Oxytocin-induced increases in cytokines and clinical effect on the core social features of autism: Analyses of RCT datasets.

Journal: Brain, behavior, and immunity

Volume: 118

Issue: 

Year of Publication: 

Affiliated Institutions:  Department of Psychiatry, Hamamatsu University School of Medicine, -- Handayama, Higashi-ku, Hamamatsu, Shizuoka -, Japan. Department of Psychiatry, Hamamatsu University School of Medicine, -- Handayama, Higashi-ku, Hamamatsu, Shizuoka -, Japan; Center for Health and Environmental Risk Research, National Institute for Environmental Studies, - Onogawa, Tsukuba, Ibaraki -, Japan. Biostatistics Section, Department of Data Science, Center for Clinical Science, National Center for Global Health and Medicine, -- Toyama, Shinjuku-ku, Tokyo -, Japan. Department of Child Development, United Graduate School of Child Development at Hamamatsu, -- Handayama, Higashi-ku, Hamamatsu, Shizuoka -, Japan. Department of Child Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, -- Hongo, Bunkyo-ku, Tokyo -, Japan. Graduate School of Psychology, Kanazawa Institute of Technology, - Ohgigaoka, Nonoichi, Ishikawa -, Japan. Child Development and Education, Faculty of Humanities, Wayo Women's University, -- Konodai, Ichikawa, Chiba -, Japan. Department of Psychology, Faculty of Liberal Arts, Teikyo University, -- Kaga, Itabashi-ku, Tokyo -, Japan. Department of Psychiatry, Hamamatsu University School of Medicine, -- Handayama, Higashi-ku, Hamamatsu, Shizuoka -, Japan; Department of Child Development, United Graduate School of Child Development at Hamamatsu, -- Handayama, Higashi-ku, Hamamatsu, Shizuoka -, Japan. Research Center for Child Mental Development, Kanazawa University, - Takara-machi, Kanazawa, Ishikawa -, Japan. Department of Child and Adolescent Psychiatry, Hamamatsu University School of Medicine, -- Handayama, Higashi-ku, Hamamatsu, Shizuoka -, Japan. Department of Pharmacology, Hamamatsu University School of Medicine, -- Handayama, Higashi-ku, Hamamatsu, Shizuoka -, Japan. Department of Medical Technique, Nagoya University Hospital, Tsurumai-cho, Showa-ku, Nagoya, Aichi -, Japan. Department of Psychiatry, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya, Aichi -, Japan. Department of Child and Adolescent Psychiatry, Hokkaido University Hospital, Kita , Nishi , Kita-ku, Sapporo, Hokkaido -, Japan. Department of Psychiatry, Graduate School of Medicine, Tohoku University, - Seiryo-machi, Aoba-ku, Sendai, Miyagi -, Japan. Department of Psychiatry, Osaka University Graduate School of Medicine, -, Yamadaoka, Suita, Osaka -, Japan; United Graduate School of Child Development, Osaka University, -, Yamadaoka, Suita, Osaka -, Japan. Department of Psychiatry, Osaka University Graduate School of Medicine, -, Yamadaoka, Suita, Osaka -, Japan. Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, -- Maidashi, Higashi-ku, Fukuoka -, Japan. Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, -- Maidashi, Higashi-ku, Fukuoka -, Japan; Department of Psychiatry, Division of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki, Kiyotake-cho, Kihara, Miyazaki, Miyazaki -, Japan. National Hospital Organization Sakakibara Hospital, Sakakibara-cho, Tsu, Mie -, Japan. Pathophysiology of Mental Disorders, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya, Aichi -, Japan. Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, - Matsuoka, Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui -, Japan. Department of Psychiatry, Hamamatsu University School of Medicine, -- Handayama, Higashi-ku, Hamamatsu, Shizuoka -, Japan; Department of Child Development, United Graduate School of Child Development at Hamamatsu, -- Handayama, Higashi-ku, Hamamatsu, Shizuoka -, Japan. Electronic address: yamasue@hama-med.ac.jp.

Abstract summary 

Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (P) < 0.001), IL-9 (56.64, 20.46 to 92.82, P < 0.001) and MIP-1b (18.27, 4.96 to 31.57, P < 0.001) compared with placebo. Inverted U-shape dose-response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (P < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = -0.05, -0.10 to 0.003, P = 0.067; IL-9: -0.01, -0.02 to -0.003, P = 0.005; MIP-1b: -0.02, -0.04 to -0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed. Trial registration: UMIN000015264, NCT03466671/UMIN000031412.

Authors & Co-authors:  Wakuda Benner Uemura Nishimura Kojima Kuroda Matsumoto Kanai Inada Harada Kameno Munesue Inoue Umemura Yamauchi Ogawa Kushima Suyama Saito Hamada Kano Honda Kikuchi Seto Tomita Miyoshi Matsumoto Kawaguchi Kanai Ikeda Nakamura Isomura Hirano Onitsuka Ozaki Kosaka Okada Kuwabara Yamasue

Study Outcome 

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Citations : 
Authors :  39
Identifiers
Doi : 10.1016/j.bbi.2024.03.013
SSN : 1090-2139
Study Population
Males
Mesh Terms
Other Terms
Clinical trial;Cytokine;Neuroinflammation;Neuropeptide;Oxytocin;Proteomics
Study Design
Study Approach
Country of Study
Publication Country
Netherlands