¹National Center of Neurology and Psychiatry, Department of Preventive Intervention for Psychiatric Disorders, National Institute of Mental Health, Tokyo, Japan, ²Tohoku University, Department of Psychiatry, Graduate School of Medicine, Sendai, Japan, ³Osaka International University Faculty of Human Sciences, Department of Health Science, Osaka, Japan, ⁴Toho University Faculty of Medicine, Department of Neuropsychiatry, Tokyo, Japan, ⁵Nara Medical University School of Medicine, Department of Psychiatry, Nara, Japan, ⁶Tohoku University Hospital, Department of Psychiatry, Sendai, Japan, ⁷University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Department of Neuropsychiatry, Toyama, Japan, ⁸Kurume University School of Medicine, Department of Neuropsychiatry, Fukuoka, Japan, ⁹National Center of Neurology and Psychiatry, Department of Clinical Data Science, Clinical Research & Education Promotion Division, Tokyo, Japan, ¹⁰National Center of Neurology and Psychiatry, Department of Sleep-Wake Disorders, National Institute of Mental Health, Tokyo, Japan, ¹¹Akitsukounoike Hospital, Department of Psychiatry, Nara, Japan, ¹²Tokyo Metropolitan Matsuzawa Hospital, Department of Psychiatry, Tokyo, Japan, ¹³Chiba University, Center for Forensic Mental Health, Chiba, Japan, ¹⁴Akita University Graduate School of Medicine, Department of Neuropsychiatry, Akita, Japan, ¹⁵Janssen Pharmaceutical K.K., Medical Affairs Division, Tokyo, Japan, ¹⁶National Center of Neurology and Psychiatry, Department of Psychiatry, National Center Hospital, Tokyo, Japan

Background: Individuals at ultra-high risk for psychosis (UHR) exhibit an elevated vulnerability to psychosis as a result of excessive stress, rendering resilience of critical importance. As a biological marker for UHR, blood levels of cytokines are gaining attention. Specifically, serum concentrations of transforming growth factor-β1 (TGF-β1), a neuroprotective cytokine, have been suggested to maintain social functioning in UHR individuals.

Aims & Objectives: The present study examined longitudinal changes in serum concentrations of several inflammatory and neuroprotective cytokines among UHR individuals before and after the first state of emergency declared in response to COVID-19 on April 7, 2020, in Japan, which imposed strong nationwide behavioral restrictions.

Method: A multicenter, longitudinal cohort study was conducted which included seven hospitals affiliated with academic institutions in Japan, i.e., the National Center of Neurology and Psychiatry, the University of Toyama, Toho University, Nara Medical University, Tohoku University, Kurume University, and Chiba University. This study was also a joint collaborative study with Janssen Pharmaceutical K.K. of Johnson and Johnson in Japan.

Results: Participants included 52 subjects with UHR and 28 healthy volunteers as a control group (HC). Serum concentrations of brain-derived neurotrophic factor, which has been demonstrated to decrease in response to psychological stressors, exhibited a decrease following the state of emergency declaration in comparison to levels prior to the declaration in both UHR (p < 0.001) and HC (p < 0.001). Especially in UHR, blood concentrations of TGF-β1 (p < 0.001) and TGF-β2 (p < 0.001), which possess neuroprotective effects, were increased, while levels of the inflammatory cytokines, e.g., interferon-γ (p < 0.001), interleukin-6 (p = 0.002), and interleukin-12p70 (p < 0.001), were decreased compared to pre-declaration levels. Mixed-effects models for repeated measures revealed a significant increase in TGF-β1 and TGF-β2 concentrations as well as a significant decrease in inflammatory cytokine levels only in the UHR, but not in the HC.

Discussion & Conclusions: Increased levels of neuroprotective cytokines in response to psychological stress for individuals with UHR may suggest compensatory mechanisms that could support resilience during the course of the pandemic which may avert the exacerbation of psychiatric symptoms due to neuroinflammation. The findings in this study provide potential insights for the development of strategies aimed at preventing the onset of psychosis and facilitating early intervention in individuals with UHR.