Oxytocin and psychotherapy: A pilot study of its physiological, behavioral and subjective effects in males with depression Intranasal Oxytocin Enhances Connectivity in the Neural Circuitry Supporting Social Motivation and Social Perception in Children with Autism Oxytocin increases amygdala reactivity to threatening scenes in females Intranasal Oxytocin Normalizes Amygdala Functional Connectivity in Posttraumatic Stress Disorder The Effects of Intranasal Oxytocin Administration on Sensitive Caregiving in Mothers with Postnatal Depression Effects of intranasal oxytocin on neural processing within a socially relevant neural circuit A randomized controlled trial of intranasal oxytocin as an adjunct to exposure therapy for social anxiety disorder Intranasal oxytocin administration prior to exposure therapy for arachnophobia impedes treatment response. Effects of oxytocin and vasopressin on the neural response to unreciprocated cooperation within brain regions involved in stress and anxiety in men and women 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 Kinetics and Dose Dependency of Intranasal Oxytocin Effects on Amygdala Reactivity Effects of Intranasal Oxytocin on the Neural Basis of Face Processing in Autism Spectrum Disorder Oxytocin differentially alters resting state functional connectivity between amygdala subregions and emotional control networks: Inverse correlation with depressive traits Low-dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized four-way crossover trial with nasal cavity dimension assessment Intranasal oxytocin increases neural responses to social reward in post-traumatic stress disorder Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample
Individual psychotherapy is an important treatment for a number of psychiatric conditions and involves a unique form of human attachment . This raises the question of whether oxytocin ( OT ) , the paradigmatic " attachment hormone " , may have benefits in this context . In this r and omized , double-blind , crossover trial , we gave male psychiatric out patients with major depressive disorder 40 IU  intranasal OT or placebo before a videotaped session with a therapist and measured a number of subjective , physiological , and behavioral parameters . We report three main findings . Surprisingly - in contrast to prior reports of OT 's anxiolytic properties - we found OT caused an increase in anxiety over the course of the therapy session . Secondly , though it had no main effect on cortisol , eye contact , or overall behavior , we did find that OT caused a decrease in nonverbal behaviors that cut off social contact , after controlling for level of depressive symptoms . Lastly , we replicated prior findings that OT improves social cognition ( performance on the reading the mind in the eyes test ( RMET ) ) , albeit in a depressed patient group . These results inform future studies of oxytocin and psychotherapy and suggest that in certain clinical population s and context s , OT has heterogeneous subjective effects which may include acute anxiogenesis . Moreover , the similarity of some of these acute effects to those of single-dose serotonergic antidepressants raises interesting questions about the potential antidepressant benefits of chronic OT administration Oxytocin ( OT ) has become a focus in investigations of autism spectrum disorder ( ASD ) . The social deficits that characterize ASD may relate to reduced connectivity between brain sites on the mesolimbic reward pathway ( nucleus accumbens ; amygdala ) that receive OT projections and contribute to social motivation , and cortical sites involved in social perception . Using functional magnetic resonance imaging and a r and omized , double blind , placebo-controlled crossover design , we show that OT administration in ASD  increases activity in brain regions important for perceiving social-emotional information . Further , OT  enhances connectivity between nodes of the brain ’s reward and socioemotional processing systems , and does so preferentially for social ( versus nonsocial ) stimuli . This effect is observed both while viewing coherent versus scrambled biological motion , and while listening to happy versus angry voices . Our findings suggest a mechanism by which intranasal OT may bolster social motivation — one that could , in future , be harnessed to augment behavioral treatments for ASD The neuropeptide oxytocin ( OT ) is well known for its profound effects on social behavior , which appear to be mediated by an OT-dependent modulation of amygdala activity in the context of social stimuli . In humans , OT decreases amygdala reactivity to threatening faces in males , but enhances amygdala reactivity to similar faces in females , suggesting sex-specific differences in OT-dependent threat-processing . To further explore whether OT generally enhances amygdala-dependent threat-processing in females , we used functional magnetic resonance imaging ( fMRI ) in a r and omized within-subject crossover design to measure amygdala activity in response to threatening and non-threatening scenes in 14 females following intranasal administration of OT or placebo .  Participants ' eye movements were recorded to investigate whether an OT-dependent modulation of amygdala activity is accompanied by enhanced exploration of salient scene features . Although OT had no effect on participants ' gazing behavior , it increased amygdala reactivity to scenes depicting social and non-social threat . In females , OT may , thus , enhance the detection of threatening stimuli in the environment , potentially by interacting with gonadal steroids , such as progesterone and estrogen The neuropeptide oxytocin ( OT ) has been suggested as a promising pharmacological agent for medication-enhanced psychotherapy in posttraumatic stress disorder ( PTSD ) because of its anxiolytic and prosocial properties . We therefore investigated the behavioral and neurobiological effects of a single intranasal OT administration ( 40 IU ) in PTSD patients . We conducted a r and omized , placebo-controlled , cross-over resting-state fMRI study in male and female police officers with ( n=37 , 21 males ) and without PTSD ( n=40 , 20 males ) . We investigated OT administration effects on subjective anxiety and functional connectivity of basolateral ( BLA ) and centromedial ( CeM ) amygdala subregions with prefrontal and salience processing areas . In PTSD patients , OT administration result ed in decreased subjective anxiety and nervousness . Under placebo , male PTSD patients showed diminished right CeM to left ventromedial prefrontal cortex ( vmPFC ) connectivity compared with male trauma-exposed controls , which was reinstated after OT administration . Additionally , female PTSD patients showed enhanced right BLA to bilateral dorsal anterior cingulate cortex ( dACC ) connectivity compared with female trauma-exposed controls , which was dampened after OT administration . Although caution is warranted , our findings tentatively suggest that OT has the potential to diminish anxiety and fear expression of the amygdala in PTSD , either via increased control of the vmPFC over the CeM ( males ) or via decreased salience processing of the dACC and BLA ( females ) . Our findings add to accumulating evidence that OT administration could potentially enhance treatment response in PTSD Postnatal depression ( PND ) is common and negatively affects the mother – infant relationship ; oxytocin ( OT ) has been found to have positive effects on parenting , although psychiatric disorders may reduce these effects . Thus , we explored the role of OT in mothers diagnosed with PND . A within-subject , r and omized controlled double-blind design was used to test the effects of nasal administration of OT or placebo on sensitive caregiving . The outcome measures were perceptual and caregiving responses to prerecorded cry sounds , as well as observed maternal sensitivity . We found that in the OT condition mothers with PND were more likely to rate an infant cry as more urgent and they were more likely to indicate they would chose a harsh caregiving strategy in response . There was no effect of OT on maternal sensitive interaction with their own baby . Further research is required prior to consideration of OT administration in depressed mothers of infants Dysregulation of the Mirror Neuron System ( MNS ) in schizophrenia ( SCZ ) may underlie the cognitive and behavioral manifestations of social dysfunction associated with that disorder . In healthy subjects  intranasal ( IN ) oxytocin ( OT ) improves neural processing in the MNS and is associated with improved social cognition . OT 's brain effects can be measured through its modulation of the MNS by suppressing EEG mu-b and electrical activity ( 8 - 13Hz ) in response to motion perception . Although IN OT 's effects on social cognition have been tested in SCZ , OT 's impact on the MNS has not been evaluated to date . Therefore , we design ed a study to investigate the effects of two different OT doses on biological motion-induced mu suppression in SCZ and healthy subjects .  EEG recordings  were taken after each subject received a single IN administration of placebo , OT-24IU and OT-48IU in r and omized order in a double-blind crossover design . The results provide support for  OT 's  regulation of the MNS in both healthy and SCZ subjects , with the optimal dose dependent on diagnostic group and sex of subject . A statistically significant response was seen in SCZ males only , indicating a heightened sensitivity to those effects , although sex hormone related effects can not be ruled out . In general , OT appears to have positive effects on neural circuitry that supports social cognition and socially adaptive behaviors In humans , oxytocin nasal administration reduces social-threat perception and improves processes involved in communication and the encoding of positive social cues . The aim of this study was to determine whether oxytocin given as an adjunct to exposure therapy improves treatment for  social anxiety disorder ( SAD ) as indicated by a comprehensive set of symptom outcome measures . In a r and omized , double-blind , placebo-controlled trial , we administered 24 IU of oxytocin or a placebo in combination with exposure therapy to twenty-five participants who met primary diagnosis for SAD . Participants administered with oxytocin showed improved positive evaluations of appearance and speech performance as exposure treatment sessions progressed . These effects did not generalize to improve overall treatment outcome from exposure therapy . Participants who received oxytocin or placebo reported similar levels of symptom reduction following treatment across symptom severity , dysfunctional cognition , and life-impairment measures . This study shows that the administration of oxytocin improves mental representations of self , following exposure therapy . These effects may be either short term or situation specific . Future research is now needed to determine whether oxytocin can enhance treatment outcomes for SAD when used with greater frequency , with a wider variety of social learning experiences , and in conjunction with interventions that more specifically target change in broader dysfunctional cognitions BACKGROUND Recent years have seen the emergence of a new paradigm for treatment of anxiety disorders focusing on development of drugs that facilitate psychotherapies via targeted effects on neuroplasticity . One compound that has generated interest in this regard is oxytocin ( OT ) , a mammalian neuropeptide that modulates activity of the neurocircuit mediating fear extinction and memory processes . Recent research in healthy humans has suggested that intranasal OT administered prior to fear extinction training enhances fear extinction performance , supporting its potential to augment exposure-based psychotherapy . Here , we tested the hypothesis that OT treatment would facilitate response to exposure therapy in patients with specific phobia . METHODS We conducted a small proof-of-concept trial investigating the effect of pretreatment intranasal OT administration on a brief , single-session exposure treatment for arachnophobia ( fear of spiders ) . The study was r and omized , double-blind , and placebo controlled ( n = 13 placebo , 11 females ; n = 10 OT , 8 females ) with 1-week and 1-month follow-up assessment s. Dependent measures attended to arachnophobia symptoms ( self-report ) , phobic behavior ( behavioral avoidance of spider task ) , and treatment credibility/therapeutic alliance . RESULTS Administration of OT prior to exposure therapy tended to impede treatment response as measured by self-report of symptoms at both follow-up periods . OT treatment did not significantly affect behavioral measures of fear . Immediately after OT administration but before therapy , the OT group trended toward less confidence in the treatment . The OT group also trended toward lower ratings of therapeutic alliance than placebo . CONCLUSIONS These results suggest that OT administration effects on extinction may vary depending on conditions and population Anxiety disorders are characterized by hyperactivity in both the amygdala and the anterior insula . Interventions that normalize activity in these areas may therefore be effective in treating anxiety disorders . Recently , there has been significant interest in the potential use of oxytocin ( OT ) , as well as vasopressin ( AVP ) antagonists , as treatments for anxiety disorders . In this double-blind , placebo-controlled , pharmaco- fMRI study , 153 men and 151 women were r and omized to treatment with either 24 IU intranasal OT , 20 IU intranasal AVP , or placebo and imaged with fMRI as they played the iterated Prisoner ’s Dilemma game with same-sex human and computer partners . In men , OT attenuated the fMRI response to unreciprocated cooperation ( CD ) , a negative social interaction , within the amygdala and anterior insula . This effect was specific to interactions with human partners . In contrast , among women , OT unexpectedly attenuated the amygdala and anterior insula response to unreciprocated cooperation from computer but not human partners . Among women , AVP did not significantly modulate the response to unreciprocated cooperation in either the amygdala or the anterior insula . However , among men , AVP attenuated the BOLD response to CD outcomes with human partners across a relatively large cluster including the amygdala and the anterior insula , which was contrary to expectations . Our results suggest that OT may decrease the stress of negative social interactions among men , whereas these effects were not found in women interacting with human partners . These findings support continued investigation into the possible efficacy of OT as a treatment for anxiety disorders UNLABELLED 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 underst and 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 r and omized , 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 . clinical trials.gov ; NCT01983514 ) and as EudraCT no. 2013 - 001608 - 12 BACKGROUND Current neuroimaging perspectives on a variety of mental disorders emphasize dysfunction of the amygdala . The neuropeptide oxytocin ( OXT ) , a key mediator in the regulation of social cognition and behavior , accumulates in cerebrospinal fluid after intranasal administration in macaques and humans and modulates amygdala reactivity in both species . However , the translation of neuromodulatory OXT effects to novel treatment approaches is hampered by the absence of studies defining the most effective dose and dose-response latency for targeting the amygdala . METHODS To address this highly relevant issue , a total of 116 healthy men underwent functional magnetic resonance imaging using a r and omized , double-blind , placebo-controlled crossover study design . The experimental rationale was to systematic ally vary dose-test latencies ( 15 - 40 , 45 - 70 , and 75 - 100 minutes ) and doses of OXT ( 12 , 24 , and 48 international units ) in order to identify the most robust effects on amygdala reactivity . During functional magnetic resonance imaging , subjects completed an emotional face recognition task including stimuli with varying intensities ranging from low ( highly ambiguous ) to high ( less ambiguous ) . RESULTS Our results indicate that the OXT-induced inhibition of amygdala responses to fear was most effective in a time window between 45 and 70 minutes after administration of a dose of 24 international units . Furthermore , the observed effect was most evident in subjects scoring high on measures of autistic-like traits .  Behavioral response patterns suggest that OXT specifically reduced an emotional bias in the perception of ambiguous faces . CONCLUSIONS These findings provide initial evidence of the most effective dose and dose-test interval for future experimental or therapeutic regimens aim ed at targeting amygdala functioning using intranasal OXT administration BACKGROUND Autism spectrum disorder ( ASD ) is associated with altered face processing and decreased activity in brain regions involved in face processing . The neuropeptide oxytocin has been shown to promote face processing and modulate brain activity in healthy adults . The present study examined the effects of oxytocin on the neural basis of face processing in adults with Asperger syndrome ( AS ) . METHODS A group of 14 individuals with AS and a group of 14 neurotypical control participants performed a face-matching and a house-matching task during functional magnetic resonance imaging . The effects of a single dose of 24 IU intranasally administered oxytocin were tested in a r and omized , placebo-controlled , within-subject , cross-over design . RESULTS Under placebo , the AS group showed decreased activity in the right amygdala , fusiform gyrus , and inferior occipital gyrus compared with the control group during face processing . After oxytocin treatment , right amygdala activity to facial stimuli increased in the AS group . CONCLUSIONS These findings indicate that oxytocin increases the saliency of social stimuli and in ASD and suggest that oxytocin might promote face processing and eye contact in individuals with ASD as prerequisites for neurotypical social interaction ABSTRACT The hypothalamic neuropeptide oxytocin ( OT ) has received increasing attention for its role in modulating social‐emotional processes across species . Previous studies on using intranasal‐OT in humans point to a crucial engagement of the amygdala in the observed neuromodulatory effects of OT under task and rest conditions . However , the amygdala is not a single homogenous structure , but rather a set of structurally and functionally heterogeneous nuclei that show distinct patterns of connectivity with limbic and frontal emotion‐processing regions . To determine potential differential effects of OT on functional connectivity of the amygdala subregions , 79 male participants underwent resting‐state fMRI following r and omized intranasal‐OT or placebo administration .  In line with previous studies OT increased the connectivity of the total amygdala with dorso‐medial prefrontal regions engaged in emotion regulation . In addition , OT enhanced coupling of the total amygdala with cerebellar regions . Importantly , OT differentially altered the connectivity of amygdala subregions with distinct up‐stream cortical nodes , particularly prefrontal/parietal , and cerebellar down‐stream regions . OT‐induced  increased connectivity with cerebellar regions were largely driven by effects on the centromedial and basolateral subregions , whereas increased connectivity with prefrontal regions were largely mediated by right superficial and basolateral subregions . OT decreased connectivity of the centromedial subregions with core hubs of the emotional face processing network in temporal , occipital and parietal regions . Preliminary findings suggest that effects on the superficial amygdala‐prefrontal pathway were inversely associated with levels of sub clinical depression , possibly indicating that OT modulation may be blunted in the context of increased pathological load . Together , the present findings suggest a subregional‐specific modulatory role of OT on amygdala‐centered emotion processing networks in humans . HighlightsEffects of oxytocin ( OT ) on amygdala subregional rsFC were examined . OT differentially altered rsFC of amygdala subregions . Increased connectivity with PFC regions were driven by SF and BLA.OT  decreased rsFC of the CM with the face processing network . Effects on the SF‐mPFC pathway were associated with depression Despite the promise of intranasal oxytocin ( OT ) for modulating social behavior , recent work has provided mixed results . This may relate to suboptimal drug deposition achieved with conventional nasal sprays , inter-individual differences in nasal physiology and a poor underst and ing of how intranasal OT is delivered to the brain in humans . Delivering OT using a novel ‘ Breath Powered ’ nasal device previously shown to enhance deposition in intranasal sites targeted for nose-to-brain transport , we evaluated dose-dependent effects on social cognition , compared response with intravenous ( IV ) administration of OT , and assessed nasal cavity dimensions using acoustic rhinometry . We adopted a r and omized , double-blind , double-dummy , crossover design , with 16 healthy male adults completing four single-dose treatments ( intranasal 8 IU ( international units ) or 24 IU OT , 1 IU OT IV and placebo ) . The primary outcome was social cognition measured by emotional ratings of facial images . Secondary outcomes included the pharmacokinetics of OT , vasopressin and cortisol in blood and the association between nasal cavity dimensions and emotional ratings . Despite the fact that all the treatments produced similar plasma OT increases compared with placebo , there was a main effect of treatment on anger ratings of emotionally ambiguous faces . Pairwise comparisons revealed decreased ratings after 8 IU OT in comparison to both placebo and 24 IU OT . In addition , there was an inverse relationship between nasal valve dimensions and anger ratings of ambiguous faces after 8-IU OT treatment . These findings provide support for a direct nose-to-brain effect , independent of blood absorption , of low-dose OT delivered from a Breath Powered device Abstract Therapeutic alliance and perceived social support are important predictors of treatment response for post-traumatic stress disorder ( PTSD ) . Intranasal oxytocin administration may enhance treatment response by increasing sensitivity for social reward and thereby therapeutic alliance and perceived social support . As a first step to investigate this therapeutical potential , we investigated whether intranasal oxytocin enhances neural sensitivity to social reward in PTSD patients . Male and female police officers with ( n = 35 ) and without PTSD ( n = 37 ) were included in a double-blind , r and omized , placebo-controlled cross-over fMRI study . After intranasal oxytocin ( 40 IU ) and placebo administration , a social incentive delay task was conducted to investigate neural responses during social reward and punishment anticipation and feedback . Under placebo , PTSD patients showed reduced left anterior insula ( AI ) responses to social rewards ( i.e. happy faces ) compared with controls . Oxytocin administration increased left AI responses during social reward in PTSD patients , such that PTSD patients no longer differed from controls under placebo . Furthermore , in PTSD patients , oxytocin  increased responses to social reward in the right putamen . By normalizing abberant insula responses and increasing putamen responses to social reward , oxytocin administration may enhance sensitivity for social support and therapeutic alliance in PTSD patients . Future studies are needed to investigate clinical effects of oxytocin Fragile X syndrome ( FXS ) is a rare inherited genetic disorder causing severe intellectual disability and autistic-like symptoms . Individuals with FXS , males in particular , often exhibit extreme eye gaze avoidance and hyperarousal when they encounter stressful social situations . We investigated whether oxytocin ( OT ) , a hormone with prosocial and anxiolytic effects , could alleviate symptoms of social anxiety in this population . A r and omized double-blind placebo-controlled single-dose trial was performed with intranasal administration of placebo , 24 IU OT and 48 IU OT . Measures of eye gaze frequency , heart rate , respiratory sinus arrhythmia ( RSA ) , heart rate variability ( HRV ) and salivary cortisol were obtained during a structured social challenge conducted 50 min following OT administration . Ten low-functioning males with FXS ( aged 13 - 28 years ) traveled to Stanford for the initial visit : 8 completed the study .  Eye gaze frequency improved significantly in response to the 24 IU OT dose and salivary cortisol levels decreased significantly in response to the 48 IU OT dose . There was no effect of OT on heart rate , RSA or HRV although individual plots of the heart rate data suggested that OT increased heart rate in some participants and decreased heart rate in others . These findings suggest that intranasal administration of OT may ameliorate some symptoms of social anxiety in patients with FXS . Further double-blind placebo-controlled studies of OT , conducted in combination with behavioral treatment programs , may be warranted Rationale To improve outcomes for patients undergoing extinction-based therapies ( e.g. , exposure therapy ) for anxiety disorders such as post-traumatic stress disorder ( PTSD ) , there has been interest in identifying pharmaceutical compounds that might facilitate fear extinction learning and recall . Oxytocin ( OT ) is a mammalian neuropeptide that modulates activation of fear extinction-based neural circuits and fear responses . Little is known , however , about the effects of OT treatment on conditioned fear responding and extinction in humans . Objectives The purpose of the present study was to assess the effects of OT in a fear-potentiated startle task of fear conditioning and extinction . Methods A double-blind , placebo-controlled study of 44 healthy human participants was conducted . Participants underwent a conditioned fear acquisition procedure , after which they were r and omized to treatment group and delivered OT ( 24 IU ) or placebo via intranasal ( IN ) spray . Forty-five minutes after treatment , participants underwent extinction training . Twenty-four hours later , subjects were tested for extinction recall . Results Relative to placebo , the OT group showed increased fear-potentiated startle responding during the earliest stage of extinction training relative to placebo ; however , all treatment groups showed the same level of reduced responding by the end of extinction training . Twenty-four hours later , the OT group showed significantly higher recall of extinction relative to placebo . Conclusions The current study provides preliminary evidence that OT may facilitate fear extinction recall in humans . These results support further study of OT as a potential adjunctive treatment for extinction-based therapies in fear-related disorders
Results showed no significant effects on core symptomatology .
In conclusion , up to date , evidence regarding the potential utility of IN-OT in treating anxiety and depression is still inconclusive .
Several studies have demonstrated the neuromodulating function of oxytocin ( OT ) in response to anxiogenic stimuli as well as its potential role in the pathogenesis of depression .
Consequently , intranasal OT ( IN-OT ) has been proposed as a potential treatment of  anxiety and depressive disorders .
The present systematic review aim ed to summarize the r and omized controlled trials ( RCTs ) evaluating the effect of IN-OT on anxiety and depressive symptoms .