Oxytocin

A pilot study on the role of the oxytocinergic system in gut microbiome composition in children with autism: baseline associations and effects of intranasal oxytocin.

Evenepoel Margaux, Tuerlinckx Elise, Derrien Muriel +8 more

Autistic children often experience behavioral difficulties alongside nutritional and gastro-intestinal (GI) problems, including gut dysbiosis. Recent research has highlighted important interactions between the oxytocinergic system and gut microbiome compositions, however, insights into how exogenous administration of oxytocin may influence GI health remain largely unexplored. Here, we first examined whether nutrition, GI symptoms and microbiome compositions vary in autistic versus non-autistic children, and how alterations link to clinical-behavioral difficulties and oxytocinergic signaling. Next, we examined the effect of a four-week intranasal oxytocin administration regimen on GI health/dysbiosis in autistic children enrolled in a randomized placebo-controlled trial. Compared to non-autistic children, autistic children consumed more soft drinks, and fewer vegetables and experienced abdominal pain more frequently over the past three months. Notably, epigenetic variations in the oxytocin receptor gene (OXTR) were associated with stool consistency, indicating that children with looser stools exhibited lower OXTR methylation levels, indicative of increased receptor expression. Additionally, a higher abundance of Romboutsia was associated with OXTR hypo-methylation and more anxiety-like behavior. In autistic children, the four-week oxytocin regimen had no effect on bacterial diversity but did modify stool consistency, leading to less dense stools with an overall more normal stool consistency, and an increased abundance of the potentially anti-inflammatory genus Fusicatenibacter. To conclude, this study provides novel insights into the role of the oxytocinergic system in GI symptoms and gut microbiome compositions in autistic children, and preliminary evidence suggesting a modulatory effect of exogenously administered oxytocin on these parameters.

Current options for the treatment of anxiety in adults with autism spectrum disorder.

Carmen Lopez-Arvizu, Jonathan Muniz

Anxiety affects approximately 30-40% of adults with autism spectrum disorder (ASD), yet its diagnosis and treatment remain underrepresented in the literature. Autism is a lifelong condition and addressing it across lifespan while considering its developmental stage is essential. Tailored clinical approaches are needed to accommodate communication, cognitive, and sensory differences.

Identification of intranasal oxytocin plasma proteome signatures.

Lauren Breithaupt, Stephanie G Harshman, Patrick M Botros +10 more

Oxytocin beyond social bonding: Advancing neuromodulation, synaptic plasticity, and epigenetic precision in CNS disorders.

Supratim Paul, Janvi Verma, Sidharth Mehan

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.

Impact of chronic oxytocin on gaze and pupil dynamics during live dyadic interactions in children with autism.

Jellina Prinsen, Nicky Daniels, Matthijs Moerkerke +2 more

Reciprocal gaze, the mutual exchange of eye contact, plays a key role in human communication and bonding, yet it is often experienced as challenging for individuals with autism. In recent years, administration of the neuropeptide oxytocin is increasingly considered a novel approach for supporting social experiences in children with autism, but insights regarding its effects on mutual gaze or pupil dynamics remain limited-particularly regarding how chronic, repeated dosing impacts these processes. This double-blind, randomized, placebo-controlled trial examined the effects of four weeks of chronic intranasal oxytocin administration on gaze behavior and pupil dynamics during live dyadic interactions in school-aged children with autism (aged 8-12 years, 15 oxytocin, 20 placebo). While the overall duration of fixations toward the face remained unchanged, oxytocin altered the distribution of gaze, resulting in a more balanced pattern of looking toward and away from the face of a live interaction partner, an effect observed only in the oxytocin group and not in the placebo group. In addition, the four-week oxytocin administration period induced a relative increase in pupil dilation, an index of sympathetic arousal and attentional engagement, with this heightened autonomic responsivity showing a moderate association with children's self-reported feelings of secure attachment. Together, these findings indicate that repeated oxytocin administration may modulate gaze parameters in live social interactions in children with autism. While cautiously encouraging, future work will be needed to further delineate whether these changes meaningfully reflect ameliorated experience and comfort in social settings.

Recent Advances in Pharmacological Management of Autism: A Narrative Review.

Pallavi Abhilasha, Monika Sharma

Autism Spectrum Disorders (ASD) are a highly heterogeneous neurodevelopmental conditions defined by impairments in social communication, reciprocal interaction, and the presence of restricted or repetitive behaviors. While its "spectrum" nature highlights variability in symptom severity and presentation, ASD often coexists with conditions like attention deficit hyperactivity disorder (ADHD), anxiety, depression, epilepsy, digestive, metabolic, and immune disorders. No pharmacological treatments currently address the core deficits of ASD; instead, behavioral and educational interventions remain central. Medications, including US Food and Drug Administration (FDA)‑approved antipsychotics such as risperidone and aripiprazole, are used to manage comorbid irritability and aggression, stimulants and non‑stimulants (e.g., methylphenidate, atomoxetine, clonidine, guanfacine) to treat ADHD-like symptoms, and melatonin for sleep disturbances. Other off‑label agents like selective serotonin reuptake inhibitor (SSRIs) for anxiety/obsessive compulsive disorder (OCD), anticonvulsants or mood stabilizers for mood dysregulation. Emerging compounds such as intranasal oxytocin and N‑acetylcysteine are under investigation but have not yet been formally approved. The future of ASD care hinges on the development of objective, biologically based diagnostic tools ranging from EEG and neuroimaging biomarkers to proteomic and metabolomic panels that could enable early, precise identification and guide personalized treatment strategies.

Design of Experiments (DoE)-Optimized Polymeric Oxytocin Nanoparticles for Enhanced Nose-to-Brain Delivery.

Naveed Ahmad, Shunping Han, Rifka Utami +9 more

Oxytocin (OT) is a promising candidate for regulating social behavior in autism spectrum disorder (ASD). However, its inconsistent efficacy can be attributed to the lack of an efficient delivery system that selectively target the brain without inducing peripheral side effects following intranasal (IN) administration. In this study, OT is encapsulated within an FDA-approved poly (lactic-co-glycolic acid) (PLGA) nanoparticles (OT-NP) to improve nose-to-brain (NTB) delivery. A PEGylated version (OT-NP-PEG) is developed to improve nasal mucosal diffusion. Optimization using a design of experiments (DoE) approach produced nanoparticles with hydrodynamic diameters of ≈93-116 nm, polydispersity index ≈0.20, zeta potential -21 to -33 mV, and drug loading ≈2.8-3.5% (w/w). The stable OT-NP-PEG showed sustained release (>42% and 58% at 24 and 72 h) and greater diffusion through simulated nasal mucus. [14C] OT is synthesized with chemical and radiochemical yields of 74% and 53%, respectively. Following IN administration in mice, [14C] OT-NP-PEG demonstrated rapid brain uptake, particularly in the olfactory bulb and frontal cortex, with reduced blood and liver exposure compared with free [14C] OT. Finally, IN OT-NP-PEG significantly increased self-grooming frequency in mice, indicating maintained bioactivity and behavioral effects. Overall, OT-NP-PEG offers a rationally designed nanoplatform for brain-targeted OT delivery in ASD and other neuropsychiatric disorders.

Oxytocin: a neglected hormone in pituitary disease - From function to the diagnosis of a deficiency, resulting clinical relevance, and potential treatment options in endocrinology.

Svenja Leibnitz, Mirjam Christ-Crain, Cihan Atila

Oxytocin (OXT) is a neuropeptide hormone that plays a central role in numerous physiological and socio-emotional processes. Similar to arginine vasopressin (AVP), it is synthesized in the supraoptic and paraventricular hypothalamic nuclei and released both centrally and peripherally. Peripherally, OXT regulates uterine contractions during childbirth and milk ejection during lactation, metabolism, bone health, and cardiovascular functions. Centrally, it modulates social behavior, influencing trust, empathy, stress regulation, and emotional processing. Despite its close connection to AVP, the clinical significance of OXTDeficiency has only recently gained attention, particularly in patients with hypothalamic or pituitary damage with concomitant AVP-Deficiency. OXT-Deficiency may contribute to various neuropsychological symptoms seen in these patients, including social dysfunction, anxiety disorders, and reduced quality of life. However, a major challenge lies in accurately measuring OXT and thereby diagnosing a potential OXT-Deficiency. Basal plasma levels are unreliable, and most studied provocation tests only stimulate to a limited degree; hence, stronger provocation tests (e.g., using MDMA) and new surrogate parameters such as neurophysin I (NP-I) are gaining traction. Preliminary evidence from case reports and one small study suggests that intranasal OXT administration in patients with hypothalamic disorders may have beneficial effects on social behavior and emotion recognition. However, there is a clear need for larger, well-designed clinical trials, and several trials are currently underway to investigate the therapeutic potential of OXT in patients with AVP-Deficiency. OXT is also being explored as a possible treatment option in psychiatric conditions such as autism spectrum disorder, borderline personality disorder, and social anxiety disorder, with controversial results so far.

An overview of oxytocin integrative mechanisms in autism spectrum disorder.

Nand Lal, Bin Song, Chi Zhang +8 more

Autism Spectrum Disorder (ASD) is a multifaceted neurodevelopmental condition characterized by impairments in social interaction, communication, and repetitive behaviors. Its etiology involves a complex interplay of genetic, environmental, and neurobiological factors. The oxytocin (OT) system, central to social behavior and emotional regulation, has emerged as a key area of interest in ASD research. This review synthesizes current evidence, highlighting that dysregulation of OT and its receptor (OTR) signaling, often characterized by lower baseline OT levels and altered OTR expression due to genetic and epigenetic factors, contributes to the social and behavioral deficits observed in ASD. While aberrant OT/OTR signaling presents a potential target for therapeutic intervention, the narrative has evolved beyond simple peptide replacement. Critical analysis reveals that intranasal OT administration, as a standalone treatment, yields inconsistent results due to its non-specific delivery and inability to address core circuit-level dysfunctions established during neurodevelopment. Promising future avenues include the development of selective OTR agonists, epigenetic modulation to correct OTR expression, and the use of OT as a targeted adjunct to enhance behavioral therapy efficacy. This paper provides a comprehensive and critical overview of the integrative mechanisms linking OT/OTR signaling to ASD, evaluates the therapeutic potential of correcting this pathway, and emphasizes the necessity for personalized, biomarker-driven approaches to improve social cognition and neural connectivity in individuals with ASD.

Contextual modulation of endogenous oxytocin signaling and its influence on exogenous oxytocin effects: A conceptual framework.

Kaat Alaerts, Eimi Van Weert, Lotte Theunissen +2 more

Dose-response effects of exogenous oxytocin on social cognition: A systematic review.

Simon Barton, Annika Pruin, Janna Schulze +3 more

Oxytocin, a neuropeptide known for its role in social bonding, has garnered considerable attention for its potential to enhance social cognition in humans. Intranasal administration of oxytocin is the standard method in exogenous oxytocin research. This systematic review critically examines the effects of exogenously administered oxytocin on three core components of social cognition: emotion recognition, empathy, and interpersonal trust. By comparing findings across studies using intranasal oxytocin doses ranging from 1 IU to 48 IU in healthy adult humans, we evaluate evidence for a potential dose-response relationship. The majority of studies administered a standard dose of 24 IU and generally reported significant improvements in emotion recognition, empathy, and trust. However, divergent findings at this dose have also been observed. Evidence for both lower and higher doses remains mixed. Much of the support for the Inverted-U Curve hypothesis - suggesting that oxytocin's effects follow a nonlinear trajectory with optimal outcomes at moderate doses - comes from studies lacking direct dose comparisons. Furthermore, the effects of oxytocin on social cognition appear to be strongly moderated by individual and contextual factors, raising questions about the generalizability of the Inverted-U model. Additional research is necessary to clarify the conditions under which dose-dependent effects occur.

Oxytocin modulation of resting-state functional connectivity network topology in individuals with higher autistic traits.

Abraham Tonny Hagan, Lei Xu, Juan Kou +7 more

Altered connectivity patterns in socio-emotional brain networks are characteristic of individuals with autism spectrum disorder. Despite recent research on intranasal oxytocin's modulation effects of network topology in autism, its specific effects on the functional connectivity network topology remain underexplored.

Oxytocin enhances oligodendrocyte development and improves social deficits in autistic rats.

Min Wen, Shuang Zheng, Hongbo Luo +2 more

Autism spectrum disorder (ASD) is a neurodevelopmental condition with complex etiological factors, including genetic predisposition and environmental influences. In particular, exposure to environmental stressors in utero has increasingly been implicated in disrupting fetal neurodevelopment and potentially contributing to the pathogenesis of ASD in offspring. The aim of this study was to investigate the therapeutic potential of oxytocin and to elucidate its underlying molecular mechanisms in a valproic acid (VPA) exposure-induced rat model of ASD.

Endogenous and exogenous oxytocin modulate interpersonal motor resonance in autism: A context-dependent and person-specific approach.

Jellina Prinsen, Kaat Alaerts

Understanding and interpreting non-verbal actions are critical components of social cognition, which are often challenging for autistic individuals. Oxytocin, a neuropeptide known to modulate social behavior and enhance the salience of social stimuli, is being explored as a therapeutic option for improving social mirroring. However, its effects are mediated by context- and person-dependent factors. This study examines the impact of a single intranasal dose of oxytocin (24 IU) on interpersonal motor resonance in young adult men with and without autism. Neurophysiological assessments of corticomotor excitability were performed using transcranial magnetic stimulation while participants observed real-time hand movements displayed by an experimenter demonstrating varying social intent (i.e. showing direct vs averted gaze). While no overall effect of oxytocin on interpersonal motor resonance was observed across groups, person-specific factors significantly influenced outcomes. In the autism group, individuals with higher endogenous oxytocin levels exhibited greater motor resonance during action observation. Autistic individuals with heightened social difficulties or avoidant attachment styles showed enhanced motor resonance following oxytocin administration. These findings highlight the nuanced role of both endogenous and exogenous oxytocin in shaping neurophysiological motor resonance and emphasize the importance of individual variability in assessing oxytocin's therapeutic potential for addressing social challenges in autism.Lay abstractThis study explores how oxytocin, a hormone that influences social behaviors, affects the ability to interpret and respond to non-verbal cues, particularly in autistic adults. Understanding others' actions and intentions, often guided by observing body language and eye contact, is a critical part of social interaction. Autistic individuals frequently face challenges in these areas. Using a safe, non-invasive brain stimulation technique, the study measured participants' brain responses as they observed real-time hand movements paired with the interaction partner's direct eye contact or averted gaze. Participants included young autistic and non-autistic adult men who received a placebo and a single dose of oxytocin via nasal spray. Results showed no overall differences between the two groups in their brain responses to these movements. However, in the autism group, several factors significantly influenced the effects of oxytocin. Participants with higher natural oxytocin levels or those who reported greater social challenges showed stronger responses after oxytocin administration, particularly when observing hand movements combined with direct gaze. These findings suggest that oxytocin may enhance social understanding in autistic individuals, especially for those experiencing greater difficulties. This highlights the potential of personalized approaches when considering oxytocin as a therapeutic option to improve social interactions.

Random forest and Shapley Additive exPlanations predict oxytocin targeted effects on brain functional networks involved in salience and sensorimotor processing, in a randomized clinical trial in autism.

Elissar Andari, Kaundinya Gopinath, Erin O'Leary +7 more

Intranasal oxytocin (IN-OXT) has shown some promises in rescuing social deficits in autism spectrum disorder (ASD) as well as some inconsistencies in long-term trials. We conducted a target engagement study to study the precise effects of different doses of IN-OXT on brain resting-state functional connectivity (rsFC) in ASD. We examined the effects of varying doses of IN-OXT (0 IU, 8 IU, 24 IU, 48 IU) on rsFC in a double-blind, placebo-controlled, within-subject design in 30 male adults with ASD and 17 neurotypical controls (NT) receiving placebo. Random forest analysis was used to classify individuals as ASD or NT. Shapely Additive explanations values were calculated to rank brain functional networks by level of contribution to ASD deficits and to evaluate IN-OXT dose effects. The model predicted ASD diagnosis with an AUC of 94%. Hypoconnectivity between salience/empathy and visual networks, and hyperconnectivity between reward and sensorimotor networks and theory of mind networks were among the strongest predictors of ASD deficits. IN-OXT had a dose-dependent effect on rescuing both deficits described above. Overall, 48 IU dose was more effective, and 24 IU dose was more effective in those who have lower DNA OXT receptor methylation and lower severity of clinical symptoms. Higher doses of OXT might be necessary to enhance empathic responses, and ASD individuals with less support needs and with a preserved OXT system might benefit most from OXT treatment. Applying machine learning approaches in OXT research can provide data-driven unbiased results that can inform future clinical trials.

Complexity of the Hypothalamic Oxytocin System and its Involvement in Brain Functions and Diseases.

Xiao Cui, Lei Xiao

Oxytocin is classically termed a 'prosocial neuropeptide' because of its evolutionarily conserved role in promoting affiliative behaviors. Endogenous oxytocin is mainly synthesized by hypothalamic oxytocin neurons and signals through oxytocin receptors (OxtRs). Recent studies with cell type-specific and circuit-specific interrogation have uncovered that oxytocin signals exert pleiotropic neuromodulatory effects through anatomically widespread axonal projections and ubiquitously distributed OxtRs. Dysfunctions of oxytocin signals are closely relevant to brain disorders/diseases. While intranasal oxytocin administration has been demonstrated to be one potential strategy to alleviate some brain disorders/diseases, such as autism, obesity, and anxiety, conflicting clinical outcomes highlight the imperative for precision-targeted neuromodulation strategies. Dissecting the molecular, cellular, and neural circuitry mechanisms underlying oxytocinergic modulation is a prerequisite to achieving this goal. This review provides an overview of the current understanding of the oxytocin system in terms of anatomical structure, neuronal modulation, and signal pathways, and discusses the modulatory roles of oxytocin in social, feeding, emotional, and sensory-related brain functions and brain diseases.

Oxytocin can ameliorate social deficits and brain developmental impairments in a rat model of early life excessive screen time exposure.

Mozhan Parsa, Monireh Mansouri, Hamidreza Pouretemad

In recent years studies have shown that early life excessive screen time exposure may significantly contribute to the emergence of social deficits and autistic-like behaviors. However, the exact underlying mechanisms and the optimal treatment strategies are not completely understood, with conflicting results of preceding findings. This study investigates the effect of oxytocin on autism-related behaviors, and associated brain structure abnormalities induced by excessive audiovisual stimulation (EAVS) as an early life excessive screen exposure model in rats. Neonatal rat pups were exposed to EAVS from postnatal day (PND) 12 to PND 35, and intranasal oxytocin (OXT) at a dose of 0.8 IU/kg was administrated from PND21 to PND35. Behavioral assessment including social interaction, repetitive behavior, locomotor activity, and anxiety-like behavior, along with three-dimensional brain structure measurements were done during adolescence (PND50-PND55). The results revealed EAVS-induced anomalies in social interaction, hyperactivity, and changes in the volume, and neuron number of brain regions including the amygdala and anterior cingulate cortex (ACC) in the EAVS group which were modulated by oxytocin. Our findings suggest that OXT may mitigate adverse effects of early life excessive exposure to digital screens, enhancing social preferences through modulating brain plasticity. The observed neuroanatomical and behavioral alterations highlight the vulnerability of the developing brain to early life excessive screen exposure and suggest a potential therapeutic path through OXT to tackle social impairments induced by EAVS.

Oxytocin and autism: Insights from clinical trials and animal models.

Chuan Xing, Xiang Yu

Autism spectrum disorder is a highly heritable and heterogeneous neurodevelopmental disorder, characterized by impaired social interactions and repetitive behaviors. Despite its complex etiology, increasing evidence has linked autism to the oxytocin system. The oxytocin peptide has long been known as the "social hormone," and has been shown to increase attention to social cues, elevate salience of socially relevant stimuli, and increase learning and reward in social situations. Reduced oxytocin levels and mutations in the oxytocin system have been reported in autism patients, while exogenously delivered oxytocin has been shown to alleviate social interaction deficits in both patients and animal models. Here, we summarize the results of recent clinical trials using oxytocin nasal spray to treat individuals with autism, as well as studies of autism animal models with oxytocin system deficits, and the rescue of their social behavior deficits by oxytocin. Finally, we discuss factors influencing clinical outcomes and reflect on future directions.

Oxytocin improves maternal licking behavior deficits in autism-associated Shank3 mutant dogs.

Wen Lyu, Yuan Li, Aiyu Yao +7 more

Impaired social interaction and repetitive behavior are key features observed in individuals with autism spectrum disorder (ASD). SHANK3 is a high-confidence ASD risk gene that encodes an abundant scaffolding protein in the postsynaptic density. In wild-type (WT) domestic dogs, maternal behaviors such as licking and nursing (largely milk feeding) of puppies are most commonly observed. To address whether SHANK3 plays a role in social behaviors especially maternal behaviors, we analyzed Shank3 mutant dogs generated by CRISPR/Cas9 methodology. We found that Shank3 mutant dams exhibited a fewer and shorter licking behavior, as well as reduced nursing frequency when compared with WT dams. Additionally, a significant decrease in blood oxytocin (OXT) concentration was detected in Shank3 mutant dams. We thus conducted a vehicle-controlled experiment to examine whether a two-week intranasal OXT treatment, initiated on the 8th postpartum day, could rescue the maternal licking deficits in Shank3 mutant dams. We found that the decreased licking behavior in Shank3 mutant dams was significantly attenuated both acutely and chronically by OXT treatment. The rescue effect of OXT implicates an oxytocinergic contribution to the maternal defects in Shank3 mutant dams, suggesting a potential therapeutic strategy for SHANK3-associated ASD.

Oxytocin lipidation expanding therapeutics for long-term reversal of autistic behaviors in rats.

Honglin Li, Ya Chen, Yue Qiu

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and repetitive, stereotyped behaviors. There is no universally effective pharmacological treatment targeting its core symptoms.Oxytocin, an endogenous polypeptide known as the "social hormone", has shown potential in improving emotional recognition and social interactions in individuals with ASD. However, its clinical application has been limited due to its short half-life and poor blood-brain barrier penetration. To address these challenges, we utilized peptide lipidation technology to enhance the pharmacokinetic properties and brain bioavailability of oxytocin. A series of lipidated oxytocin analogs was designed and synthesized, exhibiting superior brain distribution and pharmacokinetic profiles in valproic acid-induced autistic rat models compared to unmodified oxytocin. Among theseanalogs, C16-modified oxytocin (C16-OT), administered intrathecally, achieved the most extensive brain distribution with limited presence in the blood, resulting in long-lasting improvements in autistic behaviors. These improvements, including enhanced social behaviors and reduced stereotypical actions, were sustained for up to 42 days, contrasting with the brief effects typically reported in previous studies. Furthermore, a comparison of administration routes revealed that intrathecal injection achieved higher brain concentrations and more prolonged social behavioral improvements than intranasal delivery. These findings provide robust preclinical evidence that C16-OT, through optimized lipidation and intrathecal delivery, offers sustained central nervous system activity and significant, long-term reversal of social behavioral deficits in rats with autism.

Predictors of Placebo Response in the Study of Oxytocin in Autism to Improve Reciprocal Social Behaviors.

Alyssa Verdes, Suvekcha Bhattachan, Alexander Kolevzon +17 more

Background: Although randomized clinical trials (RCTs) have investigated several treatments for social communication difficulties and repetitive behavior in autism, none has yet shown consistent superiority over placebo. Placebo response in autism RCTs may impede the ability to detect meaningful treatment effects. Objective: We sought to identify individual-level predictors of placebo response in Study of Oxytocin in Autism to improve Reciprocal Social Behaviors (SOARS-B), a 24-week RCT of intranasal oxytocin for social impairment in autistic youth. In our primary analysis, we examined predictors of change in the Aberrant Behavior Checklist-modified Social Withdrawal (ABC-mSW) score at 24 weeks in SOARS-B participants taking placebo. Secondary analyses examined predictors of ABC-mSW change at 12 weeks and of Clinical Global Impressions-Improvement at 24 and 12 weeks. We also examined predictors of response among SOARS-B participants taking oxytocin. Methods: For each analysis, we first used lasso (least absolute shrinkage and selection operator) regression to identify potentially influential predictors from a large group that included demographic factors, rating scale data, and prescribed medications. We then estimated an unpenalized linear regression model for the outcome of interest that included only variables retained by the optimal lasso. We considered variables with statistically significant coefficients to be influential predictors. Results: Higher baseline ABC-mSW score was the only significant predictor of greater ABC-mSW change in the placebo group at 24 and 12 weeks. Conclusions: In SOARS-B, higher baseline severity on a measure of reciprocal social communication predicted greater placebo response. This is consistent with the finding that lower social communication adaptive functioning was associated with greater placebo response in recent RCTs of balovaptan for social impairment in autism. However, it contrasts with findings from a trial of citalopram for repetitive behavior in autism, in which lower baseline severity of a composite of autistic and mood symptoms predicted greater placebo response. This may indicate that different factors contribute to placebo response in different symptom domains.

The neurobiological impact of oxytocin in mental health disorders: a comprehensive review.

Ram Prasad Chaulagain, Yelona Shrestha, Harisharan Shrestha +2 more

Oxytocin, a neuropeptide, plays a significant role in modulating social behavior and has been widely studied for its potential impact on mental health disorders. This review examines the neurobiological mechanisms through which oxytocin influences mental health and its therapeutic potential in conditions such as autism spectrum disorder, schizophrenia, post-traumatic stress disorder, anxiety, and depression. Oxytocin enhances social bonding, trust, and empathy by modulating neural circuits linked to social interactions. Studies indicate that oxytocin's ability to regulate the hypothalamic-pituitary-adrenal axis plays a vital role in stress response and emotional regulation. Therapeutic applications, particularly intranasal administration of oxytocin, have shown promise in alleviating symptoms and improving patient outcomes. However, personalized approaches are essential to optimize treatment effectiveness. Despite its potential, challenges remain in understanding the mechanisms underlying its effects and identifying the patient populations that would benefit most from such therapies. Future research should focus on elucidating these mechanisms, exploring the long-term efficacy of oxytocin-based interventions, and advancing personalized medicine to maximize its clinical utility.

Oxytocin's social and stress-regulatory effects in children with autism and intellectual disability: a protocol for a randomized placebo-controlled trial.

G Ricchiuti, A Taillieu, E Tuerlinckx +5 more

Oxytocin is increasingly considered as a new pharmacological option for mitigating social difficulties and regulating stress in autism spectrum disorder. However, in prior trials, autistic individuals with co-occurring intellectual disability (ID) have largely been overlooked, despite their high prevalence, poorer outcome, and the enhanced need but reduced availability of therapeutic interventions. Prior studies have also overlooked the importance of standardizing the context in which oxytocin is administered, rendering outcomes from prior trials inconclusive.

Toward effective oxytocin interventions in autism: Overcoming challenges and harnessing opportunities.

Grazia Ricchiuti, Elise Tuerlinckx, Aymara Taillieu +4 more

Intranasal administration of oxytocin is emerging as a potential pharmacological option for mitigating social difficulties and regulating stress in autism spectrum disorder. However, initial single-dose and multiple-dose trials showed mixed results, with some demonstrating improvements in social and repetitive behavior and others showing no benefit over placebo. This perspective aims to elucidate factors contributing to this variability and to highlight pitfalls and opportunities in the field. We identified two major factors: design-related elements and individual participant characteristics. Pertaining to design-related elements, optimal dosing regimens have yet to be established, but appear to favor moderate intervention durations (i.e., 4-6 weeks) with intermittent and intermediate dosing (i.e., 24-32 IU every other day). Also, the context of the intervention seems crucial, as enhanced outcomes are mainly observed when oxytocin administration is paired with a socially stimulating and supporting environment. In addition, more adequate outcome measures have to be established to effectively assess oxytocin's impact, including behavioral scales and objective biophysiological markers tapping into stress and neurophysiological regulation. Future research should also account for individual participant differences in biological sex, developmental stage and cognitive and adaptive functioning, and incorporate (epi)genetic screening to identify responders. Overall, refining study designs and personalizing intervention protocols are essential for optimizing oxytocin's prosocial and anxiolytic effect in autism.

Optimal dose of oxytocin to improve social impairments and repetitive behaviors in autism spectrum disorders: meta-analysis and dose-response meta-analysis of randomized controlled trials.

Yingying Zhang, Xiaolu Zhang, Linghong Huang

Social impairments and repetitive behaviors are at the core symptoms of autism spectrum disorder (ASD). Intranasal administration of the neuropeptide oxytocin (OXT) is a promising treatment. However, there have been inconsistencies in the effects of OXT on social impairments and repetitive behaviors.

Impact of chronic intranasal oxytocin administration on face expression processing in autistic children: a randomized controlled trial using fMRI.

Matthijs Moerkerke, Nicky Daniels, Stephanie Van der Donck +6 more

Difficulties with (non-verbal) social communication, including facial expression processing, constitute a hallmark of autism. Intranasal administration of oxytocin has been considered a potential therapeutic option for improving social difficulties in autism, either by enhancing the salience of social cues or by reducing the social stress and anxiety experienced in social encounters.

Acute, chronic and conditioned effects of intranasal oxytocin in the mu-opioid receptor knockout mouse model of autism: Social context matters.

Fani Pantouli, Camille N Pujol, Cécile Derieux +9 more

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders whose diagnosis relies on deficient social interaction and communication together with repetitive behaviours. Multiple studies have highlighted the potential of oxytocin (OT) to ameliorate behavioural abnormalities in animal models and subjects with ASD. Clinical trials, however, yielded disappointing results. Our study aimed at assessing the behavioural effects of different regimens of OT administration in the Oprm1 null mouse model of ASD. We assessed the effects of intranasal OT injected once at different doses (0.15, 0.3, and 0.6 IU) and time points (5, 15, and 30 min) following administration, or chronically, on ASD-related behaviours (social interaction and preference, stereotypies, anxiety, nociception) in Oprm1+/+ and Oprm1-/- mice. We then tested whether pairing intranasal OT injection with social experience would influence its outcome on ASD-like symptoms, and measured gene expression in the reward/social circuit. Acute intranasal OT at 0.3 IU improved social behaviour in Oprm1-/- mice 5 min after administration, with limited effects on non-social behaviours. Chronic (8-17 days) OT maintained rescuing effects in Oprm1 null mice but was deleterious in wild-type mice. Finally, improvements in the social behaviour of Oprm1-/- mice were greater and longer lasting when OT was administered in a social context. Under these conditions, the expression of OT and vasopressin receptor genes, as well as marker genes of striatal projection neurons, was suppressed. We detected no sex difference in OT effects. Our results highlight the importance of considering dosage and social context when evaluating the effects of OT treatment in ASD.

Oxytocin treatment rescues irritability-like behavior in Cc2d1a conditional knockout mice.

Kuan-Hsiang Cheng, Yu-Chieh Hung, Pin Ling +1 more

Irritability, a state of excessive reactivity to negative emotional stimuli, is common in individuals with autism spectrum disorder (ASD). Although it has a significant negative impact of patients' disease severity and quality of life, the neural mechanisms underlying irritability in ASD remain largely unclear. We have previously demonstrated that male mice lacking the Coiled-coil and C2 domain containing 1a (Cc2d1a) in forebrain excitatory neurons recapitulate numerous ASD-like behavioral phenotypes, including impaired social behaviors and pronounced repetitive behaviors. Here, using the bottle-brush test (BBT) to trigger and evaluate aggressive and defensive responses, we show that Cc2d1a deletion increases irritability-like behavior in male but not female mice, which is correlated with reduced number of oxytocin (OXT)-expressing neurons in the paraventricular nucleus (PVN) of the hypothalamus. Intranasal OXT administration or chemogenetic activation of OXT neurons in the PVN rescues irritability-like behavior in Cc2d1a conditional knockout (cKO) mice. Administration of a selective melanocortin receptor 4 agonist, RO27-3225, which potentiates endogenous OXT release, also alleviates irritability-like behavior in Cc2d1a cKO mice, an effect blocked by a specific OXT receptor antagonist, L-368,899. We additionally identify a projection connecting the posterior ventral segment of the medial amygdala (MeApv) and ventromedial nucleus of the ventromedial hypothalamus (VMHvl) for governing irritability-like behavior during the BBT. Chemogenetic suppression of the MeApv-VMHvl pathway alleviates irritability-like behavior in Cc2d1a cKO mice. Together, our study uncovers dysregulation of OXT system in irritability-like behavior in Cc2d1a cKO mice during the BBT and provide translatable insights into the development of OXT-based therapeutics for clinical interventions.

Disengagement of somatostatin neurons from lateral septum circuitry by oxytocin and vasopressin restores social-fear extinction and suppresses aggression outbursts in Prader-Willi syndrome model.

Yann Dromard, Amélie M Borie, Prabahan Chakraborty +4 more

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.

Administration of Atosiban, an oxytocin receptor antagonist, ameliorates autistic-like behaviors in a female rat model of valproic acid-induced autism.

Chunhua Liu, Zhengyang Guo, Jiyi Pang +4 more

Autism spectrum disorder (ASD) is a pervasive developmental disorder with gender differences. Oxytocin (OXT) is currently an important candidate drug for autism, but the lack of data on female autism is a big issue. It has been reported that the effect of OXT is likely to be different between male and female ASD patients. In the study, we specifically explored the role of the OXT signaling pathway in a VPA-induced female rat's model of autism. The data showed that there was an increase of either oxytocin or its receptor expressions in both the hippocampus and the prefrontal cortex of VPA-induced female offspring. To determine if the excess of OXT signaling contributed to autism symptoms in female rats, exogenous oxytocin and oxytocin receptor antagonists Atosiban were used in the experiment. It was found that exogenous oxytocin triggered autism-like behaviors in wild-type female rats by intranasal administration. More interestingly, several autism-like deficits including social interaction, anxiety, and repeat stereotypical sexual behavior in the VPA female offspring were significantly attenuated by oxytocin receptor antagonists Atosiban. Moreover, Atosiban also effectively improved the synaptic plasticity impairment induced by VPA in female offspring. Our results suggest that oxytocin receptor antagonists significantly improve autistic-like behaviors in a female rat model of valproic acid-induced autism.