OXYTOCIN-INDUCED INCREASES IN CYTOKINES AND CLINICAL EFFECT ON THE CORE SOCIAL SYMPTOMS OF AUTISM

Abstract Background Oxytocin may provide a novel treatment for the core symptoms of autism spectrum disorder (ASD). However, previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms including interactions with other molecules remain unclear. Aims & Objectives The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical improvements of autism social core symptom. Method 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. Results 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 (PFDR) = 0.009), IL-9 (56.64, 20.46 to 92.82, PFDR = 0.017) and MIP-1b (18.27, 4.96 to 31.57, PFDR = 0.017) compared with placebo. Inverted U-shape dose-response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P = 0.025; IL-9: P = 0.002; MIP- 1b: P = 0.010). Increased IL-7 in participants with ASD after 6 weeks oxytocin administration compared with placebo was verified in the confirmatory Syntocinon trial dataset (19.74, 0.31 to 39.18, P = 0.047). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed correlations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: r = −.347, P = 0.089; IL-9: r = −.489, P = 0.013; MIP-1b: r = −.527, P = 0.007). Discussion & Conclusion These findings provide the first evidence for the role of interaction between oxytocin and neuroinflammation in the treatment of ASD core social symptoms, and support the potential role of this interaction as a novel therapeutic seed.