Oxytocin is a peptide hormone that is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and is directly projected into other brain areas, where it acts as a neurotransmitter. It is also released into the bloodstream, via the posterior pituitary gland, to peripheral targets.1,2 Animal studies highlight the importance of oxytocin in parturition, milk letdown, protective aggression, social behaviors, and bonding between mothers and infants and in mating pairs.3 Human studies have confirmed oxytocin’s role as a social hormone that mediates many social behaviors involved in forming attachments.4 In healthy controls, oxytocin decreases both cortisol release and anxiety in response to social stress,5 reduces amygdala activity in response to fearful or threatening visual images6 or emotional faces,7 increases trust behavior in a money-transferring game,8 increases the ability to interpret mental states,9 and increases the amount of time spent gazing at the eyes when viewing faces.10 Van Ijzendorn and Bakermans-Kranenburg11 provide a meta-analysis supporting the notion that intranasal oxytocin in healthy individuals enhances the recognition of emotion and elevates the level of trust in established relationships. In addition to its prosocial effects, it has also been shown to be involved in jealousy, gloating, and out-group discrimination.12–15 Given the effect of oxytocin on these basic interpersonal interactions, a growing body of research has investigated the possible involvement of oxytocin in the pathophysiology of neuropsychiatric disorders that affect social functioning, such as autism, schizophrenia, and depression.
Many studies have examined the relationship between oxytocin and parent-child interactions.16–20 (For a detailed review see Galbally et al.)21 For example, studies have demonstrated decreased urinary oxytocin levels in children placed in orphanages shortly after birth22 and decreased oxytocin levels in the cerebrospinal fluid (CSF) of adult women exposed to childhood maltreatment.23 Men with a history of early parental separation had altered cortisol response to exogenous oxytocin,24 and oxytocin caused healthy controls with more anxious attachment styles to remember their mothers as less caring, whereas those with less anxious attachments remembered their mothers as more caring.25 Also, in males classified as having “insecure” attachments, oxytocin increased the level of attachment security in the majority of participants.26 Clearly, the interrelationship between oxytocin and an individual’s experience of early childhood attachment is complex, and it remains unclear to what extent this connection influences the role of oxytocin in the pathophysiology of psychiatric disorders.
This review summarizes in detail the evidence of oxytocin dysfunction and its therapeutic potential in various neuropsychiatric disorders. Studies were found by performing a PubMed search using Boolean combinations of oxytocin with the following search terms: anxiety disorders, autism, mood disorders, personality disorders, psychiatry, and schizophrenia. Abstracts were reviewed, followed by detailed evaluations of all relevant articles, whose references helped identify additional sources. Only human studies in the English language were included, and the date range was restricted to publications from 1970 to the present.
Due to space considerations, specific information about single nucleotide polymorphisms (SNPs) and allelic variations in the various genetics studies is included in the textonly as it pertains to the discussion of similarities and differences between the various studies. This detailed information can befound in Table 1, however, which providesacomprehensive picture of what is known regarding oxytocingeneticsin psychiatric disorders. Inconsistencies in the table reflect the inconsistencies in the reviewed studies. Also due to space considerations, specific methodological limitations of individual studies are not presented in detail. Instead, the authors’ synthesis of broader limitations extending across studies will be presented in the concluding section.
This article discusses published research studies of oxytocin in psychiatric disorders. Oxytocin is not approved by the FDA for use in any of the disorders discussed.
OXYTOCIN AND AUTISM
Mouse models have demonstrated oxytocin’s role in social recognition, attachment, and stereotyped behaviors,111–113 which correlate with core deficits in autism spectrum disorders (ASD). Oxytocin has thus been investigated both for its role in the pathophysiology of ASD and as a potential therapeutic target for these disorders.
Modahl and colleagues27 found lower mean plasma oxytocin levels in children with autism compared to age-matched healthy controls. Elevated oxytocin levels were associated with higher scores on the Vineland Adaptive Behavior Scale (VABS) for the typically developing children but with lower VABS scores for the children with autism. A follow-up study of individuals with autism demonstrated that decreased plasma oxytocin was associated with increased extended-peptide oxytocin—inactive forms of oxytocin derived from the same prohormone as oxytocin itself—indicating a defect in peptide processing of oxytocin.28
In sharp contrast, Jansen and colleagues29 compared adults with ASD and healthy controls, and found that adults with ASD showed increased basal plasma oxytocin levels. Differences in oxytocin levels between these studies may be related to differences in development (adults versus children), diagnostic subgroups, or intellectual development. In the adult study, oxytocin levels did not correlate with impaired social interaction, communication, or stereotyped behavior as measured by the Autism Diagnostic Interview–Revised.114
These studies suggest that ASD may be associated with a dysfunction in oxytocin processing and that the oxytocin system of individuals with ASD may change over the course of the lifespan. Further longitudinal studies or larger studies of broader age ranges, with adequate control for intellectual development across age groups, are necessary to confirm this hypothesis.
Several studies have investigated the association between autism and genetic variants in genes encoding oxytocin and the oxytocin receptor. Wu and colleagues30 reported a family-based association test of four single-nucleotide polymorphisms (SNPs) within the oxytocin receptor gene (OXTR) of Chinese Han autism proband-parent trios. An association between autism and two of the SNPs was found (see Table 1). Haplotype-specific family-based association tests demonstrated a number of haplotypes (combinations of alleles in adjacent locations on the chromosome that are likely transmitted together) that were associated with autism. Jacob and colleagues31 attempted to replicate this finding in Caucasian autism proband-parent trios. They were able to detect an association at rs2254298, but a different allele was associated with autism at this location than in the study by Wu and colleagues.30 The authors postulated that an undiscovered genetic variant associated with autism may be transmitted along with rs2254298 but with different alleles in different populations.
Lerer and colleagues32 performed family-based association tests on all 18 identified SNPs within the OXTR region in Israeli participants with ASD, their parents, and unaffected siblings. They also evaluated how OXTR variants were associated, if at all, with intelligence quotient (IQ) and Vineland Adaptive Behavior Scale scores. SNP analysis revealed 2 SNPs associated with ASD, 2 SNPs associated with IQ, and 2 SNPs associated with total VABS scores, as well as 8 SNPs associated with individual VABS subdomains (communication, daily-living skills, and socialization). Several haplotypes were also associated with ASD, IQ, and VABS scores.
Yrigollen and colleagues33 examined associations of both the oxytocin gene (OXT; 2 SNPs) and OXTR (3 SNPs) with autism in primarily Caucasian ASD probands. Association with diagnosis was found with one SNP within OXTR, and association with stereotyped behaviors was found with one SNP within OXT. In a Japanese population,34 no association was found in family-based association tests of 11 SNPs within OXTR; however, in a population-based, case‐control analysis, differences were observed in allelic frequencies of 4 SNPs. Tansey and colleagues35 examined three independent autism samples from Ireland, Portugal, and the United Kingdom for association of 18 SNPs in OXTR, and found no association with autism in any of the samples. However, the SNP most often implicated in previous studies—rs2254298—was not examined.
Wermter and colleagues36 performed single-marker and haplotype family-based association tests of 22 SNPs in the OXTR region in patients with high-functioning ASD. They found nominal associations of one SNP and one haplotype with autism—which did not withstand corrections for multiple comparisons. Patients carrying the implicated haplotype showed impairments, compared to noncarriers, in social interaction and communication as assessed with the Autism Diagnostic Interview–Revised. Of note, the SNP with strongest evidence for association in other studies,rs2254298, was not associated with autism. In the largest study to date, Campbell and colleagues37 performed family-based association tests on 25 SNPs in OXTR in over 1000 families. They reported association of 3 SNPs previously implicated in prior studies, and these markers were associated with various measures of social-communication dysfunction as assessed by the Autism Diagnostic Interview–Revised, Autism Diagnostic Observation Schedule,115 and Social Responsiveness Scale.116
Table 1 demonstrates the lack of consistency among studies in terms of specific alleles or variants associated with ASD. As with many candidate-gene approaches to studying complex neuropsychiatric phenotypes, replicable findings are lacking. Given the heterogeneous nature of ASD, however, the associations with OXT and OXTR that are found across multiple studies indicate that this hormone system may indeed play some role in the pathophysiology of ASD.
Gregory and colleagues38 studied an autism proband containing an inherited deletion in chromosome region 3p25.3, which includes the oxytocin receptor gene. Interestingly, the proband had a brother with autism who did not inherit the deletion; however, bisulfite sequencing analysis demonstrated that a critical region previously shown to regulate expression of OXTR 117 was heavily methylated in the affected sibling. The authors also performed bisulfite sequencing analysis of peripheral blood cells from typically developing controls and individuals with autism. Three of the sites identified as hypermethylated in the proband’s sibling also displayed greater methylation in individuals with autism compared to controls. The authors then evaluated methylation of OXTR in postmortem temporal cortex from individuals with autism and age- and sex-matched controls. Again, hypermethylation was seen in the autism cases compared to healthy controls. Thus, even when no direct genetic evidence indicates alterations in oxytocin-related genes, the expression of these genes may be affected by epigenetic modification, providing a different mechanism for oxytocin’s role in the clinical phenotype of ASD.
Response to Exogenous Oxytocin
Several studies have investigated the response of individuals with ASD to the administration of exogenous oxytocin peripherally or intranasally. Hollander and colleagues39,40 enrolled adults with ASD in a randomized, double-blind, within-individual, placebo-controlled study. Each participant received a continuous intravenous infusion of synthetic oxytocin (10–15 IU) or placebo over four hours on the first day of testing, and received the other on the second testing day. In the first experiment,39 severity of six repetitive behaviors was assessed at baseline and at several points during the infusion. A greater reduction in repetitive behaviors over time was present during oxytocin infusion compared to placebo.
In the second experiment,40 the participants were presented with four sentences of neutral content with one of four emotional intonations (happy, indifferent, angry, sad) and were asked to identify the emotional mood of the speaker. The task was repeated at baseline and several times over the course of the infusion. The authors report a time × treatment × order effect for the comprehension of affective speech. During the first testing day, participants improved from baseline to endpoint regardless of whether they received placebo or oxytocin. During the second testing day, those who had received oxytocin the first day retained their high performance at baseline, and their performance did not change from baseline to endpoint. Those who received placebo during the first day first showed a drop in score at baseline, which then improved again over the course of oxytocin infusion. The authors interpret this result as demonstrating that oxytocin increases retention of social cognition.
Guastella and colleagues41 performed an emotion-recognition experiment with a more difficult and more sensitive task. Their study involved adolescent males with ASD. In a double-blind, placebo-controlled, crossover design, they administered oxytocin nasal spray (18–24 IU) or placebo to participants, who then completed the Reading the Mind in the Eyes Task (RMET), which involves identifying emotion based on the viewing of eyes. Oxytocin improved performance on the RMET for 60% of the participants. The effect of oxytocin was primarily for the easier items, with no difference between oxytocin and placebo for the harder items. In a similar experiment performed in healthy adult males,9 intranasal oxytocin (24 IU) improved scores on difficult RMET items more than the easy items and showed a ceiling effect in the healthy controls. Bartz and colleagues42 measured baseline social competency in healthy adult males with the Autism Spectrum Quotient (AQ) and then, after administering intranasal oxytocin (24 IU) or placebo to participants, measured their empathic accuracy by having them rate the emotions of individuals in a video. Participants with low AQ scores performed well on the task in placebo condition and maintained this performance in the oxytocin condition. However, those with high AQ scores (indicating lower social-cognitive performance) performed poorly in the placebo condition but better in the oxytocin condition. In the oxytocin condition the low AQ and high AQ participants showed no difference in scores.
Andari and colleagues43 performed a series of elegant experiments, reported together, with adults with ASD and healthy controls. The participants played a computerized ball-toss game with computerized players A, B, and C, in which the participant could choose to throw the ball to one of the three players. Player A was programmed to eventually throw the ball 70% of the time back to the participant, player B, 30% of the time, and player C, 10% of the time. Participants received an intranasal dose of 24 IU oxytocin or placebo prior to playing the game. In healthy participants more balls were thrown to player A than to the other two players. Under placebo treatment, the participants with ASD did not discriminate between the three players; however, when they received oxytocin, they engaged more often with player A compared to player C. Trust and preference ratings expressed toward the three players did not differ in participants with ASD receiving placebo but were more similar to the ratings of healthy controls after receiving oxytocin. Interestingly, participants with ASD classified as seeking social contact but in a socially inappropriate or one-sided manner tended to respond to oxytocin, whereas those classified as actively rejecting social contact tended to show little response to oxytocin. In a second experiment, eye gaze when viewing faces was analyzed. Intranasal oxytocin (24 IU) increased total gaze time spent on face regions in participants with ASD, largely accounted for by increased fixation time on the eye region. Oxytocin effects on social game performance (i.e., computerized ball toss) were only weakly correlated with effects on face-perception tasks (i.e., the eye gaze), indicating that a different cohort of individuals tended to respond to oxytocin in the respective tasks. Oxytocin’s effects therefore appear to differ across individuals and may have beneficial effects on different aspects of social functioning in different individuals.
Few reports have been published on the long-term daily administration of oxytocin in individuals with ASD. Kosaka and colleagues44 reported the case of a 16-year-old female with ASD receiving 8 IU of intranasal oxytocin daily for two months. Subjective assessment of her social interactions and social communication demonstrated improvement from a Clinical Global Impression–Severity score of 6 (“severely ill”) to 3 (“mildly ill”), and improvements were seen in irritability and hyperactivity on the Aberrant Behavior Checklist. The first randomized, controlled trial of intranasal oxytocin in ASD was reported by Anagnostou and colleagues.45 Nineteen adults with ASD (16 males aged 33.20 ± 13.29 years) received intranasal oxytocin (24 IU twice daily; n = 10) or placebo (n = 9) for six weeks. Oxytocin participants had a significant improvement in Reading the Mind in the Eyes Task scores—a measurement of social cognition—compared to the placebo group but no improvement in the Diagnostic Analysis of Nonverbal Accuracy, another measure of social perception. There was also no significant difference in Clinical Global Impression–Improvement or Social Responsiveness Scale scores in groups receiving oxytocin or placebo. There was a trend toward improvement in stereotyped and self-injurious repetitive behaviors, and a significant improvement in the emotional/social subscales of the World Health Organization Quality of Life Questionnaire.
These preliminary trials of oxytocin delivered to human participants with ASD provide some hope that it may be a useful treatment agent for improving some aspects of social cognition and for reducing repetitive behaviors. With the exception of one very small randomized, controlled trial, most of the experimental studies to date have been of single-dose administration. The one longer-term study shows some promise of a positive clinical effect, but the study was not appropriately powered to detect small to medium effect sizes. At this point, it can only be said that oxytocin is a promising agent that should be explored in larger, placebo-controlled trials designed to detect changes in well-validated measures of social cognition, social perception, and repetitive behaviors.
OXYTOCIN AND SCHIZOPHRENIA
Given that oxytocin affects cognition, memory, and social functioning, it has long been studied as having a potential role in the pathophysiology of schizophrenia. Preclinical mouse models have demonstrated that oxytocin has a potential antipsychotic effect through inhibitory regulation of mesolimbic dopamine and that the oxytocin system is affected in mouse models of psychosis.118
Earlier human studies measured the levels of human neurophysin (NP) II (hNPII) rather than oxytocin. hNPII is a protein carrier of oxytocin that is more easily measured because it is more stable than oxytocin and is released simultaneously at the synaptic level with the active peptide in proportional amounts.119,120 Linkowski and colleagues46 found greater CSF levels of hNPII in individuals with schizophrenia than in age-matched, nondepressed neurological controls. Beckmann and colleagues47 reported similar findings of increased CSF oxytocin levels in adult males with paranoid schizophrenia compared to controls with nonspecific neurological symptoms. Likewise, Legros and colleagues48 found increased basal levels of serum hNPII in male patients with schizophrenia compared to healthy male volunteers. Also, no change in hNPII levels was found in patients after an apomorphine (dopamine agonist) challenge compared to a twofold increase in hNPII in healthy volunteers. Importantly, basal hNPII was higher in the paranoid subgroup than in the nonparanoid subgroup. In contrast to the above findings, several studies reported no differences in CSF49 or plasma50 oxytocin concentrations between patients with schizophrenia and healthy controls.
Some studies have measured associations of plasma oxytocin levels with clinical measures in schizophrenia. Keri and colleagues51 measured plasma oxytocin levels in patients and controls after neutral and trust-related interpersonal interactions. No difference in oxytocin levels was identified between groups after neutral interactions; oxytocin levels increased in controls, but not in patients, after trust-related interactions. Low oxytocin levels after trust-related interactions were correlated with negative symptoms of schizophrenia as measured by Positive and Negative Syndrome Scale (PANSS) scores.121 Sasayama and colleagues53 also found that plasma oxytocin levels were negatively correlated both with the use of second-generation antipsychotics and with negative symptom scores on the PANSS.
Rubin and colleagues52 measured plasma oxytocin levels and PANSS scores in patients with schizophrenia and in healthy controls. No difference in oxytocin levels was found between the groups or across phases of the menstrual cycle in female patients or controls. In female patients only, higher oxytocin levels were associated with lower scores (less symptoms) on the PANSS total symptom, positive symptom, and general psychopathology scores, and with a trend toward association with lower negative symptom scores. In all patients, higher oxytocin levels were associated with better prosocial scores on the PANSS.
In general, these studies present conflicting data about whether or not differences in oxytocin levels are associated with schizophrenia. Some studies suggest higher levels of oxytocin in the CSF, but others indicate no difference. While it is unclear whether plasma levels correlate with brain oxytocin levels (because of the blood‐brain barrier), some studies have indicated that lower plasma oxytocin levels correlate with more psychotic symptoms as indicated by the PANSS. Further study is needed to determine if differences in various studies may be explained by phenotypic differences in patient populations.
Few studies have examined the genetic association of OXT and OXTR variants with schizophrenia. Souza and colleagues54 found one variant of OXT in a family-based association study and two variants of OXT in a case-control study that were associated with schizophrenia, but none remained significant after correction for multiple testing. They also identified one haplotype block within OXT that was nominally associated with schizophrenia in the case‐control sample. Montag and colleagues57 also performed a case‐control analysis of individuals with schizophrenia and healthy controls, and found two different OXTR SNPs that were associated with schizophrenia.
Based on rat studies demonstrating that clozapine enhances oxytocin release from neurons, the same research group55 evaluated OXT and OXTR variants for association with symptom severity and response to clozapine in individuals with schizophrenia treated for a minimum of six months. One variant within OXT was associated with treatment response and nominally associated with negative symptoms. Variants in OXTR were associated with the severity of overall symptoms and with the improvement of positive symptoms on clozapine. The OXT variant had also been previously associated with stereotyped behaviors in autism.33
Finally, Teltsh and colleagues56 examined the association of OXT variants with schizophrenia in a large clan of Arab-Israeli individuals. They further sought to confirm results in a group of nuclear families of Arab-Israeli origin and a Jewish case‐control sample. In the large clan study, one variant in the 5’-promoter region of OXT and a previously reported variant in the 3’-promoter region were associated with schizophrenia after correction for multiple testing. One haplotype of the seven gene variants studied was also found to be associated with schizophrenia after multiple corrections, and affected individuals with this haplotype demonstrated prominent negative symptoms.
The genetic evidence for association of OXT and OXTR variants with schizophrenia is weaker than that for ASD, and two more recent reports have not found an association between genetic variants and diagnosis.58,59 Most of the variants that have been associated have not been replicated and have not withstood statistical corrections for multiple comparisons (see Table 1). Taking the combination of equivocal studies of plasma or CSF oxytocin levels and the inconsistent findings in genetic studies, the evidence is weaker for a clear dysfunction in the oxytocin system in patients with schizophrenia than it is for ASD.
Response to Exogenous Oxytocin
Although the evidence for dysfunction in the oxytocin system in schizophrenia remains equivocal, a line of evidence supports the possible therapeutic use of oxytocin in these disorders. Nearly four decades ago, Bujanow122,123 reported that after giving patients daily injections of IV or intramuscular oxytocin (10–25 IU), therapeutic effects were “favorable” and “rapid,” and that hospitalization was prevented. A decade later, Bakharev and colleagues60 ran the first controlled study of oxytocin, with men with the “simple form of schizophrenia” receiving IV or intranasal oxytocin (5 IU twice daily) or placebo during two nonconsecutive weeks. The authors reported positive effects—particularly in negative symptoms and depressed mood—in patients receiving oxytocin.
More recently, interest has revived in the use of oxytocin as a therapeutic agent in schizophrenia. Averbeck and colleagues64 administered intranasal oxytocin (24 IU) or placebo in a randomized, double-blind, crossover study to individuals with schizophrenia and healthy controls in two sessions separated by approximately one week. Following administration, participants carried out an emotion-discrimination task in which they were asked to identify various facial emotions. At baseline, compared to control participants, individuals with schizophrenia had deficits in recognizing fear, happiness, and surprise. Although the overall performance was improved on oxytocin, the absolute effect was modest, and no improvement was seen in recognizing any particular emotion.
Goldman and colleagues62 performed a detailed study in which they administered two different doses of intranasal oxytocin (10 IU, 20 IU) or placebo to three groups: healthy controls and polydipsic and nonpolydipsic patients with schizophrenia. Following administration, individuals were asked to rate the presence and intensity of various facial emotions. Emotion recognition decreased in both patient groups on the lower dose of oxytocin, due to the increased propensity to identify all emotions, whether or not they were present (nonspecific positive bias). In the polydipsic, but not the nonpolydipsic, patients, emotion recognition improved following the higher dose of oxytocin, primarily because of a decreased propensity to identify fear in nonfearful faces. Despite limitations in interpretation (due to the small sample sizes), it appears that the effects of oxytocin on emotion recognition are dose-, emotion-, and patient characteristic–dependent.
Feifel and colleagues61 performed a randomized, double-blind, crossover study of patients with residual symptoms. Patients were given three weeks of daily intranasal oxytocin (40 IU twice daily) or placebo as adjunctive treatment to their stable psychotropic regimens. Oxytocin reduced scores on the PANSS total score, PANSS positive symptoms subscale, and PANSS negative symptoms subscale (effect sizes ranging from 0.40 to 0.50) and on the Clinical Global Impressions–Improvement scale (effect size = 0.74) compared to placebo at endpoint. Feifel and colleagues65 also reported that patients receiving the same course of oxytocin improved on several verbal-memory learning tasks compared to placebo, indicating that oxytocin has the potential to improve cognition in schizophrenia. Trials with higher doses, longer treatments, or in groups not on stable antipsychotic regimens may result in more substantial effects.
Pedersen and colleagues63 conducted a randomized, placebo-controlled, two-week treatment trial in patients with schizophrenia receiving intranasal oxytocin (24 IU twice daily) or placebo. PANSS scores declined in the oxytocin group but not in the placebo group, and included improvements in the suspiciousness/persecutory, anxiety, and paranoia subscales. In addition, on the Brune Theory of Mind Picture Stories Task (a social-cognition measure), the oxytocin group demonstrated improvements in identifying second-order false beliefs and trends toward improvement in recognizing deception.
Finally, Modabbernia and colleagues66 reported a double-blind, placebo-controlled, eight-week study in 40 patients with schizophrenia who had partial remission of symptoms on a stable dose of risperidone (5 or 6 mg/day). Patients were randomized to receive intranasal oxytocin (n = 20; 20 IU twice daily for 1 week, followed by 40 IU twice daily for 7 weeks) or placebo (n = 20). The group receiving oxytocin had a greater response on the PANSS total score (p < 0.001), positive subscale (p < 0.001), negative subscale (p < 0.001), and psychopathology score (p = 0.021). Effect sizes ranged from 0.8 to 1.9, indicating medium to large effects.
Overall, oxytocin shows great promise in small, preliminary studies as being a possible effective adjunctive treatment for residual positive and negative symptoms of schizophrenia. Larger studies are needed to determine the generalizability of the findings to broader populations and to use validated measures of overall functioning and quality of life to determine the magnitude of oxytocin’s clinical effect.
OXYTOCIN AND MOOD DISORDERS
Oxytocin inhibits stress-induced activity in the hypothalamic-pituitary axis in rats124 and plays an important role in the response to stress through its close association with corticotrophin-releasing factor.125 It has therefore been studied extensively for its connection to mood and anxiety disorders. Many studies have examined oxytocin levels in both major depressive disorder (MDD) and bipolar disorder (BD), with sometimes conflicting results. The aggregate of studies summarized here indicates a complex relationship between oxytocin levels and mood disorders, with multiple factors contributing to the observed pathophysiological state in any given patient.
Legros and colleagues67 measured CSF hNPII levels in patients with MDD and patients with BD, currently depressed. Levels in those with MDD were no different from neurologic controls, whereas the bipolar depressed group had higher levels (replicated in Linkowski and colleagues).46 Several studies demonstrate consistently that patients with MDD do not differ from healthy controls in CSF hNPII levels,46 plasma hNPII levels,74 CSF oxytocin levels,69 or plasma oxytocin levels.53,70 Plasma oxytocin levels were also not correlated with measures of motor activity71 or neuropsychological testing results.72
In contrast to these findings, Frasch and colleagues68,126 compared nocturnal plasma oxytocin levels in patients with MDD and healthy controls. Eighty-three percent showed a reduction of plasma oxytocin compared to age-matched controls. Differences were more pronounced in older patients, who tended to have lower plasma oxytocin levels than younger patients. Supporting the finding of lower plasma oxytocin levels in patients with MDD, Anderberg and Uvnas-Moberg73 reported lower levels in female patients with both MDD and fibromyalgia than in healthy controls or patients with fibromyalgia without MDD. Low oxytocin levels were also seen in patients who self-reported high daily levels of pain, stress, and depression. A negative correlation was found between oxytocin levels and the scores for depression and anxiety, and a positive correlation was found between oxytocin levels and the scores for happiness.
Ozsoy and colleagues78 reported decreased serum oxytocin levels in inpatients with MDD or BD, currently depressed, compared to healthy controls. Levels were decreased both pre- and post-treatment with antidepressants or electroconvulsive therapy (ECT), and were unaffected by either treatment. The difference in oxytocin was also gender specific, with female patients having lower levels than female controls, whereas no difference was seen between the male groups. In this study, no difference was found between patients with MDD and those with BD, currently depressed. A single study79 of small sample size (11 MDD, 19 healthy controls) reported an increase in nocturnal plasma oxytocin levels in patients with MDD compared to healthy controls, with the difference most apparent during the nocturnal peak of oxytocin levels.
Recent studies have begun to elucidate patient characteristics that may contribute to the differing results across studies. Scantamburlo and colleagues76 found a negative correlation in patients with MDD between plasma oxytocin levels and Hamilton Depression Rating Scale scores (HAM-D), in line with some of the above reports. However, they also found that oxytocin levels were negatively correlated with anxiety scores on the State-Trait Anxiety Inventory, indicating that comorbid anxiety may moderate the effects of oxytocin in depression. In a nuanced study of correlations with personality dimensions using the Temperament and Character Inventory in outpatients with MDD, Bell and colleagues75 demonstrated a positive correlation of plasma oxytocin levels with the temperament dimensions of reward dependence and novelty seeking, indicating a relationship between temperament factors and oxytocin levels that may confound results in studies that fail to control for this relationship. Finally, using plasma levels, Cyranowski and colleagues77 demonstrated that a group of women with MDD had greater variability in pulsatile oxytocin release during two one-hour experimental task sessions than a group of healthy controls, and greater oxytocin concentrations during a guided imagery task focused on attachment-related images. During this task, oxytocin concentrations were also positively correlated with clinician-observed depressive symptoms and with self-reported depressive and anxiety symptoms. These findings demonstrate that MDD may be associated with a dysregulation of oxytocin release that may be task dependent, with the consequence that measuring oxytocin levels at particular times or in different circumstances may produce conflicting results.
Response of Oxytocin Levels to ECT
In the wake of multiple reports that ECT for unipolar and bipolar depression increases oxytocin levels, researchers have been investigating the possible importance of oxytocin in the therapeutic response to ECT. Early reports identified an increase of approximately 50%–70% in plasma hNPII levels within the first minute following seizure during ECT, with a return to baseline within 60 minutes.127,128 Scott and colleagues80,81 reported that peak plasma hNPII response to ECT was greater in patients who recovered from depression than in those who did not, and that the increase in hNPII concentration correlated with improved scores on the HAM-D and Montgomery-Åsberg Depression Rating Scale. A later study by the same group replicated this effect,129 which further demonstrated that it was the release of hNPII after the first ECT treatment that correlated with improvement over the course of ECT. In this study, neither basal levels nor the peak response of hNPII changed between the first and last treatment.
Studies of plasma oxytocin levels show an initial peak level after the first ECT, approximately ninefold higher than baseline83,84 and greater than the previously reported response of hNPII. In a study within the same group of patients, the initial increase in oxytocin level was approximately fourfold greater than the increase in hNPII.82 Also, unlike the response of hNPII, the increase of oxytocin was attenuated by the third treatment to an approximately fivefold increase over baseline.84 Riddle and colleagues130 demonstrated that the mean plasma oxytocin level shortly after ECT was greater after supra-threshold stimulation than after threshold stimulation. Similar to hNPII, no change was found in baseline plasma oxytocin levels following a course of ECT,78,85 indicating that any relationship to clinical response is not due to an underlying change in peptide concentrations. In a study of patients with MDD,84 no association was found between clinical outcome and either baseline plasma oxytocin levels or peak responses following ECT. In a larger study of patients with MDD,85 peak responses of plasma oxytocin after the second treatment were not correlated with clinical response; however, a trend-level association was found between higher peak oxytocin response after the ninth ECT treatment and clinical response. These studies collectively suggest that the therapeutic effect of ECT may at least be partly modulated through its effects on the release of oxytocin and its related carrier protein, hNPII.
Two studies86,87 have reported on neuropathological differences in oxytocin-related functioning in patients with mood disorders compared to healthy controls. Purba and colleagues86 evaluated postmortem brain tissue of patients and age-matched controls, staining for oxytocin in the paraventricular nucleus of the hypothalamus. The number of oxytocin-producing neurons in patients was increased by 23%, with no differences found between subgroups of patients with MDD, BD, and depressive disorder not otherwise specified (NOS). Correspondingly, Meynen and colleagues87 performed quantitative oxytocin mRNA in-situ hybridization in the paraventricular nucleus of postmortem samples of patients with MDD and controls. They found an increase of oxytocin mRNA in melancholic depressive patients compared to nonmelancholic depressive patients and a trend toward higher oxytocin mRNA levels in the melancholic patients compared to controls. These neuropathologic studies confirm the impression that patient characteristics and endophenotypic differences influence the overall functioning of the oxytocin system in mood disorder patients.
Two published studies have examined genetic associations between the oxytocin receptor and mood disorders. Costa and colleagues88 studied OXTR in a cohort of adult patients with MDD, BD I, or BD II, and age-matched controls. No differences were identified between MDD patients and healthy controls in two SNPs that had previously been found to be associated with ASD. No difference was found between the BD group and the controls.
Thompson and colleagues89 focused on the rs2254298 polymorphism because a previous study had shown an association between heterozygosity (AG) at this genetic site and loneliness in adolescents.131 They studied the interaction of early adverse parental environment and the polymorphism in predicting poor psychosocial outcomes by interviewing girls (ages 9–14 years) and their mothers. They measured depressive and anxiety symptoms in the girls, and performed genotyping. Heterozygous (AG) girls with maternal history of recurrent MDD reported higher symptoms of depression, physical anxiety, and social anxiety than did girls without maternal history of MDD or with homozygous (GG) genotype. The difference between this study and the previous one,88 which showed an association between the GG genotype and MDD, may be due to developmental differences between adolescents and adults. Supporting this difference are previous findings131 of different patterns of association between the rs2254298 genotypes and loneliness in adolescents compared to adults.
Response to Exogenous Oxytocin
Given the evidence of oxytocinergic dysfunction in depression and the response of oxytocin to ECT, it might be expected that administering oxytocin may have an effect on individuals experiencing depressive symptoms. Pincus and colleagues90 enrolled adults with MDD and matched healthy controls in a double-blind, placebo-controlled, crossover trial with a wrap-around fMRI study. Each participant performed the Reading the Mind in the Eyes Task in the fMRI scanner. The experiment was repeated before and after administration of 40 IU intranasal oxytocin or placebo. Healthy controls showed decreased reaction time to the task after oxytocin administration, whereas patients with MDD had increased reaction time. No difference was found in the accuracy of response between groups or after administration of oxytocin. Oxytocin differentially activated the brain in the two groups during the RMET. In controls, oxytocin enhanced activation of the amygdala, caudate, inferior frontal, parahippocampal, and superior temporal regions. In individuals with MDD, oxytocin enhanced activation in the cingulate, inferior frontal, insula, middle frontal, precentral, superior frontal, superior temporal, and supramarginal regions. This brief experiment found no effect of oxytocin on general mood state or depressive scores.
No randomized, placebo-controlled, long-term studies have been published on the effects of oxytocin on MDD. There is one case report of a 38-year-old man with MDD with multiple failed antidepressant trials who had a decrease in depressive and anxiety-related symptoms, as measured by a reduction in HAM-D and Spielberger State-Anxiety Inventory scores, during a three-week trial of adjunctive intranasal oxytocin (8 IU twice daily) while on escitalopram 20 mg daily.91
Given the suggestive preclinical evidence that oxytocin plays a role in the stress response, coupled with the evidence for a complex interrelationship of the oxytocin system and mood, larger clinical studies are needed on oxytocin in mood disorder patients. Currently, the lack of available data prevents any supposition about its potential role in treating mood disorders.
OXYTOCIN AND OTHER DISORDERS
While human studies of oxytocin in clinical populations have largely taken place in ASD, schizophrenia, and mood disorders, its roles in the stress response, repetitive behaviors, and temperamental differences have also led to preliminary investigations into anxiety disorders, obsessive-compulsive disorder (OCD), and personality disorders.
Hoge and colleagues92 measured plasma oxytocin levels in patients with Generalized Social Anxiety Disorder (GSAD) and healthy controls. No difference in oxytocin levels was found between patients and controls. Within the GSAD sample, however, higher social anxiety symptom severity (adjusted for age and gender) was associated with higher oxytocin levels. In another study,93 patients with GSAD had similar plasma oxytocin levels to a group of healthy controls at baseline but lower oxytocin levels after completing a trust game with a partner.
Pitman and colleagues94 measured heart rate, skin conductance, and electromyographic responses in Vietnam veterans with PTSD during personal combat–imagery exercises. The patients were randomized to receive a single dose of intranasal vasopressin (20 IU), intranasal oxytocin (20 IU), or placebo one hour before the exercises. A trend toward lower physiological response to personal combat–related imagery was present in the oxytocin group but without any subjective response reported by the patients.
Two studies examined the effect of a single dose of intranasal oxytocin (24 IU) compared to placebo in a group of male patients with GSAD and a group of healthy males, specifically examining fMRI activation patterns when viewing emotional faces.96,97 Relative to the control group, patients with GSAD displayed hyperactivity of the bilateral amygdala when viewing fearful faces96 and hyperactivity of the medial prefrontal cortex extending into the anterior cingulate cortex when viewing sad faces.97 No differences between groups was found in the response to angry or happy faces. Oxytocin had no effect in either study on the control group; however, in the GSAD patients the heightened activity in response to fearful and sad faces was attenuated and “normalized” such that the hyperactivity relative to controls was reduced or eliminated. No subjective change in mood or anxiety was reported by patients or controls following administration of oxytocin.
Guastella and colleagues95 randomized male patients with GSAD to receive intranasal oxytocin (24 IU) or placebo at the start of the second through fifth therapy sessions of a five-session weekly group exposure therapy. Following each administration, the participants gave a speech in front of group members about increasingly difficult topics. In general, a reduction in self-reported symptoms was found on measures of anxiety between pre- and post-treatment that was maintained at one-month follow-up, with no differences between those receiving oxytocin or placebo. There was no main effect of drug and no interaction between treatment session and drug for self-reported anxiety during the speech task across the treatment sessions. Participants who received oxytocin rated their appearance and performance as improved as sessions progressed. In a similar study with healthy controls, administration of oxytocin prior to an impromptu speech presentation decreased the negative self-appraisal in individuals with high trait anxiety.132 The authors posit that future studies are warranted to determine if oxytocin’s benefit on negative self-appraisal can be enhanced by more frequent administrations or by administration in a broader array of contexts, potentially having an additive effect that more robustly alters overall symptoms and functioning.
Swedo and colleagues98 found that CSF oxytocin concentration was positively correlated with depressive symptoms in children with severe obsessive-compulsive disorder. Comorbid anxiety disorder was also associated with increased CSF oxytocin levels. No correlation was found between oxytocin concentrations and OCD symptoms. Leckman and colleagues99 compared patients with OCD, patients with Tourette’s syndrome, and healthy controls. They found increased CSF oxytocin levels in the patients with OCD compared to the other two groups, but the elevation was significant only in a subgroup of patients without a personal or family history of tic disorder. They found that the oxytocin level correlated with the current severity of OCD symptoms in the non-tic-related OCD group only. In this study no correlations were found between ratings of depression or anxiety and oxytocin levels. Altemus and colleagues100 also measured CSF oxytocin levels in patients with OCD and healthy controls, and found no differences between the groups. The differences between these studies may have been due to small sample sizes, differences in participants, or different collection times of CSF.
Interest in oxytocin as a potential treatment for OCD heightened after a case report of a hospitalized patient with severe OCD symptoms who had a dramatic reduction in OCD symptoms after four weeks of daily intranasal oxytocin therapy (14.4 IU).101 However, this patient also developed psychotic symptoms in the context of emerging hyponatremia and possibly developed delirium due to the electrolyte imbalance, which may have masked his OCD symptoms. Several attempts to replicate the findings have been unsuccessful. The effects of oxytocin in patients with OCD have been presented in two case reports (10 IU intramuscular daily),102 a double-blind, placebo-controlled study (4.5–13.5 IU intranasal four times daily),103 a single-dose study (8 IU intranasal),104 a placebo-controlled, crossover study in patients with trichotillomania (40 IU intranasal four times daily),105 and a placebo-controlled, crossover study in patients with comorbid OCD and MDD (40–80 IU intranasal four times daily).106 None of these studies identified any effect on OCD symptoms, with only a small decrease in Beck Depression Inventory scores in the comorbid depression study. In short, no evidence supports the effectiveness of oxytocin in treating OCD, although the total number of patients studied is small (n = 29).
On the basis of animal experiments demonstrating a connection between socially aggressive behavior and oxytocin, Lee and colleagues107 postulated a connection between oxytocin levels and socially aggressive behavior in humans. In a study of individuals with a DSM-IV diagnosis of a personality disorder (see Table 1 for specific diagnoses) and healthy controls, CSF oxytocin level was inversely correlated with Lifetime History of Aggression (LHA) scores. Exploratory analysis indicated that the only subscale that was an independent predictor of CSF oxytocin level was the history of a suicide attempt, with attempters having lower oxytocin levels than non-attempters. This relationship was independent of personality disorder diagnosis. Bertsch and colleagues108 demonstrated lower plasma oxytocin levels in females with borderline personality disorder (BPD) that correlated negatively with experiences of childhood emotional neglect and abuse.
To date, studies evaluating oxytocin for the treatment of BPD have shown some possible benefit but also some risk. In a pilot study of BPD patients and healthy controls,110 participants received intranasal oxytocin (40 IU) or placebo in double-blind, randomized order followed by a social-stress test involving public speaking and a mental arithmetic task in front of an audience. Subjective dysphoria and plasma cortisol levels were followed. Greater attenuation of stress-induced dysphoria was present in the BPD group relative to controls after oxytocin administration, and a trend toward greater attenuation of cortisol was present in the BPD group after oxytocin administration. In the combined sample the difference between stress-induced dysphoria after oxytocin versus placebo was predicted by the presence of childhood trauma, whereas the difference in stress-induced cortisol surge after oxytocin versus placebo was predicted by a measure of insecure attachment.
Bartz and colleagues109 demonstrated that oxytocin may have very different, even opposite, effects in BPD patients than in healthy controls. It had been shown previously that in healthy controls, oxytocin administration increased trusting behavior in a social-dilemma game8 and increased the perceived trustworthiness of faces.133 In healthy adults and adults with BPD, Bartz and colleagues administered intranasal oxytocin (40 IU) or placebo in a double-blind, randomized study. Following administration, the participants played an Assurance Game, in which the individual plays a game with a “partner.” BPD participants had decreased expectations of their partner’s cooperativeness following oxytocin administration (decreased “trust”), and they were more likely to defect in response to partner’s hypothetical cooperation even though their payoff would be less for defection. Healthy controls, by contrast, demonstrated increased “trust” and more cooperation in response to partner’s hypothetical cooperation following oxytocin administration, although neither of these comparisons reached statistical significance. Thus, whereas oxytocin in healthy controls leads to a more trusting, collaborative strategy in which both partners “win,” BPD patients respond to oxytocin by becoming less trusting and developing a more competitive strategy.
CLINICAL IMPLICATIONS AND LIMITATIONS
The implications of the growing evidence for the role of oxytocin in neuropsychiatric disorders are far-reaching. First, the evidence suggests a role of oxytocin in the pathophysiology of some psychiatric disorders, particularly those characterized by impairments in social functioning. However, the preliminary nature of the currently available data precludes a clear understanding of the exact nature of this role. Perhaps it is not surprising that a hormone that so directly affects interpersonal and social functioning has implications in diagnostic groups ranging from ASD to schizophrenia spectrum disorders to mood disorders, all of which demonstrate significant interpersonal and social dysfunction as core features. The genetic risk associated with variations in OXTR also appears similar across disorders, with several polymorphisms identified as risk variants in multiple disorders. Second, the complex and sometimes contradictory aspects of oxytocin dysfunction within these disorders point to the role of individual variation in the presentation of oxytocin dysfunction and to the need for more research into the core underlying dysfunctions. For example, the finding that low-functioning children with ASD have lower plasma oxytocin levels, whereas high-functioning adults with ASD have higher baseline levels, indicates that as yet poorly understood developmental and individual factors may contribute to the underlying pathophysiology of the disorders.
The effects of oxytocin seem to be determined by individual factors that may be related to clinical presentation. For example, the effects of oxytocin on trust behaviors in patients with BPD are opposite those in healthy controls. Likewise, oxytocin had differential effects in healthy controls on memories of maternal care and closeness, depending on the participant’s baseline level of anxious attachment.25 Indeed, the evidence suggests that rather than being a truly “prosocial” hormone, oxytocin may reinforce and enhance the saliency of attachment representations that already exist. Therefore, those patients with BPD who may be predisposed to view interpersonal interactions negatively are more prone to negatively respond to oxytocin administration. This idea cannot be broadly assumed to be true, however, given the positive social response of oxytocin in individuals with ASD, who may be expected to be predisposed to have limited attachment capability. That said, even in ASD the evidence suggests that those actively avoiding social contact were less responsive to oxytocin than those who sought out social contact but in a socially inappropriate manner.43
The accumulation of evidence of some therapeutic benefit associated with the administration of oxytocin is heartening. Particularly in individuals with ASD and schizophrenia, some evidence suggests that oxytocin may affect the core deficits in these disorders, improving social cognition in autism and decreasing positive and negative symptoms in schizophrenia. More limited evidence is available indicating a therapeutic benefit in MDD and in social anxiety disorder. Overall, the effect sizes are small. However, an important caveat to all treatment studies to date is the inherent limitation of the currently available delivery methods for oxytocin. Given that intravenous dosing is not a practical clinical alternative, intranasal delivery is the only available method that allows for frequent dosing and a chance of crossing the blood‐brain barrier. Nevertheless, while many of these studies have assumed that intranasal delivery of peptides can achieve transport across the blood‐brain barrier,134 there is still debate about this point and whether intranasally administered oxytocin reaches the pertinent receptors in the brain to influence neural activity.135 The matter of delivery is further complicated by the evidence that oxytocin acts in a positive feed-forward mechanism, in which small doses of oxytocin might have sustained effects beyond the short half-life of the peptide (about 20 minutes); elevated levels of salivary oxytocin were measured for more than two hours after administration of a relatively small dose (16 IU) of intranasal oxytocin.136 This feed-forward mechanism may have contributed to the finding in one reviewed study of greater effect on emotion recognition in schizophrenia at lower doses.62 Thus, even with multiple daily dosing, it is not clear whether such dosing results in pulsatile or sustained levels of oxytocin in the central nervous system. Critical research questions remain regarding the pharmacokinetics and pharmacodynamics of intranasal oxytocin that can be answered only by larger, randomized, controlled trials before appropriate dosing strategies for these various disorders can be developed.
It is unknown whether other therapeutic strategies for targeting the oxytocin system—ones that have been demonstrated in animal models—would have more efficacy in human studies. For example, oxytocin receptor agonists have been developed that can be delivered orally and stimulate the oxytocin receptor,137,138 and evidence suggests that melanocortin-4 receptor agonists stimulate the central release of oxytocin in rats.139 Given the evidence presented here of the potentially broad and diverse impact of oxytocin across a range of neuropsychiatric disorders, drug development along these lines would presumably be advantageous for a wide number of patients. Importantly, the studies to date have been primarily experimental or preclinical in nature, and proper clinical trials are only recently being undertaken. These studies should provide a better understanding of the extent and limitations of the clinical effects of externally delivered oxytocin.
Overall, the search for genetic contributions of the oxytocin and oxytocin receptor genes to the disorders reviewed here is plagued by the limitations of the candidate gene approach to studying complex psychiatric phenotypes that are likely multifactorial in origin. Nonetheless, the multiple studies indicating a possible link between polymorphisms and these disorders suggest that there is indeed a role for this peptide and receptor system in the pathophysiology of the various disorders. However, the inconsistency of the individual findings and identified SNPs across studies indicates that no single finding is likely to have more than a small additive role in the complex genetics and gene-environment interactions that underlie the various psychiatric disorders discussed here. While these findings contribute to the body of knowledge about the involvement of the oxytocin system in these disorders, pursuit of this candidate gene approach has been disappointing in terms of major breakthroughs in our understanding of these disorders.
In summary, the evidence for the role of oxytocin in a broad range of neuropsychiatric disorders is accumulating, and further research is needed to determine the exact nature of its role and to translate these findings into a better understanding of the underlying pathophysiology of the disorders and effective treatment strategies targeting the oxytocinergic system.
Declaration of interest: Dr. Frazier receives research grant support from GlaxoSmithKline, Pfizer Inc., Roche Pharmaceuticals, and Seaside Therapeutics.
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