic resonance spectroscopy studies. Mol Psychiatry. 2022;27:744–57. https://doi.org/10.1038/s41380-021-01297-6.

    Article  CAS  PubMed  Google Scholar 

  59. Macpherson T, Hikida T. Role of basal ganglia neurocircuitry in the pathology of psychiatric disorders. Psychiatry Clin Neurosci. 2019;73:289–301.

    Article  PubMed  Google Scholar 

  60. Javitt DC. Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. Int Rev Neurobiol. 2007;78:69–108.

    Article  CAS  PubMed  Google Scholar 

  61. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51:199–214.

    Article  CAS  PubMed  Google Scholar 

  62. Morgan CJA, Curran HV. Acute and chronic effects of ketamine upon human memory: a review. Psychopharmacology. 2006;188:408–24.

    Article  CAS  PubMed  Google Scholar 

  63. Jones CA, Watson DJG, Fone KCF. Animal models of schizophrenia. Br J Pharm. 2011;164:1162–94.

    Article  CAS  Google Scholar 

  64. Neill JC, Barnes S, Cook S, Grayson B, Idris NF, McLean SL, et al. Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism. Pharm Ther. 2010;128:419–32.

    Article  CAS  Google Scholar 

  65. Patton MH, Bizup BT, Grace AA. The infralimbic cortex bidirectionally modulates mesolimbic dopamine neuron activity via distinct neural pathways. J Neurosci. 2013;33:16865–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci. 2007;27:11496–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Schobel SA, Chaudhury NH, Khan UA, Paniagua B, Styner MA, Asllani I, et al. Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron. 2013;78:81–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Floresco SB, Todd CL, Grace AA. Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. J Neurosci. 2001;21:4915–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zimmerman EC, Grace AA. The nucleus reuniens of the midline thalamus gates prefrontal-hippocampal modulation of ventral tegmental area dopamine neuron activity. J Neurosci. 2016;36:8977–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Jay TM, Witter MP. Distribution of hippocampal CA1 and subicular efferents in the prefrontal cortex of the rat studied by means of anterograde transport of Phaseolus vulgaris-leucoagglutinin. J Comp Neurol. 1991;313:574–86.

    Article  CAS  PubMed  Google Scholar 

  71. Herman JP, Mueller NK. Role of the ventral subiculum in stress integration. Behav Brain Res. 2006;174:215–24.

    Article  CAS  PubMed  Google Scholar 

  72. Sirota A, Montgomery S, Fujisawa S, Isomura Y, Zugaro M, Buzsáki G. Entrainment of neocortical neurons and gamma oscillations by the hippocampal theta rhythm. Neuron. 2008;60:683–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Grace AA. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci. 2016;17:524–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gulchina Y, Xu S-J, Snyder MA, Elefant F, Gao W-J. Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia. J Neurochem. 2017;143:320–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Flagstad P, Mørk A, Glenthøj BY, van Beek J, Michael-Titus AT, Didriksen M. Disruption of neurogenesis on gestational day 17 in the rat causes behavioral changes relevant to positive and negative schizophrenia symptoms and alters amphetamine-induced dopamine release in nucleus accumbens. Neuropsychopharmacology. 2004;29:2052–64.

    Article  CAS  PubMed  Google Scholar 

  76. Iwata Y, Nakajima S, Plitman E, Caravaggio F, Kim J, Shah P, et al. Glutamatergic neurometabolite levels in patients with ultra-treatment-resistant schizophrenia: a cross-sectional 3t proton magnetic resonance spectroscopy study. Biol Psychiatry. 2019;85:596–605.

    Article  CAS  PubMed  Google Scholar 

  77. Egerton A, Broberg BV, Van Haren N, Merritt K, Barker GJ, Lythgoe DJ, et al. Response to initial antipsychotic treatment in first episode psychosis is related to anterior cingulate glutamate levels: a multicentre 1H-MRS study (OPTiMiSE). Mol Psychiatry. 2018;23:2145–55.

    Article  CAS  PubMed  Google Scholar 

  78. Fukuyama K, Kato R, Murata M, Shiroyama T, Okada M. Clozapine normalizes a glutamatergic transmission abnormality induced by an impaired NMDA receptor in the thalamocortical pathway via the activation of a group III metabotropic glutamate receptor. Biomolecules [Internet]. 2019;9:234. Available from: https://doi.org/10.3390/biom9060234.

  79. Yao Y, Belcher J, Berger AJ, Mayer ML, Lau AY. Conformational analysis of NMDA receptor GluN1, GluN2, and GluN3 ligand-binding domains reveals subtype-specific characteristics. Structure. 2013;21:1788–99.

    Article  CAS  PubMed  Google Scholar 

  80. Uno Y, Coyle JT. Glutamate hypothesis in schizophrenia. Psychiatry Clin Neurosci. 2019;73:204–15.

    Article  PubMed  Google Scholar 

  81. Tanahashi S, Yamamura S, Nakagawa M, Motomura E, Okada M. Clozapine, but not haloperidol, enhances glial D-serine and L-glutamate release in rat frontal cortex and primary cultured astrocytes: Enhanced serine and glutamate release by clozapine. Br J Pharm. 2012;165:1543–55.

    Article  CAS  Google Scholar 

  82. Yamamori H, Hashimoto R, Fujita Y, Numata S, Yasuda Y, Fujimoto M, et al. Changes in plasma D-serine, L-serine, and glycine levels in treatment-resistant schizophrenia before and after clozapine treatment. Neurosci Lett. 2014;582:93–8.

    Article  CAS  PubMed  Google Scholar 

  83. Tsai G, Yang P, Chung LC, Lange N, Coyle JT. D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 1998;44:1081–9.

    Article  CAS  PubMed  Google Scholar 

  84. Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, Lichtenstein M. Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry. 1999;56:29–36.

    Article  CAS  PubMed  Google Scholar 

  85. Heresco-Levy U, Ermilov M, Lichtenberg P, Bar G, Javitt DC. High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry. 2004;55:165–71.

    Article  CAS  PubMed  Google Scholar 

  86. Heresco-Levy U, Javitt DC, Ebstein R, Vass A, Lichtenberg P, Bar G, et al. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry. 2005;57:577–85.

    Article  CAS  PubMed  Google Scholar 

  87. Tsai GE, Yang P, Chung LC, Tsai IC, Tsai CW, Coyle JT. D-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry. 1999;156:1822–5.

    Article  CAS  PubMed  Google Scholar 

  88. Evins AE, Fitzgerald SM, Wine L, Rosselli R, Goff DC. Placebo-controlled trial of glycine added to clozapine in schizophrenia. AJP. 2000;157:826–8.

    Article  CAS  Google Scholar 

  89. Miyazaki T, Nakajima W, Hatano M, Shibata Y, Kuroki Y, Arisawa T, et al. Visualization of AMPA receptors in living human brain with positron emission tomography. Nat Med. 2020;26:281–8.

    Article  CAS  PubMed  Google Scholar 

  90. Miyazaki T, Abe H, Uchida H, Takahashi T. Translational medicine of the glutamate AMPA receptor. Proc Jpn Acad Ser B Phys Biol Sci. 2021;97:1–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Carlsson A, Waters N, Carlsson ML. Neurotransmitter interactions in schizophrenia–therapeutic implications. Biol Psychiatry. 1999;46:1388–95.

    Article  CAS  PubMed  Google Scholar 

  92. Taylor SF, Tso IF. GABA abnormalities in schizophrenia: a methodological review of in vivo studies. Schizophr Res. 2015;167:84–90.

    Article  PubMed  Google Scholar 

  93. Krystal JH, Anticevic A, Yang GJ, Dragoi G, Driesen NR, Wang X-J, et al. Impaired tuning of neural ensembles and the pathophysiology of schizophrenia: a translational and computational neuroscience perspective. Biol Psychiatry. 2017;81:874–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Foss-Feig JH, Adkinson BD, Ji JL, Yang G, Srihari VH, McPartland JC, et al. Searching for cross-diagnostic convergence: neural mechanisms governing excitation and inhibition balance in schizophrenia and autism spectrum disorders. Biol Psychiatry. 2017;81:848–61.

    Article  PubMed  PubMed Central  Google Scholar 

  95. de Jonge JC, Vinkers CH, Hulshoff Pol HE, Marsman A. GABAergic mechanisms in schizophrenia: linking postmortem and in vivo studies. Front Psychiatry. 2017;8:118.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Petroff OAC. GABA and glutamate in the human brain. Neuroscientist. 2002;8:562–73.

    Article  CAS  PubMed  Google Scholar 

  97. Volk DW, Pierri JN, Fritschy J-M, Auh S, Sampson AR, Lewis DA. Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. Cereb Cortex. 2002;12:1063–70.

    Article  PubMed  Google Scholar 

  98. Zink M, Schmitt A, May B, Müller B, Demirakca T, Braus DF, et al. Differential effects of long-term treatment with clozapine or haloperidol on GABAA receptor binding and GAD67 expression. Schizophr Res. 2004;66:151–7.

    Article  PubMed  Google Scholar 

  99. Yonezawa Y, Kuroki T, Kawahara T, Tashiro N, Uchimura H. Involvement of gamma-aminobutyric acid neurotransmission in phencyclidine-induced dopamine release in the medial prefrontal cortex. Eur J Pharm. 1998;341:45–56.

    Article  CAS  Google Scholar 

  100. Grace AA, Gomes FV. The circuitry of dopamine system regulation and its disruption in schizophrenia: insights into treatment and prevention. Schizophr Bull. 2019;45:148–57.

    Article  PubMed  Google Scholar 

  101. Sonnenschein SF, Gomes FV, Grace AA. Dysregulation of midbrain dopamine system and the pathophysiology of schizophrenia. Front Psychiatry. 2020;11:613.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Perez SM, Lodge DJ. Hippocampal interneuron transplants reverse aberrant dopamine system function and behavior in a rodent model of schizophrenia. Mol Psychiatry. 2013;18:1193–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Arrúe A, Dávila R, Zumárraga M, Basterreche N, González-Torres MA, Goienetxea B, et al. GABA and homovanillic acid in the plasma of schizophrenic and bipolar I patients. Neurochem Res. 2010;35:247–53.

    Article  PubMed  CAS  Google Scholar 

  104. Bowery NG, Hudson AL, Price GW. GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience. 1987;20:365–83.

    Article  CAS  PubMed  Google Scholar 

  105. Duncan CE, Webster MJ, Rothmond DA, Bahn S, Elashoff M, Shannon, Weickert C. Prefrontal GABA(A) receptor alpha-subunit expression in normal postnatal human development and schizophrenia. J Psychiatr Res. 2010;44:673–81.

    Article  PubMed  Google Scholar 

  106. Beneyto M, Abbott A, Hashimoto T, Lewis DA. Lamina-specific alterations in cortical GABA(A) receptor subunit expression in schizophrenia. Cereb Cortex. 2011;21:999–1011.

    Article  PubMed  Google Scholar 

  107. Marques TR, Ashok AH, Angelescu I, Borgan F, Myers J, Lingford-Hughes A, et al. GABA-A receptor differences in schizophrenia: a positron emission tomography study using [11C]Ro154513. Mol Psychiatry [Internet]. 2020 Available from: https://doi.org/10.1038/s41380-020-0711-y.

  108. Fatemi SH, Folsom TD, Thuras PD. Deficits in GABA(B) receptor system in schizophrenia and mood disorders: a postmortem study. Schizophr Res. 2011;128:37–43.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Harte M, O’Connor WT. Evidence for a selective prefrontal cortical GABA(B) receptor-mediated inhibition of glutamate release in the ventral tegmental area: a dual probe microdialysis study in the awake rat. Neuroscience. 2005;130:215–22.

    Article  CAS  PubMed  Google Scholar 

  110. Lodge DJ, Behrens MM, Grace AA. A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia. J Neurosci. 2009;29:2344–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Grent-’t-Jong T, Gross J, Goense J, Wibral M, Gajwani R, Gumley AI, et al. Resting-state gamma-band power alterations in schizophrenia reveal E/I-balance abnormalities across illness-stages. Elife [Internet]. 2018;7. Available from: https://elifesciences.org/articles/37799.

  112. Thuné H, Recasens M, Uhlhaas PJ. The 40-Hz auditory steady-state response in patients with schizophrenia: a meta-analysis. JAMA Psychiatry. 2016;73:1145–53.

    Article  PubMed  Google Scholar 

  113. Grent-‘t-Jong T, Gajwani R, Gross J, Gumley AI, Krishnadas R, Lawrie SM, et al. Association of magnetoencephalographically measured high-frequency oscillations in visual cortex with circuit dysfunctions in local and large-scale networks during emerging psychosis. JAMA Psychiatry. 2020;77:852–62.

    Article  PubMed  Google Scholar 

  114. Hirano Y, Oribe N, Kanba S, Onitsuka T, Nestor PG, Spencer KM. Spontaneous gamma activity in schizophrenia. JAMA Psychiatry. 2015;72:813–21.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Hirano Y, Oribe N, Onitsuka T, Kanba S, Nestor PG, Hosokawa T, et al. Auditory cortex volume and gamma oscillation abnormalities in schizophrenia. Clin EEG Neurosci. 2020;51:244–51.

    Article  PubMed  Google Scholar 

  116. Edgar JC. Identifying electrophysiological markers of autism spectrum disorder and schizophrenia against a backdrop of normal brain development. Psychiatry Clin Neurosci. 2020;74:1–11.

    Article  PubMed  Google Scholar 

  117. Oribe N, Hirano Y, Del Re E, Mesholam-Gately RI, Woodberry KA, Ueno T, et al. Longitudinal evaluation of visual P300 amplitude in clinical high-risk subjects: An event-related potential study. Psychiatry Clin Neurosci. 2020;74:527–34.

    Article  CAS  PubMed  Google Scholar 

  118. Koshiyama D, Miyakoshi M, Joshi YB, Nakanishi M, Tanaka-Koshiyama K, Sprock J, et al. Source decomposition of the frontocentral auditory steady-state gamma band response in schizophrenia patients and healthy subjects. Psychiatry Clin Neurosci. 2021;75:172–9.

    Article  PubMed  Google Scholar 

  119. Uhlhaas PJ, Singer W. Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci. 2010;11:100–13.

    Article  CAS  PubMed  Google Scholar 

  120. Farzan F, Vernet M, Shafi MMD, Rotenberg A, Daskalakis ZJ, Pascual-Leone A. Characterizing and modulating brain circuitry through transcranial magnetic stimulation combined with electroencephalography. Front Neural Circuits. 2016;10:73.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Ferrarelli F, Massimini M, Peterson MJ, Riedner BA, Lazar M, Murphy MJ, et al. Reduced evoked gamma oscillations in the frontal cortex in schizophrenia patients: a TMS/EEG study. Am J Psychiatry. 2008;165:996–1005.

    Article  PubMed  Google Scholar 

  122. Ferrarelli F, Sarasso S, Guller Y, Riedner BA, Peterson MJ, Bellesi M, et al. Reduced natural oscillatory frequency of frontal thalamocortical circuits in schizophrenia. Arch Gen Psychiatry. 2012;69:766–74.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Noda Y. Toward the establishment of neurophysiological indicators for neuropsychiatric disorders using transcranial magnetic stimulation-evoked potentials: A systematic review. Psychiatry Clin Neurosci. 2020;74:12–34.

    Article  PubMed  Google Scholar 

  124. Radhu N, de Jesus DR, Ravindran LN, Zanjani A, Fitzgerald PB, Daskalakis ZJ. A meta-analysis of cortical inhibition and excitability using transcranial magnetic stimulation in psychiatric disorders. Clin Neurophysiol. 2013;124:1309–20.

    Article  PubMed  Google Scholar 

  125. Li X, Honda S, Nakajima S, Wada M, Yoshida K, Daskalakis ZJ, et al. TMS-EEG research to elucidate the pathophysiological neural bases in patients with schizophrenia: a systematic review. J Pers Med [Internet]. 2021;11. Available from: https://doi.org/10.3390/jpm11050388.

  126. Wu Y, Blichowski M, Daskalakis ZJ, Wu Z, Liu CC, Cortez MA, et al. Evidence that clozapine directly interacts on the GABAB receptor. Neuroreport. 2011;22:637–41.

    Article  CAS  PubMed  Google Scholar 

  127. Nair PC, McKinnon RA, Miners JO, Bastiampillai T. Binding of clozapine to the GABAB receptor: clinical and structural insights. Mol Psychiatry. 2020;25:1910–9.

    Article  PubMed  Google Scholar 

  128. Kaster TS, de Jesus D, Radhu N, Farzan F, Blumberger DM, Rajji TK, et al. Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia. Schizophr Res. 2015;165:157–62.

    Article  PubMed  Google Scholar 

  129. Haijma SV, Van Haren N, Cahn W, Koolschijn PCMP, Hulshoff Pol HE, Kahn RS. Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophr Bull. 2013;39:1129–38.

    Article  PubMed  Google Scholar 

  130. Kubo K-I. Increased densities of white matter neurons as a cross-disease feature of neuropsychiatric disorders. Psychiatry Clin Neurosci. 2020;74:166–75.

    Article  PubMed  Google Scholar 

  131. Sasabayashi D, Takayanagi Y, Takahashi T, Nemoto K, Furuichi A, Kido M, et al. Increased brain gyrification in the schizophrenia spectrum. Psychiatry Clin Neurosci. 2020;74:70–6.

    Article  PubMed  Google Scholar 

  132. Dong D, Wang Y, Chang X, Luo C, Yao D. Dysfunction of large-scale brain networks in schizophrenia: a meta-analysis of resting-state functional connectivity. Schizophr Bull. 2018;44:168–81.

    Article  PubMed  Google Scholar 

  133. Wolfers T, Rokicki J, Alnaes D, Berthet P, Agartz I, Kia SM, et al. Replicating extensive brain structural heterogeneity in individuals with schizophrenia and bipolar disorder. Hum Brain Mapp. 2021;42:2546–55.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Wolfers T, Doan NT, Kaufmann T, Alnæs D, Moberget T, Agartz I, et al. Mapping the heterogeneous phenotype of schizophrenia and bipolar disorder using normative models. JAMA Psychiatry. 2018;75:1146–55.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Li J, Cao X, Liu S, Li X, Xu Y. Efficacy of repetitive transcranial magnetic stimulation on auditory hallucinations in schizophrenia: A meta-analysis. Psychiatry Res. 2020;290:113141.

    Article  PubMed  Google Scholar 

  136. Pardiñas AF, Nalmpanti M, Pocklington AJ, Legge SE, Medway C, King A, et al. Pharmacogenomic variants and drug interactions identified through the genetic analysis of clozapine metabolism. Am J Psychiatry. 2019;176:477–86.

    Article  PubMed  Google Scholar 

  137. Legge SE, Clozapine-Induced Agranulocytosis Consortium, Hamshere ML, Ripke S, Pardinas AF, Goldstein JI, et al. Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia [Internet]. Mol Psychiatry. 2017;22:1502–8.

    Article  CAS  PubMed  Google Scholar 

  138. Saito T, Ikeda M, Mushiroda T, Ozeki T, Kondo K, Shimasaki A, et al. Pharmacogenomic study of clozapine-induced agranulocytosis/granulocytopenia in a Japanese population. Biol Psychiatry. 2016;80:636–42.

    Article  CAS  PubMed  Google Scholar 

  139. Takeuchi H, Siu C, Remington G, Fervaha G, Zipursky RB, Foussias G, et al. Does relapse contribute to treatment resistance? Antipsychotic response in first- vs. second-episode schizophrenia. Neuropsychopharmacology. 2019;44:1036–42.

    Article  CAS  PubMed  Google Scholar 

  140. Furuyashiki T, Kitaoka S. Neural mechanisms underlying adaptive and maladaptive consequences of stress: Roles of dopaminergic and inflammatory responses. Psychiatry Clin Neurosci. 2019;73:669–75.

    Article  CAS  PubMed  Google Scholar 

  141. Wang G, Zheng W, Li X-B, Wang S-B, Cai D-B, Yang X-H, et al. ECT augmentation of clozapine for clozapine-resistant schizophrenia: A meta-analysis of randomized controlled trials. J Psychiatr Res. 2018;105:23–32.

    Article  PubMed  Google Scholar 

  142. Petrides G, Malur C, Braga RJ, Bailine SH, Schooler NR, Malhotra AK, et al. Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study. Am J Psychiatry. 2015;172:52–8.

    Article  PubMed  Google Scholar 

  143. Zheng W, Cao X-L, Ungvari GS, Xiang Y-Q, Guo T, Liu Z-R, et al. Electroconvulsive therapy added to non-clozapine antipsychotic medication for treatment resistant schizophrenia: meta-analysis of randomized controlled trials. PLoS One. 2016;11:e0156510.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Sinclair DJ, Zhao S, Qi F, Nyakyoma K, Kwong JS, Adams CE. Electroconvulsive therapy for treatment-resistant schizophrenia. Cochrane Database Syst Rev. 2019;3:CD011847.

    PubMed  Google Scholar 

  145. Chan CYW, Abdin E, Seow E, Subramaniam M, Liu J, Peh CX, et al. Clinical effectiveness and speed of response of electroconvulsive therapy in treatment-resistant schizophrenia. Psychiatry Clin Neurosci. 2019;73:416–22.

    Article  PubMed  Google Scholar 

  146. Sienaert P, Dhossche DM, Vancampfort D, De Hert M, Gazdag G. A clinical review of the treatment of catatonia. Front Psychiatry. 2014;5:181.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Fink M, Taylor MA. The catatonia syndrome: forgotten but not gone. Arch Gen Psychiatry. 2009;66:1173–7.

    Article  PubMed  Google Scholar 

  148. Kocamer Şahin Ş, Demir B, Elboğa G, Altındağ A, Elmalı E. The effects of maintenance electroconvulsive therapy on hospitalization rates. J Nerv Ment Dis. 2021;209:155–8.

    Article  PubMed  Google Scholar 

  149. Kellner CH, Husain MM, Knapp RG, McCall WV, Petrides G, Rudorfer MV, et al. A novel strategy for continuation ECT in geriatric depression: phase 2 of the PRIDE study. AJP. 2016;173:1110–8.

    Article  Google Scholar 

  150. Chanpattana W, Chakrabhand ML, Sackeim HA, Kitaroonchai W, Kongsakon R, Techakasem P, et al. Continuation ECT in treatment-resistant schizophrenia: a controlled study. J ECT. 1999;15:178–92.

    Article  CAS  PubMed  Google Scholar 

  151. Danenberg R, Ruimi L, Shelef A, Paleacu, Kertesz D. A pilot study of cognitive impairment in longstanding electroconvulsive therapy-treated schizophrenia patients versus controls. J ECT. 2021;37:24–9.

    Article  CAS  PubMed  Google Scholar 

  152. Bansod A, Sonavane SS, Shah NB, De Sousa AA, Andrade C. A randomized, nonblind, naturalistic comparison of efficacy and cognitive outcomes with right unilateral, bifrontal, and bitemporal electroconvulsive therapy in schizophrenia. J ECT. 2018;34:26–30.

    Article  PubMed  Google Scholar 

  153. Tor P-C, Ying J, Ho NF, Wang M, Martin D, Ang CP, et al. Effectiveness of electroconvulsive therapy and associated cognitive change in schizophrenia: a naturalistic, comparative study of treating schizophrenia with electroconvulsive therapy. J ECT. 2017;33:272–7.

    Article  PubMed  Google Scholar 

  154. Moon S-Y, Kim M, Lho SK, Oh S, Kim SH, Kwon JS. Systematic review of the neural effect of electroconvulsive therapy in patients with schizophrenia: hippocampus and insula as the key regions of modulation. Psychiatry Investig. 2021;18:486–99.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Thomann PA, Wolf RC, Nolte HM, Hirjak D, Hofer S, Seidl U, et al. Neuromodulation in response to electroconvulsive therapy in schizophrenia and major depression. Brain Stimul. 2017;10:637–44.

    Article  PubMed  Google Scholar 

  156. Wang J, Tang Y, Curtin A, Xia M, Tang X, Zhao Y, et al. ECT-induced brain plasticity correlates with positive symptom improvement in schizophrenia by voxel-based morphometry analysis of grey matter. Brain Stimul. 2019;12:319–28.

    Article  CAS  PubMed  Google Scholar 

  157. Jiang Y, Xu L, Li X, Tang Y, Wang P, Li C, et al. Common increased hippocampal volume but specific changes in functional connectivity in schizophrenia patients in remission and non-remission following electroconvulsive therapy: A preliminary study. Neuroimage Clin. 2019;24:102081.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Jiang Y, Xia M, Li X, Tang Y, Li C, Huang H, et al. Insular changes induced by electroconvulsive therapy response to symptom improvements in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2019;89:254–62.

    Article  PubMed  Google Scholar 

  159. Paus T, Castro-Alamancos MA, Petrides M. Cortico-cortical connectivity of the human mid-dorsolateral frontal cortex and its modulation by repetitive transcranial magnetic stimulation. Eur J Neurosci. 2001;14:1405–11.

    Article  CAS  PubMed  Google Scholar 

  160. Pascual-Leone A, Valls-Solé J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain. 1994;117:847–58.

    Article  PubMed  Google Scholar 

  161. Chen R, Classen J, Gerloff C, Celnik P, Wassermann EM, Hallett M, et al. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology. 1997;48:1398–403.

    Article  CAS  PubMed  Google Scholar 

  162. Anderson VM, Goldstein ME, Kydd RR, Russell BR. Extensive gray matter volume reduction in treatment-resistant schizophrenia. Int J Neuropsychopharmacol. 2015;18:yv016.

    Article  CAS  Google Scholar 

  163. Kubera KM, Sambataro F, Vasic N, Wolf ND, Frasch K, Hirjak D, et al. Source-based morphometry of gray matter volume in patients with schizophrenia who have persistent auditory verbal hallucinations. Prog Neuropsychopharmacol Biol Psychiatry. 2014;50:102–9.

    Article  PubMed  Google Scholar 

  164. Zugman A, Gadelha A, Assunção I, Sato J, Ota VK, Rocha DL, et al. Reduced dorso-lateral prefrontal cortex in treatment resistant schizophrenia. Schizophr Res. 2013;148:81–6.

    Article  PubMed  Google Scholar 

  165. Bilder RM, Wu H, Chakos MH, Bogerts B, Pollack S, Aronowitz J, et al. Cerebral morphometry and clozapine treatment in schizophrenia. J Clin Psychiatry. 1994;55:53–6.

    PubMed  Google Scholar 

  166. Arango C, Breier A, McMahon R, Carpenter WT Jr, Buchanan RW. The relationship of clozapine and haloperidol treatment response to prefrontal, hippocampal, and caudate brain volumes. Am J Psychiatry. 2003;160:1421–7.

    Article  PubMed  Google Scholar 

  167. Molina V, Reig S, Sarramea F, Sanz J, Francisco Artaloytia J, Luque R, et al. Anatomical and functional brain variables associated with clozapine response in treatment-resistant schizophrenia. Psychiatry Res. 2003;124:153–61.

    Article  CAS  PubMed  Google Scholar 

  168. Ganella EP, Bartholomeusz CF, Seguin C, Whittle S, Bousman C, Phassouliotis C, et al. Functional brain networks in treatment-resistant schizophrenia. Schizophr Res. 2017;184:73–81.

    Article  PubMed  Google Scholar 

  169. Ochi R, Noda Y, Tsuchimoto S, Tarumi R, Honda S, Matsushita K, et al. White matter microstructural organizations in patients with severe treatment-resistant schizophrenia: A diffusion tensor imaging study. Prog Neuropsychopharmacol Biol Psychiatry. 2020;100:109871.

    Article  PubMed  Google Scholar 

  170. Siskind D, Honarparvar F, Hasan A, Wagner E, Sinha S, Orr S, et al. rTMS for clozapine refractory schizophrenia - A systematic review and pairwise meta-analysis. Schizophr Res. 2019;211:113–4.

    Article  PubMed  Google Scholar 

  171. Aleman A, Enriquez-Geppert S, Knegtering H, Dlabac-de Lange JJ. Moderate effects of noninvasive brain stimulation of the frontal cortex for improving negative symptoms in schizophrenia: Meta-analysis of controlled trials. Neurosci Biobehav Rev. 2018;89:111–8.

    Article  PubMed  Google Scholar 

  172. Osoegawa C, Gomes JS, Grigolon RB, Brietzke E, Gadelha A, Lacerda ALT, et al. Non-invasive brain stimulation for negative symptoms in schizophrenia: An updated systematic review and meta-analysis. Schizophr Res. 2018;197:34–44.

    Article  PubMed  Google Scholar 

  173. Jiang Y, Guo Z, Xing G, He L, Peng H, Du F, et al. Effects of high-frequency transcranial magnetic stimulation for cognitive deficit in schizophrenia: a meta-analysis. Front Psychiatry. 2019;10:135.

    Article  PubMed  PubMed Central  Google Scholar 

  174. Garg S, Sinha VK, Tikka SK, Mishra P, Goyal N. The efficacy of cerebellar vermal deep high frequency (theta range) repetitive transcranial magnetic stimulation (rTMS) in schizophrenia: A randomized rater blind-sham controlled study. Psychiatry Res. 2016;243:413–20.

    Article  PubMed  Google Scholar 

  175. Chauhan P, Garg S, Tikka SK, Khattri S. Efficacy of intensive cerebellar intermittent theta burst stimulation (iCiTBS) in treatment-resistant schizophrenia: a randomized placebo-controlled study. Cerebellum. 2021;20:116–23.

    Article  CAS  PubMed  Google Scholar 

  176. Tikka SK, Garg S, Sinha VK, Nizamie SH, Goyal N. Resting state dense array gamma oscillatory activity as a response marker for cerebellar-repetitive transcranial magnetic stimulation (rTMS) in schizophrenia. J ECT. 2015;31:258–62.

    Article  PubMed  Google Scholar 

  177. Demirtas-Tatlidede A, Freitas C, Cromer JR, Safar L, Ongur D, Stone WS, et al. Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia. Schizophr Res. 2010;124:91–100.

    Article  PubMed  PubMed Central  Google Scholar 

  178. Brady RO Jr, Gonsalvez I, Lee I, Öngür D, Seidman LJ, Schmahmann JD, et al. Cerebellar-prefrontal network connectivity and negative symptoms in schizophrenia. Am J Psychiatry. 2019;176:512–20.

    Article  PubMed  PubMed Central  Google Scholar 

  179. Shergill SS, Brammer MJ, Williams SC, Murray RM, McGuire PK. Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging. Arch Gen Psychiatry. 2000;57:1033–8.

    Article  CAS  PubMed  Google Scholar 

  180. Paillère-Martinot M-L, Galinowski A, Plaze M, Andoh J, Bartrés-Faz D, Bellivier F, et al. Active and placebo transcranial magnetic stimulation effects on external and internal auditory hallucinations of schizophrenia. Acta Psychiatr Scand. 2017;135:228–38.

    Article  PubMed  Google Scholar 

  181. Koops S, Slotema CW, Kos C, Bais L, Aleman A, Blom JD, et al. Predicting response to rTMS for auditory hallucinations: Younger patients and females do better. Schizophr Res. 2018;195:583–4.

    Article  PubMed  Google Scholar 

  182. Potkin SG, Alva G, Fleming K, Anand R, Keator D, Carreon D, et al. A PET study of the pathophysiology of negative symptoms in schizophrenia. Positron Emiss Tomogr Am J Psychiatry. 2002;159:227–37.

    Google Scholar 

  183. Vita A, Bressi S, Perani D, Invernizzi G, Giobbio GM, Dieci M, et al. High-resolution SPECT study of regional cerebral blood flow in drug-free and drug-naive schizophrenic patients. Am J Psychiatry. 1995;152:876–82.

    Article  CAS  PubMed  Google Scholar 

  184. Galderisi S, Merlotti E, Mucci A. Neurobiological background of negative symptoms. Eur Arch Psychiatry Clin Neurosci. 2015;265:543–58.

    Article  PubMed  Google Scholar 

  185. Shukla DK, Chiappelli JJ, Sampath H, Kochunov P, Hare SM, Wisner K, et al. Aberrant frontostriatal connectivity in negative symptoms of schizophrenia. Schizophr Bull. 2019;45:1051–9.

    Article  PubMed  Google Scholar 

  186. Picard H, Amado I, Mouchet-Mages S, Olié J-P, Krebs M-O. The role of the cerebellum in schizophrenia: an update of clinical, cognitive, and functional evidences. Schizophr Bull. 2008;34:155–72.

    Article  PubMed  Google Scholar 

  187. Andreasen NC, Nopoulos P, O’Leary DS, Miller DD, Wassink T, Flaum M. Defining the phenotype of schizophrenia: cognitive dysmetria and its neural mechanisms. Biol Psychiatry. 1999;46:908–20.

    Article  CAS  PubMed  Google Scholar 

  188. Andreasen NC, Paradiso S, O’Leary DS. “Cognitive dysmetria” as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? Schizophr Bull. 1998;24:203–18.

    Article  CAS  PubMed  Google Scholar 

  189. Cao H, Cannon TD. Cerebellar dysfunction and schizophrenia: from “cognitive dysmetria” to a potential therapeutic target. AJP. 2019;176:498–500.

    Article  Google Scholar 

  190. Anteraper SA, Guell X, Collin G, Qi Z, Ren J, Nair A, et al. Abnormal function in dentate nuclei precedes the onset of psychosis: a resting-state fMRI study in high-risk individuals. Schizophr Bull [Internet]. 2021 May 6; Available from: https://doi.org/10.1093/schbul/sbab038.

  191. Kim NY, Hsu J, Talmasov D, Joutsa J, Soussand L, Wu O, et al. Lesions causing hallucinations localize to one common brain network. Mol Psychiatry. 2021;26:1299–309.

    Article  PubMed  Google Scholar 

  192. Billeri L, Naro A A narrative review on non-invasive stimulation of the cerebellum in neurological diseases. Neurol Sci [Internet]. 2021 Mar 23; Available from: https://doi.org/10.1007/s10072-021-05187-1

  193. Pauly MG, Steinmeier A, Bolte C, Hamami F, Tzvi E, Münchau A, et al. Cerebellar rTMS and PAS effectively induce cerebellar plasticity. Sci Rep. 2021;11:3070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Palaniyappan L, White TP, Liddle PF. The concept of salience network dysfunction in schizophrenia: from neuroimaging observations to therapeutic opportunities. Curr Top Med Chem. 2012;12:2324–38.

    Article  CAS  PubMed  Google Scholar 

  195. Mallikarjun PK, Lalousis PA, Dunne TF, Heinze K, Reniers RL, Broome MR, et al. Aberrant salience network functional connectivity in auditory verbal hallucinations: a first episode psychosis sample. Transl Psychiatry. 2018;8:1–9.

    Article  Google Scholar 

  196. Palaniyappan L, Liddle PF. Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction. J Psychiatry Neurosci. 2012;37:17–27.

    Article  PubMed  PubMed Central  Google Scholar 

  197. Cash RFH, Weigand A, Zalesky A, Siddiqi SH, Downar J, Fitzgerald PB, et al. Using brain imaging to improve spatial targeting of transcranial magnetic stimulation for depression. Biol Psychiatry [Internet]. 2020 Jun 7; Available from: https://doi.org/10.1016/j.biopsych.2020.05.033

  198. Ozdemir RA, Tadayon E, Boucher P, Momi D, Karakhanyan KA, Fox MD, et al. Individualized perturbation of the human connectome reveals reproducible biomarkers of network dynamics relevant to cognition. Proc Natl Acad Sci USA. 2020;117:8115–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Chase HW, Boudewyn MA, Carter CS, Phillips ML. Transcranial direct current stimulation: a roadmap for research, from mechanism of action to clinical implementation. Mol Psychiatry. 2019;25:397–407.

    Article  PubMed  PubMed Central  Google Scholar 

  200. Yang F, Fang X, Tang W, Hui L, Chen Y, Zhang C, et al. Effects and potential mechanisms of transcranial direct current stimulation (tDCS) on auditory hallucinations: A meta-analysis. Psychiatry Res. 2019;273:343–9.

    Article  PubMed  Google Scholar 

  201. Kim J, Iwata Y, Plitman E, Caravaggio F, Chung JK, Shah P, et al. A meta-analysis of transcranial direct current stimulation for schizophrenia: “Is more better?”. J Psychiatr Res. 2019;110:117–26.

    Article  PubMed  Google Scholar 

  202. McCracken CB, Grace AA. High-frequency deep brain stimulation of the nucleus accumbens region suppresses neuronal activity and selectively modulates afferent drive in rat orbitofrontal cortex in vivo. J Neurosci. 2007;27:12601–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. de la Fuente-Sandoval C, León-Ortiz P, Azcárraga M, Stephano S, Favila R, Díaz-Galvis L, et al. Glutamate levels in the associative striatum before and after 4 weeks of antipsychotic treatment in first-episode psychosis: a longitudinal proton magnetic resonance spectroscopy study. JAMA Psychiatry. 2013;70:1057–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. de la Fuente-Sandoval C, Reyes-Madrigal F, Mao X, León-Ortiz P, Rodríguez-Mayoral O, Jung-Cook H, et al. Prefrontal and striatal gamma-aminobutyric acid levels and the effect of antipsychotic treatment in first-episode psychosis patients. Biol Psychiatry. 2018;83:475–83.

    Article  PubMed  CAS  Google Scholar 

  205. Plitman E, de la Fuente-Sandoval C, Reyes-Madrigal F, Chavez S, Gómez-Cruz G, León-Ortiz P, et al. Elevated myo-inositol, choline, and glutamate levels in the associative striatum of antipsychotic-naive patients with first-episode psychosis: a proton magnetic resonance spectroscopy study with implications for glial dysfunction. Schizophr Bull. 2016;42:415–24.

    Article  PubMed  Google Scholar 

  206. Mikell CB, McKhann GM, Segal S, McGovern RA, Wallenstein MB, Moore H. The hippocampus and nucleus accumbens as potential therapeutic targets for neurosurgical intervention in schizophrenia. Stereotact Funct Neurosurg. 2009;87:256–65.

    Article  PubMed  PubMed Central  Google Scholar 

  207. Perez SM, Shah A, Asher A, Lodge DJ. Hippocampal deep brain stimulation reverses physiological and behavioural deficits in a rodent model of schizophrenia. Int J Neuropsychopharmacol. 2013;16:1331–9.

    Article  CAS  PubMed  Google Scholar 

  208. Lippmann B, Barmashenko G, Funke K. Effects of repetitive transcranial magnetic and deep brain stimulation on long-range synchrony of oscillatory activity in a rat model of developmental schizophrenia. Eur J Neurosci. 2021;53:2848–69.

    Article  PubMed  Google Scholar 

  209. Ewing SG, Grace AA. Deep brain stimulation of the ventral hippocampus restores deficits in processing of auditory evoked potentials in a rodent developmental disruption model of schizophrenia. Schizophr Res. 2013;143:377–83.

    Article  PubMed  Google Scholar 

  210. Demjaha A, Egerton A, Murray RM, Kapur S, Howes OD, Stone JM, et al. Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol Psychiatry. 2014;75:e11–3.

    Article  CAS  PubMed  Google Scholar 

  211. Nakajima S, Takeuchi H, Plitman E, Fervaha G, Gerretsen P, Caravaggio F, et al. Neuroimaging findings in treatment-resistant schizophrenia: A systematic review: Lack of neuroimaging correlates of treatment-resistant schizophrenia. Schizophr Res. 2015;164:164–75.

    Article  PubMed  PubMed Central  Google Scholar 

  212. Corripio I, Roldán A, Sarró S, McKenna PJ, Alonso-Solís A, Rabella M, et al. Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial. EBioMedicine. 2020;51:102568.

    Article  PubMed  PubMed Central  Google Scholar 

  213. Cascella N, Butala AA, Mills K, Kim MJ, Salimpour Y, Wojtasievicz T, et al. Deep brain stimulation of the substantia nigra pars reticulata for treatment-resistant schizophrenia: a case report. Biol Psychiatry [Internet]. 2021 Apr 24 [cited 2021 Apr 27];0. Available from: http://www.biologicalpsychiatryjournal.com/article/S0006322321011124/abstract

  214. Roldán A, Portella MJ, Sampedro F, Alonso-Solís A, Sarró S, Rabella M, et al. Brain metabolic changes in patients with treatment resistant schizophrenia treated with deep brain stimulation: A series of cases. J Psychiatr Res. 2020;127:57–61.

    Article  PubMed  Google Scholar 

  215. Wang Y, Zhang C, Zhang Y, Gong H, Li J, Jin H, et al. Habenula deep brain stimulation for intractable schizophrenia: a pilot study. Neurosurg Focus. 2020;49:E9.

    Article  PubMed  Google Scholar 

  216. Namboodiri VMK, Rodriguez-Romaguera J, Stuber GD. The habenula. Curr Biol. 2016;26:R873–7.

    Article  CAS  PubMed  Google Scholar 

  217. Aizawa H, Zhu M. Toward an understanding of the habenula’s various roles in human depression. Psychiatry Clin Neurosci. 2019;73:607–12.

    Article  PubMed  Google Scholar 

  218. Mc Glanaghy E, Turner D, Davis GA, Sharpe H, Dougall N, Morris P, et al. A network meta-analysis of psychological interventions for schizophrenia and psychosis: Impact on symptoms. Schizophr Res. 2021;228:447–59.

    Article  Google Scholar 

  219. Jones C, Hacker D, Xia J, Meaden A, Irving CB, Zhao S, et al. Cognitive behavioural therapy plus standard care versus standard care for people with schizophrenia. Cochrane Database Syst Rev. 2018;12:CD007964.

    PubMed  Google Scholar 

  220. Wykes T, Steel C, Everitt B, Tarrier N. Cognitive behavior therapy for schizophrenia: effect sizes, clinical models, and methodological rigor. Schizophr Bull. 2008;34:523–37.

    Article  PubMed  Google Scholar 

  221. Velthorst E, Koeter M, van der Gaag M, Nieman DH, Fett A-KJ, Smit F, et al. Adapted cognitive-behavioural therapy required for targeting negative symptoms in schizophrenia: meta-analysis and meta-regression. Psychol Med. 2015;45:453–65.

    Article  CAS  PubMed  Google Scholar 

  222. Laws KR, Darlington N, Kondel TK, McKenna PJ, Jauhar S. Cognitive Behavioural Therapy for schizophrenia - outcomes for functioning, distress and quality of life: a meta-analysis. BMC Psychol. 2018;6:32.

    Article  PubMed  PubMed Central  Google Scholar 

  223. Burns AMN, Erickson DH, Brenner CA. Cognitive-behavioral therapy for medication-resistant psychosis: a meta-analytic review. Psychiatr Serv. 2014;65:874–80.

    Article  PubMed  Google Scholar 

  224. Kirkpatrick B, Galderisi S. Deficit schizophrenia: an update. World Psychiatry. 2008;7:143–7.

    Article  PubMed  PubMed Central  Google Scholar 

  225. Cascella NG, Fieldstone SC, Rao VA, Pearlson GD, Sawa A, Schretlen DJ. Gray-matter abnormalities in deficit schizophrenia. Schizophr Res. 2010;120:63–70.

    Article  PubMed  Google Scholar 

  226. Fischer BA, Keller WR, Arango C, Pearlson GD, McMahon RP, Meyer WA, et al. Cortical structural abnormalities in deficit versus nondeficit schizophrenia. Schizophr Res. 2012;136:51–4.

    Article  PubMed  PubMed Central  Google Scholar 

  227. Takayanagi M, Wentz J, Takayanagi Y, Schretlen DJ, Ceyhan E, Wang L, et al. Reduced anterior cingulate gray matter volume and thickness in subjects with deficit schizophrenia. Schizophr Res. 2013;150:484–90.

    Article  PubMed  PubMed Central  Google Scholar 

  228. Takayanagi Y, Sasabayashi D, Takahashi T, Komori Y, Furuichi A, Kido M, et al. Altered brain gyrification in deficit and non-deficit schizophrenia. Psychol Med. 2019;49:573–80.

    Article  PubMed  Google Scholar 

  229. Voineskos AN, Foussias G, Lerch J, Felsky D, Remington G, Rajji TK, et al. Neuroimaging evidence for the deficit subtype of schizophrenia. JAMA Psychiatry. 2013;70:472–80.

    Article  PubMed  Google Scholar 

  230. Chee TT, Chua L, Morrin H, Lim MF, Fam J, Ho R. Neuroanatomy of patients with deficit schizophrenia: an exploratory quantitative meta-analysis of structural neuroimaging studies. Int J Environ Res Public Health [Internet]. 2020 Aug 27;17. Available from: https://doi.org/10.3390/ijerph17176227

  231. Wheeler AL, Wessa M, Szeszko PR, Foussias G, Chakravarty MM, Lerch JP, et al. Further neuroimaging evidence for the deficit subtype of schizophrenia: a cortical connectomics analysis. JAMA Psychiatry. 2015;72:446–55.

    Article  PubMed  Google Scholar 

  232. Kronick J, Sabesan P, Burhan AM, Palaniyappan L Assessment of treatment resistance criteria in non-invasive brain stimulation studies of schizophrenia. Schizophr Res [Internet]. 2021 Jun 25; Available from: https://doi.org/10.1016/j.schres.2021.06.009

  233. Osório FL, Loureiro SR, Hallak JEC, Machado-de-Sousa JP, Ushirohira JM, Baes CVW, et al. Clinical validity and intrarater and test-retest reliability of the Structured Clinical Interview for DSM-5 - Clinician Version (SCID-5-CV). Psychiatry Clin Neurosci. 2019;73:754–60.

    Article  PubMed  Google Scholar 

  234. Rubio JM, Lencz T, Barber A, Moyett A, Ali S, Bassaw F, et al. Striatal functional connectivity in psychosis relapse: A hypothesis generating study. Schizophr Res [Internet]. 2021 Jun 25; Available from: https://doi.org/10.1016/j.schres.2021.06.010

  235. Tamminga CA, Clementz BA, Pearlson G, Keshavan M, Gershon ES, Ivleva EI, et al. Biotyping in psychosis: using multiple computational approaches with one data set. Neuropsychopharmacology. 2020;46:143–55.

    Article  PubMed  PubMed Central  Google Scholar 

  236. Clementz BA, Sweeney JA, Hamm JP, Ivleva EI, Ethridge LE, Pearlson GD, et al. Identification of distinct psychosis biotypes using brain-based biomarkers. Focus. 2018;16:225–36.

    Article  PubMed  PubMed Central  Google Scholar 

  237. Ivleva EI, Clementz BA, Dutcher AM, Arnold SJM, Jeon-Slaughter H, Aslan S, et al. Brain structure biomarkers in the psychosis biotypes: findings from the bipolar-schizophrenia network for intermediate phenotypes. Biol Psychiatry. 2017;82:26–39.

    Article  PubMed  Google Scholar 

  238. Ji L, Meda SA, Tamminga CA, Clementz BA, Keshavan MS, Sweeney JA, et al. Characterizing functional regional homogeneity (ReHo) as a B-SNIP psychosis biomarker using traditional and machine learning approaches. Schizophr Res. 2020;215:430–8.

    Article  PubMed  Google Scholar 

  239. Doucet GE, Moser DA, Luber MJ, Leibu E, Frangou S. Baseline brain structural and functional predictors of clinical outcome in the early course of schizophrenia. Mol Psychiatry. 2020;25:863–72.

    Article  PubMed  Google Scholar 

  240. Legge SE, Dennison CA, Pardiñas AF, Rees E, Lynham AJ, Hopkins L, et al. Clinical indicators of treatment-resistant psychosis. Br J Psychiatry. 2020;216:259–66.

    Article  PubMed  Google Scholar 

  241. Ambrosen KS, Skjerbæk MW, Foldager J, Axelsen MC, Bak N, Arvastson L, et al. A machine-learning framework for robust and reliable prediction of short- and long-term treatment response in initially antipsychotic-naïve schizophrenia patients based on multimodal neuropsychiatric data. Transl Psychiatry. 2020;10:1–13.

    Article  CAS  Google Scholar 

  242. Lizano P, Lutz O, Xu Y, Rubin LH, Paskowitz L, Lee AM, et al. Multivariate relationships between peripheral inflammatory marker subtypes and cognitive and brain structural measures in psychosis. Mol Psychiatry. 2020;26:3430–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  243. Zanos S. Closed-loop neuromodulation in physiological and translational research. Cold Spring Harb Perspect Med [Internet]. 2019 Nov 1;9. Available from: https://doi.org/10.1101/cshperspect.a034314.

  244. Jackson A, Mavoori J, Fetz EE. Long-term motor cortex plasticity induced by an electronic neural implant. Nature. 2006;444:56–60.

    Article  CAS  PubMed  Google Scholar 

  245. Dan Y, Poo M-M. Spike timing-dependent plasticity of neural circuits. Neuron. 2004;44:23–30.

    Article  CAS  PubMed  Google Scholar 

  246. Little S, Pogosyan A, Neal S, Zavala B, Zrinzo L, Hariz M, et al. Adaptive deep brain stimulation in advanced Parkinson disease. Ann Neurol. 2013;74:449–57.

    Article  PubMed  PubMed Central  Google Scholar 

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Author information

Author notes

  1. These authors jointly supervised this work: Ariel Graff-Guerrero, Shinichiro Nakajima.

Authors and Affiliations

  1. Department of Neuropsychiatry, Keio University, School of Medicine, Tokyo, Japan

    Masataka Wada, Yoshihiro Noda, Sakiko Tsugawa, Kazunari Yoshida, Hideaki Tani, Haruyuki Katayama, Fumihiko Ueno, Teruki Koizumi, Hiroyuki Uchida, Masaru Mimura & Shinichiro Nakajima

  2. Department of Neuropsychiatry, University of Yamanashi Faculty of Medicine, Yamanashi, Japan

    Yusuke Iwata & Takefumi Suzuki

  3. Tanenbaum Centre for Pharmacogenetics, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Kazunari Yoshida & Daniel J. Müller

  4. Azrieli Adult Neurodevelopmental Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Kazunari Yoshida

  5. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Kazunari Yoshida, Fumihiko Ueno, Fernando Caravaggio, Philip Gerretsen, Daniel J. Müller, Gary Remington & Ariel Graff-Guerrero

  6. Department of Neuropsychiatry, Kyushu University, Fukuoka, Japan

    Yoji Hirano

  7. Neural Dynamics Laboratory, Research Service, VA Boston Healthcare System, and Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Yoji Hirano

  8. Center for Evolutionary Cognitive Sciences, Graduate School of Art and Sciences, The University of Tokyo, Tokyo, Japan

    Shinsuke Koike

  9. Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan

    Daiki Sasabayashi

  10. Research Center for Idling Brain Science, University of Toyama, Toyama, Japan

    Daiki Sasabayashi

  11. Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Eric Plitman

  12. Department of Psychiatry, Gifu University Graduate School of Medicine, Gifu, Japan

    Kazutaka Ohi

  13. Brain Health Imaging Centre, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada

    Fumihiko Ueno, Fernando Caravaggio, Philip Gerretsen, Ariel Graff-Guerrero & Shinichiro Nakajima

  14. Department of Psychiatry, National Hospital Organization Shimofusa Psychiatric Medical Center, Chiba, Japan

    Teruki Koizumi

  15. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Philip Gerretsen & Ariel Graff-Guerrero

  16. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Philip Gerretsen, Daniel J. Müller, Gary Remington & Ariel Graff-Guerrero

  17. Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA, USA

    Anthony A. Grace

Authors
  1. Masataka Wada
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  2. Yoshihiro Noda
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  3. Yusuke Iwata
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  4. Sakiko Tsugawa
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  6. Hideaki Tani
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  7. Yoji Hirano
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  8. Shinsuke Koike
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  20. Masaru Mimura
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  23. Ariel Graff-Guerrero
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  24. Shinichiro Nakajima
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Contributions

MW contributed to perform a critical review of the literature, write and revise the manuscript. MW, YN, and SN designed the study and were in charge of overall direction and planning. ST, KY, HK wrote some part of the manuscript. YI, KY, HT, YH, SK, DS, EP, KO, FU, FC, TK, PG, TS, HU, DM, MM, GR, AG, and AG-G supported the critical review of the literature, the writing, and the revision of the article. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Shinichiro Nakajima.

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Competing interests

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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