Effect of a novel nasal oxytocin spray with enhanced bioavailability on autism: a randomized trial

Abstract

Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration–time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose–response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0–14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose–response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = −0.5; 95% CI: −1.1 to 0.1; per protocol set: P = 0.012, mean difference = −0.8; 95% CI: −1.3 to −0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose–response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.

Integrative analysis prioritised oxytocin-related biomarkers associated with the aetiology of autism spectrum disorder

“…All these factors may contribute to the statistically non-significant difference in oxytocin response among different patients with ASD. Moreover, it should be acknowledged that the therapeutic responses to oxytocin treatment for ASD core symptoms may be associated with various treatment factors, such as dosage or dose frequency of oxytocin intervention in different developmental stages, 14 , 30 , 86 , 87 OXTR genetics, 39 and the interactions of dose frequency with OXTR genetics. 33 , 38 Notably, ∼17.47% (80 of 458) of potential oxytocin-related molecular biomarkers and ∼19.72% (156 of 791) of non-PC-OTRGs (Supplemental Table 19) were significantly differentially expressed through modification of histone and/or DNA methylation in ASD cortex compared with that in control.…”

“… 4 Although an increasing number of clinical trials have investigated the efficacy of intranasal oxytocin intervention, the conclusions vary and are controversial. 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 Certain studies supported the beneficial effects of oxytocin intervention in social functioning and within non-social domains (repetitive behaviour) in patients with ASD, 20 whereas other studies support only one of these effects 19 , 20 , 21 , 22 , 23 , 24 , 25 , 28 , 29 , 30 , 31 , 32 , 33 or neither. 26 , 27 , 34 , 35 Given that these clinical trials employed different experimental designs, inclusion and exclusion criteria for recruiting participants, intervention methods, and approaches for evaluating intervention efficiencies, inconsistencies in the outcomes are inevitable.…”

Effects of multiple-dose intranasal oxytocin treatment on social responsiveness in children with autism: A randomized, placebo-controlled trial

“…In multiple-dose OT trials with individuals with ASD, daily dosing ranged from 8-80 IU and durations from 4 continual days to 24 weeks, but strong empirical support for favoring one dosing scheme over another is currently lacking. Some earlier single-dose trials suggested dose-response curves to exhibit U-shaped forms (Lieberz et al, 2020; Spengler et al, 2017), a notion that is supported by a recent chronic four-week OT administration trial in ASD, identifying a daily total dose of 6 IU of TTA-121 (a new formulation of intranasal OT spray with an enhanced bioavailability) to be the most efficacious one, compared to a lower (3 IU) or higher (10 IU) daily dose (Yamasue et al, 2022). Furthermore, in terms of dosing scheme, recent work showed that intermittent (every other day) administration may be therapeutically more efficient than continual administration to obtain anxiolytic effects and reduce amygdala reactivity (Kou et al, 2020).…”

Impact of Magnesium on Oxytocin Receptor Function

“…In a separate ongoing study (and so not directly comparable), we have similarly found that 128 μg demonstrates a significant drop in efficacy compared to lower doses that were preventable by the addition of Mg 2+ . Inverted U dose responses have been widely reported for various systems, including social recognition [ 28 ], opioid-induced respiratory depression [ 29 ], and, very recently, in an autism spectrum clinical trial [ 30 ]. Although it is not unknown for peptide neurotransmitters to have an inverted U dose-response, the specific reason for a decrease in withdrawal latency at a higher OT dose is still unclear.…”