Association of oxytocin augmentation with postpartum hemorrhage: a systematic review and meta-analysis.

OBJECTIVE: The current study aims to evaluate the correlation between oxytocin augmentation and postpartum hemorrhage. METHOD: PubMed, Web of Science, and Scopus has been searched for studies assessing the correlation between oxytocin augmentation and postpartum hemorrhage up to January 24, 2024. The search strategy included relevant keywords related to PPH and oxytocin augmentation. The risk of bias assessment was conducted by two reviewers using the Newcastle-Ottawa Scale (NOS). To pool the effects sized of included studies odds ratios (OR) of interest outcome with their 95% confidence interval (CI) were used. RESULTS: Eight studies were included in this meta-analysis. The pooled analysis of the included studies showed a statistically significant association between oxytocin augmentation and increased odds of PPH (pooled odds ratio [OR] = 1.27, 95% confidence interval [CI]: 1.05-1.53; I2 = 84.94%; p = 0.01). Publication bias was assessed using funnel plots, which appeared relatively asymmetrical, indicating significant publication bias. Galbraith plot and trim and fill plot were used for publication bias. Sensitivity analyses were performed by leave one out method. CONCLUSION: This meta-analysis suggests that using oxytocin for labor augmentation is linked to a significant increase in the risk of PPH. It highlights the need for careful monitoring and consideration when using oxytocin, especially in low and middle-income countries where guidelines and supervision are crucial.

Patterns of oxytocin use for induction and augmentation of labour among healthcare providers in Nigeria.

BACKGROUND: The practice of intrapartum use of oxytocin for induction and augmentation of labour is increasing worldwide with documented wide variations in clinical use, especially dose administrations. There is also evidence of intrapartum use by unauthorized cadre of staff. AIM: This study assessed the patterns - frequency of intrapartum use of oxytocin, the doses and routes of administration for induction and augmentation of labour, and identified the predictors of oxytocin use for induction and augmentation of labour by healthcare providers in Nigeria. METHODS: This was a cross-sectional study conducted among healthcare providers - doctors, nurses/midwives and community health workers (CHWs) in public and private healthcare facilities across the country's six geopolitical zones. A multistage sampling technique was used to select 6,299 eligible healthcare providers who use oxytocin for pregnant women during labour and delivery. A self-administered questionnaire was used to collect relevant data and analysed using STATA 17 statistical software. Summary and inferential statistics were done and further analyses using multivariable regression models were performed to ascertain independent predictor variables of correct patterns of intrapartum oxytocin usage. The p-value was set at < 0.05. RESULTS: Of the 6299 respondents who participated in the study, 1179 (18.7%), 3362 (53.4%), and 1758 (27.9%) were doctors, nurses/midwives and CHWs, respectively. Among the respondents, 4200 (66.7%) use oxytocin for augmentation of labour while 3314 (52.6%) use it for induction of labour. Of the 1758 CHWs, 37.8% and 49% use oxytocin for induction and augmentation of labour, respectively. About 10% of the respondents who use oxytocin for the induction or augmentation of labour incorrectly use the intramuscular route of administration and about 8% incorrectly use intravenous push. Being a doctor, and a healthcare provider from government health facilities were independent positive predictors of the administration of correct dose oxytocin for induction and augmentation of labour. The CHWs were most likely to use the wrong route and dose administration of oxytocin for the induction and augmentation of labour. CONCLUSION: Our study unveiled a concerning clinical practice of intrapartum oxytocin use by healthcare providers in Nigeria - prevalence of intrapartum use of oxytocin, inappropriate routes of administration for induction and augmentation of labour, varied and inappropriately high start dose of administration including unauthorized and high intrapartum use of oxytocin among CHWs.

Intranasal Oxytocin for Obesity.

BACKGROUND: Accumulating preclinical and preliminary translational evidence shows that the hypothalamic peptide oxytocin reduces food intake, increases energy expenditure, and promotes weight loss. It is currently unknown whether oxytocin administration is effective in treating human obesity. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned adults with obesity 1:1 (stratified by sex and obesity class) to receive intranasal oxytocin (24 IU) or placebo four times daily for 8 weeks. The primary end point was change in body weight (kg) from baseline to week 8. Key secondary end points included change in body composition (total fat mass [g], abdominal visceral adipose tissue [cm2], and liver fat fraction [proportion; range, 0 to 1; higher values indicate a higher proportion of fat]), and resting energy expenditure (kcal/day; adjusted for lean mass) from baseline to week 8 and caloric intake (kcal) at an experimental test meal from baseline to week 6. RESULTS: Sixty-one participants (54% women; mean age ± standard deviation, 33.6 ± 6.2 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 36.9 ± 4.9) were randomly assigned. There was no difference in body weight change from baseline to week 8 between oxytocin and placebo groups (0.20 vs. 0.26 kg; P=0.934). Oxytocin (vs. placebo) was not associated with beneficial effects on body composition or resting energy expenditure from baseline to week 8 (total fat: difference [95% confidence interval], 196.0 g [-1036 to 1428]; visceral fat: 3.1 cm2 [-11.0 to 17.2]; liver fat: -0.01 [-0.03 to 0.01]; resting energy expenditure: -64.0 kcal/day [-129.3 to 1.4]). Oxytocin compared with placebo was associated with reduced caloric intake at the test meal (-31.4 vs. 120.6 kcal; difference [95% confidence interval], -152.0 kcal [-302.3 to -1.7]). There were no serious adverse events. Incidence and severity of adverse events did not differ between groups. CONCLUSIONS: In this randomized, placebo-controlled trial in adults with obesity, intranasal oxytocin administered four times daily for 8 weeks did not reduce body weight. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT03043053.).

The impact of oxytocin on emotion recognition and trust: Does disordered eating moderate these relationships?

OBJECTIVES: The current study aimed to investigate the impact of oxytocin on emotion recognition, trust, body image, affect, and anxiety and whether eating disorder (ED) symptoms moderated any of these relationships. METHOD: Participants (n = 149) were female university students, who were randomly allocated to receive in a double-blind nature, a single dose of oxytocin intranasal spray (n = 76) or a placebo (saline) intranasal spray (n = 73). Participants were asked to complete an experimental measure of emotion recognition and an investor task aimed to assess trust. RESULTS: The oxytocin group exhibited better overall performance on the emotion recognition task (especially with recognising positive emotions), and a decline in state positive affect than the control group at post-intervention. However, these effects were not moderated by ED symptom severity, nor were effects found for state anxiety, negative affect, body image and recognising negative emotions in the emotion recognition task. CONCLUSION: The current findings contribute to the growing literature on oxytocin, emotion recognition and positive affect and suggest that ED pathology does not moderate these relationships. Future research would benefit from examining the efficacy of an oxytocin intervention using a within-subjects, cross-over design, in those with sub-clinical and clinical EDs, as well as healthy controls.

Oxytocin-Augmented Modular-Based Group Intervention for Loneliness: A Proof-Of-Concept Randomized Controlled Trial.

INTRODUCTION: Loneliness poses a significant health problem and existing psychological interventions have shown only limited positive effects on loneliness. Based on preliminary evidence for impaired oxytocin signaling in trait-like loneliness, the current proof-of-concept study used a randomized, double-blind, placebo-controlled design to probe intranasal oxytocin (OT) as an adjunct to a short-term modular-based group intervention for individuals suffering from high trait-like loneliness (HL, UCLA Loneliness Scale ≥55). METHODS: Seventy-eight healthy HL adults (56 women) received five weekly group psychotherapy sessions. HL participants received OT or placebo before the intervention sessions. Primary outcomes were trait-like loneliness measured at baseline, after the intervention, and again at two follow-up time points (3 weeks and 3 months), and, assessed at each session, state loneliness (visual analog scale), perceived stress (Perceived Stress Scale, PSS-10), quality of life (World Health Organization Five Well-Being Index, WHO-5), and the therapeutic relationship (Group Questionnaire, GQ-D). RESULTS: The psychological intervention was associated with significantly reduced perceived stress and improved trait-like loneliness across treatment groups, which was still evident at the 3-month follow-up. OT had no significant effect on trait-like loneliness, quality of life, or perceived stress. However, compared to placebo, OT significantly facilitated the decrease in state loneliness within sessions and significantly improved positive bonding between the group members. CONCLUSION: Despite significantly improved trait-like loneliness after the intervention, OT did not significantly augment this effect. Further studies are needed to determine optimal intervention designs to translate the observed acute effects of OT into long-term benefits.

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

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.

Boosting decision-making in rat models of early-life adversity with environmental enrichment and intranasal oxytocin.

Impaired decision-making constitutes a fundamental issue in numerous psychiatric disorders. Extensive research has established that early life adversity (ELA) increases vulnerability to psychiatric disorders later in life. ELA in human neonates is associated with changes in cognitive, emotional, as well as reward-related processing. Maternal separation (MS) is an established animal model of ELA and has been shown to be associated with decision-making deficits. On the other hand, enriched environment (EE) and intranasal oxytocin (OT) administration have been demonstrated to have beneficial effects on decision-making in humans or animals. Given these considerations, our investigation sought to explore the impact of brief exposure to EE and intranasal OT administration on the decision-making abilities of adolescent rats that had experienced MS during infancy. The experimental protocol involved subjecting rat pups to the MS regimen for 180 min per day from postnatal day (PND) 1 to PND 21. Then, from PND 22 to PND 34, the rats were exposed to EE and/or received intranasal OT (2 µg/µl) for seven days. The assessment of decision-making abilities, using a rat gambling task (RGT), commenced during adolescence. Our findings revealed that MS led to impaired decision-making and a decreased percentage of advantageous choices. However, exposure to brief EE or intranasal OT administration mitigated the deficits induced by MS and improved the decision-making skills of maternally-separated rats. Furthermore, combination of these treatments did not yield additional benefits. These results suggest that EE and OT may hold promise as therapeutic interventions to enhance certain aspects of cognitive performance.

Intranasal oxytocin as a treatment for anxiety and autism: From subclinical to clinical applications.

Animal and human studies have demonstrated that intranasal oxytocin (OT) can penetrate the brain and induce cognitive, emotional, and behavioral changes, particularly in social functioning. Consequently, numerous investigations have explored the potential of OT as a treatment for anxiety and autism, conditions characterized by social deficits. Although both subclinical and clinical studies provide converging evidence of the therapeutic effects of OT in reducing anxiety levels and improving social symptoms in autism, results are not always consistent. Additionally, the pharmacological mechanism of OT requires further elucidation for its effective clinical application. Therefore, this review aims to examine the contentious findings concerning the effects of OT on anxiety and autism, offer interpretations of the inconsistent results from the perspectives of individual differences and varying approaches to OT administration, and shed light on the underlying mechanisms of OT. Ultimately, standardization of dosage, frequency of administration, formulation characteristics, and nasal spray devices is proposed as essential for future human studies and clinical applications of OT treatment.

Intranasal oxytocin suppresses seizure-like behaviors in a mouse model of NGLY1 deficiency.

NGLY1 deficiency is a genetic disease caused by biallelic mutations of the Ngly1 gene. Although epileptic seizure is one of the most severe symptoms in patients with NGLY1 deficiency, preclinical studies have not been conducted due to the lack of animal models for epileptic seizures in NGLY1 deficiency. Here, we observed the behaviors of male and female Ngly1-/- mice by video monitoring and found that these mice exhibit spontaneous seizure-like behaviors. Gene expression analyses and enzyme immunoassay revealed significant decreases in oxytocin, a well-known neuropeptide, in the hypothalamus of Ngly1-/- mice. Seizure-like behaviors in Ngly1-/- mice were transiently suppressed by a single intranasal administration of oxytocin. These findings suggest the therapeutic potential of oxytocin for epileptic seizure in patients with NGLY1 deficiency and contribute to the clarification of the disease mechanism.

Quantifying abnormal emotion processing: A novel computational assessment method and application in schizophrenia.

Abnormal emotion processing is a core feature of schizophrenia spectrum disorders (SSDs) that encompasses multiple operations. While deficits in some areas have been well-characterized, we understand less about abnormalities in the emotion processing that happens through language, which is highly relevant for social life. Here, we introduce a novel method using deep learning to estimate emotion processing rapidly from spoken language, testing this approach in male-identified patients with SSDs (n = 37) and healthy controls (n = 51). Using free responses to evocative stimuli, we derived a measure of appropriateness, or "emotional alignment" (EA). We examined psychometric characteristics of EA and its sensitivity to a single-dose challenge of oxytocin, a neuropeptide shown to enhance the salience of socioemotional information in SSDs. Patients showed impaired EA relative to controls, and impairment correlated with poorer social cognitive skill and more severe motivation and pleasure deficits. Adding EA to a logistic regression model with language-based measures of formal thought disorder (FTD) improved classification of patients versus controls. Lastly, oxytocin administration improved EA but not FTD among patients. While additional validation work is needed, these initial results suggest that an automated assay using spoken language may be a promising approach to assess emotion processing in SSDs.

Design of a randomized clinical trial of brief couple therapy for PTSD augmented with intranasal oxytocin.

BACKGROUND: Leveraging military veterans' intimate relationships during treatment has the potential to concurrently improve posttraumatic stress disorder (PTSD) symptoms and relationship quality. Cognitive-Behavioral Conjoint Therapy (CBCT) and an 8-session Brief Cognitive-Behavioral Conjoint Therapy (bCBCT) are manualized treatments designed to simultaneously improve PTSD and relationship functioning for couples in which one partner has PTSD. Although efficacious in improving PTSD, the effects of CBCT on relationship satisfaction are small, especially among veterans. Intranasal oxytocin, which targets mechanisms of PTSD and relationship quality, may enhance the efficacy of bCBCT. METHOD/DESIGN: The purpose of this 4-year clinical trial is to compare the outcomes of bCBCT augmented with intranasal oxytocin versus bCBCT plus placebo. We will also explore potential mechanisms of action: self-reported communication skills, empathy, and trust. We will recruit 120 dyads (i.e., veteran with PTSD and their intimate partner) from the VA San Diego Healthcare System. Veterans will be administered 40 international units of oxytocin (n = 60) or placebo (n = 60) 30 min before each of 8 bCBCT sessions delivered via telehealth. Clinical and functioning outcomes will be assessed at five timepoints (baseline, mid-treatment, post-treatment, and 3- and 6-month follow-up). CONCLUSION: Study findings will reveal the efficacy of oxytocin-assisted brief couple therapy for PTSD, which could serve as highly scalable option for couples coping with PTSD, as well as provide preliminary evidence of interpersonal mechanisms of change. CLINICALTRIALS: govIdentifier:NCT06194851.

Maintenance oxytocin in the immediate postpartum period: Frequency, determinants and practices in a tertiary maternity unit.

OBJECTIVE: To prevent post-partum haemorrhage (PPH), national and international guidelines recommend the administration of a prophylactic injection of oxytocin after all vaginal births. Although additional maintenance oxytocin is not recommended in the immediate postpartum, its administration is quite common (30 % of French births in 2021). To assess in a single center, the frequency and determinants associated with the administration of maintenance oxytocin in immediate postpartum. STUDY DESIGN: A retrospective observational single-centre study was conducted in a tertiary-care university centre in Paris (France), with data from April-May 2022. All women who gave birth vaginally at or after 37 weeks, except for those with immediate PPH. Univariate and multivariate analysis were performed to compare determinants between the group receiving maintenance oxytocin and the control group without this intervention. A sensitivity analysis in a population of women at low risk of PPH was performed. Maternal, obstetrical, perinatal and organisational determinants were collected. RESULTS: This study included 584 patients, 278 (47.6 %) of whom received maintenance oxytocin. We observed a significantly higher rate of maintenance oxytocin administration to parous women (OR 1.57, 90 %CI 1.09-2.27) and women with a history of PPH (OR 2.88, 90 %CI 1.08-9.08). Additional maintenance oxytocin was also administered more often when the midwife handling the birth had more than 5 years of practice since completion of training (OR 1.77, 1.24-2.53) or during night-time births (OR 1.47, 90 %CI 1.03-2.10). CONCLUSION: Maintenance oxytocin administration is a frequent practice, performed for almost half the patients in our center. This practice is associated with maternal and obstetric factors, but also with health professionals' individual decisions and practices.

Impact of combined propranolol and oxytocin on the process and outcomes of labor: a meta-analysis of randomized controlled trials.

PURPOSE: To systematically review the impact of propranolol combined with oxytocin on the process and outcomes of labor. METHODS: A comprehensive literature search was performed across multiple databases, including China National Knowledge Infrastructure (CNKI), VIP, Wanfang, China Biomedical Literature Database, PubMed, Embase, and the Cochrane Library. All publicly published randomized controlled trials (RCTs) of propranolol combined with oxytocin compared to the use of oxytocin alone in labor were collected. After screening the literature and extracting data, the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 recommended bias risk assessment tool was used to assess the quality of the included studies. A meta-analysis was conducted using RevMan 5.3 software, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to rate the quality of evidence for outcome measures. RESULTS: Meta-analysis results showed that the group receiving propranolol combined with oxytocin was more capable of reducing the cesarean section rate (eight studies, 815 women, RR = 0.67, 95% CI (0.53, 0.86), P = 0.001) and shortening the duration of the latent phase (two studies, 206 women, MD = - 1.20, 95% CI (- 1.97, - 0.43), P = 0.002) and the duration of the active phase on day 1 (two studies, 296 women, MD = - 0.69, 95% CI (- 0.83, - 0.54), P < 0.00001), compared to the oxytocin monotherapy group. No significant difference was found between the two groups in terms of the 5-min Apgar score (five studies, 609 women, MD = - 0.05, 95% CI (- 0.14, 0.04), P = 0.32) and the rate of admissions to the Neonatal Intensive Care Unit (NICU) (three studies, 359 women, RR = 0.82, 95% CI (0.38, 1.79), P = 0.62). CONCLUSION: The combined use of propranolol and oxytocin can significantly reduce the cesarean section rate, shorten the duration of the latent phase and the duration of the active phase on day 1, and is safe. However, due to the limitations, the conclusions of this article still need to be verified by large-sample, multicenter, rigorously designed high-quality clinical RCTs. TRIAL REGISTRATION: Registration number is INPLASY202390107.

Routine vaginal examination to assess labor progress at 8 compared to 4 hours after early amniotomy following Foley balloon ripening in the labor induction of multiparas: a randomized trial.

BACKGROUND: Vaginal examination to monitor labor progress is recommended at least every 4 hours, but it can cause pain and embarrassment to women. Trial data are limited on the best intensity for vaginal examination. Vaginal examination is not needed for oxytocin dose titration after an amniotomy has been performed and oxytocin infusion started. The Foley balloon commonly ripens the cervix without strong contractions. Amniotomy and oxytocin infusion are usually required to drive labor. OBJECTIVE: This study aimed to evaluate the first vaginal examination at 8 vs 4 hours after amniotomy-oxytocin after Foley ripening in multiparous labor induction. STUDY DESIGN: A randomized controlled trial was conducted from October 2021 to September 2022 at the University Malaya Medical Center, Kuala Lumpur, Malaysia. Multiparas at term were recruited at admission for labor induction. Participants were randomized to a first routine vaginal examination at 8 or 4 hours after Foley balloon ripening and amniotomy. Titrated oxytocin infusion was routinely commenced after amniotomy to initiate contractions. The 2 primary outcomes were the time from amniotomy to delivery (noninferiority hypothesis) and maternal satisfaction (superiority hypothesis). Data were analyzed using the Student t test, Mann-Whitney U test, and chi-square test (or Fisher exact test), as suitable for the data. RESULTS: A total of 204 women were randomized, 102 to each arm. Amniotomy to birth intervals were 4.97±2.47 hours in the 8-hour arm and 5.79±3.17 hours in the 4-hour arm (mean difference, -0.82; 97.5% confidence interval, -1.72 to 0.08; P=.041; Bonferroni correction), which were noninferior within the prespecified 2-hour upper margin, and the maternal satisfaction scores (11-point 0-10 numerical rating scale) with allocated labor care were 9 (interquartile range, 8-9) in the 8-hour arm and 8 (interquartile range, 7-9) in the 4-hour arm (P=.814). In addition, oxytocin infusion to birth interval difference was noninferior within the 97.5% confidence interval (-1.59 to 0.23) margin of 1.3 hours. Of the maternal outcomes, the amniotomy to first vaginal examination intervals were 3.9±1.8 hours in the 8-hour arm and 3.4±1.3 hours in the 4-hour arm (P=.026), and the numbers of vaginal examinations were 2.00 (interquartile range, 2.00-3.00) in the 8-hour arm and 3.00 (interquratile range, 2.00-3.25) in the 4-hour arm (P<.001). For the 8-hour arm, the first vaginal examination was less likely to be as scheduled and more likely to be indicated by sensation to bear down (P<.001), and the epidural analgesia rates were lower (13/102 participants [12.7%] in the 8-hour arm vs 28/102 participants [27.5%] in the 4-hour arm; relative risk, 0.46; 95% confidence interval, 0.26-0.84; P=.009). Other outcomes of the mode of delivery, indications for cesarean delivery, and delivery blood loss were not different. Neonatal outcomes were not different. CONCLUSION: Routine first vaginal examination at 8 hours compared with that at 4 hours was noninferior for the time to birth but did not improve maternal satisfaction.

Optimal starting dosing regimen of intravenous oxytocin for labor induction based on the population kinetic-pharmacodynamic model of uterine contraction frequency.

BACKGROUND: Intravenous oxytocin is commonly used for labor induction. However, a consensus on the initial dosing regimen is lac with conflicting research findings and varying guidelines. This study aimed to develop a population kinetic-pharmacodynamic (K-PD) model for oxytocin-induced uterine contractions considering real-world data and relevant influencing factors to establish an optimal starting dosing regimen for intravenous oxytocin. METHODS: This retrospective study included pregnant women who underwent labor induction with intravenous oxytocin at Peking University Third Hospital in 2020. A  population K-PD model was developed to depict the time course of uterine contraction frequency (UCF), and covariate screening identified significant factors affecting the pharmacokinetics and pharmacodynamics of oxytocin. Model-based simulations were used to optimize the current starting regimen based on specific guidelines. RESULTS: Data from 77 pregnant women with 1095 UCF observations were described well by the K-PD model. Parity, cervical dilation, and membrane integrity are significant factors influencing the effectiveness of oxytocin. Based on the model-based simulations, the current regimens showed prolonged onset times and high infusion rates. This study proposed a revised approach, beginning with a rapid infusion followed by a reduced infusion rate, enabling most women to achieve the target UCF within approximately 30 min with the lowest possible infusion rate. CONCLUSION: The K-PD model of oxytocin effectively described the changes in UCF during labor induction. Furthermore, it revealed that parity, cervical dilation, and membrane integrity are key factors that influence the effectiveness of oxytocin. The optimal starting dosing regimens obtained through model simulations provide valuable clinical references for oxytocin treatment.

Connectome dysfunction in patients at clinical high risk for psychosis and modulation by oxytocin.

Abnormalities in functional brain networks (functional connectome) are increasingly implicated in people at Clinical High Risk for Psychosis (CHR-P). Intranasal oxytocin, a potential novel treatment for the CHR-P state, modulates network topology in healthy individuals. However, its connectomic effects in people at CHR-P remain unknown. Forty-seven men (30 CHR-P and 17 healthy controls) received acute challenges of both intranasal oxytocin 40 IU and placebo in two parallel randomised, double-blind, placebo-controlled cross-over studies which had similar but not identical designs. Multi-echo resting-state fMRI data was acquired at approximately 1 h post-dosing. Using a graph theoretical approach, the effects of group (CHR-P vs healthy control), treatment (oxytocin vs placebo) and respective interactions were tested on graph metrics describing the topology of the functional connectome. Group effects were observed in 12 regions (all pFDR < 0.05) most localised to the frontoparietal network. Treatment effects were found in 7 regions (all pFDR < 0.05) predominantly within the ventral attention network. Our major finding was that many effects of oxytocin on network topology differ across CHR-P and healthy individuals, with significant interaction effects observed in numerous subcortical regions strongly implicated in psychosis onset, such as the thalamus, pallidum and nucleus accumbens, and cortical regions which localised primarily to the default mode network (12 regions, all pFDR < 0.05). Collectively, our findings provide new insights on aberrant functional brain network organisation associated with psychosis risk and demonstrate, for the first time, that oxytocin modulates network topology in brain regions implicated in the pathophysiology of psychosis in a clinical status (CHR-P vs healthy control) specific manner.

Age-dependent effects of oxytocin in brain regions enriched with oxytocin receptors.

Although intranasal oxytocin administration to tap into central functions is the most commonly used non-invasive means for exploring oxytocin's role in human cognition and behavior, the way by which intranasal oxytocin acts on the brain is not yet fully understood. Recent research suggests that brain regions densely populated with oxytocin receptors may play a central role in intranasal oxytocin's action mechanisms in the brain. In particular, intranasal oxytocin may act directly on (subcortical) regions rich in oxytocin receptors via binding to these receptors while only indirectly affecting other (cortical) regions via their neural connections to oxytocin receptor-enriched regions. Aligned with this notion, the current study adopted a novel approach to test 1) whether the connections between oxytocin receptor-enriched regions (i.e., the thalamus, pallidum, caudate nucleus, putamen, and olfactory bulbs) and other regions in the brain were responsive to intranasal oxytocin administration, and 2) whether oxytocin-induced effects varied as a function of age. Forty-six young (24.96 ± 3.06 years) and 44 older (69.89 ± 2.99 years) participants were randomized, in a double-blind procedure, to self-administer either intranasal oxytocin or placebo before resting-state fMRI. Results supported age-dependency in the effects of intranasal oxytocin administration on connectivity between oxytocin receptor-enriched regions and other regions in the brain. Specifically, compared to placebo, oxytocin decreased both connectivity density and connectivity strength of the thalamus for young participants while it increased connectivity density and connectivity strength of the caudate for older participants. These findings inform the mechanisms underlying the effects of exogenous oxytocin on brain function and highlight the importance of age in these processes.

Intranasal oxytocin in a genetic animal model of autism.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders mainly characterized by deficient sociability and repetitive behaviors. Effective treatment for the core symptoms of ASD is still lacking. Behavioral interventions show limited effectiveness, while pharmacotherapy focuses on the amelioration of secondary symptomatology. Oxytocin (OXT) is a neuropeptide known for its prosocial impact, making it a candidate drug for ASD treatment. Its alleviating effect has been and still is widely researched, but outcomes reported by clinical studies are ambiguous. We examined the effect of daily intranasal OXT (0.8 IU/kg) administration for 4 weeks on the ASD-like phenotype in Shank3-/- adult mice. Animals treated with OXT spent twice as much time interacting with the social partner as early as after 2 weeks of treatment. Furthermore, OXT-treated mice exhibited reduced explorative behavior by 50%, after 4 weeks of treatment, and a 30% reduction in repetitive behavior, 4 weeks after treatment termination. One-fold higher sociability and 30% reduced exploration due to OXT lasted up to 4 weeks following the treatment termination. However, social disinterest was elevated by roughly 10% as well, indicating a form of social ambivalence. Obtained results support the therapeutic potential of intranasally administered OXT in alleviating social shortfalls in a genetic model of ASD. Subsequent research is necessary to elucidate the benefits and risks of the long-term OXT administration, as well as its applicability in other ASD models and the potential treatment effect on social communication, which was not measured in the present study.

Comparative study between oxytocin and combination of tranexamic acid and ethamsylate in reducing intra-operative bleeding during emergency and elective cesarean section after 38 weeks of normal pregnancy.

OBJECTIVE: Cesarean Section (CS) is associated with an increased risk of hemorrhage. Many drugs are used to decrease this risk. We aim to compare the combination of ethamsylate and tranexamic acid, oxytocin, and placebo in women undergoing CS. METHODS: We conducted a double-blinded, randomized, placebo-controlled trial between October and December 2020 in four university hospitals in Egypt. The study included all pregnant women in labor without any complications who accepted to participate in the study between October and December 2020. The participants were divided into three groups. The subjects were randomly allocated to receive either oxytocin (30 IU in 500 ml normal saline during cesarean section), combined one gram of tranexamic acid with 250 mg of ethamsylate once before skin incision, or distilled water. Our main outcome was the amount of blood loss during the operation. The secondary outcomes were the need for blood transfusion, hemoglobin and hematocrit changes, hospital stay, operative complications, and the need for a hysterectomy. The one-way ANCOVA test was used to compare the quantitative variables between the three groups while the Chi-square test was used to compare the qualitative variables. Post hoc analysis then was performed to compare the difference between every two groups regarding the quantitative variables. RESULTS: Our study included 300 patients who were divided equally into three groups. Tranexamic acid with ethamsylate showed the least intra-operative blood loss (605.34 ± 158.8 ml) compared to oxytocin (625.26 ± 144.06) and placebo (669.73 ± 170.69), P = 0.015. In post hoc analysis, only tranexamic acid with ethamsylate was effective in decreasing the blood loss compared to placebo (P = 0.013); however, oxytocin did not reduce blood loss compared to saline (P = 0.211) nor to tranexamic acid with ethamsylate (P = 1). Other outcomes and CS complications showed no significant difference between the three groups except for post-operative thrombosis which was significantly higher in the tranexamic and ethamsylate group, P < 0.00001 and the need for a hysterectomy which was significantly increased in the placebo group, P = 0.017. CONCLUSION: The combination of tranexamic acid and ethamsylate was significantly associated with the least amount of blood loss. However, in pairwise comparisons, only tranexamic acid with ethamsylate was significantly better than saline but not with oxytocin. Both oxytocin and tranexamic acid with ethamsylate were equally effective in reducing intra-operative blood loss and the risk of hysterectomy; however, tranexamic acid with ethamsylate increased the risk of thrombotic events. Further research with a larger number of participants is needed. TRIAL REGISTRATION: The study was registered on Pan African Clinical Trials Registry with the following number: PACTR202009736186159 and was approved on 04/09/2020.

The relationship between oxytocin and empathy for others' pain: Testing the mediating effect of first-hand pain sensitivity.

Although previous studies have shown that oxytocin attenuates first-hand pain sensitivity, studies of its effects on empathetic reactions to the observation of others' pain have yielded inconsistent and controversial results. Given the link between first-hand pain and empathy for others' pain, we hypothesized that oxytocin affects empathy for others' pain by modulating first-hand pain sensitivity. Using a double-blind, placebo-controlled, between-participant experimental design, healthy participants (n = 112) were randomly assigned to either an intranasal oxytocin or placebo group. Pain sensitivity was evaluated by pressure pain threshold, and empathetic responses were assessed by ratings in response to viewing video clips depicting others in physically painful scenarios. Results showed that pressure pain thresholds decreased over time in both groups, indicating increased sensitivity to first-hand pain after repeated measurements. However, this decrease was smaller for participants who received intranasal oxytocin, indicative of oxytocin-induced attenuation of first-hand pain sensitivity. In addition, although empathetic ratings were comparable between oxytocin and placebo groups, first-hand pain sensitivity fully mediated the impact of oxytocin on pain empathetic ratings. Thus, intranasal oxytocin can indirectly affect pain empathetic ratings by reducing first-hand pain sensitivity. These findings expand our understanding of the relationship among oxytocin, pain, and empathy.