Dose Of Intranasal Oxytocin Research Articles

A phase II randomised controlled trial of intranasal oxytocin in anorexia nervosa

BackgroundAnorexia nervosa (AN) is an eating disorder (ED) with high mortality rates and limited response to existing treatments, prompting the need to identify effective agents and adjuncts. There is evidence for an emerging role for the neuropeptide oxytocin (OT) in the pathophysiology of AN, with studies showing a perturbed oxytocinergic system in patients with AN. Preliminary evidence has demonstrated that intranasal OT (IN-OT) can produce anxiolytic effects in AN, as well as reducing concern about eating, and dysfunctional attentional biases related to the disorder. IN-OT is a non-invasive treatment option for AN that requires investigation as an adjunct to nutritional rehabilitation. MethodsThis multi-site study (Trial Registration:ACTRN1261000897460) sought to replicate and extend a previous randomised placebo-controlled pilot trial of repeated dose IN-OT in patients with AN hospitalised for nutritional rehabilitation. Patients with AN (N=61) received daily IN-OT (18 IU twice per day) or placebo for four weeks, whilst undergoing inpatient hospital treatment. Outcome measures included ED psychopathology (primary) as measured by the Eating Disorder Examination (EDE) and Body Mass Index (BMI; secondary). Participants were assessed pre- and post-treatment, and at six months following the intervention. The effects of the first and last doses of IN-OT on responses (anxiety ratings and salivary cortisol) to a high-energy snack were also examined. ResultsSixty-one female inpatients (Mage=24.36,SD=7.87) with an average BMI of 16.24 (range: 11.43–18.55), were recruited into the study. No significant differences were found between placebo and OT groups at any of the time points on the outcomes of interest, but significant improvements in almost all psychological parameters in both groups were evident over time. IN-OT did not significantly reduce anxiety nor salivary cortisol in response to a high-calorie snack. ConclusionThis is the largest randomised placebo-controlled trial of repeated dose intranasal OT in people with AN, during refeeding. The therapeutically promising findings of the pilot study were not replicated. Limitations and reasons for the non-replication included relatively large variance, baseline psychopathology scores being higher in this patient group, potential ceiling effects in BMI and ED psychopathology as well as differing comorbidities.

Oxytocin modulates neurocomputational mechanisms underlying prosocial reinforcement learning.

Humans often act in the best interests of others. However, how we learn which actions result in good outcomes for other people and the neurochemical systems that support this 'prosocial learning' remain poorly understood. Using computational models of reinforcement learning, functional magnetic resonance imaging and dynamic causal modelling, we examined how different doses of intranasal oxytocin, a neuropeptide linked to social cognition, impact how people learn to benefit others (prosocial learning) and whether this influence could be dissociated from how we learn to benefit ourselves (self-oriented learning). We show that a low dose of oxytocin prevented decreases in prosocial performance over time, despite no impact on self-oriented learning. Critically, oxytocin produced dose-dependent changes in the encoding of prediction errors (PE) in the midbrain-subgenual anterior cingulate cortex (sgACC) pathway specifically during prosocial learning. Our findings reveal a new role of oxytocin in prosocial learning by modulating computations of PEs in the midbrain-sgACC pathway.

The effect of intranasal oxytocin application and mindfulness-based group therapy for patients with schizophrenia spectrum disorders – A study protocol

IntroductionResearch indicates improvements in negative symptoms and empathy for schizophrenia spectrum disorders (SSD) after mindfulness-based interventions (MBI). Current treatment approaches for SSD remain limited regarding their effectiveness on negative symptoms and sociocognitive deficits. After oxytocin (OXT) administration, especially in a positive social context, an increase in empathy could be shown. The effect of mindfulness in combination with OXT has not yet been examined.ObjectivesThis study investigates the additional effect of OXT administration combined with MBI on empathy and negative symptoms in patients with SSD.MethodsAn experimental, randomised, triple-blinded, placebo-controlled study is proposed. Based on power calculations, 140 participants with SSD will be recruited at Charité – Universitätsmedizin Berlin. A dose of intranasal oxytocin with 24 I.U. or placebo will be administered 45 minutes before each session. Following each administration, a total of four MBI interventions will take place for two weeks. Empathy as primary outcome will be measured using validated psychometric questionnaires. Outcomes, including negative symptoms and OXT plasma levels, will be measured at baseline and post-intervention. A 2x2 mixed-model ANCOVA design with time as within- and group as between-subject factor will be calculated to assess empathy and negative symptom changes.ResultsThe study hypothesises that applying intranasal oxytocin in combination with MBI will increase empathy and reduce negative symptoms in patients with SSD.ConclusionsFindings could provide insight into enhancing therapies like MBI by utilising OXT as a possible supplementary treatment option. Findings could therefore pave the way for a personalised psychiatric medicine treatment for individuals with SSD.DisclosureNo significant relationships.

Intranasal oxytocin drives coordinated social approach

Coordinated responses to challenge are essential to survival for bonded monogamous animals and may depend on behavioral compatibility. Oxytocin (OT) context-dependently regulates social affiliation and vocal communication, but its role in pair members’ decision to jointly respond to challenge is unclear. To test for OT effects, California mouse females received an intranasal dose of OT (IN-OT) or saline after bonding with males either matched or mismatched in their approach response to an aggressive vocal challenge. Pair mates were re-tested jointly for approach response, time spent together, and vocalizations. Females and males converged in their approach after pairing, but mismatched pairs with females given a single dose of IN-OT displayed a greater convergence that resulted from behavioral changes by both pair members. Unpaired females given IN-OT did not change their approach, indicating a social partner was necessary for effects to emerge. Moreover, IN-OT increased time spent approaching together, suggesting behavioral coordination beyond a further increase in bonding. This OT-induced increase in joint approach was associated with a decrease in the proportion of sustained vocalizations, a type of vocalization that can be associated with intra-pair conflict. Our results expand OT’s effects on behavioral coordination and underscore the importance of emergent social context.

Investigating resting brain perfusion abnormalities and disease target-engagement by intranasal oxytocin in women with bulimia nervosa and binge-eating disorder and healthy controls

Advances in the treatment of bulimia nervosa and binge-eating disorder (BN/BED) have been marred by our limited understanding of the underpinning neurobiology. Here we measured regional cerebral blood flow (rCBF) to map resting perfusion abnormalities in women with BN/BED compared with healthy controls and investigate whether intranasal oxytocin (OT), proposed as a potential treatment, can restore perfusion in disorder-related brain circuits. Twenty-four women with BN/BED and 23 healthy women participated in a randomized, double-blind, crossover, placebo-controlled study. We used arterial spin labelling MRI to measure rCBF and the effects of an acute dose of intranasal OT (40 IU) or placebo over 18–26 min post dosing, as we have previously shown robust OT-induced changes in resting rCBF in men in a similar time-window (15–36 min post dosing). We tested for effects of treatment, diagnosis and their interaction on extracted rCBF values in anatomical regions-of-interest previously implicated in BN/BED by other neuroimaging modalities, and conducted exploratory whole-brain analyses to investigate previously unidentified brain regions. We demonstrated that women with BN/BED presented increased resting rCBF in the medial prefrontal and orbitofrontal cortices, anterior cingulate gyrus, posterior insula and middle/inferior temporal gyri bilaterally. Hyperperfusion in these areas specifically correlated with eating symptoms severity in patients. Our data did not support a normalizing effect of intranasal OT on perfusion abnormalities in these patients, at least for the specific dose (40 IU) and post-dosing interval (18–26 min) examined. Our findings enhance our understanding of resting brain abnormalities in BN/BED and identify resting rCBF as a non-invasive potential biomarker for disease-related changes and treatment monitoring. They also highlight the need for a comprehensive investigation of intranasal OT pharmacodynamics in women before we can fully ascertain its therapeutic value in disorders affecting predominantly this gender, such as BN/BED.

Oxytocin increases eye gaze in schizophrenia

Abnormal eye gaze is common in schizophrenia and linked to functional impairment. The hypothalamic neuropeptide oxytocin modulates visual attention to social stimuli, but its effects on eye gaze in schizophrenia are unknown. We examined visual scanning of faces in men with schizophrenia and neurotypical controls to quantify oxytocin effects on eye gaze.In a randomized, double-blind, crossover study, 33 men with schizophrenia and 39 matched controls received one dose of intranasal oxytocin (40 IU) and placebo on separate testing days. Participants viewed 20 color photographs of faces while their gaze patterns were recorded. We tested for differences in fixation time on the eyes between patients and controls as well as oxytocin effects using linear mixed-effects models. We also tested whether attachment style, symptom severity, and anti-dopaminergic medication dosage moderated oxytocin effects.In the placebo condition, patients showed reduced fixation time on the eyes compared to controls. Oxytocin was associated with an increase in fixation time among patients, but a decrease among controls. Higher attachment anxiety and greater symptom severity predicted increased fixation time on the eyes on oxytocin versus placebo. Anti-dopaminergic medication dosage and attachment avoidance did not impact response to oxytocin.Consistent with findings that oxytocin optimizes processing of social stimuli, intranasal oxytocin enhanced eye gaze in men with schizophrenia. Further work is needed to determine whether changes in eye gaze impact social cognition and functional outcomes. Both attachment anxiety and symptom severity predicted oxytocin response, highlighting the importance of examining potential moderators of oxytocin effects in future studies.

Oxytocin modulates hippocampal perfusion in people at clinical high risk for psychosis

Preclinical and human studies suggest that hippocampal dysfunction is a key factor in the onset of psychosis. People at Clinical High Risk for psychosis (CHR-P) present with a clinical syndrome that can include social withdrawal and have a 20–35% risk of developing psychosis in the next 2 years. Recent research shows that resting hippocampal blood flow is altered in CHR-P individuals and predicts adverse clinical outcomes, such as non-remission/transition to frank psychosis. Previous work in healthy males indicates that a single dose of intranasal oxytocin has positive effects on social function and marked effects on resting hippocampal blood flow. The present study examined the effects of intranasal oxytocin on hippocampal blood flow in CHR-P individuals. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using pseudo-continuous Arterial Spin Labelling on 2 occasions, once after 40IU intranasal oxytocin and once after placebo. The effects of oxytocin on left hippocampal blood flow were examined in a region-of-interest analysis of data acquired at 22–28 and at 30–36 minutes post-intranasal administration. Relative to placebo, administration of oxytocin was associated with increased hippocampal blood flow at both time points (p = .0056; p = .034), although the effect at the second did not survive adjustment for the effect of global blood flow. These data indicate that oxytocin can modulate hippocampal function in CHR-P individuals and therefore merits further investigation as a candidate novel treatment for this group.

Low-dose intranasal oxytocin delivered with Breath Powered device modulates pupil diameter and amygdala activity: a randomized controlled pupillometry and fMRI study.

Little is known about how intranasally administered oxytocin reaches the brain and modulates social behavior and cognition. Pupil dilation is a sensitive index of attentional allocation and effort, and inter-individual variability in pupil diameter during performance of social-cognitive tasks may provide a better assessment of pharmacological effects on the brain than behavioral measures. Here, we leverage the close relationship between pupil and neural activity to inform our understanding of nose-to-brain oxytocin routes and possible dose-response relationships. To this end, we assessed pupil diameter data from a previously reported functional magnetic resonance imaging (fMRI) study under four treatment conditions-including two different doses of intranasal oxytocin using a novel Breath Powered nasal device, intravenous (IV) oxytocin, and placebo-and investigated the association with amygdala activation in response to emotional stimuli. The study used a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults administering a single-dose of these four treatments. A significant main effect of treatment condition on pupil diameter was observed. Posthoc tests revealed reduced pupil diameter after 8IU intranasal oxytocin compared to placebo, but no significant difference between 8IU intranasal oxytocin and either 24IU intranasal oxytocin or IV oxytocin treatment conditions. Analysis also showed a significant relationship between pupil diameter and right amygdala activation after 8IU intranasal oxytocin. Although there was no significant difference between 8IU intranasal oxytocin and IV oxytocin on right amygdala activity and pupil diameter, the significant difference between 8IU intranasal oxytocin and placebo is consistent with the hypothesis that oxytocin can travel to the brain via a nose-to-brain route.

Effects of chronic oxytocin on attention to dynamic facial expressions in infant macaques

Studies in a variety of species have reported enhanced prosocial effects after an acute administration of the neuromodulating hormone, oxytocin (OT). Although the exact mechanisms underlying these effects are not fully understood, there is broad interest in developing OT into a treatment for social deficits. Only a few studies, however, have examined the effects of OT if given repeatedly during early development, the period when early intervention is likely to have the greatest benefits for reversing the progression towards social impairment. Those studies, exclusively in rodents, report mixed results. Some have shown enhancement of prosocial behavior, including increased social exploration, but others have shown anti-social effects, including increased aggression. In the present study, infant rhesus macaques were treated with a high-frequency (3× per week) or low-frequency (1× per week) dose of intranasal oxytocin (IN-OT) or placebo (IN-saline) between two and six months of age, after which their reactions to dynamic facial expressions (neutral, lipsmacking and threats) were measured. Results showed that IN-OT, compared to placebo, increased the time monkeys spent viewing the expression videos, but selectively reduced attention to the eyes in neutral faces in a dose dependent manner. The mechanism for this non-prosocial effect may be that repeated IN-OT administration down-regulates the expression of OT receptors in brain regions important for regulating social attention. Consequently, our results raise questions about the efficacy of implementing chronic IN-OT as a pharmacotherapy for the treatment of social deficits, particularly if given early in development. More work is needed, not only to identify optimal treatment schedules, but also to understand how IN-OT exerts its influences on the brain and behavior.

Low dose intranasal oxytocin delivered with Breath Powered device dampens amygdala response to emotional stimuli: A peripheral effect-controlled within-subjects randomized dose-response fMRI trial

It is unclear if and how exogenous oxytocin (OT) reaches the brain to improve social behavior and cognition and what is the optimal dose for OT response. To better understand the delivery routes of intranasal OT administration to the brain and the dose-response, we compared amygdala response to facial stimuli by means of functional magnetic resonance imaging (fMRI) in four treatment conditions, including two different doses of intranasal OT using a novel Breath Powered device, intravenous (IV) OT, which provided similar concentrations of blood plasma OT, and placebo. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults administering a single-dose of these four treatments. We observed a treatment effect on right amygdala activation during the processing of angry and happy face stimuli, with pairwise comparisons revealing reduced activation after the 8IU low dose intranasal treatment compared to placebo. These data suggest the dampening of amygdala activity in response to emotional stimuli occurs via direct intranasal delivery pathways rather than across the blood-brain barrier via systemically circulating OT.Trial registration: This trial is registered at the U.S. National Institutes of Health clinical trial registry (www.clinicaltrials.gov; NCT01983514) and as EudraCT no. 2013-001608-12.

Intranasal Oxytocin Administration is Associated With Enhanced Endogenous Pain Inhibition and Reduced Negative Mood States

This study examined whether the administration of intranasal oxytocin was associated with pain sensitivity, endogenous pain inhibitory capacity, and negative mood states. A total of 30 pain-free, young adults each completed 3 laboratory sessions on consecutive days. The first session (baseline) assessed ischemic pain sensitivity, endogenous pain inhibition via conditioned pain modulation (CPM), and negative mood using the Profile of Mood States. CPM was tested on the dominant forearm and ipsilateral masseter muscle using algometry (test stimulus) and the cold pressor task (conditioning stimulus; nondominant hand). For the second and third sessions, participants initially completed the State-Trait Anxiety Inventory and then self-administered a single (40 IU/1 mL) dose of intranasal oxytocin or placebo in a randomized counterbalanced order. Thirty minutes postadministration, participants again completed the State-Trait Anxiety Inventory and repeated assessments of ischemic pain sensitivity and CPM followed by the Profile of Mood States. Findings demonstrated that ischemic pain sensitivity did not significantly differ across the 3 study sessions. CPM at the masseter, but not the forearm, was significantly greater following administration of oxytocin compared to placebo. Negative mood was also significantly lower following administration of oxytocin compared to placebo. Similarly, anxiety significantly decreased following administration of oxytocin but not placebo. This study incorporated a placebo-controlled, double-blind, within-subjects crossover design with randomized administration of intranasal oxytocin and placebo. The data suggest that the administration of intranasal oxytocin may augment endogenous pain inhibitory capacity and reduce negative mood states including anxiety.

Oxytocin for frontotemporal dementia: a randomized dose-finding study of safety and tolerability.

To determine the safety and tolerability of 3 doses of intranasal oxytocin (Syntocinon; Novartis, Bern, Switzerland) administered to patients with frontotemporal dementia (FTD). We conducted a randomized, parallel-group, double-blind, placebo-controlled study using a dose-escalation design to test 3 clinically feasible doses of intranasal oxytocin (24, 48, or 72 IU) administered twice daily for 1 week to 23 patients with behavioral variant FTD or semantic dementia (clinicaltrials.gov registration number NCT01386333). Primary outcome measures were safety and tolerability at each dose. Secondary measures explored efficacy across the combined oxytocin vs placebo groups and examined potential dose-related effects. All 3 doses of intranasal oxytocin were safe and well tolerated. A multicenter trial is warranted to determine the therapeutic efficacy of long-term intranasal oxytocin for behavioral symptoms in FTD. This study provides Class I evidence that for patients with FTD, intranasal oxytocin is not significantly associated with adverse events or significant changes in the overall neuropsychiatric inventory.

Oxytocin and enhancement of the positive valence of social affiliation memories: An autobiographical memory study

Intranasal oxytocin has been shown to alter self-perceptions of personality (e.g., more trusting, increased extraversion). To follow up these findings, we examined the acute effects of two doses of intranasal oxytocin (24 IU and 48 IU) on another form of self-referential cognition: autobiographical memory. Changes in autobiographical memory (personal memories for the past) could conceivably effect change in self-perception and consequently alter social behaviors. We predicted that oxytocin would increase the number of specific personal memories recalled, and promote the recall of positive social affiliation memories. Seventeen male participants self-administered a placebo or oxytocin (24 IU, 48 IU) using a nasal spray on three separate occasions in a placebo-controlled, double-blind, and within-subject experiment. Participants completed the Autobiographical Memory Test (AMT) 110 minutes later. Analyses revealed a quadratic dose–response curve for the effects of intranasal oxytocin on autobiographical memory recall. The 24 IU dose, relative to the 48 IU dose and placebo, increased the number of specific personal memories recalled and promoted the recall of social affiliation memories that were rated more positively. The lack of effect with the 48 IU dose could be due to saturation of the oxytocin receptors at higher doses. Changes in autobiographical memory may be one mechanism by which oxytocin alters prosocial worldviews.

Divergent effects of two different doses of intranasal oxytocin on facial affect discrimination in schizophrenic patients with and without polydipsia

Hyponatremia and dexamethasone resistance in polydipsic schizophrenic patients are attributable to changes in hippocampal-modulated antidiuretic and stress hormone activity, respectively. The relationship of the neuroendocrine findings to the psychiatric illness, however, is unknown. An impaired ability to identify facial emotions has been linked to core features of schizophrenia and to diminished levels of the closely related hormone, oxytocin, in the polydipsic subset. Intranasal oxytocin enhances facial affect discrimination in healthy subjects. The aim of this study is to explore if oxytocin reverses impaired facial affect discrimination in schizophrenic patients with, relative to that in patients without, polydipsia. Intranasal oxytocin (10 or 20 IU) and placebo were administered on three occasions to five polydipsic schizophrenic patients, eight nonpolydipsic patients, and 11 healthy controls. Subsequently, subjects rated the presence and intensity of six facial emotions. Emotion recognition fell in both patient groups following 10 IU of oxytocin due to an increased propensity to identify all emotions regardless of whether they were displayed. By contrast, emotion recognition improved following 20 IU in polydipsic relative to nonpolydipsic patients due primarily to divergent effects on the bias to identify fear in nonfearful faces. The effects of 20 IU oxytocin support the hypothesis that altered neuroendocrine function in polydipsic patients contributes to their psychiatric illness. Further studies are warranted to confirm these findings and assess if oxytocin treatment improves social functioning in this subset. This is the first psychopharmacologic study to compare different doses of oxytocin in the same subject, thus the significance of the opposing responses is unclear.