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A single dose of oxytocin nasal spray improves higher-order social cognition in schizophrenia

Schizophrenia Research, Volume 168, Issue 3, November 2015, Pages 628 - 633


Schizophrenia is associated with significant impairments in both higher and lower order social cognitive performance and these impairments contribute to poor social functioning. People with schizophrenia report poor social functioning to be one of their greatest unmet treatment needs. Recent studies have suggested the potential of oxytocin as such a treatment, but mixed results render it uncertain what aspects of social cognition are improved by oxytocin and, subsequently, how oxytocin might best be applied as a therapeutic. The aim of this study was to determine whether a single dose of oxytocin improved higher-order and lower-order social cognition performance for patients with schizophrenia across a well-established battery of social cognition tests. Twenty-one male patients received both a single dose of oxytocin nasal spray (24 IU) and a placebo, two weeks apart in a randomized within-subjects placebo controlled design. Following each administration, participants completed the social cognition tasks, as well as a test of general neurocognition. Results revealed that oxytocin particularly enhanced performance on higher order social cognition tasks, with no effects on general neurocognition. Results for individual tasks showed most improvement on tests measuring appreciation of indirect hints and recognition of social faux pas. These results suggest that oxytocin, if combined to enhance social cognition learning, may be beneficial when targeted at higher order social cognition domains. This study also suggests that these higher order tasks, which assess social cognitive processing in a social communication context, may provide useful markers of response to oxytocin in schizophrenia.

Keywords: Neuropeptides, Emotion recognition, Social behavior, Psychosis, Hormone.

1. Introduction

Schizophrenia is characterized by a heterogeneous presentation of positive, negative, and disorganized symptoms, cognitive and motor impairments, and restricted affective expressions ( APA, 2000 ). Among these characteristic clinical features, cognitive deficits have been argued to be at least partially independent of other symptoms in schizophrenia, present before the diagnosis of the illness and stable over time ( Fett et al., 2011 ).

Social cognition is a specialized neurocognitive domain that facilitates social communication and social skill ( Green et al., 2012 ). Social cognition can be described as an ability to understand the thoughts and intentions of others and is often argued to include a range of higher order (reflective, controlled and integrative) and lower order (automatic, fast) skills. For example, ‘theory of mind’ is regarded as a higher order social cognition skill. It refers to the cognitive ability to attribute mental states such as thoughts, beliefs and intentions that are separate from reality to the self or others, and in doing so, to explain, manipulate and predict behavior ( Sprong et al., 2007 ). It requires one to reflect upon, deliberate and to make complex social inferences ( Woolley et al., 2014 ). Alternatively, lower order social cognition processes are relatively automatic and typically involve fast cue detection (e.g., eye gaze detection) and judgments (e.g., emotion recognition). These differing social cognitive processes are believed to be underpinned by different underlying brain structures ( Lieberman, 2007 ). Despite this, there is a wealth of evidence demonstrating deficits across both lower and higher order social cognition in schizophrenia ( Mehta et al., 2013 ).

Recent evidence has highlighted a critical role for the neuropeptide and hormone oxytocin in the regulation of social behavior (Meyer-Lindenberg et al, 2011, Guastella and MacLeod, 2012, and Bakermans-Kranenburg and van I Jzendoorn, 2013). Across a variety of mammalian models, the administration of oxytocin enhances social recognition and bonding, and reduces anxiety associated with social threat. In schizophrenia, single-dose administration studies have shown effects of oxytocin on social cognition, including lower order facial emotion recognition (Averbeck et al, 2011 and Goldman et al, 2011) and higher order social cognitive task performance (such as detection of sarcasm, deception and empathy) (Davis et al, 2013 and Woolley et al, 2014). However, currently, a wide variety of tests have been used and a lack of consistency across studies, including failures to replicate ( Horta de Macedo et al., 2014 ), has resulted in debate about the specific benefits from oxytocin treatment across different social cognitive domains in people with schizophrenia.

Understanding how oxytocin influences social cognition is important for a number of reasons. First these studies provide important information regarding the biology underlying social cognitive deficits in schizophrenia. Second, they provide guidance as to how oxytocin could be employed for therapeutic purposes to improve social cognitive functioning. For example, oxytocin influences lower order social cognition in healthy adults and this may suggest a combinatorial strategy of delivering oxytocin with emotion recognition training for therapeutic purposes in clinical conditions. This is particularly important in light of recent debate that in Schizophrenia specifically, the effect of oxytocin may be only beneficial for a limited number of tests assessing very specific higher order, rather than lower order ( Horta de Macedo et al., 2014 ), social cognitive processes ( Davis et al., 2014 ). Such an argument has also been used to explain why some longer term administration studies that included lower-order social cognition skill training found no additional benefit of oxytocin in psychosis ( Cacciotti-Saija et al., 2015 ). Finally, it would be useful to identify reliable markers of response to oxytocin in different clinical populations, to be able to predict who is receiving adequate dosing and likely to respond to treatment ( Guastella and MacLeod, 2012 ). Currently, there is little understanding as to what constitutes a reliable response to oxytocin, although some social cognitive tests, such as emotion recognition, have shown promise as potential markers in healthy populations (Guastella and MacLeod, 2012 and Shahrestani et al, 2013).

Thus, the aim of this study was to further explore the different domains of social cognition in patients with schizophrenia following intranasal administration of oxytocin. We utilized well-known and established tests of higher order and lower order social cognition to further test recent claims ( Davis et al., 2013 ) that oxytocin has specific effects on higher order in comparison to lower order social cognition tasks.

2. Experimental materials and methods

2.1. Study design

Participants were enrolled in a within-subjects crossover, double-blind, randomized controlled trial at the Brain & Mind Research Institute (BMRI), University or Sydney. Participants were recruited from specialized tertiary referral services for the assessment and intervention of mental health problems (Youth Mental Health Clinic at the BMRI, and the Mental Health Service, Liverpool Hospital) and from the Australian Schizophrenia Research Bank. The study was approved by the Human Research Ethics Committee at the University of Sydney (11268) and the South Western Sydney Local Health District (10/051) was registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12609000528257). After a complete description of the study to the participants, written informed consent was obtained.

2.2. Participants

Eligible participants were male adults over the age of 16 years with a confirmed current diagnosis of schizophrenia or schizoaffective disorder according to DSM-IV criteria. Exclusion criteria included female sex due to likely interactions of treatment with menstrual cycle and contraceptive pill control, a verbal IQ lower than 75, experiencing acute exacerbation of psychiatric symptoms (including severe suicidal thoughts and/or actions), recurrent substance abuse problems within the last six months causing significant impairment, current physical health conditions (for example, cardiovascular disease, kidney disease) or hypersensitivity to preservatives in the nasal spray (in particular E 216, E 218, or chlorobutanol hemihydrates). Concurrent medication use was stabilized for at least eight weeks prior to entering the study and maintained over the course of participation in the trial (See Consort diagram; Fig. 1 ).


Fig. 1 Consort diagram.

2.3. Interventions and adverse reporting

Nasal sprays were developed and randomized by a local compounding chemist with an identical placebo containing all ingredients except the active oxytocin (all sprays contained sorbitol, benzyl alcohol glycerol, and distilled water, contained within an amber 7 ml glass nasal spray with metered dose pump). Participants received either 24 international units (IU) of oxytocin or placebo (4 IU per spray, 3 sprays per nostril) at each administration (Phases A and B). Nasal sprays were labeled with sequential numbers and Phase A or Phase B; blocking was in sets of 6 (3 active and 3 placebo sprays) in a randomly generated order. All research staff members conducting assessments and participants were blind to treatment allocation and unaware of randomization.

To assess for any potential adverse effects from the nasal spray, participants were asked to report any side effects and what drug they thought they had taken by free response at the end of each visit. A safety monitoring board (comprising of IBH; PBW and others) was involved to oversee any adverse events.

2.4. Diagnostic assessments

Diagnostic tests included the Diagnostic Interview for Psychoses (DIP), assessing occurrence of relevant symptoms and signs across the patient's lifetime to confirm diagnosis ( Castle et al., 2006 ) and the Scales for the Assessment of Positive and Negative Symptoms (SAPS/SANS), to rate positive and negative symptoms experienced over the past month (Andreasen, 1983 and Andreasen, 1984). To estimate IQ, we used the verbal subscale of the Wechsler Abbreviated Scale of Intelligence ( Weschler, 1999 ) due to its lower susceptibility to the impact of psychosis ( O'Connor et al., 2012 ).

2.5. Outcome measures

2.5.1. Lower order social cognition

The paralanguage and face subtasks of the Diagnostic Analysis of Non-Verbal Accuracy (DANVA: ( Nowicki and Duke, 1994 )). The DANVA measures individual differences in nonverbal emotion recognition accuracy. We used the adult stimuli. In the paralanguage subtask, the ability to correctly process nonverbal information about affect from tones of voice is assessed, while the faces subtask tests the ability to correctly process nonverbal information about affect from photographs of faces. Facial Expressions of Emotions Task (FEEST, ( Young et al., 2002 )): In this task, accuracy in emotion recognition from a standardized set of photos of faces ( Ekman and Friesen, 1976 ) is assessed. Finally, we included the Reading the Mind in the Eyes Task (RMET( Baron-Cohen et al., 2001 )). This test requires participants to identify the best emotion descriptor that matches the expression displayed by the eye region of 36 faces. It has well established reliability and validity, and was included as previous studies have demonstrated sensitivity to oxytocin administration on this task in healthy ( Domes et al., 2007 ) and autistic samples ( Guastella et al., 2010 ).

2.5.2. Higher order social cognition

False Belief Picture Sequencing Task (FBPSTL) ( Langdon et al., 1997 ): This task assesses theory of mind by requiring individuals to sequence a set of picture card stories for which correct sequencing requires inferences of false beliefs by story characters ( Langdon and Coltheart, 1999 ). The original task included control sequences, however for this study we focused on positioning scores totaled for the four false-belief stories (range 0–24). Two versions of the task were created by varying order of sequences presented at Phases A and B. Hinting Task: This task is designed to assess the ability of a participant to infer communicative intentions behind indirect speech. The stimuli (Corcoran et al, 1995 and Marjoram et al, 2005) were used to create two versions of the task, each comprising ten short passages presenting a verbal exchange between two characters. One of these characters drops a hint and the participant is asked what the character means by their words. The Faux Pas Recognition Task ( Baron-Cohen et al., 1999 ): The original 20 stories were used to create two versions of the task, each comprising 10 scenarios in which one of the characters does or does not make a faux pas. Participants are asked whether the character said something they shouldn't have and, if so, why. Scores are generated for correct detection and explanation in the faux pas condition and for correct recognition that a faux pas did not occur in the non faux pas condition ( Baron-Cohen et al., 1999 ). Poor performance in the former condition indicates reduced sensitivity to other's thoughts and feelings when a social faux pas occurs, while poor performance in the latter indicates inappropriate attributions of a transgression or insult by another.

2.5.3. Neurocognition

We included a general measure of neurocognition, Versions A and B of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) ( Randolph et al., 1998 ) and report results for the overall score and subscale scores including immediate memory, delayed memory, visuospatial/constructional, language, and attention.

2.6. Procedure

After confirmation of diagnosis, participants returned on a separate day (morning of afternoon) to self-administer in front of the experimenter either an oxytocin or placebo nasal spray following the instructions provided by researchers. Participants were instructed to abstain from caffeine and nicotine on the day of the study and from food or drinks other than water in the 2 h prior to participation. After a standard wait-period of 45 min after oxytocin administration, experimental tasks and side effect reports were completed. Two weeks later, participants returned to receive the alternative nasal spray and complete the experimental measures.

2.7. Statistical analyses

All analysis was completed using Statistical Package for the Social Sciences Version 22 ( IBM Corp., 2013 ). Initially, analysis of variance was used to confirm that the groups randomly assigned to each order of drug presentation did not differ on basic demographics and clinical characteristics. Subsequently, multivariate analyses of variance were conducted to examine the impact of oxytocin versus placebo on a grouping of lower order social cognition variables (DANVA faces, DANVA paralinguistic, FEEST and the RMET) and then on the remaining higher order social cognition variables (FBPST, Hinting Task, faux pas and non faux pas conditions of the Faux Pas Recognition Test), with drug assignment (oxytocin, placebo) as the within subjects factor and order of administration as a between factor. Within these overall analyses, follow-up linear contrasts examining the effect of drug were also conducted to explore the source potential effects of drug on any individual test. Assumption testing was conducted to check for normality, linearity, univariate and multivariate outliers, homogeneity of variance–covariance matrices, and multicollinearity. Any missing data was imputed. Significance was set at p < 0.05.

3. Results

3.1. Recruitment and baseline characteristics

Participant recruitment occurred between August 2009 and October 2012. One participant was removed from analysis due to outlier performance across multiple tests within the study. Inclusion of this participant did not alter the MANOVA and follow-up paired t-tests. This left twenty-one participants who completed the trial and were included in analyses, with a mean age of 37.42 (Range 22 to 57; SD = 11.14) and verbal IQ was within the normal range (Mean = 106.00, SD = 18.32, Range 78 to 139). Both age and Verbal IQ were normally distributed across the sample (smallest p = 0.56). Severity of positive (Mean = 4.47, Range 0–13; SD = 3.43) and negative symptoms (Mean = 11.39, Range 4–21; SD = 4.74) summed respectively across the SAPS and SANS global ratings were within the expected range. On average, two participants had missing data that was imputed on each outcome measure with the overall group mean.

3.1.1. Lower order social cognition effects

The overall analysis did not show a main effect of oxytocin in comparison to placebo on lower order social cognition performance F(4, 16) = 2.71, p = 0.07, no main effect of drug order, F(4, 16) = 1.13, p > 0.05, and no interaction with order of drug administration F(4, 16) = 1.19, p > 0.05. When we further considered the individual variables using a linear contrast of the effect of drug, only performance on the DANVA paralinguistic scale showed significant improvement of oxytocin above placebo, F (1,19) = 7.81, p = 0.01 (see Table 1 ).

Table 1 Performance on higher and lower order tests of social cognition following oxytocin and placebo administration.

  Oxytocin Placebo  
Mean SD Mean SD f, p value ETA squared
Lower Order Social Cognition Tests
DANVA Faces 17.69 2.25 17.30 3.04 0.40, p = 0.53 0.02
DANVA Paralinguistic 18.28 2.47 17.32 2.77 7.81, p = 0.01 0.29
Ekman Total 46.57 6.69 48.24 6.76 3.58, p = 0.07 − 0.16
RMET Total 25.24 4.58 23.81 5.59 3.48, p = 0.08 0.16
Higher Order Social Cognition Tests
False Belief Picture Sequencing Task 19.31 5.40 19.53 5.45 0.07, p = 0.79 0.004
Faux Pas 14.41 3.72 14.34 3.96 0.01, p = 0.92 0.001
Non Faux Pas 9.61 0.71 8.72 1.69 6.37, p = 0.02 0.25
Hinting Task 17.50 2.60 16.83 2.90 5.38, p = 0.03 0.22

p < 0.05.

3.1.2. Higher order social cognition effects

Results showed a significant main effect of drug, suggesting that oxytocin significantly improved higher order social cognition performance above placebo, F (4, 16) = 4.05, p = 0.02. There was also a main effect of drug order, F(4, 16) = 3.22, p = 0.04, such that those participants who received oxytocin last performed better overall. There was, however, no significant interaction of the main drug effect with order of actual drug administration, F (4, 16) = 2.97, p > 0.05. Follow-up contrasts for the effect of drug on each of the individual test scores showed a significant improvement from oxytocin versus placebo on both the Hinting Task F (1, 19) = 5.38, p = 0.03, and the non faux pas condition of the Faux Pas Recognition Task F(1,19) = 6.37, p = 0.02 (see Table 1 ).

3.1.3. General neurocognition

We then examined results for the overall RBANS score and its subscales of neurocognition. All results were non-significant (Total score F (1, 19) = 2.13, p = 1.16).

3.2. Side effects and treatment guess

Under the oxytocin, 47.6% of participants correctly guessed that they were administered oxytocin. Under placebo, 42.9% of participants incorrectly guessed that they were administered oxytocin (p > 0.05). In 48% of sessions, drug administration sessions resulted in no side effects being reported. Side effects included tiredness and relaxation (19% of sessions), followed by increased alertness 7%, and non-specific awareness of something being different (4.7%). Reports did not differ between drug groups (p > 0.05).

4. Discussion

The results of this study showed that when conducting overall analysis, a single dose of oxytocin nasal spray improves performance overall on higher order social cognition. This effect was significant on two individual higher order social cognition tests, the hinting task and the non-faux condition of the Faux Pas Recognition Task. In contrast, we found improvement on only one lower order social cognition test, accuracy for detecting vocal intonations of affect, and no effect on general neurocognition. There was no effect on general neurocognition. Oxytocin was well tolerated and patients seemed unable to detect the active dose in this cross-over design.

Our finding that oxytocin improves higher order social cognition is consistent with previous research that suggests oxytocin effects may be particularly powerful for these higher order processes in schizophrenia that require more complex social cognitive processing. (Davis et al, 2013, Horta de Macedo et al, 2014, and Woolley et al, 2014). It is of note that the individual tasks that showed most benefit of oxytocin, the Faux Pas Recognition Task and the Hinting Task, involve appreciation of the social nuances in communicative exchanges. Further research is now needed to link changes in brain function during higher order social cognition tasks of this type to further understand the neurobiological basis of the impact of oxytocin on social cognition in schizophrenia. This research also suggests that oxytocin may have particular potential to provide adjunctive therapeutic benefit for patients when combined specifically with higher-order social cognition training treatment approaches.

In support of other studies that have evaluated lower and higher order social cognition (Davis et al, 2013 and Woolley et al, 2014), we only found significant improvement on one lower order test, the DANVA paralinguistic scale and a trend on the Reading the Mind in the Eyes Test. There was no improvement for our overall analysis of lower-order social cognition tests, and certainly no evidence of improvement on tests that assess simple face recognition (FEEST; DANVA Faces). The DANVA Paralinguistic scale involves the assessment of processing nonverbal information of affect conveyed in vocal intonations. It has not been specifically examined in previous investigations, although improvement in recognition of emotion in vocalizations following oxytocin administration has been reported for patients with autism spectrum disorder ( Hollander et al., 2007 ). Further, children seem to respond favorably to the sound of their own mothers comforting voice under stress to cause higher levels of oxytocin being released and less distress ( Seltzer et al., 2010 ). Thus, across a number of studies, oxytocin administration may improve recognition of emotions from vocalizations. We did not show significant effects of oxytocin on the recognition of basic facial emotional expressions, particularly given the direction on both tests of basic emotion recognition was opposite to the predicted direction of change. This would suggest that even with a larger sample, benefits would not be found. We did not, however, use a speeded emotion recognition task and further studies are required to determine whether oxytocin enhances the speeded detection of emotion in faces at very early stages of processing in Schizophrenia. Given the number of studies that have now failed to show significant benefit of oxytocin on facial emotion recognition in schizophrenia (Davis et al, 2013, Horta de Macedo et al, 2014, and Woolley et al, 2014), we conclude that the consistent benefits of oxytocin identified in healthy control populations on basic facial emotion recognition performance ( Shahrestani et al., 2013 ) do not appear to generalize to schizophrenia populations. Perhaps, more fundamental neurobiological and/or visual processing deficits underlie impaired lower order social cognition performance in schizophrenia, resulting in a failure to respond to oxytocin treatment.

As information about symptomatology was only assessed at the initial assessment, in accord with common practice using the SAPS and SANS to assess symptom severity over a month, we were unable to assess whether oxytocin had any significant impact on symptoms at the time of drug administration. Although oxytocin has been shown to exhibit therapeutic effects on positive and negative symptoms, this was observed after a two-week treatment with oxytocin ( Pedersen et al., 2011 ), and psychotic symptoms are unlikely to shift with a single dose. We have also previously reported on the current limitations of oxytocin nasal spray administration ( Guastella et al., 2013 ) in single dose and longitudinal studies. Future research should endeavor to improve current delivery methods of oxytocin to central and peripheral sites of action ( Quintana et al., 2015 ). We did not assess a range of individual difference factors that have been proposed to moderate response to oxytocin ( Bartz et al., 2011 ). These include polydipsia in schizophrenia ( Goldman et al., 2011 ). We also acknowledge that our findings can only be generalized to a male schizophrenia population, and that the effects of oxytocin on other social cognitive abilities (e.g. social perception, attributional style etc.) have yet to be explored. Finally, we note the small sample size and the appearance of trends on other measures of social cognition could suggest that with more power oxytocin may influence other measures of social cognition (e.g., Reading the Mind in the Eyes Test).

In conclusion, the overall results of this study confirm the use of oxytocin nasal spray to enhance higher order social cognition performance in schizophrenia. Future studies are now needed to link these performance changes to neurobiological mechanisms (e.g., imaging, Aoki et al., 2015 ; physiological, Quintana et al., 2013 ) markers, and to link these changes to more functional measures of social behavior. Results of this study would also support further evaluation of the impact of combining oxytocin with social cognition training procedures (e.g., Cacciotti-Saija et al., 2015) but with a greater focus on learning programs that might enhance specifically higher-order social cognitive processes.

Role of funding source

This research was partly funded by a NHMRC project grant (#632624) and ARC Linkage Project (#LP110100513). This funding source had no role in the design of the study, the analysis or interpretation of the data or submission of this manuscript.


Author Guastella, Langdon, Ward, Redoblado-Hodge and Hickie designed the study and wrote the protocol. Authors Guastella, Ward, Hickie, Scott, and Langdon assisted with data collection. Authors Sharhestani, Guastella, and Langdon undertook the statistical analysis, and author Guastella, Sharhestani, and Langdon wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

Authors Guastella, Langdon, Ward, Redoblado-Hodge, Sharhestani and Scott do not report conflicts of interest. Dr Hickie is a Senior Principal Research Fellow of the Australian National Health & Medical Research Council (ID 1046899). He is the executive director of the Brain and Mind Research Institute (BMRI), at the University of Sydney, which operates two early-intervention youth services under contract to headspace. He is a commissioner of the Australian National Mental Health Commission and was previously the CEO of beyondblue: the national depression initiative and a director of headspace: the national youth mental health foundation until January 2012. Previously, he has led a range of community-based and pharmaceutical industry-supported depression awareness and education and training programs. He has led depression and other mental health research service evaluation or investigator-initiated research projects that have been supported by a variety of pharmaceutical partners. Current investigator-initiated studies are supported by Servier (manufacturers of agomelatine) and Pfizer. He has received honoraria for his contributions to professional educational seminars related to depression, youth mental health and circadian-rhythms research. He has received travel support from Servier to attend scientific meetings related specifically to circadian-rhythm disorders.


We would like to thank the participants of this study, as well as the research assistants who worked on this project including Bianca Lee, Lorraine Chan, Loretta Moore, Gail Alvares, Emily Connaughton and Nigel Chen.


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a Brain and Mind Research Institute, Central Clinical School, University of Sydney, Sydney, Australia

b ARC Centre of Excellence in Cognition and its Disorders (CCD) and Department of Cognitive Science, Macquarie University, Sydney, Australia

c School of Psychiatry, University of New South Wales, Sydney, Australia

d Schizophrenia Research Unit, Ingham Institute for Applied Medical Research, South Western Sydney Local Health District, Australia

e Child Development Unit, The Children's Hospital at Westmead, Sydney, Australia

Corresponding author at: Brain & Mind Research Institute, The University of Sydney, 100 Mallett St, Camperdown NSW 2050, Australia. Tel.: + 61 2 9351 0539; fax: + 61 2 9351 0855.