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Effects of oxytocin and genetic variants on brain and behaviour: Implications for treatment in schizophrenia
Schizophrenia Research, Volume 168, Issue 3, November 2015, Pages 614 - 627
Impairments in social cognition and poor social functioning are core features of schizophrenia-spectrum disorders. In recent years, there has been a move towards developing new treatment strategies that specifically target social cognitive and social behavioural deficits. Oxytocin (OXT) is one such strategy that has gained increasing attention. There is a strong rationale for studying OXT in psychosis, from both an evolutionary perspective and neurodevelopmental-cognitive model of schizophrenia. Thus, the aim of this review was to critique and examine the observational and clinical oxytocin trial literature in schizophrenia-spectrum disorders. A handful of clinical trials suggest that OXT treatment may be beneficial for remediating social cognitive impairments, psychiatric symptoms, and improving social outcomes. However, inconsistencies exist in this literature, which may be explained by individual differences in the underlying neural response to OXT treatment and/or variation in the oxytocin and oxytocin receptor genes. Therefore, we additionally reviewed the evidence for structural and functional neural intermediate phenotypes in humans that link genetic variants to social behaviour/thinking, and discuss the implications of such interactions in the context of dysfunctional brain networks in schizophrenia. Factors that pose challenges for future OXT clinical research include the impact of age, sex, and ancestry, task-specific effects, bioavailability and pharmacokinetics, as well as neurotransmitter and drug interactions. While initial findings from OXT single dose/clinical trial studies are promising, more interdisciplinary research in both healthy and psychiatric populations is needed before determining whether OXT is a viable treatment option/adjunct for addressing poor illness outcomes in psychotic disorders.
Keywords: Oxytocin, Schizophrenia, Neuroimaging, Single nucleotide polymorphisms, Social functioning, Genetic variants.
Despite the enthusiasm for oxytocin (OXT), very little is known about the way this neuropeptide affects brain activity and the impact this has on associated behaviour, particularly in schizophrenia. In this review we begin by considering the effects of OXT in the healthy population and outline the reasons why OXT has been proposed as a potential treatment in schizophrenia. We then review the small body of literature investigating the effects of OXT (endogenous and exogenous) in individuals with schizophrenia-spectrum disorders. Additionally, we draw on neuroimaging and genetic evidence to promote interdisciplinary designs in future clinical OXT research. Lastly, we discuss the many factors that should be considered in OXT trials and speculate on the potential pathways for future OXT research.
2. Oxytocin's role in social cognition and social brain function in healthy individuals
Oxytocin, a nine-amino-acid peptide and neurotransmitter, is widely recognised as having an important role in animal and human social behaviour, that ranges from maternal attachment to fear extinction ( Meyer-Lindenberg et al., 2011 ). In healthy individuals, a single dose of intranasal OXT, which is argued to provide a direct pathway of OXT into the brain via cerebrospinal fluid (CSF; Born et al, 2002 and Striepens et al, 2013), has been shown to significantly enhance numerous social cognitive abilities, including emotion recognition, theory of mind (ToM), social perception, empathic ability, and accurate appraisal of affect (for review see Guastella and Macleod, 2012 ). Some evidence suggests that OXT infused intravenously, can also have significant behavioural effects in humans ( Hollander et al., 2003 ). Naturally occurring OXT is synthesised in the hypothalamus and is released into the bloodstream via axon terminals in the posterior pituitary ( Ludwig and Leng, 2006 ). Moreover, OXT can be released from the dendrites of hypothalamic neurons, meaning that OXT can not only act locally at the site of release but also at more distal brain regions via diffusivity ( Ludwig and Leng, 2006 ). Oxytocin receptors (OXTRs) are present in numerous limbic and reward-related regions of the mammalian brain, primarily in the amygdala ( Huber et al., 2005 ), but also in the hippocampus, and nucleus accumbens ( Winslow and Insel, 2004 ). Specifically in humans, OXTRs have been found in the amygdala, medial preoptic area, hypoglossal and solitary nuclei, brainstem, basal nucleus of Meynert, olfactory nucleus, vertical limb of the diagonal band of Broca, septal nucleus, hypothalamus, the globus pallidus and ventral pallidum (Loup et al, 1991 and Boccia et al, 2013). There is also recent evidence showing receptors are present in the human anterior cingulate cortex ( Boccia et al., 2013 ), highlighting that OXTRs are also present in cortical regions.
An abundance of functional magnetic resonance imaging (fMRI) research has shown that OXT has significant modulatory effects on ‘social brain’ function. The ‘social brain’ refers to the systems that govern social cognition, social behaviour and affect regulation, and include the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), inferior frontal gyrus, superior temporal sulcus, temporoparietal junction, anterior and posterior cingulate cortex (ACC/PCC), precuneus, amygdala and anterior insula (for reviews see Adolphs, 2009 and Blakemore, 2008). Activation in many of these regions, as well as in the dorsolateral prefrontal cortex (DLPFC), has been shown to correlate positively with endogenous peripheral OXT levels during a social perception task ( Lancaster et al., 2015 ). Given that the DLPFC is known to be involved in cognitive control and working memory ( Badre and Wagner, 2004 ), it may be that OXT additionally acts on executive neural systems that interact with social brain processing, in order to facilitate optimal social cognitive performance.
Acute OXT administration in healthy humans has most consistently been shown to modulate amygdala activity ( Meyer-Lindenberg, 2008 ). In general, single-dose intranasal OXT dampens amygdala reactivity to fearful, angry and neutral facial expressions, and negative emotional scenes (e.g., car accident), and reduces the functional coupling of the amygdala with brain stem regions in response to fear (Kirsch et al, 2005 and Meyer-Lindenberg et al, 2011). Additionally, intranasal OXT has been shown to enhance the functional connectivity of the amygdala with other social brain regions, including the OFC, ACC, and precuneus, during a salient emotion task involving the passive listening of infant laughter ( Riem et al., 2012 ). A recent meta-analysis of 11 fMRI placebo-controlled studies that used emotion-related paradigms suggests that the largest effects of OXT are observed in the temporal lobes, with the left insula (extending to superior temporal gyrus and precentral frontal gyrus) showing significant hyperactivation with intranasal OXT administration ( Wigton et al., 2015 ). The increase in activation of this region was hypothesised to be related to minimisation of risk prediction errors (that is, participants are less likely to make misjudgements about how ‘risky’ or how trustworthy something/someone is), reward anticipation, and emotion regulation ( Wigton et al., 2015 ). Fewer studies have focused on the effects of OXT on brain activation during non-emotional paradigms. Despite this, OXT has repeatedly been shown to modulate activation in the amygdala, ACC and caudate, in relation to increased tolerance for social betrayal or increase in reciprocity, during trust game paradigms (e.g., Baumgartner et al, 2008 and Wigton et al, 2015). Lastly, a recent study by Sripada et al. (2013) showed that a single dose of intranasal OXT increased the connectivity between the amygdala and the mPFC, and ACC during rest, suggesting that OXT exerts its effects even in the absence of a functional task.
In summary, behavioural literature supports intranasal OXT as having a significant impact on a range of social cognitive abilities and emotion-related processing. Functional MRI evidence suggests that OXT acts on social brain processing as a function of increasing empathy, reward-based learning, trust and affiliation, and reducing social anxiety/stress (Bethlehem et al, 2013 and Wigton et al, 2015). Brain regions shown to be repeatedly modulated by OXT include the amygdala, mPFC, ACC, insula and temporal regions. Preliminary evidence suggests that OXT may also have a generalised effect on the degree of connectivity between social brain regions. While further work needs to be done to elucidate the underlying pathways and mechanisms of OXT's effects on social cognition and behaviour, strong evidence points towards OXT as having a global ‘pro-social’ role in the brain.
3. Rationale for oxytocin being a potential treatment option in schizophrenia
It is theorised that the social brain evolved as a result of the ever-increasing demand for complex social relationships, which gave way to social hierarchy and cohesive social environments ( Burns, 2006 ). Burns (2006) proposed that psychotic disorders are a “…costly by-product of social brain evolution in Homo sapiens” (pg., 77). Burns argued that such evolution led to greater vulnerability to neurodevelopmental disturbances, with schizophrenia representing the quintessential ‘social brain’ disorder. Crow (1995) similarly proposed that psychosis arose as a consequence of hemispheric specialisation and the evolution of language. Indeed, numerous imaging studies, including our own (e.g., Bartholomeusz et al, 2013 and Lavoie et al, 2014), show that social brain regions, as well as regions devoted to speech or communication (i.e., Broca's area, Wernicke's area) and cognitive control (i.e., DLPFC), are structurally abnormal in established schizophrenia, first episode psychosis and individuals at ultra-high risk of psychosis (Pantelis et al, 2007, Fornito et al, 2008, Fornito et al, 2009, Takahashi et al, 2009a, Takahashi et al, 2009b, Takahashi et al, 2010, Jung et al, 2010, and Mechelli et al, 2011). Schizophrenia studies correlating brain structural abnormalities with poor social cognitive performance particularly implicate regions of the medial and lateral PFC, temporal lobes and amygdala (Fujiwara et al, 2007, Namiki et al, 2007, Yamada et al, 2007, Bertrand et al, 2008, and Miyata et al, 2010).
Functional MRI studies involving social cognitive paradigms show that schizophrenia-spectrum patients typically display hypoactivations, primarily in the medial and lateral PFC and amygdala, during emotion recognition (Das et al, 2007, Reske et al, 2009, and Sugranyes et al, 2011). Patients also show reduced functional connectivity of the amygdala with the mPFC during emotion recognition tasks ( Das et al., 2007 ). During ToM paradigms, dysfunction appears to be more dispersed. For example, a meta-analysis of 9 ToM studies showed hypoactivation in the mPFC, middle and superior temporal regions and thalamus, plus hyperactivation in the PCC and somatosensory cortices of schizophrenia patients ( Sugranyes et al., 2011 ). Other regions that have been repeatedly implicated as dysfunctional (primarily under-activated) during ToM processing include the temporoparietal junction (e.g., Walter et al., 2009 ), inferior frontal cortex (e.g., Das et al., 2012 ), and insula and precuneus (e.g. Brune et al., 2008 ). Some regions, such as the temporoparietal junction, tend to show hyperactivation during the control non-social comparison tasks, suggesting that patients may over-attribute social causes or intentions to non-social events or physical objects (e.g., Walter et al., 2009 ). Taken together, the key social brain regions that are repeatedly implicated in schizophrenia-spectrum disorders include the PFC, temporal gyri and sulci, and the amygdala, which are regions that are significantly modulated by OXT administration in healthy individuals. Ergo, one rationale for OXT as a potential treatment option is based on OXT having its effect on social outcomes and social cognitive skills through its normalising action on social brain function.
4. Theoretical models of oxytocin signalling in schizophrenia
Rosenfeld et al. (2011) proposed a neurofunctional model of social cognitive deficits, which incorporates abnormal oxytocinergic signalling into the “aberrant salience” dopaminergic dysregulation hypothesis of psychotic illness (Heinz, 2002 and Kapur, 2003). Specifically, they suggest that OXT exerts its pro-social behavioural effects by interacting with the emotion-processing and dopaminergic systems of the amygdala ( Rosenfeld et al., 2011 ). In keeping with the social brain hypothesis, the aberrant OXT signalling in the amygdala is thought to contribute to the misattribution of salience to perceived stimuli, having a secondary detrimental effect not only on social behaviour and social cognition, but also giving rise to positive and negative symptoms such as paranoia and blunted affect. Similarly, Pedersen (2014) suggests that OXT may have been selected to play a crucial role in human evolution, specifically in the “up-grade of sensory-motor gating systems” that was necessary to enable higher quality proliferative social-attachments, beyond that which occurs post-parturition. Animal models of psychosis have shown that OXT administration reduces dopaminergic hyperactivity in the striatum and nucleus accumbens ( Qi et al., 2008 ), as well as alleviating pre-pulse inhibition deficits ( Caldwell et al., 2009 ), in a similar manner to antipsychotic medications (for reviews see Baskerville and Douglas, 2010 and Pedersen, 2014). OXT also interacts with the glutamatergic system, which is implicated in psychosis; rats dosed with the NMDA antagonist phencyclidine, displayed reduced social behaviour, reduced OXT mRNA in the anterior hypothalamus, and increased OXTR binding in the amygdala ( Lee et al., 2005 ). Moreover, direct injection of OXT into the amygdala resulted in restoration of normal social interaction behaviours ( Lee et al., 2005 ). Similar restorative effects have been observed in amphetamine-dosed prairie voles following OXT infusion to the mPFC, which resulted in altered dopamine levels in the nucleus accumbens ( Young et al., 2014 ). Limited animal research shows that some antipsychotic medications, including amperozide and clozapine, are associated with an elevation of plasma OXT concentrations (Uvnas-Moberg et al, 1992 and Feifel et al, 2014). It is not yet known how psychiatric medications interact with endogenous or exogenous OXT in humans. Nonetheless, given the centrality of the above-mentioned neurotransmitter systems in the pathophysiology of schizophrenia and their demonstrated interaction with OXT, there is strong rationale for exploring OXT, and its potential utility as a treatment option, in psychosis.
5. Behavioural effects of oxytocin in schizophrenia-spectrum disorders
The earliest use of OXT administration for the treatment of schizophrenia was reported by Bujanow (1972) in 1972, who used OXT in a clinical practice setting. From Bujanow's (1972) subjective observational viewpoint, 10–15 IU intravenous OXT (with 10–15 ml glucose) or 20–25 IU intramuscular OXT, as a daily dose for 6–10 weeks, seemingly led to improvements in symptoms and fewer hospitalisations ( Bujanow, 1972 ). However, evidence suggests intravenous OXT has poor blood–brain barrier permeability ( Kang and Park, 2000 ), and due to its short half-life in plasma (between 3–20 min), intranasal OXT delivery soon became the preferred choice in this field of neuroscience research.
Peripheral OXT level has been proposed as a possible biomarker of social cognitive performance ( Lancaster et al., 2015 ), which may correlate with risk for schizophrenia. Twelve studies to date have measured peripheral OXT levels in schizophrenia-spectrum samples (see Table 1 ). These studies show plasma (or CSF) OXT levels to be significantly reduced ( Jobst et al., 2014 ), significantly increased (Beckmann et al, 1985, Legros et al, 1992, and Walss-Bass et al, 2013), or no different (Glovinsky et al, 1994, Sasayama et al, 2012, and Rubin et al, 2013), in patients compared to healthy controls. These mixed findings are possibly due to confounding effects of sex and antipsychotic medications. To add to these inconsistent results, higher OXT levels have been linked to better facial emotion recognition ( Goldman et al., 2008 ), worse performance on a ToM measure ( Walss-Bass et al., 2013 ), more pro-social behaviours (Rubin et al, 2010 and Jobst et al, 2014), less severe negative symptoms (Keri et al, 2009 and Sasayama et al, 2012), and presence of delusions ( Walss-Bass et al., 2013 ). Importantly, these studies differed greatly in the sample characteristics, methodology and outcome measures used (see Table 1 for further details).
|Authors||Sample||Study design||Parameters studied||Factors/variable controlled for||Drug administration||Main findings|
|Beckmann, Lang, and Gattaz (1985)||Study (1) 28 schz (all male; mean age = 30.6 [8.0]) (15 patients were on neuroleptic drugs) 15 controls (13 male, mean age = 35.0 [15.7])
Study (2) 9 male schz (mean age = 30.4 [5.9])
|(1)Baseline lumbar puncture
(2) Baseline lumbar puncture, then 21 days of haloperidol, then a second lumbar puncture
|OXT and Vasopressin concentrations||Antipsychotic medication (butyrophenones and phenothiazines)||9 male patients from study (2) were administered haloperidol (mean dose = 25.7 [3.3] mg/day) for 21 days||CSF OXT levels were higher in patients treated with antipsychotics compared to patients without antipsychotics and controls.
No significant CSF OXT level change after three weeks of haloperidol treatment (although there was a non significant increase in OXT levels) in study (2) group.
|Brown et al. (2014)||28 schz (15 males, mean age = 33.6 [8.61])||Investigate the role of OXT levels and social approach and avoidance (AA) in schz
Bloods collected before assessment of the AAT
|Approach avoidance task (AAT). Facial Emotion Recognition and Discrimination Test (FEIT and FEDT); responses to happy and angry faces. PANSS. The Paranoia Scale.||Controlled for facial emotion recognition abilities.||–||Patients with higher OXT levels avoided angry faces more. Greater avoidance of angry faces was associated with more positive and general symptoms and greater paranoia.|
|Glovinsky, Kalogeras, Kirch, Suddath, and Wyatt (1994)||51 CSF samples obtained from 40 schz patients (31 males, mean age = 29) (11 patients underwent lumbar puncture both while on and off neuroleptic treatment)
20 neuroleptic treated schz
31 neuroleptic-withdrawn schz
15 controls (10 males, mean age = 30)
|CSF sample obtained through lumbar puncture. One-way ANOVA was used to compare the CSF OXT concentrations of each group of participants.||Drug free interval of 48 days for neuroleptic withdrawn participants||CSF OXT levels did not differ between neuroleptic withdrawn and neuroleptic-treated patients or between all patients combined and controls.|
|Goldman, Marlow-O'Connor, Torres, and Carter (2008)||6 polydipsic hyponatremic schz (PHS) (4 males, mean age = 44.7 [2.4])
4 polydipsic normonatremic schz (PNS) (2 males, mean age = 43.5 [9.2])
5 nonpolydipsic normonatremic schz (NNS) (2 males, mean age = 34.2 [8.9])
7 controls (males, mean age = 34.7 [10.1])
|Sampling occurred at regular intervals (3 samples obtained prior to cold pressor and four after the cold pressor).||Medial temporal lobe volume. Hippocampal-mediated hypothalamic–pituitary–adrenal axis (HPA) feedback.
Facial affect discrimination. Stressor - Cold pressor. PANSS
|Controlled for group and time effect. Age and gender were covariates.||All participants stabilised on clinically determined doses of antipsychotics (haloperidol, risperidone or ziprasadone).||Plasma OXT levels were lower in PHS group compared to the other three groups.
Trend of higher PANSS negative scores in those with low OXT.
Anterior hippocampal volume was associated with higher OXT levels across all groups
Higher OXT levels directly correlated with the integrity of hippocampal-mediated HPA feedback.
Higher OXT levels predicted schizophrenia patients' ability to correctly identify facial emotions.
|Jobst et al. (2014)||41 non-acute schz (all males)
45 matched controls
|Investigated whether OXT and AVP levels are altered in men with schz compared with healthy controls||OXT levels. AVP levels. PANSS.||–||Patients had lower OXT levels than healthy controls. _OXT levels were associated with higher PANSS negative scores.|
|Keri, Kiss, and Kelemen (2009)||50 schz (16 males, age = 47.9 [9.0])
50 controls (16 males, age = 47.8 [7.3])
|Day 1) Participant and experimenter exchanged neutral notes, and then blood was drawn.
Day 2) Patients and experimenter exchanged secrets on paper (requiring trust or trustworthiness), then blood was drawn again.
Neuropsychological testing. Sharing secrets vs. neutral information (trust task).
|Medication||All patients stabilised on antipsychotic medications (olanzapine, quetiapine, risperidone, ariprazole, clozapine, zuclopenthixol and haloperidol)||Trust-related interactions were associated with higher OXT levels in controls. This effect was not observed in patients.
No significant difference in OXT levels between patients and controls after neutral interactions.
Patients had significantly lower OXT levels than controls after trust-related task. Low OXT levels after trust interactions was associated with negative PANSS symptoms of schz.
|Legros et al. (1992)||9 schz (all male, mean age = 28.4 [3.5])
14 controls (all male, mean age = 24.3 [0.9])
|Apomorphine challenge tests (0.5 mg SC).
Apomorphine injected then blood taken 20, 40, 60 and 120 min after injection.
|Vasopressin-neurophysin. Oxytocin-neurophysin.||–||Apomorphine (0.5 mg SC)||Baseline OXT level was increased in schz compared with controls.
Apomorphine was not associated with changes in OXT.
|Rubin et al. (2010)||23 schz (all female, mean age = 30.65 [5.73])
27 schz (all males, mean age = 31.19 [6.60])
58 controls (31 females, mean age = 27.55 [6.67]; 27 males, mean age = 27.93 [5.99])
|Women were evaluated once during days 2–4 and once during days 20–22 of their menstrual cycle (approx. 42 days apart).
Men were tested in separate sessions approximately 42 days apart.
|Plasma hormone assays obtained;
|2 sessions during 2 separate menstrual cycles (approximately 42 days apart).||84% of patients were prescribed atypical antipsychotic medication.
46% of patients were taking anti-depressants.
4% were taking mood stabilisers.
|OXT levels did not vary between stages.
In female patients, higher OXT levels were associated with lower scores on total symptoms, positive symptoms as well as general psychopathology. In both males and females, higher OXT levels were associated with more pro-social behaviours.
|Rubin et al. (2011)||48 schz (26 males, mean age = 31.4 [6.5])
57 controls (26 males, mean age = 27.5 [5.8])
|Emotion recognition and plasma hormone levels were obtained at two stages of the menstrual cycle||Penn Emotion Acuity Test (PEAT). Facial emotion recognition & perception task.
Plasma hormone assays obtained for;
|During two menstrual cycle phases:
1) Days 2–4; low oestrogen/progesterone 2) Days 20–22; high oestrogen/progesterone.
Controlled for negative symptoms, suspiciousness/paranoia, antipsychotic medication dose (Chlorpromazine equivalents)
|–||OXT levels did not vary across menstrual cycle stages.
Higher OXT levels associated with a positive bias (i.e. perceiving faces as happier) in female patients and controls but not in males.
|Rubin et al. (2013)||38 first-episode schz (24 males, mean age = 21.8[5.3])
38 controls (24 males, mean age = 27.6[3.3])
|Investigate OXT and AVP levels and association with neuropsychological tests.||PANSS
Serum hormone assays of OXT and AVP
|All patients were antipsychotic free for at least 3 days||–||Patients showed similar OXT levels to controls.
Trend of higher AVP levels associated with OXT in controls.
OXT levels were not associated with clinical symptoms, verbal learning, or cognitive functioning in either male or female patients.
|Sasayama et al. (2012)||27 schz (all male, mean age = 42.6 [8.5])
17 MDD (all male, mean age = 39.5 [8.0])
21 controls (all male, mean age = 38.3 [15.3])
|Lumbar puncture, then immediately after schizophrenia and depressive symptoms were assessed||Lumbar puncture
|Chlorpromazine and imipramine were examined as possible confounders (due to some research suggesting they may increase OXT secretion)||59.3% schz on typical antipsychotics
66.7% schz on atypical antipsychotics
|CSF OXT levels did not differ between healthy controls and patients with schz or MDD. CSF OXT levels in schz negatively correlated with atypical antipsychotic dose, but not with typical antipsychotics. Higher OXT levels associated with less severe symptoms of schizophrenia (after controlling for atypical antipsychotics).|
|Walss-Bass, Fernandes, Roberts, Service, and Velligan (2013)||60 schz (45 males, mean age = 42.1 [10.8])
20 controls (14 males, mean age = 39.7 [11.5])
|Investigated the association between OXT plasma levels and social cognitive capacity and bias & inflammation.||Blood sample for assay of OXT and inflammatory markers. Waiting Room Task (WRT) assesses;
1) Gaze accuracy
3)Gaze bias (incorrectly identified away gaze as direct)
4) ToM bias (incorrectly identified non self-referential thought as self-referential).
|–||–||Higher OXT levels in patients compared with controls.
OXT levels were higher in patients with delusions compared to those without.
Positive correlation between OXT and ToM bias and negative correlation between OXT and both gaze and ToM capacity in patients with delusions.
Positive correlation between OXT and both gaze and ToM bias in healthy controls. OXT was associated with inflammation in patients without delusions.
Note: Schz — schizophrenia; OXT — oxytocin; PEAT — Penn emotion acuity test; SC — Subcutaneous; WRT — Waiting room task ToM — Theory of mind; AAT — Approach avoidance task; FEIT and FEDT — Facial emotion recognition and discrimination test; PANSS — Positive and negative symptom scale; BPRS — Brief psychiatric rating scale; AVP — Arginine–Vasopressin; CSF — Cerebrospinal fluid; PHS — Polydipsic hyponatremic schizophrenia; PNS — Polydipsic normonatremic schizophrenia; NNS — Nonpolydipsic normonatremic schizophrenia; HPA — hypothalamic–pituitary–adrenal axis; mg — milligrammes; MDD — Major depressive disorder.
Single-dose intranasal OXT has been found to enhance higher-order social cognitive processing including social perception and ToM (Davis et al, 2013 and Woolley et al, 2014) and interpersonal (kinship) perception ( Fischer-Shofty et al., 2013a ), in patients with established schizophrenia-spectrum disorders (see Table 2 ). However, two studies found no effect of single-dose OXT on lower-order automatic facial emotion recognition tasks (Davis et al, 2013, Horta de Macedo et al, 2014, and Woolley et al, 2014), while others found improvement in global emotion recognition ( Averbeck et al., 2012 ) as well as recognition specifically of fearful faces ( Fischer-Shofty et al., 2013b ) with 24 IU OXT. Interestingly, Goldman et al. (2011) found a dose-dependent effect, where 20 IU OXT had an enhancing effect, yet 10 IU had a detrimental effect on facial fear recognition. This negative effect with the lower OXT dose was unexpected and according to the investigators unexplainable.
|Authors||Sample||Study duration||Study design||Parameters studied||Factors/variable controlled for||Drug administration||Main findings|
|Averbeck, Bobin, Evans, and Shergill (2012)||21 schz (all male; mean age = 38.3 [1.8])||Single-dose study||Double-blind, placebo-controlled crossover study.
Assessed 45 min post OXT/placebo administration.
|Hexagon emotion recognition
|IQ||Adjunctive intranasal OXT (24 IU single dose). All participants remained on their pre-study medication regimen and dose (two participants on SSRIs, one on benzodiazepine, one on an anti-cholinergic and one on a vesicular monoamine transport inhibitor).||OXT improved emotion recognition overall, but not for individual emotions.|
|Davis et al. (2013)||23 schz (all male)
11 in OXT group (mean age = 48.6 [6.6])
12 in placebo group (mean age = 48.6 [9.1])
|Single-dose study||Randomised, double-blind, placebo-controlled study.
Assessed 30 min post OXT/placebo administration.
|ToM; Awareness of Social Inference test (TASIT-III)
Empathy; Emotional Perspective Taking Task (EPTT)
Social perception: Half Profile of Nonverbal Sesitivity
Facial affect recognition
|Controlled for baseline value of corresponding endpoint as a covariate||Adjunctive intranasal OXT (40 IU single dose).
All participants remained on their pre-study medication regimen and dose.
|No OXT effect on social measures overall or in the low-level processes. OXT improved performance on high-level social cognition (TASIT- Part II detection of sarcasm, EPTT). No improvement on positive, negative or general symptoms.|
|Fischer-Shofty et al. (2013a)||35 schz (31 males, mean age = 32.4 [6.5])
46 controls (39 males, mean age = 30.04 [5.8])
|Single-dose study||Double-blind, placebo-controlled, within subjects crossover.
Assessed 45 min post OXT/placebo administration
|Recognition of kinship and intimacy (Interpersonal Perception Task). PANSS
|-||Adjunctive intranasal OXT (24 IU single dose).
All participants remained on their pre-study medication regimen and dose.
|Participants were more accurate in judging intimacy and kinship after OXT administration compared with placebo.
Only recognition of kinship improved significantly in the patient group.
|Fischer-Shofty et al. (2013b)||30 schz (27 males, mean age = 31.8 [6.5])
35 controls (32 males, mean age = 29.5 [5.6])
|Single-dose study||Double blind within-subject crossover design.
Assessed 45 min post OXT/placebo administration.
|Face morphing task to test ability to recognise happiness and fear.
|-||Adjunctive intranasal OXT (24 IU single dose).
All participants remained on their pre-study medication regimen and dose.
|Both patients and controls recognised fearful (but not happy) facial expressions more accurately following OXT compared with placebo.
No difference in emotion recognition as a result of OXT in patients and healthy controls.
No OXT effect on mood in either group.
|Goldman, Gomes, Carter, and Lee (2011)||13 outpatients: 5 polydipsic (3 males; mean age = 53 ) 8 non-polydipsic (4 males; mean age = 44 )
11 controls (4 males; mean age = 38 )
|Single-dose study||Double-blind, placebo, healthy controlled.
Assessed 45 min post OXT/placebo administration.
|Presence and intensity of facial emotions
neuroleptic dose, age, gender, Benton scores, change in plasma osmolality were controlled for by adding them individually as covariates to the regression models.
|Adjunctive intranasal OXT (10 IU or 20 IU single dose).
All participants remained on their pre-study medication regimen and dose.
|10 IU dose of OXT decreased emotion recognition in both patient groups. 20 IU dose improved emotion recognition (identifying fear) in polydipsic patients.|
|Horta de Macedo, Zuardi, Machado-de-Sousa, Chagas, and Hallak (2014)||20 schz (all male, mean age = 29.6 [6.8])
20 controls (all male, mean age = 29.7 [9.29])
|Single-dose study||Double-blind, randomised, placebo-controlled, within subjects design.||Facial emotion matching task
|Adjunctive intranasal OXT (48 IU single dose).
All schz were on one or more antipsychotic
All participants remained on their pre-study medication regimen and dose.
|OXT did not improve facial affect processing.|
|Woolley et al. (2014)||29 schz (all male, mean age = 45)
31 controls (all male, mean age = 42)
|Single-dose study||Randomised, double-blind, placebo-controlled, cross-over study.||The Awareness of Social Inference Test (TASIT).
Reading the Mind in the Eyes Test (RMET).
Automatic social cognition (ability to read emotional cues in voices, faces and body language). Controlled social cognition (comprehension of indirectly expressed emotions, thoughts, intentions).
|Adjunctive intranasal OXT (40 IU single dose).
All participants remained on their pre-study medication regimen and dose.
|OXT improved patients' controlled social cognition, but not automatic social cognition.
OXT had limited effects on healthy controls.
|Cacciotti-Saija et al. (2014)||52 early psychosis
27 in OXT group (18 males, mean age = 22.5 [4.2])
25 in placebo group (18 males, mean age = 22.3 [4.4])
Assessments at baseline, post-treatment and 3-month follow up
|Double-blind, randomised, placebo-controlled||Reading the Mind in the Eyes Test
Secondary measures (self-report behavioural assessments of social cognition, symptom severity and social functioning
|-||Adjunctive intranasal OXT 24 IU twice-daily + additional dose of OXT before
each weekly Social Cognition Training (SCT) session (2 × 1 h weekly for 6 weeks)
All participants remained on their pre-study medication regimen and dose.
|No benefit of OXT on primary or secondary outcomes at either post-treatment or follow-up.
Post hoc analyses showed OXT was associated with a reduction in negative symptoms.
|Feifel et al. (2010)||15 schz outpatients (12 males; mean age = 48 [8.9]) with residual symptoms.||3 weeks of OXT and 3 weeks of placebo (one week washout between treatments).||Double-blind, placebo controlled, crossover study.||PANSS,
|Treatment sequence was a between-subjects factor to evaluate possible carryover effects||Adjunctive intranasal OXT (20 IU twice a day (1st week), 40 IU twice a day (2nd and 3rd weeks). All participants remained on their pre-study medication regimen and dose.||The OXT group showed a decrease in total, positive and negative PANSS scores. The OXT group showed a decrease in CGI-I scores at the 3-week end point (no benefit was seen at the early time point).|
|Feifel, Macdonald, Cobb, and Minassian (2012)
Same Cohort and study as Feifel et al., 2010
|15 schz (12 males; mean age = 48 [8.9])||As per Feifel et al. (2010)||As per Feifel et al. (2010)||As per Feifel et al., 2010 + two cognitive tests performed at baseline and after 3 weeks of treatment;
1) CVLT (California Verbal Learning Test)
2) LNS (Letter Number Sequence)
|As per Feifel et al. (2010)||As per Feifel et al. (2010)||No difference between placebo and OXT on LNS performance. OXT group performed better on subtests of the CVLT (total Recall trials, short delayed free recall and total recall discrimination).|
|Gibson et al. (2014)||14 schz
8 OXT group (6 males, mean age = 38.8 [7.2])
6 placebo group (5 males; mean age = 35.7 [9.0])
|6 weeks||Randomised, double-blind, placebo-controlled trial||The Emotion Recognition-40 Theory of Mind Picture Stories Task
The Eyes Test The Interpersonal Reactivity Index The Trustworthiness Task The Ambiguous Intentions Hostility Questionnaire-Abbreviated Version
Social skills assessed through role-play
|-||Adjunctive intranasal OXT (24 IU twice daily).
All participants remained on their pre-study medication regimen and dose.
|OXT group showed improvements in fear recognition, perspective taking, and a reduction in negative symptoms|
|Lee et al. (2013)||28 schz
13 OXT group
(6 inpatients and 7 outpatients, 9 males, mean age = 44.7 [11.7]) 15 placebo group (6 inpatients and 9 outpatients, 11 males, mean age = 35.1 [8.2])
|3 weeks||Randomised, Double-blind, placebo-controlled||Olfactory identification ability
|Controlled for age and baseline values||Adjunctive intranasal OXT (20 IU twice daily).
All participants remained on their pre-study medication regimen and dose.
|No improvement in global symptomatology (or in either positive or negative symptoms).
Odour identification improved in OXT group.
|Modabbernia et al. (2013)||40 schz
20 in OXT group (17 males; mean age = 32.3 [7.4]) 20 in placebo group (16 males; mean age = 33.2 [6.9])
|8 weeks||Randomised, double-blind, placebo-controlled.||PANSS, Extrapyramidal Symptom Rating Scale||-||Adjunctive intranasal OXT (20 IU twice daily for the 1st week; 40 IU twice daily for the following 7 weeks).
Participants were inpatients on a stable dose of risperidone (5 or 6 mg/day).
|OXT group showed improvement in PANSS total score by week 4. From week 6, OXT group showed symptom reductions in general psychopathology (8%), positive symptoms (20%) and negative symptoms (7%).|
|Pedersen et al. (2011)||20 schz
11 OXT group (9 males; mean age = 39.0 [11.18])
9 Placebo (8 males; mean age = 35.8 [9.5])
|2 weeks||Randomised double-blind, placebo controlled.||PANSS
Social cognition; Brune Theory of Mind Picture Story Task
|Controlled for baseline measure of the dependent variable (in order to compare treatment groups over time).||Adjunctive intranasal OXT (24 IU twice a day).
All participants remained on their pre-study medication regimen and dose.
|OXT improved PANSS scores (reductions in negative and positive symptoms). OXT improved recognition of deception, and untrustworthy faces. OXT improved identification of second-order false beliefs.|
Note: Schz — schizophrenia; OXT — oxytocin; IU — International units; CGI — Clinical global impression; SCT — Social cognition training; SOFAS — Social and occupational functioning assessment scale; ToM — Theory of mind; PANSS — Positive and negative symptom scale; BPRS — Brief psychiatric rating scale; mg — milligrammes; CVLT — California verbal learning test; LNS — Letter number sequence; EPTT — Emotional perspective taking task; TASIT-III — The awareness of social inference test; RMET — Reading the mind in the eyes test; IQ — Intelligence quotient.
Short-term treatment (2–8 weeks) with twice-daily intranasal OXT has recently been trialled in schizophrenia using randomised placebo-controlled designs (see Table 2 ). The first trial found significant improvements in overall psychopathology, negative symptoms, verbal memory and global functioning after 3 weeks of OXT treatment in comparison to placebo (Feifel et al, 2010 and Feifel et al, 2012), with Pedersen et al. replicating these findings on overall psychopathology with just 2 weeks of OXT treatment ( Pedersen et al., 2011 ). Pedersen et al. (2011) additionally found that patients improved significantly in ToM ability, but not social perception. Aside from an 8-week trial in a larger sample conducted by Modabbernia et al. (2013) , the majority of these initial studies, summarised in Table 2 , comprised small sample sizes and were likely underpowered to detect small or even moderate sized effects. A recent exploratory meta-analysis of 105 psychosis patients from 7 clinical trials ( Table 2 ) suggests that OXT has moderate effects (Cohen's d = .52) on overall symptomatology ( Gumley et al., 2014 ). However, heterogeneity between studies was significant (two studies were single-dose trials), making it difficult to draw conclusions from the current findings.
The first and only study to have investigated OXT effects in an early psychosis sample combined 6-weeks daily intranasal treatment with social cognitive training ( Cacciotti-Saija et al., 2014 ). A non-significant improvement was found in emotion recognition of disgust in the OXT group. However, generally there were no effects of OXT treatment on primary measures (‘reading the mind in the eyes test’, Scale for the Assessment of Negative Symptoms and Social and Occupational Functioning Assessment Scale scores) or secondary measures (self-report behavioural assessments of social cognition, symptom severity and social functioning). This may have been because both OXT and placebo groups received the social cognitive training, and significant improvements over time were observed for the whole sample on measures of social cognition, symptomatology and global functioning ( Cacciotti-Saija et al., 2014 ). Thus the effects of social cognitive training in this small study may have masked any impact of OXT. Multi-arm studies with appropriate control conditions that match each active condition are needed to examine combined treatments.
Overall, findings suggest that OXT treatment has considerable potential to enhance general functioning, symptomatology and social cognitive abilities in psychotic illness. However, findings are somewhat mixed and may be related to a number of factors (which we discuss in detail in Section 7 ). Earlier, we highlighted that dysfunctional social brain regions in schizophrenia overlap with the same regions that are affected by intranasal OXT in healthy individuals. Thus, at this point we consider the questions: how does the dysfunctional brain respond to OXT administration? And do changes in underlying neural activations following OXT administration correspond to changes in social cognition and behaviour?
6. Oxytocin and neuroimaging in psychiatric populations
To our knowledge, no peer-reviewed study has been published that investigates the effects of intranasal OXT on brain activation in psychotic illness. However, Menon et al. (2013) , who presented fMRI findings at the International Congress of Schizophrenia Research 2013, showed that a single dose OXT (40 IU) reduced activity in midbrain regions, the ventral striatum and nucleus accumbens (regions highly connected with frontal and limbic structures) of schizophrenia patients during a social ‘trust’ game paradigm. However, while there were significant activation effects, there were no differences on task performance between the OXT and placebo conditions.
Pioneering fMRI research in social anxiety disorder has shown that acute intranasal OXT reduces or ‘normalises’ hyperactivation of the amygdala, mPFC and ACC, and enhances amygdala connectivity with the insula and regions of the cingulate, in response to negative facial expressions (e.g., Labuschagne et al, 2010, Labuschagne et al, 2011, and Gorka et al, 2015). Dodhia et al. (2014) recently found OXT to normalise resting-state functional connectivity of the left and right amygdala with rostral ACC/mPFC, which is typically hypoconnected in social anxiety disorder patients. Another single-dose study in depressed patients performing an emotion attribution task involving ToM, found OXT to increase activity in the middle frontal gyrus, superior temporal gyrus/temporoparietal junction, ACC and insula, which differed from healthy controls who had increased ventral regional activations ( Pincus et al., 2010 ). Lastly, a recent study in adults with autism spectrum disorder (ASD) showed that OXT increased right amygdala activity during face processing, a region that is abnormally underactivated in ASD ( Domes et al., 2013 ). The two latter studies are particularly pertinent given that normalisation of neural activity was in the general direction as that which would be required for normalisation of the abnormal emotion recognition- and ToM-related activation typically observed in schizophrenia patients. Taken together, OXT appears to normalise previously abnormal neural activation in key social brain regions, including normalising connectivity between these regions, in people with mental illnesses that are inherently characterised by social dysfunction. Given that OXT modulates neural activation by both increasing and decreasing the BOLD response, the direction of the effect may be dependent on several factors, including i) the nature of the baseline dysfunctional activation, ii) the condition under which activation is being measured (i.e., emotion vs. ToM vs. rest) and iii) the brain region being activated. Further research is needed to investigate the effects of intranasal OXT, both single-dose and longer duration, on social brain function in schizophrenia populations, and to address the critical questions relating to whether brain changes equate to improvements in social cognition and real-world social outcomes. Such research should additionally consider the possibility of inter-individual variation in the context of response to OXT treatment, which may be mediated by genetic factors.
7. The oxytocin receptor gene and links to social phenotypes, mental illness and the social brain
The OXTR gene on chromosome 3p25 spans ~ 19 kbp and contains 4 exons and 3 introns. It is a 389-amino-acid polypeptide with 7 transmembrane domains belonging to the class I G-protein-coupled receptor family. Given the well-documented role of OXT in mammalian social behaviour, and the previously mentioned effects of OXT administration on social abilities in humans, it is perhaps not surprising that OXTR SNPs have been associated with a range of general social phenotypes in the healthy population, including emotional processing, empathy, reward dependence, prosocial behaviour, positive affect, stress reactivity, moral judgement, ToM and global social cognition (for review see Meyer-Lindenberg et al., 2011 ). The impetus for exploring these associations was not only to better understand human sociality, but to also investigate risk for social cognitive and behavioural deficits and related psychiatric conditions (for review see Cochran et al., 2013 ). The strongest evidence supports OXTR polymorphisms as being significantly associated with risk for ASD and autistic traits (e.g., Liu et al, 2010 and Di Napoli et al, 2014). However, variations in OXT SNPs rs4813625, rs4813626 and rs3761248 (Souza et al, 2010b and Teltsh et al, 2012) and OXTR SNPs rs53576, rs237885 (Souza et al, 2010a and Montag et al, 2013), have been linked to risk for schizophrenia (see Table 3 for details). In addition, several SNPs have been associated with the severity of overall psychopathology (rs237885, rs237887), and general (rs53576, rs2254298), positive (rs11706648, rs4686301, rs237899) and negative (rs237902, rs2740204) symptoms in schizophrenia (Souza et al, 2010a, Montag et al, 2012, and Montag et al, 2013). Davis et al. (2014) recently found the rs2268493 T-allele (one of 7 SNPs investigated) was associated with poorer performance on the composite social cognition index, as well as on individual measures of ToM and social perception in schizophrenia. However, they failed to find any SNP association with symptomatology. This limited body of literature is highly variable and discrepancies are likely related to variation in participants' ancestry and sample size to detect differences, particularly in SNPs with minor allele frequencies of < 15% (e.g., rs2254298).
|Davis et al. (2014)||74 schz (53 male; mean age = 46.1 [10.5])||61% Caucasian
|OXTR||rs2268493||Association between OXTR SNPs and social cognition index + mentalizing and social perception tests
Half-Profile of Nonverbal Sensitivity (PONS)
The Awareness of Social Inference Test — Part III (TASIT)
Mayer–Salovey–Caruso Emotional Intelligence 2.0 (MSCEIT)
|rs2268493T allele was associated with poorer social cognition, particularly in mentalizing and social perception tests.
None of the SNPs were associated with clinical symptoms.
rs1042778 showed trend level associations with TASIT scores.
|Montag et al. (2012)||145 schz (aged between 18 and 69)
|Interpersonal Reactivity Index (IRI) assessed ‘perspective taking’, affective ‘empathic concern’ and self-related ‘personal distress’PANSS||No group differences in genotype frequencies. Main and interaction effect (genotype rs2254298 [A > GG] by diagnosis) with ‘empathic concern’.
rs2254298A allele associated with higher PANSS general psychopathology scores (but not positive or negative symptoms).
No associations found for rs53576.
|Montag et al. (2013)||Participants overlap with above mentioned study ( Montag et al., 2012 ).
406 schz (aged between 18 and 69)
406 healthy controls matched to age and gender
|European descent||OXT and OXTR||OXTR SNPs
rs53576 rs237885(OXTR rs53576 rs237902
|Investigate association between OXT and OXTR genetic variations and schizophrenia susceptibility||Associations between OXTR SNPs rs53576 (A>G) and rs237885(T>G) with a diagnosis of schizophrenia.Post-hoc revealed significant associations of OXTR SNPs rs53576 with general psychopathology and rs237902 with negative symptoms in schizophrenic patients.|
|Souza, de Luca, Meltzer, Lieberman, and Kennedy (2010)||140 schz
(mean age = 36 )
|82% Caucasian||OXT and OXTR||OXT
rs11706648, rs4686301, rs237899
|Investigate symptom severity and clozapine treatment responseBPRS||rs2740204 variant in the OXT gene was associated with treatment response and negative symptomsrs237885, rs237887 variants in the OXTR gene were associated with severity of overall symptoms rs11706648, rs4686301, rs237899 of the OXTR gene were associated with the improvement of positive symptoms|
|Souza, Ismail, Meltzer, & Kennedy (2010)
Meta-analysis of data from above study (letter to the editor).
|179 schz and 358 healthy controls (228 males, mean age = 35.2 [8.4])
healthy parents of schz (147)
|All European/Caucasian background||OXT and OXTR||OXT SNPs
rs4813625 and rs3761248
|Multiple comparisons||OXT variants (rs4813625 and rs3761248) were associated with risk for schz in the case–control sample. None of these results remained significant after corrections for multiple comparisons.|
|Teltsh et al. (2012)||56 family members (25 affected with schz)
52 Arab-Israeli nuclear families (186 individuals, 90 affected with schz)
272 Jewish schz (136 males, mean age = 40.9,),
273 control participants (137 males, mean age = 38.3)
|Association between OXT SNPs and schizophrenia||rs4813626 was the only SNP that was significantly associated with schz in all three samples|
|Watanabe et al. (2012)
Letter to the editor
|544 schz (290 males, mean age = 41.8[13.6])
healthy controls (341 males, mean age = 38.4[10.8])
family-based subjects (105 trios, made up of patients (59 males, mean age = 28.8[9.2]) and both parents
|Japanese||OXTR||rs9840864||Association between OXTR SNPs and schizophrenia||A significant association between rs9840864 and schizophrenia was identified using both samples.|
Note: *This is a direct quote, we are unsure what exactly ‘black’ includes; Schz — schizophrenia; OXT — oxytocin; OXTR — oxytocin receptor gene; SNP — single nucleotide polymorphism; rs — restriction site; TASIT — the awareness of social inference test; PONS — half-profile of nonverbal sensitivity; PANSS — positive and negative symptom scale; BPRS — brief psychiatric rating scale; MSCEIT — Mayer–Salovey–Caruso emotional intelligence; IRI — interpersonal reactivity index.
In terms of neuroimaging, the limited studies in this area have primarily focused on structural differences in social brain regions in healthy samples and in relation to OXTR risk variants for ASD using MRI (for review see Zink and Meyer-Lindenberg, 2012 ). In healthy samples, OXTR variants have been linked with differences in amygdala and ACC volume, functional activation and connectivity of the amygdala and hypothalamus, among other neurobiological phenotypes (see Table 4 for details of neuroimaging-genetic studies in healthy populations).
|Chang et al. (2014)||82 subjects (37 males, mean age = 34.69[12.46])||Han Chinese||OXTR||rs53576||Single positron emission computed tomography to measure dopamine transport (DAT) availability.
Inventory (MPI) to measure neuroticism personality traits.
|Lower striatal DAT availability in rs53576AG and rs53576GG group compared with the rs53576AA group.
OXT levels did not significantly differ between the OXTR genotypes.
rs53576G groups OXT level was negatively correlated with DAT availability in the AG/GG group.
DAT availability was positively correlated with MPI neuroticism score in the rs53576AA group with a ‘low’ OXT level.
Plasma OXT level was negatively correlated with striatal DAT availability in the OXTR rs53576G allele carriers only.
|Furman, Chen, and Gotlib (2011)||51 females genotyped (between ages 10 and 15)||From the United States||OXTR||rs2254298 (G > A)||Investigated relationship between amygdala volume and the rs2254298 alleles G and A||Individuals homozygous for the G allele had smaller bilateral amygdala volume than those with an A allele. Whole-brain VBM found an association between the G allele and smaller brainstem and dorsomedial anterior cingulate volumes.|
|Inoue et al. (2010)||208 subjects (143 males, mean age = 33.9[11.6])||Japanese||OXTR||rs2254298A||Investigated relationship between amygdala volume and seven SNPs and one haplotype-block||OXTR rs2254298A allele was associated with larger bilateral amygdala volume (allele-load dependent trend). rs2254298G allele was associated with smaller bilateral amygdala volume.|
|Loth et al. (2014)||1445 adolescents (697 boys, mean age = 14.4)||European origin||OXTR||rs237915 (T > C)||Stressful life events (SLEs) on fMRI activity in the ventral striatum (VS) and amygdala to animated angry faces.||Association between rs237915CC genotype and lower VS activity than CT/TT-carriers.
Emotional problems (in girls) and peer problems (in boys) associated with increased clinical symptoms as a function of SLEs in CT/TT-carriers but not CC-carriers. Low SLEs, CC-carriers had more emotional problems (girls) and peer problems (boys). In CC-carriers, reduced VS activity was related to more peer problems.
|Sauer, Montag, Reuter, and Kirsch (2013)||55 males (mean age = 24.6[2.6])||European||Gene coding for the transmembrane protein CD38
|CD38 rs2796863||OXT cross-over design during fMRI,
Investigate OXT and DA interactions and the activation of the amygdala, VTA, VS and fusiform gyrus during a social stimulus.
|Amygdala activation; no gene main effect, no gene by substance interaction effect, but a significant gene by gene by substance interaction. During placebo, the effect of CD38 on amygdala activation to the social stimulus was modulated by the COMT genotype.|
|Tost et al. (2010)||212 subjects had VBM and OXTR genotyping (102 males, mean age = 32.0 [10.0])
309 subjects had OXTR genotype and reward dependence using the TPG (145 males, mean age = 20.8 [9.2])
228 subjects had fMRI data during emotionally salient stimuli (investigated functional connectivity and activation) (103 males, mean age = 29.9 [9.0])
(A > G)
(A > G) and hypothalamus and amygdala, and dACG (using VBM)
Tridimensional Personality Questionnaire to investigate genotype effects on self-reported prosocial temperament
Processing of emotional stimuli [human facial expressions, face-matching task]
|Rs53576A allele associated with decreased sociality.
rs53576 A allele associated with decrease GM volume of the hypothalamus (mostly driven by male A allele-carriers) and increased amygdala volume (mostly driven by male A allele-carriers for the right amygdala).
Increase in structural connectivity (covariance of regional volumes not wm projections) of the hypothalamus and dACG in rs53576A allele carriers.
Increased functional coupling between the hypothalamus and amygdala in rs53576A allele carriers.
|Tost et al. (2011)||212 subjects had VBM and OXTR genotyping (102 males, mean age = 32.0 [10.0])
228 subjects had fMRI data during emotionally salient stimuli (103 males, mean age = 29.9 [9.0])
(A > G)
|Investigated association of OXTR rs2254298 and limbic circuitry (hypothalamus, amygdala and dACG)||rs2254298A carriers were associated with smaller hypothalamus volume (largely driven by male risk allele carriers). No effect was found on amygdala volume. Association between rs2254298A carriers and increased structural coupling of hypothalamus and dACG. rs2254298 was associated with reduced deactivation of dACG during emotion processing. Reduced functional connectivity of hypothalamus with dACG and amygdala in male rs2254298 carriers.|
|Yamasue (reply to Tost)||206 subjects||Japanese||OXTR||rs 2254298||GM volume||rs2254298A was associated with smaller GM volume of the dACG and right hypothalamus (females only).|
|Wang et al. (2013)||270 subjects (125 males, mean age = 24.0 (2.3)||Chinese||OXTR||rs53576 (AA genotype)||Local functional connectivity density (FCD) using resting-state fMRI||Lower FCD of the hypothalamus in male AA homozygotes compared to male G-allele carriers. Weaker resting state functional connectivity between the hypothalamus and left dlPFC associated with AA male homozygotes compared to G-allele carriers.|
|Wang et al. (2014)||290 subjects (136 males; mean age = 23.5[2.6])||Chinese||OXTR||rs53576 (AA genotype)||Tridimensional Personality Questionnaire Grey matter volume Resting-state functional connectivity||Females with AA genotype showed increased harm avoidance relative to G-carrier females.Females with AA genotype had smaller amygdala volumes bilaterally compared with G-carrier females.
Females with AA genotype showed reduced resting-state functional coupling between the prefrontal cortex and amygdala bilaterally (allele-load dependent trend).
Note: schz — schizophrenia; OXT — oxytocin; OXTR — oxytocin receptor gene; SNP — single nucleotide polymorphism; rs — restriction site; DAT — dopamine transport; MPI — Maudsley personality inventory; VBM — voxel-based morphometry; SLE — stressful life event; VS — ventral striatum; fMRI — functional magnetic resonance imaging; COMT — catechol-O-methyltransferase; DA — dopamine; VTA — ventral tegmentum; dACG — dorsal anterior cingulate gyrus; GM — grey matter; dlPFC — dorsolateral prefrontal cortex; CD38 — cluster of differentiation 38.
Studies in healthy participants also point towards potential intermediate functional phenotypes that link OXTR genotype with social cognition and, to a lesser extent, social behaviour (see Table 4 for details of social/cognitive behavioural findings in healthy populations). For example, the rs53576 AA genotype has been associated with reduced amygdala activation during emotional face processing ( Tost et al., 2010 ). As mentioned earlier, the amygdala is typically under-activated during such tasks in schizophrenia, thus it may be that higher A allelic load for this SNP is a contributing factor to this abnormal activation, especially given that the A allele of this SNP has been linked to risk for schizophrenia and general psychopathology (see above and Table 3 ). Relevant to the neurofunctional model of schizophrenia proposed by Rosenfeld et al. (2011) , evidence also suggests rs53576 influences striatal dopamine availability ( Chang et al., 2014 ). Moreover, higher availability correlated with increased neuroticism in this sample of healthy individuals, further supporting the significant impact of OXTR allelic load on behaviour of a psychopathological nature ( Chang et al., 2014 ).
A more recent study in a large sample of healthy adolescents showed that variation in rs237915 had a significant effect on activation in the striatum, cingulate cortex, inferior frontal gyrus, thalamus and cerebellum during emotion processing of angry facial expressions ( Loth et al., 2014 ). Moreover, Loth et al. (2014) not only found that C-allele homozygotes displayed lower ventral striatum activations compared to T-allele carriers, but that this reduced emotion processing-related activity in C-allele homozygotes was significantly related to more social problems with peers. Thus, putatively the rs237915 C-allele may be a significant risk biomarker, given that these same brain regions are structurally and functionally abnormal in schizophrenia, and that social-emotional disturbances are inherent to psychotic illness.
Overall, findings support a model whereby OXTR variants, and to a lesser extent OXT variants, could potentially moderate the relationship between social brain function and social cognitive/behavioural outcomes. However, at present, evidence for such a model, particularly with a demonstrated impact on social behaviour, is sparse, and no such study has been conducted in a psychosis cohort. Thus, a great deal more research is needed in this area.
8. Factors to consider in oxytocin research: Potential confounds and interactions
Oxytocin research thus far has differed greatly in methodological design. The bulk of intranasal OXT trials examined the effects of a single dose of OXT. This restricts the interpretation of findings to the immediate term. Even when considering the 2–8 week trials, OXT was typically administered twice a day and, given its short half-life, it raises the question of whether specific environmental conditions are required during the active (peak plasma) time-frame; thus, is it that participants should self-administer the drug prior to engaging in a task requiring social communication (e.g., going to a café or doctor's appointment)? If so, this would suggest that OXT might be best used as a catalyst to a targeted social cognitive intervention, which may facilitate social learning. That is, does OXT simply act by preparing the individual to be more amenable to social interactions (for example, by dampening the perception of negative social cues and increasing trust), which would aid in the interpretation and retention of skills taught within a social group setting? This also raises questions about the use of OXT as a stand-alone treatment or adjunct to antipsychotic medication, and what the mechanisms of action might be. Hence, basic scientific research is needed to determine the pharmacokinetic actions of intranasal OXT in the brain, and how it interacts with antipsychotic and anxiolytic medications. Future research should consider the timing of OXT administration, OXT half-life and time of psychological testing (for further discussion see Macdonald and Feifel, 2013 ). We additionally propose that a time-course evaluation of brain function in the context of an ‘on-off’ design with repeated fMRI over the half-life of OXT is needed.
Intranasal OXT also appears to have some sex-specific effects on brain activation, which is not surprising, given the primary roles of OXT relate to pregnancy and maternal behaviours (although endogenous serum OXT [pg/ml] levels in men are comparable to non-pregnant women; Rubin et al., 2014 ). Generally, a sex-specific increase in activation in women and decease in men is observed in the temporal lobes in response to OXT administration ( Wigton et al., 2015 ). However, Wigton et al. (2015) highlight that this divergence may also be task-related, as the studies in women predominantly used explicit emotional processing paradigms, while the studies in males employed mainly implicit emotional processing tasks. Thus, further studies are needed into the sex- and task-specific effects of OXT treatment, including non-emotion processing tasks, such as ToM paradigms.
In the healthy population, differential sex-effects of the A-allele load for rs53576 on the brain have been observed. Higher A-allele load for rs53576 has been linked to larger amygdala volumes in men ( Tost et al., 2010 ) but smaller amygdala volumes in women ( Wang et al., 2014 ). Further, during rest AA genotypes have been shown to display reduced functional connectivity between the PFC and the amygdala in females, and hypothalamus in males ( Wang et al., 2014 ). Further, Tost et al. (2011) found the relationship between rs2254298 allelic load and hypothalamic functional connectivity (with the amygdala) and volume was specific to males. However, additional interaction effects with ancestry need to be taken into account, given that Yamasue et al. (2011) found this same relationship with thalamic volume was specific to females. Lastly, the possible interactive role of OXT genes in determining how stressful life experiences and adverse environments may impact on neurodevelopmental trajectories and risk or resilience for psychotic illness, and other mental illnesses marred by social dysfunction, should be considered (for further discussion see Brune, 2012 and Pantelis and Bartholomeusz, 2014).
9. The future of oxytocin research in schizophrenia
Given that short-term OXT treatment is well-tolerated, has no real side-effects when delivered in doses of 18–40 IU ( MacDonald et al., 2011 ), and has repeatedly been shown to influence brain and behaviour in healthy individuals, it would appear that OXT research in psychosis is set to grow. However, the clinical trials that have been conducted thus far have produced mixed results, and many important questions remain unanswered. Indeed, despite the growing body of evidence fascinated by the positive outcomes of oxytocin's effects in humans, there is some evidence suggesting that long-term administration of oxytocin can lead to unintended negative consequences on social behaviour in animals, such as deficits in social recognition during pair bonding ( Bales et al., 2013 ). However, the effects may be specific to appropriate behavioural adaptation seen in animal behaviours, and effects in humans remain unknown.
Fundamental unresolved issues that need to be addressed are: i) actions in the brain — does OXT act on the dysfunctional brain in a pro-social way analogous to healthy individuals?; ii) dosage — currently 24–40 IU/day is most commonly used, but what is optimal for producing social cognitive and behavioural effects?; iii) length of treatment — what is the optimal duration and are effects sustainable post-treatment, and what (if any) side effects accompany longer-term use (longest treatment to date was 13 weeks; Ohlsson et al., 2005 )?; iv) age — do endogenous OXT levels decline with age, and does age impact on individual response sensitivity to OXT treatment?; v) sex — how do men and women differ in their response to OXT, both behaviourally and at a neural level?; and vi) genetics — initial evidence suggests OXT effects in the brain may be dependent on genetic variants, yet how this translates to social outcomes and behaviour, especially in illness populations, is unknown. Addressing these issues will be essential for determining the future clinical applicability of OXT as a viable treatment.
It is also important that future research be mindful that OXT acts in concert with various neurotransmitter systems and other hormones, including vasopressin, oestrogen and testosterone. While a summary of such interactions is beyond the scope of this review (for review see Bethlehem et al, 2013 and Gabor et al, 2012), we recommend that clinical trials record menstrual cycle phase, exclude patients who are on steroids or contraceptive medications, collect blood assay to measure and analyse changes in hormone levels, and trial OXT with a standardised stable dose of a specific atypical antipsychotic medication if feasible.
Finally, broader issues that future research should address include: whether OXT treatment is more effective in the earlier illness stages, when individuals are less removed from their premorbid baseline level of functioning; whether OXT may be useful as a preventative treatment (for discussion see Tadjibaev, 2013 ); and whether OXT effects are specific to certain psychiatric illnesses, given that evidence supports OXT as being potentially useful in autism spectrum disorders, anxiety disorders and addictions (Liu et al, 2012 and Pedersen, 2014).
At present, poor social functioning remains the largest treatment challenge for both patients and clinicians. Therefore, new treatment strategies targeting the core deficits that underlie social disability, namely social cognition, are needed. OXT is a promising candidate. Future research into alternative pharmacological compounds that target the oxytocinergic system, such as synthetic OXTR agonists ( Hicks et al., 2014 ), or agents that can directly stimulate the natural release of oxytocin in the brain ( Sabatier et al., 2003 ), is currently under development and also holds promise. The field of OXT neuroscience is young and much remains to be discovered, including the functional cellular roles of OXT and OXTR genetic variation, the impact on brain function, and whether OXT's effect on the social brain corresponds to social cognitive and behavioural changes. Future clinical trials should consider the full range of potential neurotransmitter, hormonal and pharmacological interactions with OXT, and take into account influencing factors such as sex and ancestry. Further, identification of neural functional intermediate phenotypes, which link OXT and OXTR genetic variants to social cognition and social functioning, will be clinically informative, particularly in the context of clarifying risk factors for psychotic illness, and in predicting treatment response to OXT. This interdisciplinary research is an essential step towards tailoring treatment to the individual in future clinical practice.
Role of funding source
No funding was provided for this manuscript
Dr Bartholomeusz was primarily responsible for compiling the relevant articles for the manuscript and summary/interpretation of the literature. Ms Ganella was primarily responsible for literature searchers and creating the summary tables. Drs Labuschagne and Bousman provided expertise in oxytocin and genetic research, respectively. Prof Pantelis provided expertise in neuroimaging and schizophrenia research. All authors contributed to the writing of the manuscript.
Conflict of interest
Authors have no conflicts of interest.
Dr Bartholomeusz was supported by a University of Melbourne, Department of Psychiatry, John and Betty Lynch Fellowship. Ms Ganella was supported by a University of Melbourne, Faculty of Medicine, Dentistry and Health Sciences, Ronald John Gleghorn PhD Scholarship and a Co-operative Research Centre PhD top-up Scholarship. Dr Bousman was supported by a University of Melbourne, Faculty of Medicine, Dentistry and Health Sciences, Ronald Phillip Griffith Fellowship. Prof Pantelis was supported by a NHMRC Senior Principal Research Fellowship (ID: 628386), NHMRC Program Grants (ID: 350241; 566529) and a NARSAD Distinguished Investigator Award (ID: 18722).
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a Orygen, The National Centre of Excellence in Youth Mental Health and the Centre for Youth Mental Health, The University of Melbourne, Parkville, Victoria, Australia
b Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne & Melbourne Health, Carlton South, Victoria, Australia
c School of Psychology, Australian Catholic University, Fitzroy, Victoria, Australia
d Florey Institute for Neuroscience and Mental Health, Parkville, Victoria, Australia
⁎ Corresponding author at: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne & Melbourne Health, Carlton South, Victoria, Australia. Tel.: + 61 3 9342 2800.
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