Recent Advances in the Early Intervention in Schizophrenia: Future Direction from Preclinical Findings

  • Kenji HashimotoEmail author
Schizophrenia and Other Psychotic Disorders (AK Pandurangi, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Schizophrenia and Other Psychotic Disorders


Purpose of Review

In the past decade, there has been increasing interest in the potential benefit of early intervention in schizophrenia. Patients with schizophrenia show cognitive impairment for several years preceding the onset of psychosis. The author discusses the recent topics on prevention of schizophrenia.

Recent Findings

Preclinical findings suggest that maternal immune activation (MIA) produces cognitive deficits as a prodromal symptom in juvenile offspring in rodents. Treatment with anti-inflammatory compounds, such as D-serine, 7,8-dihydroxyflavone (a TrkB agonist), sulforaphane (or its precursor glucoraphanin), and TPPU (1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea: a soluble epoxide hydrolase inhibitor), during adolescence might prevent the onset of behavioral abnormalities and parvalbumin immunoreactivity in the medial prefrontal cortex of adult offspring after MIA.


Based on the role of inflammation and cognitive impairment in the prodromal state, early intervention using anti-inflammatory compounds (i.e., D-serine, sodium benzoate, TrkB agonist, Nrf2 agonist, soluble epoxide hydrolase inhibitor) may reduce the risk of subsequent transition to schizophrenia.


D-Serine Keap1-Nrf2 Sodium benzoate Soluble epoxide hydrolase Sulforaphane TrkB agonist 



The author would like to thank the collaborators who are listed as the co-authors of our papers in the reference list.

Funding Information

This study was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant 17H042431 and Japan Agency for Medical Research and Development Grant JP19dm0107119.

Compliance with Ethical Standards

Conflict of Interest

The author declares that there are no conflicts of interest.

Human and Animal Rights and Informed Consent

This review article does not contain any original studies with humans or animal subjects performed by author.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
  2. 2.
    Elvevåg B, Goldberg TE. Cognitive impairment in schizophrenia is the core of the disorder. Crit Rev Neurobiol. 2000;14(1):21.CrossRefGoogle Scholar
  3. 3.
    Harvey PD. What is the evidence for changes in cognition and functioning over the lifespan in patients with schizophrenia? J Clin Psychiatry. 2014;75(Suppl 2):34–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Keefe RS. The longitudinal course of cognitive impairment in schizophrenia: an examination of data from premorbid through posttreatment phases of illness. J Clin Psychiatry. 2014;75(Suppl 2):2–8.CrossRefGoogle Scholar
  5. 5.
    •• Fusar-Poli P, Deste G, Smieskova R, Barlati S, Yung AR, Howes O, et al. Cognitive functioning in prodromal psychosis: a meta-analysis. Arch Gen Psychiatry. 2012;69:562–71. This is a meta-analysis of cognitive function in prodromal state. PubMedGoogle Scholar
  6. 6.
    Bora E, Murray RM. Meta-analysis of cognitive deficits in ultra-high risk to psychosis and first-episode psychosis: do the cognitive deficits progress over, or after, the onset of psychosis? Schizophr Bull. 2014;40:744–55.PubMedCrossRefGoogle Scholar
  7. 7.
    Mollon J, Reichenberg A. Cognitive development prior to onset of psychosis. Psychol Med. 2018;48:392–403.PubMedCrossRefGoogle Scholar
  8. 8.
    Hauser M, Zhang JP, Sheridan EM, Burdick KE, Mogil R, Kane JM, et al. Neuropsychological test performance to enhance identification of subjects at clinical high risk for psychosis and to be most promising for predictive algorithms for conversion to psychosis: a meta-analysis. J Clin Psychiatry. 2017;78:e28–40.PubMedCrossRefGoogle Scholar
  9. 9.
    Bolt LK, Amminger GP, Farhall J, McGorry PD, Nelson B, Markulev C, et al. Neurocognition as a predictor of transition to psychotic disorder and functional outcomes in ultra-high risk participants: findings from the NEURAPRO randomized clinical trial. Schizophr Res. 2018;206:67–74. Scholar
  10. 10.
    Bloomfield PS, Selvaraj S, Veronese M, Rizzo G, Bertoldo A, Owen DR, et al. Microglial activity in people at ultra high risk of psychosis and in schizophrenia: an [11C]PBR28 PET brain imaging study. Am J Psychiatry. 2016;173:44–52.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Di Biase MA, Zalesky A, O’keefe G, Laskaris L, Baune BT, Weickert CS, et al. PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia. Transl Psychiatry. 2017;7:e1225.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Hafizi S, Da Silva T, Gerritsen C, Kiang M, Bagby RM, Prce I, et al. Imaging microglial activation in individuals at clinical high risk for psychosis: an in vivo PET study with [18F]FEPPA. Neuropsychopharmacology. 2017;42:2474–81.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Marques TR, Ashok AH, Pillinger T, Veronese M, Turkheimer FE, Dazzan P, et al. Neuroinflammation in schizophrenia: meta-analysis of in vivo microglial imaging studies. Psychol Med. 2018:1–11.
  14. 14.
    Laskaris LE, Di Biase MA, Everall I, Chana G, Christopoulos A, Skafidas E, et al. Microglial activation and progressive brain changes in schizophrenia. Br J Pharmacol. 2016;173:666–80.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Mendelson T, Eaton WW. Recent advances in the prevention of mental disorders. Soc Psychiatry Psychiatr Epidemiol. 2018;53:325–39.PubMedCrossRefGoogle Scholar
  16. 16.
    Canetta S, Sourander A, Surcel HM, Hinkka-Yli-Salomäki S, Leiviskä J, Kellendonk C, et al. Elevated maternal C-reactive protein and increased risk of schizophrenia in a national birth cohort. Am J Psychiatry. 2014;171:960–8.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    • Estes ML, McAllister AK. Maternal immune activation: implications for neuropsychiatric disorders. Science. 2016;353:772–7. This is a review article on MIA and psychiatric disorders. PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    •• Brown AS, Meyer U. Maternal immune activation and neuropsychiatric illness: a translational research perspective. Am J Psychiatry. 2018;175:1073–83. This is a review article on MIA and psychiatric disorders. PubMedCrossRefGoogle Scholar
  19. 19.
    Boulanger-Bertolus J, Pancaro C, Mashour GA. Increasing role of maternal immune activation in neurodevelopmental disorders. Front Behav Neurosci. 2018;12:230.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Gumusoglu SB, Stevens HE. Maternal inflammation and neurodevelopmental programming: a review of preclinical outcomes and implications for translational psychiatry. Biol Psychiatry. 2019;85:107–21.PubMedCrossRefGoogle Scholar
  21. 21.
    Lydholm CN, Köhler-Forsberg O, Nordentoft M, Yolken RH, Mortensen PB, Petersen L, et al. Parental infections before, during, and after pregnancy as risk factors for mental disorders in childhood and adolescence: a nationwide Danish study. Biol Psychiatry. 2019;85:317–25.PubMedCrossRefGoogle Scholar
  22. 22.
    Smolders S, Notter T, Smolders SMT, Rigo JM, Brône B. Controversies and prospects about microglia in maternal immune activation models for neurodevelopmental disorders. Brain Behav Immun. 2018;73:51–65.PubMedCrossRefGoogle Scholar
  23. 23.
    • Fujita Y, Ishima T, Hashimoto K. Supplementation with D-serine prevents the onset of cognitive deficits in adult offspring after maternal immune activation. Sci Rep. 2016;6:37261. This is an article showing beneficial effects of D-serine in prodromal model of schizophrenia. PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    •• Han M, Zhang JC, Yao W, Yang C, Ishima T, Ren Q, et al. Intake of 7,8-dihydroxyflavone during juvenile and adolescent stages prevents onset of psychosis in adult offspring after maternal immune activation. Sci Rep. 2016;6:36087. This is an article showing beneficial effects of 7,8-dihydroxyflavone (TrkB agonist) in prodromal model of schizophrenia. PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Han M, Zhang JC, Huang XF, Hashimoto K. Intake of 7,8-dihydroxyflavone from pregnancy to weaning prevents cognitive deficits in adult offspring after maternal immune activation. Eur Arch Psychiatry Clin Neurosci. 2017;267:479–83.PubMedCrossRefGoogle Scholar
  26. 26.
    Dabbah-Assadi F, Alon D, Golani I, Doron R, Kremer I, Beloosesky R, et al. The influence of immune activation at early vs late gestation on fetal NRG1-ErbB4 expression and behavior in juvenile and adult mice offspring. Brain Behav Immun. 2019. Scholar
  27. 27.
    Hashimoto K, Malchow B, Falkai P, Schmitt A. Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci. 2013;263:367–77.PubMedCrossRefGoogle Scholar
  28. 28.
    Hashimoto K. Targeting of NMDA receptors in new treatments for schizophrenia. Expert Opin Ther Targets. 2014;18:1049–63.PubMedCrossRefGoogle Scholar
  29. 29.
    Ohgi Y, Futamura T, Hashimoto K. Glutamate signaling in synaptogenesis and NMDA receptors as potential therapeutic targets for psychiatric disorders. Curr Mol Med. 2015;15:206–21.PubMedCrossRefGoogle Scholar
  30. 30.
    Hardingham GE, Do KQ. Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis. Nat Rev Neurosci. 2016;17:125–34.PubMedCrossRefGoogle Scholar
  31. 31.
    Coyle JT. Schizophrenia: basic and clinical. Adv Neurobiol. 2017;15:255–80.PubMedCrossRefGoogle Scholar
  32. 32.
    Javitt DC, Lee M, Kantrowitz JT, Martinez A. Mismatch negativity as a biomarker of theta band oscillatory dysfunction in schizophrenia. Schizophr Res. 2018;191:51–60.PubMedCrossRefGoogle Scholar
  33. 33.
    Kantrowitz JT, Swerdlow NR, Dunn W, Vinogradov S. Auditory system target engagement during plasticity-based interventions in schizophrenia: a focus on modulation of N-methyl-D-aspartate-type glutamate receptor function. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018;3:581–90.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, et al. Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry. 2003;60:572–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Hashimoto K, Engberg G, Shimizu E, Nordin C, Lindström LH, Iyo M. Reduced D-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog Neuro-Psychopharmacol Biol Psychiatry. 2005;29:767–9.CrossRefGoogle Scholar
  36. 36.
    Guercio GD, Panizzutti R. Potential and challenges for the clinical use of D-serine as a cognitive enhancer. Front Psychiatry. 2018;9:14.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    MacKay MB, Kravtsenyuk M, Thomas R, Mitchell ND, Dursun SM, Baker GB. D-Serine: Potential therapeutic agent and/or biomarker in schizophrenia and depression? Front Psychiatry. 2018;10:25.CrossRefGoogle Scholar
  38. 38.
    Miya K, Inoue R, Takata Y, Abe M, Natsume R, Sakimura K, et al. Serine racemase is predominantly localized in neurons in mouse brain. J Comp Neurol. 2008;510:641–54.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Coyle JT, Balu DT. The role of serine racemase in the pathophysiology of brain disorders. Adv Pharmacol. 2018;82:35–56.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Wolosker H. The neurobiology of D-serine signaling. Adv Pharmacol. 2018;82:325–48.PubMedCrossRefGoogle Scholar
  41. 41.
    Ivanov AD, Mothet JP. The plastic D-serine signaling pathway: sliding from neurons to glia and vice-versa. Neurosci Lett. 2019;689:21–5.PubMedCrossRefGoogle Scholar
  42. 42.
    Perez EJ, Tapanes SA, Loris ZB, Balu DT, Sick TJ, Coyle JT, et al. Enhanced astrocytic D-serine underlies synaptic damage after traumatic brain injury. J Clin Invest. 2017;127:3114–25.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Dong C, Zhang JC, Ren Q, Ma M, Qu Y, Zhang K, et al. Deletion of serine racemase confers D-serine -dependent resilience to chronic social defeat stress. Neurochem Int. 2018;116:43–51.PubMedCrossRefGoogle Scholar
  44. 44.
    Levin R, Dor-Abarbanel AE, Edelman S, Durrant AR, Hashimoto K, Javitt DC, et al. Behavioral and cognitive effects of the N-methyl-D-aspartate receptor co-agonist D-serine in healthy humans: initial findings. J Psychiatr Res. 2015;61:188–95.PubMedCrossRefGoogle Scholar
  45. 45.
    Kantrowitz JT, Epstein ML, Lee M, Lehrfeld N, Nolan KA, Shope C, et al. Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: correlation with symptoms. Schizophr Res. 2018;191:70–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Koshiyama D, Kirihara K, Tada M, Nagai T, Fujioka M, Usui K, et al. Gamma-band auditory steady-state response is associated with plasma levels of D-serine in schizophrenia: an exploratory study. Schizophr Res. 2019;208:467–9. Scholar
  47. 47.
    Panizzutti R, Fisher M, Garrett C, Man WH, Sena W, Madeira C, et al. Association between increased serum D-serine and cognitive gains induced by intensive cognitive training in schizophrenia. Schizophr Res. 2018;207:63–9. Scholar
  48. 48.
    Chang CH, Lane HY, Tseng PT, Chen SJ, Liu CY, Lin CH. Effect of N-methyl-D-aspartate-receptor-enhancing agents on cognition in patients with schizophrenia: a systematic review and meta-analysis of double-blind randomised controlled trials. J Psychopharmacol. 2019;33:436–48. Scholar
  49. 49.
    Hagiwara H, Iyo M, Hashimoto K. Neonatal disruption of serine racemase causes schizophrenia-like behavioral abnormalities in adulthood: clinical rescue by D-serine. PLoS One. 2013;8:e62438.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Ryan A, Baker A, Dark F, Foley S, Gordon A, Hatherill S, et al. The efficacy of sodium benzoate as an adjunctive treatment in early psychosis - CADENCE-BZ: study protocol for a randomized controlled trial. Trials. 2017;18:165.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Han M, Zhang JC, Hashimoto K. Increased levels of C1q in the prefrontal cortex of adult offspring after maternal immune activation: prevention by 7,8-dihydroxyflavone. Clin Psychopharmacol Neurosci. 2017;15:64–7.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Shirai Y, Fujita Y, Hashimoto R, Ohi K, Yamamori H, Yasuda Y, et al. Dietary intake of sulforaphane-rich broccoli sprout extracts during juvenile and adolescence can prevent phencyclidine-induced cognitive deficits at adulthood. PLoS One. 2015;10:e0127244.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    •• Matsuura A, Ishima T, Fujita Y, Iwayama Y, Hasegawa S, Kawahara-Miki R, et al. Dietary glucoraphanin prevents the onset of psychosis in the adult offspring after maternal immune activation. Sci Rep. 2018;8:2158. This is an article showing beneficial effects of dietary glucoraphanin in the prevention of psychosis in offspring after MIA. PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    •• Ma M, Ren Q, Yang J, Zhang K, Xiong Z, Ishima T, et al. Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation. Proc Natl Acad Sci U S A. 2019. This is the first article showing the role of soluble epoxide hydrolase in neurodevelopmental disorders such as schizophrenia and ASD. CrossRefGoogle Scholar
  55. 55.
    CoNCERT Pharmaceuticals Inc. 2019.
  56. 56.
    •• Lane HY, Lin CH, Green MF, Hellemann G, Huang CC, Chen PW, et al. Add-on treatment of benzoate for schizophrenia: a randomized, double-blind, placebo-controlled trial of D-amino acid oxidase inhibitor. JAMA Psychiatry. 2013;70:1267–75. This is an article showing beneficial effects of sodium benzoate in patients with schizophrenia. PubMedCrossRefGoogle Scholar
  57. 57.
    Lin CH, Lin CH, Chang YC, Huang YJ, Chen PW, Yang HT, et al. Sodium benzoate, a D-amino acid oxidase inhibitor, added to clozapine for the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Biol Psychiatry. 2018;84:422–32.PubMedCrossRefGoogle Scholar
  58. 58.
    Matsuura A, Fujita Y, Iyo M, Hashimoto K. Effects of sodium benzoate on pre-pulse inhibition deficits and hyperlocomotion in mice after administration of phencyclidine. Acta Neuropsychiatr. 2015;27:159–67.PubMedCrossRefGoogle Scholar
  59. 59.
    Popiolek M, Tierney B, Steyn SJ, DeVivo M. Lack of effect of sodium benzoate at reported clinical therapeutic concentration on D-alanine metabolism in dogs. ACS Chem Neurosci. 2018;9:2832–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Brahmachari S, Jana A, Pahan K. Sodium benzoate, a metabolite of cinnamon and a food additive, reduces microglial and astroglial inflammatory responses. J Immunol. 2009;183:5917–27.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Nieto R, Kukuljan M, Silva H. BDNF and schizophrenia: from neurodevelopment to neuronal plasticity, learning, and memory. Front Psychiatry. 2013;4:45.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Rodrigues-Amorim D, Rivera-Baltanás T, Bessa J, Sousa N, Vallejo-Curto MC, Rodríguez-Jamardo C, et al. The neurobiological hypothesis of neurotrophins in the pathophysiology of schizophrenia: a meta-analysis. J Psychiatr Res. 2018;106:43–53.PubMedCrossRefGoogle Scholar
  63. 63.
    • Yang B, Ren Q, Zhang JC, Chen QX, Hashimoto K. Altered expression of BDNF, BDNF pro-peptide and their precursor proBDNF in brain and liver tissues from psychiatric disorders: rethinking the brain-liver axis. Transl Psychiatry. 2017;7:e1128. This is an article showing abnormalities in proBDNF, BDNF, and BDNF pro-peptide in the postmortem brain from schizophrenia. PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Islam F, Mulsant BH, Voineskos AN, Rajji TK. Brain-derived neurotrophic factor expression in individuals with schizophrenia and healthy aging: testing the accelerated aging hypothesis of schizophrenia. Curr Psychiatry Rep. 2017;19:36.PubMedCrossRefGoogle Scholar
  65. 65.
    Du X, Hill RA. 7,8-Dihydroxyflavone as a pro-neurotrophic treatment for neurodevelopmental disorders. Neurochem Int. 2015;89:170–80.PubMedCrossRefGoogle Scholar
  66. 66.
    Liu C, Chan CB, Ye K. 7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders. Transl Neurodegener. 2016;5:2.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Makar TK, Nimmagadda VK, Singh IS, Lam K, Mubariz F, Judge SI, et al. TrkB agonist, 7,8-dihydroxyflavone, reduces the clinical and pathological severity of a murine model of multiple sclerosis. J Neuroimmunol. 2016;292:9–20.PubMedCrossRefGoogle Scholar
  68. 68.
    Zhang JC, Yao W, Hashimoto K. Brain-derived neurotrophic factor (BDNF)-TrkB signaling in inflammation-related depression and potential therapeutic targets. Curr Neuropharmacol. 2016;14:721–31.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Ren Q, Zhang JC, Fujita Y, Ma M, Wu J, Hashimoto K. Effects of TrkB agonist 7,8-dihydroxyflavone on sensory gating deficits in mice after administration of methamphetamine. Pharmacol Biochem Behav. 2013;106:124–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Ren Q, Zhang JC, Ma M, Fujita Y, Wu J, Hashimoto K. 7,8-Dihydroxyflavone, a TrkB agonist, attenuates behavioral abnormalities and neurotoxicity in mice after administration of methamphetamine. Psychopharmacology. 2014;231:159–66.PubMedCrossRefGoogle Scholar
  71. 71.
    Zhang JC, Wu J, Fujita Y, Yao W, Ren Q, Yang C, et al. Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation. Int J Neuropsychopharmacol. 2014;18:pyu077.PubMedGoogle Scholar
  72. 72.
    Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M, et al. Comparison of ketamine, 7,8-dihydroxyflavone, and ANA-12 antidepressant effects in the social defeat stress model of depression. Psychopharmacology. 2015;232:4325–35.PubMedCrossRefGoogle Scholar
  73. 73.
    Shirayama Y, Yang C, Zhang JC, Ren Q, Yao W, Hashimoto K. Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist. Eur Neuropsychopharmacol. 2015;25:2449–58.PubMedCrossRefGoogle Scholar
  74. 74.
    Agarwal V, Blom AM. Roles of complement C1q in pneumococcus-host interactions. Crit Rev Immunol. 2015;35:173–84.PubMedCrossRefGoogle Scholar
  75. 75.
    Kouser L, Madhukaran SP, Shastri A, Saraon A, Ferluga J, Al-Mozaini M. Emerging and novel functions of complement protein C1q. Front Immunol. 2015;6:317.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    • Yamamoto M, Kensler TW, Motohashi H. The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev. 2018;98:1169–203. This is an excellent review article on Keap1-Nrf2 system. PubMedCrossRefGoogle Scholar
  77. 77.
    Hashimoto K. Essential role of Keap1-Nrf2 signaling in mood disorders: overview and future perspective. Front Pharmacol. 2018;9:1182.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    • Yao W, Zhang JC, Ishima T, Dong C, Yang C, Ren Q, et al. Role of Keap1-Nrf2 signaling in depression and dietary intake of glucoraphanin confers stress resilience in mice. Sci Rep. 2016;6:30659. This is an article showing stress resilience in Nrf2 KO mice. PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M, et al. Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation. J Nutr Biochem. 2017;39:134–44.PubMedCrossRefGoogle Scholar
  80. 80.
    Zhang JC, Yao W, Dong C, Han M, Shirayama Y, Hashimoto K. Keap1-Nrf2 signaling pathway confers resilience versus susceptibility to inescapable electric stress. Eur Arch Psychiatry Clin Neurosci. 2018;268:865–70.PubMedCrossRefGoogle Scholar
  81. 81.
    Chen H, Wu J, Zhang J, Fujita Y, Ishima T, Iyo M, et al. Protective effects of the antioxidant sulforaphane on behavioral changes and neurotoxicity in mice after the administration of methamphetamine. Psychopharmacology. 2012;222:37–45.PubMedCrossRefGoogle Scholar
  82. 82.
    Shirai Y, Fujita Y, Hashimoto K. Effects of the antioxidant sulforaphane on hyperlocomotion and prepulse inhibition deficits in mice after phencyclidine administration. Clin Psychopharmacol Neurosci. 2012;10:94–8.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    McNamara RK, Almeida DM. Omega-3 polyunsaturated fatty acid deficiency and progressive neuropathology in psychiatric disorders: a review of translational evidence and candidate mechanisms. Harv Rev Psychiatry. 2019;27:94–107.PubMedGoogle Scholar
  84. 84.
    Amminger GP, Schäfer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67:146–54.PubMedCrossRefGoogle Scholar
  85. 85.
    McGorry PD, Nelson B, Markulev C, Yuen HP, Schäfer MR, Mossaheb N, et al. Effect of ω-3 polyunsaturated fatty acids in young people at ultrahigh risk for psychotic pisorders: the NEURAPRO randomized clinical trial. JAMA Psychiatry. 2017;74:19–27.PubMedCrossRefGoogle Scholar
  86. 86.
    Davies C, Cipriani A, Ioannidis JPA, Radua J, Stahl D, Provenzani U, et al. Lack of evidence to favor specific preventive interventions in psychosis: a network meta-analysis. World Psychiatry. 2018;17:196–209.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Swardfager W, Hennebelle M, Yu D, Hammock BD, Levitt AJ, Hashimoto K, et al. Metabolic/inflammatory/vascular comorbidity in psychiatric disorders; soluble epoxide hydrolase (sEH) as a possible new target. Neurosci Biobehav Rev. 2018;87:56–66.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Hashimoto K. Role of soluble epoxide hydrolase in metabolism of PUFAs in psychiatric and neurological disorders. Front Pharmacol. 2018;10:36.CrossRefGoogle Scholar
  89. 89.
    Morisseau C, Hammock BD. Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health. Annu Rev Pharmacol Toxicol. 2013;53:37–58.PubMedCrossRefGoogle Scholar
  90. 90.
    Hashimoto K. Soluble epoxide hydrolase: a new therapeutic target for depression. Expert Opin Ther Targets. 2016;20:1149–51.PubMedCrossRefGoogle Scholar
  91. 91.
    Wagner KM, McReynolds CB, Schmidt WK, Hammock BD. Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases. Pharmacol Ther. 2017;180:62–76.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    • Ren Q, Ma M, Ishima T, Morisseau C, Yang J, Wagner KM, et al. Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress. Proc Natl Acad Sci U S A. 2016;113:E1944–52. This is the first article showing the role of soluble epoxide hydrolase in depression. PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    • Ren Q, Ma M, Yang J, Nonaka R, Yamaguchi A, Ishikawa KI, et al. Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson’s disease. Proc Natl Acad Sci U S A. 2018;115:E5815–23. This is the first article showing the role of soluble epoxide hydrolase in Parkinson’s disease and dementia with Lewy body. PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Schultze-Lutter F, Michel C, Schmidt SJ, Schimmelmann BG, Maric NP, Salokangas RK, et al. EPA guidance on the early detection of clinical high risk states of psychoses. Eur Psychiatry. 2015;30:405–16.PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Division of Clinical NeuroscienceChiba University Center for Forensic Mental HealthChibaJapan

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