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Probiotic and Oxytocin Combination Therapy in Patients with Autism Spectrum Disorder: A Randomized, Double-Blinded, Placebo-Controlled Pilot Trial.

ABSTRACT: Autism spectrum disorder (ASD) is a rapidly growing neurodevelopmental disorder. Both probiotics and oxytocin were reported to have therapeutic potential; however, the combination therapy has not yet been studied. We conducted a randomized, double-blinded, placebo-controlled, 2-stage pilot trial in 35 individuals with ASD aged 3-20 years (median = 10.30 years). Subjects were randomly assigned to receive daily Lactobacillus plantarum PS128 probiotic (6 × 10¹⁰ CFUs) or a placebo for 28 weeks; starting on week 16, both groups received oxytocin. The primary outcomes measure socio-behavioral severity using the Social Responsiveness Scale (SRS) and Aberrant Behavior Checklist (ABC). The secondary outcomes include measures of the Clinical Global Impression (CGI) scale, fecal microbiome, blood serum inflammatory markers, and oxytocin. All outcomes were compared between the two groups at baseline, 16 weeks, and 28 weeks into treatment. We observed improvements in ABC and SRS scores and significant improvements in CGI-improvement between those receiving probiotics and oxytocin combination therapy compared to those receiving placebo (p < 0.05). A significant number of favorable gut microbiome network hubs were also identified after combination therapy (p < 0.05). The favorable social cognition response of the combination regimen is highly correlated with the abundance of the Eubacterium hallii group. Our findings suggest synergic effects between probiotics PS128 and oxytocin in ASD patients, although further investigation is warranted.

SUBMITTER: Kong XJ

PROVIDER: S-EPMC8147925 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This study was a 10-week double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in youth with autism spectrum disorder (ASD). Participants were ages 5 to 17 years with ASD and clinically significant anxiety (Pediatric Anxiety Rating Scale [PARS] score ≥10). Thirty participants were randomized to mirtazapine (7.5-45 mg/day) or placebo in a 2:1 ratio. The co-primary outcome measures were the PARS and the Clinical Global Impressions-Improvement subscale (CGI-I). Mirtazapine resulted in a statistically significant within group decrease in anxiety on the PARS (ES 1.76, p < 0.001). The improvement in PARS score for mirtazapine versus placebo was clinically meaningful but not statistically significant (ES = 0.63, p = 0.64). Forty-seven percent of participants assigned to mirtazapine (95% CI 22%: 74%) and 20% assigned to placebo (95% CI 2%: 60%) were rated "much improved" (CGI-I = 2) or "very much improved" (CGI-I = 1) for anxiety, p = 0.46. No statistically significant differences in mean 10-week changes between mirtazapine and placebo occurred on any outcome measure. There were no statistically significant differences in adverse effect frequency between mirtazapine and placebo. The results are consistent with mirtazapine's safety and tolerability and meet three of four pre-specified indicators of efficacy (statistically significant change in total PARS score for mirtazapine, numerically greater reduction in total PARS score for mirtazapine than placebo, numerically higher number of responders to mirtazapine than placebo, but not greater than 50% of participants receiving mirtazapine rated as responders). Implementation of a larger randomized controlled trial of mirtazapine for the treatment of anxiety in this population is supported.Clinical trial registration information: Mirtazapine Treatment of Anxiety in Children and Adolescents with Pervasive Developmental Disorders; https://clinicaltrials.gov ; NCT01302964.

Project description:UnlabelledApproximately half of autism spectrum disorder (ASD) individuals suffer from comorbid intellectual disabilities (IDs). Oxytocin (OXT) receptors are highly expressed in temporal lobe structures and are likely to play a modulatory role in excitatory/inhibitory balance, at least based on animal model findings. Thus, it is feasible that in the highly representative group of Kanner-type ASD subjects, OXT could have a beneficial effect on social communication and social interaction. The aim of this pilot study is to investigate the feasibility and adverse events, such as epilepsy, of the long-term administration of intranasal OXT for adolescent and adult ASD subjects with ID because such patients frequently have seizures. We also addressed the question on how to scale the OXT effects to the core symptoms of social deficits because of the relative difficulty in obtaining objective measurements. Twenty-nine males (aged 15-40 years old) participated in a randomized, double-blind, and placebo-controlled crossover study (each for 8 weeks) with OXT (16 IU/day). Except for seizures experienced by one participant, other serious adverse events did not occur. The primary and secondary outcomes measured using the Childhood Autism Rating Scale and several standard scales, respectively, revealed no difference between the OXT and placebo groups. Instead, in an exploratory analysis, the social interactions observed in the play sessions or in daily life were significantly more frequent in the initial half period in the OXT-first arm of the crossover trial. There were also significant correlations between the plasma OXT concentration and subscale scores for irritability on the Aberrant Behavior Checklist. In conclusion, this pilot study demonstrates that long-term administration of intranasal OXT is tolerable in a representative cohort of ASD individuals with ID and suggests that future multicenter trials of OXT are warranted and should include measurements of reciprocal social interactions based on daily life under closer surveillance for epilepsy.Trial registrationUMIN000007250.

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Project description:BackgroundSocial impairment is a defining feature of autism spectrum disorder (ASD) with no demonstrated effective pharmacologic treatments. The goal of this study was to evaluate efficacy, safety, and tolerability of oral N-acetylcysteine (NAC), an antioxidant whose function overlaps with proposed mechanisms of ASD pathophysiology, targeting core social impairment in youth with ASD.MethodsThis study was a 12-week randomized, double-blind, placebo-controlled trial of oral NAC in youth with ASD. Study participants were medically healthy youth age 4 to 12 years with ASD, weighing ≥15 kg, and judged to be moderately ill based on the Clinical Global Impressions Severity scale. The participants were randomized via computer to active drug or placebo in a 1:1 ratio, with the target dose of NAC being 60 mg/kg/day in three divided doses. The primary outcome measure of efficacy was the Clinical Global Impressions Improvement (CGI-I) scale anchored to core social impairment. To investigate the impact of NAC on oxidative stress markers in peripheral blood, venous blood samples were collected at screen and week 12.ResultsThirty-one patients were enrolled (NAC = 16, placebo = 15). Three participants were lost to follow-up, and three left the trial due to adverse effects. The average daily dose of NAC at week 12 was 56.2 mg/kg (SD = 9.7) with dose ranging from 33.6 to 64.3 mg/kg. The frequency of adverse events was so low that comparisons between groups could not be conducted. At week 12, there was no statistically significant difference between the NAC and placebo groups on the CGI-I (p > 0.69) but the glutathione (GSH) level in blood was significantly higher in the NAC group (p < 0.05). The oxidative glutathione disulfide (GSSG) level increased in the NAC group, however only at a trend level of significance (p = 0.09). There was no significant difference between the NAC and placebo groups in the GSH/GSSG ratio, DNA strand break and oxidative damage, and blood homocysteine levels at week 12 (ps > 0.16).ConclusionsThe results of this trial indicate that NAC treatment was well tolerated, had the expected effect of boosting GSH production, but had no significant impact on social impairment in youth with ASD.Trial registrationClinicaltrials.gov NCT00453180.

Project description:ObjectivesAutism is a complicated neurodevelopmental disorder characterized by social interaction deficiencies, hyperactivity, anxiety, communication disorders, and a limited range of interests. The zebrafish (Danio rerio) is a social vertebrate used as a biomedical research model to understand social behavior mechanisms.Materials and methodsAfter spawning, the eggs were exposed to sodium valproate for 48 hr, after which the eggs were divided into eight groups. Except for the positive and control groups, there were six treatment groups based on oxytocin concentration (25, 50, and 100 μM) and time point (24 and 48 hr). Treatment was performed on days 6 and 7, examined by labeling oxytocin with fluorescein-5-isothiocyanate (FITC) and imaging with confocal microscopy and the expression levels of potential genes associated with the qPCR technique. Behavioral studies, including light-dark background preference test, shoaling behavior, mirror test, and social preference, were performed on 10, 11, 12, and 13 days post fertilization (dpf), respectively.ResultsThe results showed that the most significant effect of oxytocin was at the concentration of 50 μM and the time point of 48 hr. Increased expression of shank3a, shank3b, and oxytocin receptor genes was also significant at this oxytocin concentration. Light-dark background preference results showed that oxytocin in the concentration of 50 µM significantly increased the number of crosses between dark and light areas compared with valproic acid (positive group). Also, oxytocin showed an increase in the frequency and time of contact between the two larvae. We showed a decrease in the distance in the larval group and an increase in time spent at a distance of one centimeter from the mirror.ConclusionOur findings showed that the increased gene expression of shank3a, shank3b, and oxytocin receptors improved autistic behavior. Based on this study some indications showed that oxytocin administration in the larval stage could significantly improve the autism-like spectrum.

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Probiotic and Oxytocin Combination Therapy in Patients with Autism Spectrum Disorder: A Randomized, Double-Blinded, Placebo-Controlled Pilot Trial.

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