Oxytocin

Oxytocin, a neuropeptide predominantly produced in the hypothalamus, has garnered significant attention for its multifaceted roles extending beyond social bonding and reproduction to therapeutic applications in neurodegenerative and neuropsychiatric disorders. This review explores oxytocin's neuroprotective properties, including anti-inflammatory, antioxidant and anti-apoptotic effects, which counteract pathological mechanisms underlying diseases like Alzheimer's, Parkinson's and Epilepsy. Oxytocin's ability to modulate key neurotransmitter systems GABAergic, dopaminergic, and serotonergic pathways enhances synaptic plasticity, neurogenesis, and emotional regulation. These mechanisms have positioned oxytocin as a promising intervention for neuropsychiatric conditions such as autism, schizophrenia, depression, and anxiety. Preclinical and clinical studies have shown that intranasal administration of oxytocin improves social cognition, reduces symptom severity, and is well-tolerated, though challenges remain in standardizing dosages and measuring oxytocin levels due to individual variability. Emerging technologies, such as nanoparticle-based drug delivery systems, offer solutions to enhance oxytocin's bioavailability and brain penetration, making targeted, patient-specific therapies feasible. Epigenetic modifications of the oxytocin receptor gene including DNA methylation have been associated with variability in social and stress-related behaviors. While these findings offer insight into inter-individual differences, their application to precision medicine remains speculative and will require rigorous clinical validation. Combination therapies, integrating oxytocin with agents targeting neuroinflammation and synaptic plasticity, hold potential for synergistic effects. Despite methodological and translational challenges, oxytocin represents a transformative therapeutic agent with broad applications across neurological, psychiatric, and systemic disorders. Future research focusing on nanotechnology, epigenetics, and long-term clinical trials will be pivotal in realizing the full potential of oxytocin-based interventions for complex, multifactorial diseases.

BACKGROUND: Responding to social signals by expressing the correct behavior is not only challenged in autism, but also in diseases with high prevalence of autism, like Prader-Willi Syndrome (PWS). Clinical evidence suggests aberrant pro-social behavior in patients can be regulated by intranasal oxytocin (OXT) or vasopressin (AVP). However, what neuronal mechanisms underlie impaired behavioral responses in a socially-aversive context, and how can they be corrected, remains largely unknown. METHODS: Using the Magel2 knocked-out (KO) mouse model of PWS (crossed with CRE-dependent transgenic lines), we devised optogenetic, physiological and pharmacological strategies in a social-fear-conditioning paradigm. Pathway specific roles of OXT and AVP signaling were investigated converging on the lateral septum (LS), a region which receives dense hypothalamic inputs. RESULTS: OXT and AVP signaling promoted inhibitory synaptic transmission in the LS, which failure in Magel2KO mice disinhibited somatostatin (SST) neurons and disrupted social-fear extinction. The source of OXT and AVP deficits mapped specifically in the supraoptic nucleus→LS pathway of Magel2KO mice disrupting social-fear extinction, which could be corrected by optogenetic or pharmacological inhibition of SST-neurons in the LS. Interestingly, LS SST-neurons also gated the expression of aggressive behavior, possibly as part of functional units operating beyond local septal circuits. CONCLUSIONS: SST cells in the LS play a crucial role in integration and expression of disrupted neuropeptide signals in autism, thereby altering the balance in expression of safety versus fear. Our results uncover novel mechanisms underlying dysfunction in a socially-aversive context, and provides a new framework for future treatments in autism-spectrum disorders.

Endogenous oxytocin plays an important role in lactation, but its effectiveness as an exogenous galactagogue has been modest due to dose-limiting side effects related to off-target effects at the vasopressin V2 receptor. Merotocin (FE 202767) is a short-acting peptidic oxytocin receptor agonist with the potential to aid mothers experiencing preterm delivery and inadequate milk production by increasing their milk volume. A first-in-human, single-center, randomized, placebo-controlled study investigated single and repeated intranasal administrations (every 3 hours) at doses from 5 to 400 µg and intravenous administration at 20 µg in healthy, nonpuerperal women. Pharmacokinetic parameters were determined after all doses. Bioavailability was determined after crossover intranasal and intravenous administrations. Merotocin was rapidly absorbed and eliminated after intranasal administration, median time to maximum plasma concentration was approximately 15 minutes, and the terminal half-life was approximately 30 minutes. No accumulation was seen. Merotocin was not detected in urine, and metabolites were not detected in either plasma or urine, indicating elimination independent of the kidneys. Systemic bioavailability of merotocin after intranasal administration is low. All doses were tolerated, with few adverse events (mostly headache), all mild intensity. A maximum tolerated intranasal dose was not identified in this study. Intranasal administration of merotocin at doses up to 400 µg was tolerated by healthy women, and the pharmacokinetic and safety profiles support frequent repeated administration expected in lactation clinical practice.

Attention Deficit/Hyperactivity Disorder (ADHD) is associated with impairments in social cognition and theory of mind (ToM), potentially mediated by alterations in dopaminergic and oxytocinergic pathways. This pilot, proof-of-concept, randomized controlled trial examined the effects of intranasal oxytocin (IN-OT) on ToM and social cognition in children with ADHD. Eight participants (6 males, 2 females), all diagnosed with ADHD, were randomly assigned to receive a single dose of IN-OT or placebo in a double-blind, crossover design. Participants completed assessments of ToM, social cognition, and executive function at baseline and post-treatment. In the second phase, IN-OT was administered alongside prescribed stimulant medication. Statistical analysis was conducted by calculating the Reliable Change Index (RCI > 1.96) and assessing whether participants returned to a functional distribution (SD < 2.0). Results demonstrated improvements in mean reaction time and response consistency in tasks assessing ToM and emotion recognition following OT administration. No adverse effects were reported. While preliminary, this study suggests a possible role of IN-OT in enhancing social cognition and ToM in children with ADHD. Given the study's small sample size, larger trials are needed to confirm these effects and explore IN-OT as a potential adjunctive therapy for ADHD-related social deficits.

PURPOSE: Class III obesity (body mass index [BMI] ≥ 40 kg·m-2) is associated with high rates of Cesarean deliveries and postpartum hemorrhage, with increased maternal and fetal morbidity. The doses of oxytocin and carbetocin are two to four times higher at Cesarean delivery in patients with class III obesity. We sought to investigate the efficacy of carbetocin 80 µg iv compared with oxytocin 1 IU iv (plus infusion) at elective Cesarean delivery in parturients with class III obesity. We hypothesized that, with equipotent dosing, carbetocin would be noninferior to oxytocin. METHODS: We conducted a randomized, double-blind, noninferiority study in nonlabouring, term parturients with BMI ≥ 40 kg·m-2 undergoing elective Cesarean delivery under neuraxial anesthesia. Patients received either a 1-IU bolus of oxytocin iv followed by an infusion of 4.8 IU·hr-1 or an 80-µg carbetocin bolus iv followed by a placebo infusion. Uterine tone was determined by palpation by the obstetrician at 3, 5, and 10 min, using a verbal numerical rating score of 0 (boggy) to 10 (firm). The primary outcome was uterine tone at 3 min. Secondary outcomes included uterine tone at 5 and 10 min, blood loss, additional uterotonics, and side effects. RESULTS: Forty-seven participants were included in the analysis. Median tone at 3 min was similar for oxytocin (8; 95% confidence interval [CI], 7 to 8) and carbetocin (8; 95% CI, 8 to 9) (P = 0.06), with no difference at 5 and 10 min. Blood loss, side effects, and the need for additional uterotonics were not significantly different between the study groups. CONCLUSION: We conclude that carbetocin is noninferior to oxytocin at elective Cesarean delivery in parturients with class III obesity, with the advantage of single bolus dosing without infusion. STUDY REGISTRATION: ClinicalTrials.gov ( NCT04902729 ); first submitted 21 May 2021.

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 (PFDR) < 0.001), IL-9 (56.64, 20.46 to 92.82, PFDR < 0.001) and MIP-1b (18.27, 4.96 to 31.57, PFDR < 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 (PFDR < 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.