Effects of oxytocin on empathy, introspective accuracy, and social symptoms in schizophrenia: A 12-week twice-daily randomized controlled trial

doi:10.1016/j.schres.2018.09.013

Schizophrenia Research

Volume 204, February 2019, Pages 178-182

https://doi.org/10.1016/j.schres.2018.09.013 Get rights and content

Abstract

The effects of intranasal oxytocin, a neuropeptide involved in prosocial behavior and modulation of neural networks underlying social cognition and emotion regulation, have been studied in schizophrenia. We tested the hypothesis that twice-daily intranasal oxytocin administered for 12-weeks would improve tertiary and exploratory outcomes of self-reported social symptoms, empathy and introspective accuracy from the Jarskog et al. (2017) randomized controlled trial. Sixty-eight stable outpatients with schizophrenia or schizoaffective disorder were randomized to receive oxytocin (24 IU twice daily) or placebo. Introspective accuracy was assessed with the Specific Level of Functioning Scale and the Interpersonal Perception Task. Empathy was assessed with the Interpersonal Reactivity Index (IRI), and social symptoms were assessed with the Liebowitz Social Anxiety Scale and the Green et al. Paranoid Thoughts Scales. Outcomes were assessed at baseline, six, and twelve weeks. Results demonstrated limited effect of oxytocin with some improvement on the IRI Perspective-Taking Subscale. No additional between-group differences emerged on self-reported symptoms, empathy, or introspective accuracy.

Introduction

A promising psychopharmacological intervention for schizophrenia is the neuropeptide oxytocin (Rosenfeld et al., 2011). Oxytocin modulates networks involved in social cognition and emotion regulation and is shown to play a key role in social behaviors (Lee et al., 2009; Meyer-Lindenberg et al., 2011; Rosenfeld et al., 2011). Several studies have investigated the effects of adjunctive intranasal oxytocin in schizophrenia with mixed findings (Bradley and Woolley, 2017; Burkner et al., 2017; Cacciotti-Saija et al., 2015; Feifel et al., 2016; Mercedes Perez-Rodriguez et al., 2015; Oya et al., 2016).

To address heterogeneity in findings and the file drawer effect (Rosenthal, 1979), especially as documented in oxytocin treatment research (Lane et al., 2016), the present study presents tertiary (i.e., self-report measures) and exploratory outcomes (i.e., introspective accuracy or IA) from Jarskog et al. (2017). Previously, Jarskog et al. (2017) found limited effects of oxytocin on the secondary outcomes of social functioning (i.e., improvements in social skills) and negative symptoms but not on the primary outcomes of social cognition (i.e., emotion perception, theory of mind, attributional style). Given mixed findings and no previous research of oxytocin effects on IA, investigation of self-report and IA outcomes in the present study are exploratory.

Section snippets

Study design, participants, and randomization

Individuals with a diagnosis of schizophrenia or schizoaffective disorder participated in a double blind, randomized treatment study between June 2011 and September 2014. Participants completed screening, baseline, and assessment visits at six and 12 weeks. Participants were randomized to twice-daily intranasal oxytocin or placebo stratified by sex and total PANSS score. The Institutional Review Board at the University of North Carolina at Chapel Hill approved all procedures. Participants were

Baseline characteristics, randomization, and treatment adherence

Fig. 1 provides a CONSORT flowchart of study screening and inclusion. Thirty individuals in the placebo group and 32 in the oxytocin group were included in the study.

Baseline demographic and clinical information are presented in Table 1. The placebo group had significantly higher levels of paranoia indicated by PANSS items assessing social functioning (i.e., suspiciousness/persecution, hostility, passive/apathetic social withdrawal, uncooperativeness, and active social avoidance) compared with

Discussion

Twice-daily administration of intranasal oxytocin showed limited evidence for improving self-reported symptoms, empathy, and IA in patients with schizophrenia. Individuals in the oxytocin group showed improvement on the Perspective Taking subscale of the IRI only but not on other self-reported outcomes and IA. Improvements in empathy in the oxytocin group extend findings from an oxytocin treatment study of a shorter duration (i.e., 6 weeks) where improvements on empathic perspective taking as

Conflict of interest

The authors report no conflicts of interest.

Role of funding source

This work was supported by a grant from NIMH (grant number R01MH093529 – PIs CAP, DLP).

Acknowledgements

Odum Institute (University of North Carolina at Chapel Hill).

Contributors

CAP, DLP and LFJ designed the study and wrote the protocol. TFH wrote the first draft of the manuscript. TFH performed statistical analyses with support from the Odum Institute and certifies the accuracy of the results. All authors contributed to the data interpretation, meaningful manuscript revision, and all authors have approved the final manuscript.

References (27)

D. Feifel et al.
A review of oxytocin's effects on the positive, negative, and cognitive domains of schizophrenia
Biol. Psychiatry
(2016)
C.M. Gibson et al.
A pilot six-week randomized controlled trial of oxytocin on social cognition and social skills in schizophrenia
Schizophr. Res.
(2014)
A.J. Guastella et al.
Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research
Psychoneuroendocrinology
(2013)
M. Heinrichs et al.
Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress
Biol. Psychiatry
(2003)
H.J. Lee et al.
Oxytocin: the great facilitator of life
Prog. Neurobiol.
(2009)
M. Mercedes Perez-Rodriguez et al.
Oxytocin and social cognition in affective and psychotic disorders
Eur. Neuropsychopharmacol.
(2015)
C.A. Pedersen et al.
Intranasal oxytocin reduces psychotic symptoms and improves Theory of Mind and social perception in schizophrenia
Schizophr. Res.
(2011)
R. Rosenthal
The file drawer problem and tolerance for null results
Psychol. Bull.
(1979)
E.R. Bradley et al.
Oxytocin effects in schizophrenia: reconciling mixed findings and moving forward
Neurosci. Biobehav. Rev.
(2017)
P.C. Burkner et al.
Intranasal oxytocin may improve high-level social cognition in schizophrenia, but not social cognition or neurocognition in general: a multilevel bayesian meta-analysis
Schizophr. Bull.
(2017)

C. Cacciotti-Saija et al.

A double-blind randomized controlled trial of oxytocin nasal spray and social cognition training for young people with early psychosis

Schizophr. Bull.

(2015)

M. Costanzo et al.

Interpreting the expressive behavior of others - the interpersonal perception task

J. Nonverbal Behav.

(1989)

A. Dane et al.

The Interpersonal Perception Task (IPT-15)

(1993)

Cited by (25)

Introspective accuracy for substance use across a year of treatment for first episode psychosis
2021, Schizophrenia Research: Cognition
Citation Excerpt :
Better IA for substance use was associated with greater symptoms, consistent with the insight paradox that past research showed in this population (Davis et al., 2020; Lysaker et al., 2018, 2007; Vohs et al., 2016). While this study addressed IA in a treatment context, the only specific treatment for IA tested in recent literature had a null finding and was pharmacological (Halverson et al., 2019), so psychosocial treatments targeting IA should be tested. In clinical practice in this population, feedback on IA could offer an inroad for clinicians to talk more openly with their clients about substance use during treatment.
Substance use exacerbates psychosis, mania, depression, and poor functioning in people with first episodes of psychosis (FEP) and is associated with poor treatment outcomes, even when it does not reach the level of a formal disorder. Impaired insight and substance use are common issues that may interfere with treatment outcomes among people experiencing FEP, yet both are treatable. Improvements in these domains are associated with better outcomes. Low insight could increase risk for substance use by impairing the ability to self-appraise and assess consequences. Introspective accuracy (IA) is understudied in this area and is one way of considering self-appraisal. This study is an archival review using data collected from NAVIGATE, a coordinated specialty care program treating people with FEP. IA was operationalized as the difference between clinician and client ratings of substance use. We tested whether IA changed over one year of treatment and whether those changes occurred alongside changes in symptoms and illness self-management. No changes in IA were detected in relation to illness self-management. Changes in IA for substance use occurred midway through treatment—individuals with greater symptom remission had more overconfident IA. Prior research on insight has shown a paradox where greater insight accompanies more symptoms. However, past research has also shown a relationship between IA and functional outcomes, like illness self-management, and that overconfidence in one domain can positively bias clinician ratings in another. Our findings suggest either a positive bias for ratings associated with overconfident IA or an insight paradox type effect.
Associations between oxytocin and empathy in humans: A systematic literature review
2021, Psychoneuroendocrinology
Citation Excerpt :
Two studies involved samples of healthy subjects and used a single dose of OXT 24 IU (Bartz et al., 2010; Theodoridou et al., 2013). The remaining two studies enrolled schizophrenia patients and used a single dose of OXT 40 IU following social skills practice (Davis et al., 2014) or a continuous treatment (48 IU for 10 weeks) (Halverson et al. 2019; please see Table 4 for details). In respect to the affective component of empathy, 6 of the 11 studies that analyzed the construct reported improvements in empathy indicators following the administration of OXT, although with specificities.
This is a systematic review about the association between empathic behavior and oxytocin (OXT). Searches were conducted in the electronic databases PubMed, Web of Science, PsycINFO, SciELO, and LILACS using the search terms “oxytocin”, “empathy”, and “empathic”. Forty-four studies were reviewed. Scarce findings point to a lack of association between baseline endogenous OXT levels and empathy traits, and for a trend towards a direct relationship between oxytocinergic reactivity and empathic functioning. The results showed that variations in empathy were related to polymorphisms in the OXT receptor gene, especially in rs53576, and that this relationship seems to mediated by individual, ethnic, and cultural characteristics. Most studies on the exogenous administration of OXT tested a single dose (24 IU) with positive effects mainly on the affective domain of empathy. At the neural level, findings were inconsistent. Taken together, the results of the studies reviewed support the existence of a relationship between OXT and empathy that is complex and multifaceted. Robust evidence is still needed to elucidate existing links. Future investigations could benefit from methodological improvements aimed at increasing the reproducibility and applicability of findings, as well as the systematic assessment of the effects of exogenous OXT considering dose and frequency of administration, genotyping, and hormonal availability at the peripheral and central levels. This should lead to significant progress in the understanding of the therapeutic possibilities of OXT in the domain of empathic behavior.
Exogenous effects of oxytocin in five psychiatric disorders: a systematic review, meta-analyses and a personalized approach through the lens of the social salience hypothesis
2020, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Moreover, the effects of OT can change across the different conditions of a task. For example, OT was found to affect kinship, but not intimacy recognition of social scenes (Fischer-Shofty et al., 2013b), and to elevate cognitive but not emotional empathy levels (Halverson et al., 2019). Moreover, the level of control over the task can modulate the effect of OT in patients with more control, leading to greater improvement in performance on social cognition measures (Woolley et al., 2014).
Oxytocin (OT) has been implicated in various aspects of social behaviors. During the past decades there has been a surge of interest in the therapeutic potential of OT in psychiatric disorders, especially those characterized by social deficits, which the available therapeutic agents, cannot fully target. This systematic review and meta-analysis examines available evidence for the therapeutic role of OT in five psychiatric disorders characterized with difficulties in social abilities: autism spectrum disorder, schizophrenia, post-traumatic stress disorder, mood disorders and borderline personality disorder. For each disorder, we review the sample size, gender distribution and single versus long-term effects of OT. Moreover, we examine effects of OT through the lens of the social salience hypothesis, in order to identify individual characteristics and contexts that may affect the response to OT, across the disorders. We show that OT has diverse effects depending on symptoms and context. The meta-analyses revealed a small effect size of OT efficacy in schizophrenia and repetitive behaviors in ASD. Finally, we discuss shortcomings and provide recommendations for future research.
Social dysfunction in the neurodevelopmental model of schizophrenia in male and female rats: Behavioural and biochemical studies
2020, Neuropharmacology
Citation Excerpt :
Genetic studies suggest linkages between OXT/VP gene polymorphisms, schizophrenia symptom severity and treatment response in patients (Aydin et al., 2018; Heinrichs and Domes, 2008; Keri et al., 2009; Souza et al., 2010; Levin et al., 2009). In addition, administration of exogenous OXT and VP synthetic analogues have demonstrated efficacy in the treatment of schizophrenia symptoms (Bakharev et al., 1986; Bujanow, 1972; Born et al., 1998; Feifel et al., 2016; Brambilla et al., 1986; Halverson et al., 2019; Jarskog et al., 2017; Levin et al., 2009; Meyer-Lindenberg et al., 2011; Pedersen et al., 2011; Gibson et al., 2014). Thus, alterations in the function of the OXT and VP systems are likely to be involved in the pathophysiology of schizophrenia.
Social dysfunction is among the core symptoms of schizophrenia. The neuropeptides oxytocin (OXT) and vasopressin (VP) are involved in the regulation of social behaviour and social cognition. There are indications that both of these neurotransmitter systems are altered in schizophrenia. Prenatal (embryonic day 17) exposure to the neurotoxin methylazoxymethanol acetate (MAM; 22 mg/kg) leads to a schizophrenia-like phenotype in rats and has been used as a model of schizophrenia symptoms. Here, we examined the social phenotype of MAM-exposed female and male rats and measured concentrations of OXT, VP and their specific receptors in various brain areas involved in the control of social behaviour.
We report decreases in social behaviour and ultrasonic vocalisations (USVs) in the MAM rats during social encounters. Specifically, the duration of social interactions and number of corresponding USVs were reduced in this group. In the MAM rats, “positive” 50-kHz USVs were flatter, i.e., displayed lower bandwidth, a greater percentage of “short” calls and lower percentage of frequency-modulated calls. The MAM animals exhibited diminished interest towards social stimuli in olfactory preference tests. In the resident-intruder test, MAM exposure reduced dominance behaviour only in the males. We also report cognitive impairments, including reduced novel object recognition and cognitive inflexibility in the attentional set shifting test, and decreased OXT and OXT receptor concentrations in the prefrontal cortex and hypothalamus and VP and VP receptors in the hypothalamus in the MAM rats.
Deficits in central OXT and VP systems may underlie abnormalities present in the MAM model of schizophrenia.
Experimental empathy induction promotes oxytocin increases and testosterone decreases
2020, Hormones and Behavior
Citation Excerpt :
Indeed, the only moderately strong association of hormonal change with psychological traits was the positive correlation of IRI Perspective-Taking with oxytocin increase (found in both the bivariate and best subsets regression analyses). This finding is consistent with selective increases in the IRI-Perspective Taking subscale after oxytocin administration to patients with schizophrenia reported in two previous studies (Gibson et al., 2014; Halverson et al., 2019), and with the effects of this hormone in facilitating externally directed social attention (Yao et al., 2018), it but provides little explanatory power or insight. In addition, the Distress Response to the video was negatively correlated with testosterone change in our study, meaning that individuals who rated the video as more distressing showed greater decreases in testosterone.
Oxytocin and testosterone coordinate adaptive social behaviors with stimuli in the environment. Administration of oxytocin and testosterone is associated with increased and reduced indicators of empathy, respectively, but how levels of these hormones are jointly affected by naturalistic empathy-inducing stimuli remains unclear. In this study, salivary oxytocin and testosterone levels were measured in 173 healthy adults before and after watching a video involving a gravely ill child. Participants also completed questionnaires to assess psychological variables predicted to affect oxytocin reactivity (Autism-Spectrum Quotient, Interpersonal Reactivity Index, Empathy and Systemizing Quotients). On average, there was a 14% increase in oxytocin (p = 0.003) and 4% decrease in testosterone (p = 0.001) pre- to post-video. Opposite directional changes in hormone levels occurred together, as supported by a chi-square test (p < 0.001) and a circular statistics test (p < 0.05). Considered separately, psychological traits did not predict hormone levels or changes to any appreciable degree. However, oxytocin and testosterone changes were linked with empathy relative to systemizing such that: (1) ‘Empathy Bias’ was associated with a large oxytocin increase but little change in testosterone, while (2) ‘Systemizing Bias’ and ‘Balance’ between empathy and systemizing were associated with a decrease in testosterone but little change in oxytocin. These findings suggest that participants were divisible into ‘high oxytocin responders’ (relatively empathetic) and ‘high testosterone responders’ (balanced or systemizing-biased). These findings support a model of joint, opposite changes in oxytocin and testosterone under experimental empathy induction, with high, somewhat predictable, diversity in individual responses.
Social cognition across the schizophrenia–bipolar disorder spectrum
2024, Nature Reviews Psychology

View all citing articles on Scopus

View full text

Effects of oxytocin on empathy, introspective accuracy, and social symptoms in schizophrenia: A 12-week twice-daily randomized controlled trial

Abstract

Introduction

Section snippets

Study design, participants, and randomization

Baseline characteristics, randomization, and treatment adherence

Discussion

Conflict of interest

Role of funding source

Acknowledgements

Contributors

Biol. Psychiatry

Schizophr. Res.

Psychoneuroendocrinology

Biol. Psychiatry

Prog. Neurobiol.

Eur. Neuropsychopharmacol.

Schizophr. Res.

Psychol. Bull.

Oxytocin effects in schizophrenia: reconciling mixed findings and moving forward

Neurosci. Biobehav. Rev.

Intranasal oxytocin may improve high-level social cognition in schizophrenia, but not social cognition or neurocognition in general: a multilevel bayesian meta-analysis

Schizophr. Bull.

A double-blind randomized controlled trial of oxytocin nasal spray and social cognition training for young people with early psychosis

Schizophr. Bull.

Interpreting the expressive behavior of others - the interpersonal perception task

J. Nonverbal Behav.

The Interpersonal Perception Task (IPT-15)