Oxytocin and social cognition in affective and psychotic disorders

European Neuropsychopharmacology (]]]]) ], ]]]–]]]

http://dx.doi.org/10924-977X/& 2014 E

☆This work was peSchool of MedicineVAMC, NY.

nCorresponding auof Medicine at MounLevy Place, New Yorfax: +1 212 659 8710

E-mail address:mercedes.perez@ms

Please cite this arEuropean Neuropsy

www.elsevier.com/locate/euroneuro

Oxytocin and social cognition in affectiveand psychotic disorders$

M. Mercedes Perez-Rodrigueza,b,c,n, Katie Mahona,Manuela Russoa, Allison K. Ungara, Katherine E. Burdicka

aDepartment of Psychiatry, Icahn School of Medicine at Mount Sinai, Psychiatry Box # 1230 One Gustave L.Levy Place, New York, NY 10029, USAbThe Mental Health Patient Care Center and the Mental Illness Research Education and Clinical Center,James J. Peters Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USAcCIBERSAM, Autonoma University of Madrid, Fundacion Jimenez Diaz Hospital, Spain

Received 18 April 2014; received in revised form 10 July 2014; accepted 19 July 2014

KEYWORDSOxytocin;Schizophrenia;Major depressive dis-order;Bipolar disorder;Social cognition

0.1016/j.euroneurlsevier B.V. and E

rformed at the Deat Mount Sinai, an

thor at: Departmet Sinai, Psychiatryk, NY 10029. Tel.:.

sm.edu (M. Merce

ticle as: Mercedechopharmacology

AbstractImpairments in social cognition are now recognized as core illness features in psychotic andaffective disorders. Despite the significant disability caused by social cognitive abnormalities,treatments for this symptom dimension are lacking. Here, we describe the evidencedemonstrating abnormalities in social cognition in schizophrenia, major depressive disorder,and bipolar disorder, as well as the neurobiology of social cognition including the role ofoxytocin. We then review clinical trials of oxytocin administration in psychotic and affectivedisorders and the impact of this agent on social cognition. To date, several studies havedemonstrated that oxytocin may improve social cognition in schizophrenia; too few studieshave been conducted in affective disorders to determine the effect of oxytocin on socialcognition in these disorders. Future work is needed to clarify which aspects of social cognitionmay be improved with oxytocin treatment in psychotic and affective disorders.& 2014 Elsevier B.V. and ECNP. All rights reserved.

o.2014.07.012CNP. All rights reserved.

partment of Psychiatry, Icahnd MIRECC at James J Peters

nt of Psychiatry, Icahn SchoolBox # 1230, One Gustave L.+1 212 659 8734;

des Perez-Rodriguez).

s Perez-Rodriguez, M., et al., Ox(2014), http://dx.doi.org/10.101

1. Introduction

Social cognitive abnormalities have recently been recog-nized as a core feature of mood and psychotic disorders(Billeke and Aboitiz, 2013; Cusi et al., 2013; Millan andBales, 2013; Wolkenstein et al., 2011). Indeed, they are acritical obstacle to recovery and function (Brune et al.,2007) (Couture et al., 2006; Harvey and Bowie, 2012;Roncone et al., 2002), may cause more disability than

ytocin and social cognition in affective and psychotic disorders.6/j.euroneuro.2014.07.012

www.elsevier.com/locate/euroneuro

dx.doi.org/10.1016/j.euroneuro.2014.07.012




mailto:[email protected]





M. Mercedes Perez-Rodriguez et al.2

psychosis (Doop and Park, 2009; Hooker and Park, 2002;Malaspina and Coleman, 2003; Perlick et al., 1992), and areonly modestly improved by currently available medications(Goldberg et al., 2007; Green, 2006; Harvey and Bowie,2012; Maat et al., 2014; Millan et al., 2014). Moreover,social cognitive impairments persist during remission (Inoueet al., 2004; Montag et al., 2010) and are present in thosewith subclinical symptoms (Cusi et al., 2013) as well as indrug-naïve patients (Wang et al., 2008). Evidence suggeststhat abnormalities in social cognition may be distinct frombroader cognitive and perceptual deficits known to exist inaffective and psychotic disorders (Billeke and Aboitiz, 2013;Harvey and Bowie, 2012; Lee et al., 2005; Montag et al.,2010).

Intact social cognition is critical for social functioning andinterpersonal relationships (Tomasello et al., 2005). Inaddition, social cognitive abilities are important for suc-cessful engagement in many psychological interventions(Inoue et al., 2004). Although social cognitive impairmenthas been found to persist during periods of remission, thereis also evidence to suggest that this impairment maybecome worse as the illness progresses. For example, socialcognition impairment correlates with illness load (i.e.,illness duration and symptom severity) (McKinnon et al.,2010), supporting the need for early intervention. It is alsoassociated with lower social functioning (Couture et al.,2006; Inoue et al., 2006), higher disability (Cusi et al.,2013), and poor prognosis. Specifically, alterations in socialcognition are associated with lower social adjustment(Couture et al., 2006) and global functioning, as well ashigher relapse rates (Inoue et al., 2006). As these deficitsare known to persist in the remitted state, patients may stillhave poor social adjustment due to impairments in socialcognition even during symptomatic remission from affectiveor psychotic episodes (Inoue et al., 2004).

Despite the clinical significance of social cognitive impair-ment, pharmacological treatment for this core illnessfeature is not currently available. Several lines of evidencesuggest that the neuropeptide oxytocin may be a potentialtreatment for social cognitive deficits across diagnoses(Bakermans-Kranenburg and van, 2013; Gumley et al.,2014). Here, we review the evidence for social cognitiveabnormalities in mood and psychotic disorders as well as theclinical trials of intranasal oxytocin administration acrossdiagnoses and evaluate the evidence for improvement ofsocial cognition across disorders.

1.1. Definitions and components of socialcognition

Social cognition may be defined as the “psychologicalprocesses that enable individuals to take advantage of beingpart of a social group” (Frith, 2008), and it is crucial formaintaining social relationships (Eisenberg and Miller,1987). Therefore, it is not surprising that social cognitiveabnormalities are associated with impaired social function-ing, and, more broadly, decreased global functioning anddisability. Social cognition can be conceptualized as amultidimensional construct encompassing different subcom-ponents which can be broadly summarized into five areas:theory of mind (ToM), social perception, social knowledge,

Please cite this article as: Mercedes Perez-Rodriguez, M., et al., OxEuropean Neuropsychopharmacology (2014), http://dx.doi.org/10.101

emotion recognition and causal attribution style (Green andLeitman, 2008; van Hooren et al., 2008; Ochsner, 2008,Mancuso et al., 2011).

Theory of mind (ToM), also called mentalization ormentalizing, refers to the ability to represent others’mental states and to make inferences about others’intentions. It is a broad ability which involves the capacityto understand feelings, intentions, beliefs and metaphors(Brüne, 2005), and is closely related to the ResearchDomain Criteria (RDoC) (Insel et al., 2010) subconstruct“Understanding Mental States” within the Perception andUnderstanding of Others Construct in the Social ProcessesDomain.

Social perception refers to the ability to infer social rolesas well as rules in complex and/or ambiguous situationsfrom nonverbal and paraverbal social cues (Penn et al.,2002; Toomey et al., 2002). It also includes the capacity todetermine the nature of the relationship between peoplesuch as professional, friendly, or romantic.

Partially overlapping with social perception, social knowl-edge refers to the awareness of rules and behaviors that areexpected in social situations and/or interactions. Socialperception and social knowledge are closely linked as acorrect perception of social rules is necessary in orderto determine what rules to adhere to in different socialcontexts (Green and Leitman, 2008).

Emotion recognition indicates the ability to perceive andidentify emotion by facial expression and/or vocal prosody(Edwards et al., 2001). Emotion recognition closely overlapswith the RDoC (Insel et al., 2010) subconstruct“Reception of Facial Communication,” within the SocialCommunication Construct in the Social Processes Domain.

Attributional style refers to the tendency of an individualto assign causality to events in his or her life, includingwhether this causality is internal or external. Healthypeople usually have a self-serving bias in which they tendto attribute positive events to personal, internal factors andnegative events to external causes (Miller and Ross, 1975).

Although these domains are generally accepted as repre-senting the construct of social cognition, their boundariescannot be considered absolute and considerable overlapexists between them (Green and Leitman, 2008). Forexample, the concept of empathy, which is considered tobe a component of social cognition, is a complex multi-dimensional process that involves both cognitive and affec-tive mechanisms (Achim et al., 2011) and taps into severalof the above mentioned social cognitive domains.

Overlapping neural structures and systems subserve socialcognitive processes. Primary sensory areas and more spe-cialized structures (e.g. the fusiform face area) are involvedin social perceptual processes (e.g. Sabatinelli et al., 2011).Emotion processing is regulated in part by the amygdalawhich, in turn, interacts with the insula and withthe anterior cingulate cortex and the orbitofrontal cortex(e.g. Meyer-Lindenberg and Tost, 2012). Social attributionprocesses are partly mediated by the ventral premotorcortex, the superior temporal sulcus, the amygdala andthe insula, whereas ToM abilities are subserved by theanterior medial prefrontal cortex and the temporoparietaljunction (Meyer-Linderberg and Tost 2012). In addition tothese somewhat distinct features, there are many morecommon structures and circuits that are involved in each





3Oxytocin and social cognition in affective and psychotic disorders

domain of social cognition, and the ways in which thesecircuits interact are a focus of much current research.

2. Social cognition abnormalities acrossdiagnoses

2.1. Social cognition abnormalities inschizophrenia

Neurocognitive impairment characterizes individuals withschizophrenia (SZ) (Heinrichs and Zakzanis, 1998; Fioravantiet al., 2005; Elvevåg and Goldberg, 2000) and it has beenconsidered a core feature of the disorder since it was firstdescribed (Kraepelin, 1921). SZ patients are characterizedby a more prominent level of neurocognitive impairmentcompared to other affective psychoses; data showed thatdifferences in neurocognitive functioning between schizo-phrenia, schizoaffective and bipolar disorder are largelyquantitative with disorders presenting the same pattern ofdeficits across neurocognitive domains that vary only on aquantitative level (Martínez-Arán et al., 2002; Reichenberget al., 2009).

Social cognition has become an area of interest in SZresearch only over the last decade, with an increasingnumber of studies assessing social cognitive constructs inSZ (Penn et al., 1997; Green and Leitman, 2008). Meta-analytic studies have shown that social cognition is impairedin individuals with SZ (Brüne, 2005; Hoekert et al., 2007)and that there is a direct relationship between socialcognition and functional outcome (Couture et al., 2006;Brune et al., 2007; Fett et al., 2011).

The inclusion of a social cognitive domain as part of theneurocognitive battery developed for clinical trials in SZ,the Measurement and Treatment Research to ImproveCognition in Schizophrenia (MATRICS) (Nuechterlein et al.,2004), confirms the importance of social cognition as acrucial aspect to be considered in clinical and researchsettings. Moreover, the CNTRICS (Cognitive NeuroscienceTreatment Research to Improve Cognition in Schizophrenia)initiative has identified the development of social cognitionmeasurement paradigms that are translatable across ani-mals and humans as one of its top priorities (Millan andBales, 2013).

The majority of studies in SZ has been conducted on threeof the social cognition domains described above: theory ofmind (ToM), emotion perception/recognition and attribu-tional style (Penn et al., 2008).

2.1.1. Theory of mind (ToM)Meta-analytic studies have reported large effect sizes whencomparing the performance of SZ patients with healthycontrols (Sprong et al., 2007; Bora et al., 2009b). Specifi-cally, Bora et al. (2009b) reported large effect sizes (Cohen'sd=0.9–1.08). When the analysis was restricted to remittedpatients a moderate to large effect size (d=0.69–0.80)remained. Data on ToM in first episode SZ patients demon-strates that deficits exist and are comparable to thosepresent in chronic SZ samples (Bertrand et al., 2007;Kettle et al., 2008; Green et al., 2012; Koelkebeck et al.,2010). Green et al. (2012), in their cross-sectional studyexamining ToM across different phases of the illness


(prodromal, first episode and chronic), found that deficitswere present and comparable across all three phases andwith no evidence of either progression or improvement thatwas dependent upon illness phase.

Findings are still mixed regarding whether ToM deficitsare trait- or state-related. Although meta-analyses (Spronget al., 2007; Bora et al., 2009b) have shown that impair-ments are present during symptom remission, thus support-ing a state-independent hypothesis, some studies haveshown that performance is worse during acute phases ofthe illness (Drury et al., 1998; Corcoran and Frith, 2003) andparticularly in relation to specific illness features such asnegative symptoms (Corcoran et al., 1995; Mitchley et al.,1998) and disorganization (Sarfati et al., 1999; Mazza et al.,2001). A recent meta-analysis showed that both negativesymptoms and disorganization are moderately associatedwith social cognition (Pearson correlations ranged between�0.2 and �0.3 for disorganization and negative symptoms)(Ventura et al., 2013). Correlations between dimensionalpsychosis proneness/schizotypy and ToM impairments (Fyfeet al., 2008; Gooding and Pflum, 2011; Pflum et al., 2013),as well as the presence of social cognitive abnormalities inpatients with schizotypal personality disorder (Ripoll et al.,2013) (a non-psychotic disorder within the schizophreniaspectrum), also support the trait-like, clinical state-independent nature of social cognition deficits. Takentogether, it may be that baseline social cognitive deficitsare present during remission but that they worsen duringacute psychotic episodes.

2.1.2. Emotion recognitionIt has been shown that patients with SZ demonstrate strikingimpairments in emotion recognition compared to healthycontrols as well as to patients with other psychiatricdisorders (Gaebel, Wölwer, 1992; Addington and Addington,1998; Chan et al., 2010; Kohler et al., 2010). It has also beenreported that emotion recognition abnormalities are asso-ciated with both positive (Shea et al., 2007) and negativesymptoms (Chan et al., 2010). Results from a recent meta-analysis (Tseng et al., 2013) show that the associationbetween symptoms and the recognition of certain emotionsappears to be specific; in particular, these authors reportedan inverse correlation between the ability to recognize thevocal presentation of happiness and the severity of psychoticsymptoms. Evidence suggests that emotion recognition isnegatively associated with negative symptoms, particularlyamong negative emotions; ‘fear’ seems to be the mostdifficult to be identified (Edwards et al., 2001; Tseng et al.,2013). Abnormalities in emotional prosody recognition werefound to be associated with worse cognitive functioning(Bozikas et al., 2004) and with more severe positive symp-toms (i.e. auditory hallucinations) (Shea et al., 2007). Dataalso show that emotion recognition deficits are present insubjects at high-risk for SZ, as well as during the prodromalphase and early onset of the illness (Addington et al., 2012;Edwards et al., 2001; Pinkham et al., 2007; Amminger et al.,2012). Amminger et al. (2012) found that first episodepatients and subjects at high-risk for SZ demonstrateddeficits in emotion recognition. In particular, participants inboth groups had difficulty identifying negative emotions,such as fear and sadness, in faces and were impaired in






detecting anger in voices. Longitudinal studies show thatboth acute and remitted SZ patients demonstrate deficits infacial affect recognition (Wölwer et al., 1996; Addingtonet al., 2012). Finally, there is evidence that abnormal(restricted) visual scanpaths to faces and facial expressionscan be involved in deficits in emotional recognition; datasuggest that patients with SZ spend less time looking at theeyes and mouth, which are critical areas for inferringemotions (Streit et al., 1997; Loughland et al., 2002).

2.1.3. Attributional styleResearch on attributional style in SZ has mainly focused onparanoid SZ patients. The evidence suggests that, in gen-eral, SZ patients are characterized by an exaggerated self-serving bias (Kaney and Bentall, 1989; Garety and Freeman,1999) which may serve to preserve their self-esteem(Bentall et al., 2001; Penn et al., 2008). This exaggeratedthat bias may be state-related, as it has been most stronglydemonstrated in the context of paranoid delusions (Aakreet al., 2009; Lincoln et al., 2010) and it does not appear tobe evident in subjects at high-risk for psychosis (DeVylderet al., 2013). Nevertheless, this bias does appear to bepresent even in the first episode of psychosis, where it wasfound to be associated with more severe suspiciousness(Krstev et al., 1999).

2.2. Social cognition abnormalities in depression

Although less well studied than social cognition in schizo-phrenia, a wealth of evidence suggests that patientsexperiencing significant depressive symptoms also demon-strate impairments in social cognition (Ladegaard et al.,2013; Wolkenstein et al., 2011). The majority of theresearch in social cognition in unipolar depression con-ducted to date has focused on ToM deficits, with anemphasis on empathy, as well as facial emotion percep-tion/recognition and attributional style.

2.2.1. EmpathySeveral studies have used the Interpersonal Reactivity Index(Davis, 1983) to assess empathy in clinical and subclinicaldepression. This self-report measure quantifies the degreeto which one tends to feel empathically concerned (i.e., ageneral feeling of compassion for those who are helpless orless fortunate) and empathically distressed (i.e., feelingupset when specific negative events happen to others).A recent meta-analysis reported a significant effect size forempathic distress but not empathic concern in samplesexperiencing major depressive disorder (MDD) comparedto controls; that is, depression was associated with anincreased level of empathic distress but no differenceswere found in the level of empathic concern (Schreiteret al., 2013). However, an association between depressionand a decreased ability to tolerate negative events such asemergencies or tragedies, even if one is not directlyinvolved, may not reflect an alteration in social cognition,per se. The lack of a difference in empathic concern isperhaps more surprising and suggests that alterations insocial cognition in depression may be related to other facetsof this construct.


2.2.2. Emotion recognition/perceptionThe majority of studies that have assessed emotion recogni-tion in major depressive disorder have found that patientsare impaired relative to healthy samples (Kohler et al.,2011). For example, Leppänen et al. (2004) compareddepressed patients with matched controls and tested theirability to identify happy, sad, or neutral faces. Bothdepressed patients and healthy controls accurately identi-fied happy and sad faces, but the depressed participantswere less accurate and slower when presented with theneutral faces. Similar deficits have been reported in studiesof depressed samples performing emotion discriminationtasks (Bourke et al., 2010). Gollan et al. (2008) founddepressed patients rated neutral faces as sad and had alonger reaction time for sad faces when compared tohealthy controls. A recent meta-analysis of facial emotionperception in major depressive disorder and bipolar disorderreported a moderate effect size for impairment across thetwo disorders, with no statistically significant difference ineffect size between emotion identification or discriminationtasks and no difference between depression and bipolardisorder (Kohler et al., 2011).

2.2.3. Theory of mind (ToM)The Reading the Mind in the Eyes Test (RMET; Baron-Cohenet al., 2001) has frequently been used to assess ToM,although the distinction between ToM and emotion recogni-tion/perception when assessed using this measure isunclear. Results in depression using this task have beenmixed; several groups have reported impairments indepressed samples relative to controls (Lee et al., 2005;Wang et al., 2008), whereas others have not (Wolkensteinet al., 2011). Wang et al. (2008) compared performance onthe RMET in depressed patients with and without psychoticsymptoms and found that there were no differences inperformance between the groups, although both depressedgroups were impaired relative to controls. Kettle et al.(2008) reported that depressed patients were impaired onthe RMET compared to a sample of university students butthey showed no differences in performance when comparedwith demographically matched community controls, sug-gesting that deficits in ToM as assessed by this measure arelikely to be subtle in MDD.

2.2.4. Social perception and knowledgeSeveral other groups have examined so-called “higherorder” social cognitive functioning in depression; the focusof these studies has been on skills such as humor apprecia-tion, the ability to detect a social faux pas, and the capacityto understand implied and subtle social cues. The evidenceto date suggests that patients with current MDD tend todemonstrate impairments on such tasks (Ladegaard et al.,2013). Uekermann et al., 2008 reported that patients withMDD performed less well than controls on a task measuringhumor understanding and appreciation, and found thatdeficits on this humor task were significantly associatedwith deficits in executive functioning. A similar study foundthat patients with MDD were impaired on a test of faux pasdetection, and that depressed patients with psychoticfeatures performed worse than both controls and depressedpatients without psychotic features (Wang et al., 2008).






Two studies have tested patients with MDD using the Moviefor the Assessment of Social Cognition (MASC; Dziobeket al., 2006). This task measures mentalizing capacity andsocial perception and knowledge by requiring participantsto watch a short video featuring several actors in socialinteractions and then to answer questions based on whatthey have seen. Wilbertz et al. (2010) did not find anydifferences on MASC performance between 16 depressedpatients and 16 controls; a more recent study of acutelydepressed patients reported that they were impaired on thistask compared to controls (Wolkenstein et al., 2011),suggesting that current symptom severity may be relatedto social cognitive impairment. Most recently, Ladegaardet al. (2013) conducted a comprehensive study of higherorder social cognition in medication-naïve patients experi-encing their first major depressive episode. Results indi-cated that the depressed patients were significantlyimpaired across all tasks compared to controls; moreover,these performance differences remained after controllingfor non-social neurocognitive impairment.

2.2.5. Attributional styleDecades of research have generally supported the notionthat individuals with MDD are more likely to have anattributional style in which negative events are interpretedas due to internal, stable, and global factors (Alloy et al.,1992; Sweeney et al., 1986). Recent work suggests thatacutely depressed patients demonstrate the most severelydepressed attributional style, but that remitted patientstend to persist in attributing negative events to personalfactors more than participants who have never beendepressed (Ball et al., 2008). These data suggest that adepressive attributional style is both state- and trait-like,becoming less prominent in the remitted state and moresevere during acute mood episodes.

Although it is very likely that social cognitive impairmentsare implicated in decreased social functioning in affectivedisorders, the direct connection between social cognitionand psychosocial outcomes has rarely been tested (VanRheenen and Rossell, 2014). Nevertheless, it is clear thatsocial functioning is seriously impaired in patients with MDD(Hirschfeld et al., 2000) and bipolar disorder (Miklowitz,2011). By targeting social cognition deficits directly, it maybe possible to decrease affective symptoms as well asimprove psychosocial functioning.

2.3. Social cognition abnormalities in bipolardisorder

Unlike the majority of the studies assessing social cognitionin MDD, many social cognition studies in bipolar disorder(BD) have tested participants during euthymia. As such, it isdifficult to determine whether social cognition is differen-tially impaired between BD and MDD. The evidence to datesuggests that, even in the absence of frank mood symptoms,many patients with BD tend to demonstrate subtle yetpersistent deficits in social cognition (Samamé et al.,2012). As with the studies in depression, the focus of socialcognition investigations in BD has been on emotion recogni-tion/perception and ToM, with fewer studies examiningsocial knowledge and perception.


2.3.1. Emotion recognition/perceptionA recent meta-analysis of social cognition studies in euthy-mic BD reported a small but significant effect size (d=0.35)for impairments in facial emotion perception (Samaméet al., 2012); this is in line with a previous meta-analysisthat reported similar results (Kohler et al., 2011). Therewere no significant differences for the effect sizes betweenany of the six most commonly presented emotions in thesetasks (happiness, fear, disgust, anger, sadness, and surprise)(Samamé et al., 2012). The relatively small number ofstudies and the large degree of heterogeneity within andacross studies makes it difficult to draw firm conclusionsregarding this potential impairment. Moreover, very fewstudies controlled for more general, non-social neurocogni-tive impairment. In fact, one study reported that thedifferences in facial emotion recognition between patientsand controls were not statistically significant after generalneurocognitive impairments were controlled for (Martinoet al., 2011). Another study that reported differences infacial emotion perception reported that deficits in thepatient group were correlated with more broad neuropsy-chological deficits (Bora et al., 2005), again suggesting thatthis impairment may not be particularly social in nature butrather a more general cognitive impairment. In addition,mood state is likely to affect facial emotion perception; itappears that manic patients demonstrate deficits in thisarea relative to both controls and euthymic patients(Lembke and Ketter, 2002).

2.3.2. Theory of mind (ToM)As appears to be the case for MDD, it may be that the socialcognitive deficits in BD are related to higher order skillssuch as mentalizing. There is evidence that euthymic BDpatients demonstrate hypomentalization (Bora et al.,2009a), and that the degree of impairment may berelated to the number of previous (hypo)manic episodes(Montag et al., 2010). Little is known about the impact of ahistory of psychosis on social cognition in BD. One studyfound that although BD patients performed worse thancontrols on a naturalistic ToM task (Happé, 1994), therewere no differences between patients with and without ahistory of psychosis (Lahera et al., 2008). Mood state islikely to play a role in ToM functioning, although few studieshave assessed this. Wolf et al. (2010) reported no differ-ences between euthymic, manic, and depressed BD patientson a battery of neurocognitive and ToM tests, although thepatient group as a whole demonstrated deficits compared tocontrols. In contrast, symptomatic patients have been foundto perform worse than remitted patients and controls inseveral studies of ToM (Kerr et al., 2003; Bazin et al., 2009).

2.3.3. Attributional styleLess is known about attributional style in BD compared tounipolar depression, although there is evidence thatremitted patients with unipolar depression evidence a morevulnerable (i.e. internal, stable, and global) style fornegative events compared to both remitted patients withBD and controls (Tracy et al., 1992). Nevertheless, there issome evidence to suggest that extremely negative orpositive attributions, regardless of valence, are associatedwith affective episodes in BD (Stange et al., 2013). Recent






work has also demonstrated that depressed patients with BDare more likely to ascribe angry and intentional biasestoward neutral events; these attributional biases are asso-ciated with decreased social functioning (Lahera et al.,2008). Few studies of social cognition in BD have assessed orcontrolled for non-social cognitive impairment; of thosethat did, social cognitive deficits appeared to be onlypartially explained by general neurocognitive deficits, sug-gesting that social cognitive impairment is a distinct targetfor treatment (Lahera et al., 2008; Wolf et al., 2010).

3. Oxytocin and social cognition

Because of its anxiolytic, prosocial, and social cognitive-enhancing effects (Bakermans-Kranenburg and van, 2013;Bos et al., 2012; Gumley et al., 2014; Macdonald andMacdonald, 2010; Meyer-Lindenberg et al., 2011; Zink andMeyer-Lindenberg, 2012), oxytocin has been suggested as apromising novel treatment for patients with psychiatric anddevelopmental disorders associated with severe deficits insocial interactions and social information processing, suchas schizophrenia (Millan et al., 2014), borderline personalitydisorder and autism (Meyer-Lindenberg et al., 2011).

3.1. Biology and mechanism of intranasal oxytocin

Oxytocin is a neuropeptide hormone synthesized in magno-cellular and parvocellular neurons in the paraventricularand supraoptic nuclei of the hypothalamus. Oxytocin isstored in secretory vesicles in axonal terminals in theposterior lobe of the pituitary and is released into theperipheral circulation. There are also direct neuronalprojections of oxytocinergic neurons to other brain regionsincluding the amygdala, hippocampus, striatum, suprachias-matic nucleus, bed nucleus of stria terminalis andbrainstem, where it acts as a neuromodulator and neuro-transmitter. Finally, oxytocin exerts effects on both localand distant brain targets through dendritic release anddiffusion into the extracellular space (Meyer-Lindenberget al., 2011). Evidence suggests that a dynamic balancebetween activities of brain oxytocin and vasopressin plays akey role in regulating multiple aspects of social cognitionand behavior (Neumann and Landgraf, 2012). Humans havefour different receptors for oxytocin and vasopressin: theoxytocin receptor (OXTR), the vasopressin receptor 1A(AVPR1A), 1B (AVPR1B) and 2 (AVPR2). The distribution ofthese receptors in the human brain has not yet been fullycharacterized (Meyer-Lindenberg et al., 2011).

The oxytocin system modulates multiple social cognitivedomains, such as trust, attachment behavior, stress response,social memory, and the ability to recognize emotions andunderstand mental states in others (Bartz et al., 2011b; Boset al., 2012; Gumley et al., 2014; Meyer-Lindenberg et al.,2011). Exogenous oxytocin modulates social perception,decreases social fears and promotes social approach behaviorand trust in others (Meyer-Lindenberg et al., 2011; Zink andMeyer-Lindenberg, 2012).

Early experiments with intravenous oxytocin yielded dis-appointing results (Bakermans-Kranenburg and van, 2013),likely due to the blood–brain barrier (BBB). Intranasal admin-istration seems to circumvent the BBB given replicable


changes in brain function (Perry et al., 2010; Riem et al.,2011), perception and behavior (Bakermans-Kranenburg andvan, 2013). The nasal mucosa directly connects the centralnervous system (CNS) and the environment. Intranasal admin-istration causes systemic effects similar to those observedafter peripheral administration, and potentially higher deliv-ery to CNS targets (Zink and Meyer-Lindenberg, 2012). Nonhu-man research has shown behavioral effects after directinjection of oxytocin to specific brain targets (Bielsky andYoung, 2004) and increased brain (Neumann et al., 2013) andCSF (Meera and Young, personal communication) oxytocinafter intranasal administration, leading to assumptions thatadministration in humans also causes effects through directcentral action (Guastella et al., 2013), although research onbioavailability of intranasal oxytocin in humans is lacking(Guastella et al., 2013). However, animal studies are notalways predictive of data in humans, and further studies areneeded to elucidate target engagement and mechanisms ofaction of oxytocin in humans.

Taken together, the evidence suggests that intranasaloxytocin likely acts centrally, through modulation of anintegrated dopaminergic/oxytonergic social cognitive net-work (Love, 2014) centered on the amygdala (Li et al.,2010; Pinkham et al., 2011), which is strongly correlatedwith social functioning (Pinkham et al., 2008). Oxytocinmodulates frontolimbic networks involved in social cogni-tion and emotion regulation, including the amygdala,medial prefrontal cortex and anterior cingulate cortex(Meyer-Lindenberg et al., 2011). In healthy controls, oxyto-cin significantly increased connectivity between both amyg-dalae and rostral medial frontal cortex, regions critical tosocial cognition and emotion regulation (Sripada et al.,2013). In fact, amygdala–medial frontal cortex connectivity,which is believed to be abnormal in mood disorders, is aputative brain-based biomarker of social-affective function-ing (Sripada et al., 2013).

Oxytocin also modulates stress reactivity, has anxiolytic andantidepressant properties, and regulates stress-coping style(Neumann and Landgraf, 2012) through interactions withmonoaminergic, especially serotonergic, and corticotropin-releasing factor systems (Neumann and Landgraf, 2012).Indeed, data suggest that oxytocin reduces limbic (amygdala)and hypothalamic-pituitary-adrenal (HPA) axis reactivity tosocial stressors (Ditzen et al., 2009; Quirin et al., 2011; Zinkand Meyer-Lindenberg, 2012), and that it mediates theanxiolytic and stress-protective effects of positive socialinteraction (Meyer-Lindenberg et al., 2011).

Initial reports estimating the half-life of oxytocin atunder two hours raised questions about its clinical utility,since frequent administrations throughout the day would berequired for a sustained effect on social cognition. Morerecently, reports of longer effects after intranasal oxytocinadministration (up to 7 h) (Bakermans-Kranenburg and van,2013) support its suitability for sustained long-term use inclinical settings (Bakermans-Kranenburg and van, 2013).Moreover, exogenous oxytocin may stimulate a ‘feedfor-ward’ release of endogenous oxytocin, prolonging the effectbeyond its half-life (Bakermans-Kranenburg and van, 2013).Another potential clinical application of oxytocin, in whicha short half-life would be desirable, is in combinationwith psychotherapy (e.g., administration immediatelybefore a therapy session to enhance its effect [Bryant and






Hung, 2013; Guastella et al., 2009; MacDonald et al.,2013]), as is done with other drugs such as D-cycloserine(Andero and Ressler, 2012). Of note, other psychotropicmedications used in clinical settings have very short half-lives as well (e.g., stimulants, some benzodiazepines) andare used during specific periods of time or on an as-neededbasis to target intermittent symptoms.

Changes in emotion recognition and understanding ofmental states after oxytocin may be mediated by changesin the salience or rewarding properties of social stimuli(Groppe et al., 2013; Stavropoulos and Carver, 2013).Recent evidence suggests that oxytocin-induced increasesin social cognitive ability are correlated with increasedpupil dilation, which is in turn coupled with increased firingof the locus coeruleus (Prehn et al., 2013); (Leknes et al.,2013). In addition, increased attention toward the eyeregion of facial stimuli (measured by eye gaze or reactiontime) has been found after oxytocin administration (Bertschet al., 2013; Brune et al., 2013; Domes et al., 2013;Tollenaar et al., 2013). There is also evidence that oxytocinaffects social cognition through modulation of subcorticalattention/orienting networks and amygdala activity (Liet al., 2010; Pinkham et al., 2011).

There are, in general, two theoretical models of theeffect of intranasal oxytocin on social cognition (Bartzet al., 2011b; Meyer-Lindenberg et al., 2011). The “opti-mizing” model (Meyer-Lindenberg et al., 2011; Simeonet al., 2011) postulates that oxytocin optimizes socialcognitive functioning in all populations, regardless of base-line social cognitive skills (Meyer-Lindenberg et al., 2011).Conversely, the “interactionist” model (Bartz et al., 2011b)suggests that oxytocin's effects on social cognition aremodulated by baseline social cognition skills (Bartz et al.,2010; Fischer-Shofty et al., 2013a, 2013b; Leknes et al.,2013). According to the interactionist model (see Fig. 1),there is a “sweet spot” of oxytocinergic tone/social cogni-tion (i.e., optimal emotion recognition, mentalizing, sal-ience, and attention to emotional stimuli), below which

Fig. 1 Interactionist Model of the Effect of Oxytocin on SocialCognition. Oxytocin's effects on social cognition and functioningare modulated by baseline social cognition skills. There is asweet spot of oxytocinergic tone/social cognition (i.e., optimalemotion recognition, mentalizing, salience and attention toemotional stimuli) and social functioning, below which socialcognition is deficient (as in schizophrenia and autism, withpositive effects of exogenous oxytocin) and beyond whichsocial cognition is excessive/distorted (as in borderline person-ality disorder, with potentially negative effects of exogenousoxytocin).


social cognition is deficient (with positive effects of exo-genous oxytocin) and beyond which social cognition isexcessive/distorted (with negative effects of exogenousoxytocin) (Bartz et al., 2011b).

Per the interactionist model, individuals can be classifiedinto three distinct groups according to baseline socialcognitive skills. The first group includes those with baselineoptimal social cognition (e.g., healthy controls). They haveoptimal social cognitive brain network activity, emotionrecognition, mentalizing accuracy, salience/reward proces-sing and attention towards social stimuli. The second groupis characterized by social cognitive deficits at baseline(e.g., SZ spectrum, autism). These individuals have lowactivity and altered emotional modulation of social cogni-tive networks, poor emotion recognition, low mentalizingaccuracy, hypomentalizing errors (Montag et al., 2011),deficient salience/reward processing of social information,and low attention to social cues. These deficits areimproved by oxytocin (Feifel et al., 2012, 2010; Goldmanet al., 2011; Leknes et al., 2013; Macdonald and Feifel,2012; Pedersen et al., 2011). Finally, the third groupincludes those with baseline social cognitive distortions(e.g., borderline personality disorder). They are character-ized by poor mentalizing accuracy, excessive, distortedmentalizing (hypermentalizing) (Sharp et al., 2011, 2013)and excessive salience/attention towards social stimuli,with attentional biases (Bartz et al., 2011a, 2011b). Inthese populations, the effects of oxytocin are mixed,ranging from positive (decreased emotional responses andcortisol levels after social stress induction, decreasedattentional biases and emotional reactions to angry faces,etc.) to negative (decreased trust and cooperation) (Bartzet al., 2011a; Bertsch et al., 2013; Brune et al., 2013; Ebertet al., 2013; Simeon et al., 2011).

Despite some evidence of attentional biases to emotionalstimuli and social cognitive distortions (e.g., extremelynegative or positive attributions associated with affectiveepisodes in BD [Stange et al., 2013] or an exaggerated self-serving bias in paranoid patients [Kaney and Bentall, 1989;Garety and Freeman, 1999]), whether those individuals withbipolar disorder and actively psychotic paranoid schizophre-nia belong to this third group remains largely unexplored.

Furthermore, the effects of oxytocin appear to bemodulated by other factors, including gender, context,attachment style, and history of childhood adversity(Bakermans-Kranenburg and van, 2013; Bartz et al.,2011b; Domes et al., 2010). For example, the effects ofintranasal oxytocin on functional connectivity between theposterior cingulate cortex and the cerebellum and post-central gyrus were only observed among those healthyindividuals with supportive family backgrounds (i.e., thosewho had experienced low levels of maternal love with-drawal in childhood) (Riem et al., 2013).

3.2. Clinical trials of intranasal oxytocinadministration in schizophrenia

To date, approximately 10 clinical trials (summarized inTable 1) have been conducted in patients with SZ to test theefficacy of oxytocin in ameliorating social cognitive deficitsand psychopathology.





Table 1 Overview of clinical trials of the effect of oxytocin on social cognition and psychopathology in schizophrenia.

Study Samplea Oxytocin(OT)intranasaldose

Design Outcome measure Results

Goldmanet al.(2011)

13 SZ 10 IU or 20 IUonce a week

Double- blind,placebo-controlledcrossover3-week trial

� Facial affect recognition Facial affect intensity was greater in patientswith PD compared to HCs across the treatmentconditions but there was no difference betweenthe two patients groups.

� 5 with PD;age=5373;males=3

� 8 without PD;age=4479;males=4

The low OT dose (10 IU) increased intensity in thePD group compared to HCs but not to the nonPDgroup. The 20 IU dose showed a decrease inintensity in the PD group relative to the nonPDgroup but there were no differences compared tothe HCs.

11 HCs� (age=38713;

males=4)Among emotions, only ‘fear’ was altered by OT:PD patients showed a reduction in fear comparedto the nonPD patients.Recognition deteriorated in both SZ groups on the10 IU dose but improved with 20 IU dose in SZwith PD.Overall emotion recognition improved with the 20IU dose in the PD patients compared to the nonPDpatients.

Feifel et al.(2010)

15 SZ 20 IU twice aday (firstweek);

Double- blind,placebo-controlledcrossover3-week trial

� Positive and Negative SymptomsScale (PANSS)

� Clinical Global Impression (CGI)

Reduction of symptoms with improvement ofPANSS and CGI scores at the 3 week endpoint inOT group vs the placebo group.

� 6 in the OT group� 9 in the

placebo group 40 IU twice aday for thesubsequenttwo weeks

Sample age=4878.9;males=12

Study supports the hypothesis that OT hasantipsychotic properties with effects on bothnegative and positive symptoms but morestatistically robust for positive symptoms.

Pedersenet al.(2011)

20 SZ 24 IU twicedaily

Randomized,double-blind,placebo-controlled2-week trial

� Brune Theory of Mind PictureStories Task

� Trustworthiness task� Positive and Negative Symptoms

Scale (PANSS)� Paranoia Scale

The OT group improved in accurate identificationin second order false beliefs (Brune task) butthere were no other significant differences inother measures of the Brune task.

� 11 in the OT group;age=39711.2;males=9

� 9 in the placebogroupage=35.879.5;males=8

The OT group also showed reduction in PANSS(positive, total, general subscale andsuspiciousness/persecutory items) and ParanoiaScale scores.

Averbecket al.(2012)

21 SZ 24 IU singledose

Double- blind,placebo-controlled

� Facial affect recognition: facialexpression of emotion in still imagesfrom the standardized items developed

The OT group showed an overall betterperformance on facial emotion recognition, but� 10 in the OT group

� 11 in the

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crossover2-week trial

by Ekman none of the individual emotions showed asignificant difference.

placebo groupSample age=38.271.8;males=21 The OT group performance remained lower

compared to that of a control group used in aprevious experiment in the study.

Feifel et al.(2012)

15 SZ 20 IU twice aday (firstweek);

Double- blind,placebo-controlledcrossover study

� Verbal memory: CaliforniaVerbal Learning Test (CVLT)

� Working Memory: LNS (from WAIS-III)

The OT group vs the placebo groups showedsignificant effect on CVLT but not on LNS.� 6 in the OT group

� 9 placebo in theplacebo group 40 IU twice a

day for theother twoweeks

Sample age=4878.9;males=12

The effect of OT was significant in CVLT totalrecall trials 1–5, short delayed free recall andtotal recall discrimination. However, it wasstronger for short-term recall than for long-term.Authors suggest that this might be due to the factthat OT modulates only neural processes involvedin short-term verbal memory.

Modabberniaet al.(2013)

40 SZ 20 IU twicedaily for the1st week;


� Positive and NegativeSymptoms Scale (PANSS)

� Extrapyramidal Symptom RatingScale (ESRS)

OT group showed improvement in PANSS totalscore by week 4 with a total 11.2% symptomsreduction from baseline. Positive and negativesymptoms and general psychopathology subscalescores showed that in the OT group at the studyendpoint there was a symptoms reduction (of20%, 7% and 8% respectively) starting fromweek 6.

� 20 in the OT group,age=32.377.4;males=17

� 20 in the placebogroup,age=33.276.9;males=16

40 IU twicedaily for thefollowing7 weeks

No changes were detected in ESRS score betweenthe OT and the placebo group.

Davis et al.(2014)

23 SZ Single doseof 40 IU

Randomized,double-blind,placebo-controlled study

� Theory of mind: The Awareness of SocialInference test (TASIT-III)

� Empathy: Emotional Perspective TakingTask (EPTT)

� Social perception: Half Profile of NonverbalSensitivity (Half-PONS)

� Facial affect recognition: assessed askingparticipants to identify facial expression ofemotion in still images from the standardizeditems developed by Ekman

OT did not significantly improve performanceeither in the social composite measure(combination of all the social tasks) or in the low-level processes score (TASIT- Part III detection oflies, Half-PONS and Facial Affect RecognitionTask). However, OT significantly improvedperformance on high-level social cognition(TASIT- Part III detection of sarcasm, EPTT) with alarge effect size (d=1.0).

� 11 in the OT group,age=48.676.6;males=11

� 12 in the placebogroup,age=48.979.1;males=12

No improvement on positive, negative or generalsymptoms.

Fischer-Shoftyet al.(2013a)


Double- blind,within-subjectscrossover2-week trial

� Social Perception: the InterpersonalPerception task (IPT). Participants needed todiscriminate between 2 categories ofrelationship: kinship (familial relationship)and intimacy (romantic relationship)

� Depression: Depression Adjective CheckList (DACL)

There was no general effect of OT on mood.� age=32.476.4;

males=31However a positive effect on social perceptionperformance was found after administration inthe OT group compared to placebo.48 HCs

� age=30.475.8;males=39

In patients, the OTand placebo group significantlydiffered in the identification of kinshiprelationships but not intimacy while no sucheffect was detected in the control group.

9Oxytocin

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acology(2014),





Table 1 (continued )

Study Samplea Oxytocin(OT)intranasaldose

Design Outcome measure Results

Fischer-Shoftyet al.(2013b)


Double- blind,within-subjectscrossover2-week trial

� Facial Emotion Recognition: theFacemorphing Task

� Depression: Depression Adjective CheckList (DACL)

There was no general effect of OT on mood.� age=31.876.5;

males=27In all participants, regardless of their psychiatricstatus, the OT administration showed higheraccuracy recognition for the ‘fearful’ but not for‘happy’ faces. Also, independently of psychiatricstatus, OT administration improved theperformance of those participants whose basicfear recognition was below the median.

35 HCs� age=29.575.6;

males=32

Lee et al.(2013)

28 SZ or SAD 20 IU twicedaily


� Olfactory identification ability (neutral,pleasant and unplesant odors): the Universityof Pennsylvania smell identification test(UPSIT)

� Symptomatology: Brief Psychiatric RatingScale (BPRS)

� Scale for the Assessment of NegativeSymptoms (SANS)

Improvement in the OT group in the total UPSITscore and in the subscore for the pleasant smells(no effects for neutral or unpleasant smells).

� 13 (6 inpatients and7 outpatients) in theOT group;age=44.7711.8;males=9

� 15 (6 inpatients and9 outpatients) in theplacebo groups;age=35.178.2;males=11

The placebo group showed improved globalsymptomatology (BPRS). The inpatient group thatreceived OT had a better total SANS (d=0.85) atweek 3 while no differences were detected forthe outpatient group. The motivational/pleasuresubscale of the SANS showed improvement in theOT inpatient group (d=0.74).

SZ=schizophrenia; SAD=schizoaffective; HCs=healthy controls; PD=polydipsia OT=oxytocin; IU= International Unit.aAll SZ subjects across the clinical trials reported in the table maintained their pre-study antipsychotic medication.

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The most commonly administered doses of oxytocin inclinical trials in SZ were 20–24 IU (International Units) and40 IU. Most of the studies showed that intranasal oxytocinenhanced facial affect recognition in SZ individuals com-pared to placebo groups (Goldman et al., 2011; Averbecket al., (2012); Fischer-Shoftly et al., 2013b) and a specificityfor the recognition of fearful faces was found in one study(Fischer-Shoftly et al., 2013b). Only Davis et al. (2014)failed to find significant improvements in facial affectrecognition. However, this group found a large effect size(d=1.0) for high level social cognition processes as mea-sured by a ToM task (the sarcasm subscale of The Awarenessof Social Inference Test [TASIT-III; McDonald et al., 2006])and an empathy task (the Emotional Perspective Taking Task[EPTT; Derntl et al., 2009]). Similarly, a positive effect onToM was also detected by Pedersen et al. (2011), but onlywithin more complex tasks of second order beliefs. Fischer-Shoftly et al. (2013a) reported an improvement in theability to discriminate the correct nature of a presentedrelationship (i.e. kinship compared to romantic) afteroxytocin administration. Regarding oxytocin's effect onnonsocial cognition, one study examined the influence ofoxytocin on memory in SZ (Feifel et al., 2012) and foundthat oxytocin has a beneficial effect on short-term verbalmemory whereas no such effect was present in workingmemory.

With regard to the antipsychotic effect of oxytocin,results are mixed. Improvement in overall psychopathology(Lee et al., 2013; Feifel et al., 2010; Pedersen et al., 2011;Modabbernia et al., 2013) seems to be linked to a higheroxytocin dosage and to a longer duration of treatment.Studies that administered a single dose of oxytocin did notreport any amelioration of symptoms (Davis et al., 2014;Fischer-Shoftly et al., 2013a, 2013b).

3.3. Clinical trials of intranasal oxytocinadministration in depression

Although several studies have demonstrated a relationshipbetween depressive symptoms and endogenous oxytocin(e.g. Cyranowski et al., 2008; Scantamburlo et al., 2007;Gordon et al., 2008), reports have been small and incon-sistent. Nevertheless, given the evidence for social cogni-tive impairments in depression, it may be worthwhile toexamine the effect of intranasal oxytocin on social cognitionand related symptoms. To date, only two placebo-controlledtrials of oxytocin have been conducted in MDD. Mah et al.,2013 administered a single dose of 24 IU oxytocin orplacebo, about one week apart, to 25 women with post-partum depression and measured mood and expressedemotion 45 min after administration. The results of thiswithin-subject crossover design showed that in the oxytocincondition, the participants rated their mood as significantlysadder than in the control condition. Moreover, underthe oxytocin condition, participants were more likely todescribe their babies as difficult while at the same time,they reported that their relationship with their babies wasmore positive relative to the placebo condition. Thesesomewhat conflicting results are difficult to interpret butseem to suggest that oxytocin has little effect on mood butthat it may enhance salient relationship features, at least in


mothers regarding their infants. A subset of these partici-pants underwent a test of parental protectiveness underoxytocin and placebo conditions; the results indicate thatoxytocin significantly enhanced parental protectiveness(Mah et al., 2014). Only one other study to date hasinvestigated the effects of intranasal oxytocin on socialcognition in major depressive disorder. MacDonald et al.(2013) administered a single-dose of oxytocin 40 IU orplacebo immediately before a mock therapy session. Intra-nasal oxytocin was associated with improvement in socialcognition (increased accuracy in a task measuring theunderstanding of mental states) and increased prosocialbehavior (reduction in non-verbal behaviors that cut offsocial contact). However, oxytocin was also associated withhigher anxiety during the psychotherapy session. Of note,higher anxiety during an initial therapy session may beunderstood as a positive sign of engagement in the therapy(MacDonald et al., 2013). Moreover, the therapists in thisstudy had been instructed to provide “minimal or neutralinteraction with the subjects,” which may have contributedto increased anxiety in the context of increased prosocialityby oxytocin (MacDonald et al., 2013).

A study of nonclinical university students reported thatthere was a significant interaction between depressivesymptoms and the ability to inhibit the processing of sadfaces after a single administration of 24 IU of intranasaloxytocin (Ellenbogen et al., 2013). Using an affectivepriming paradigm, results suggested that participants withhigher levels of depressive symptoms were unable to inhibitthe processing of sad faces in the oxytocin conditioncompared to the placebo condition; there was no significantinteraction between inhibition and oxytocin among theparticipants with lower levels of depressive symptoms.These results raise the question of whether oxytocin mayenhance salient social stimuli in patients with depression,thereby improving social cognition. Conversely, it is possiblethat the bias toward negative social stimuli already presentin individuals with depression (e.g. Leppänen, 2006) may beexacerbated by oxytocin, as per the interactionist model.

3.4. Clinical trials of intranasal oxytocinadministration in bipolar disorder

There is very little information regarding oxytocin and BD.Intranasal oxytocin has not been administered to BDpatients as of yet, and only one study to date has examinedthe relationship between endogenous serum oxytocin andBD (Turan et al., 2013). Turan et al. (2013) reported thatserum oxytocin was significantly higher in patients com-pared to controls, and that patients experiencing a manicepisode demonstrated significantly higher levels of oxytocincompared to remitted and depressed patients with BD.Oxytocin was measured at baseline and at the point atwhich patients had achieved a 50% reduction of symptomsafter treatment with appropriate medications; no differ-ences in pre- and post-treatment oxytocin were found, andpost-treatment levels of oxytocin in the patients continuedto be higher than baseline oxytocin levels in controls.Clearly, more work is needed to understand the relationshipbetween endogenous oxytocin levels and symptoms of BD.Nevertheless, given the social cognitive deficits in BD, it






may be worthwhile to explore intranasal oxytocin as apotential treatment for these deficits. Future work isrequired to test whether the administration of oxytocin topatients with BD would improve social cognitive impair-ments in BD, or whether the potentially increased salienceof social stimuli resulting from oxytocin administration mayperhaps exacerbate deficits in social cognition in BD.

3.5. Clinical trials combining oxytocin withpsychotherapy

While there is a growing literature regarding oxytocin's effectson social cognition and affiliation in clinical populations, todate only two studies have examined the effect of oxytocin incombination with psychotherapy (MacDonald et al., 2013;Guastella et al., 2009; Table 2). One additional study lookedat the effect of oxytocin combined with hypnosis (Bryant andHung, 2013). These studies suggest that augmentation ofpsychotherapy with oxytocin as compared to placebo leadsto improvements in social cognition, as well as in self-perceptions during the induction of social anxiety. Theevidence indicates that oxytocin may also result in anenhancement of hypnotizability, which may have implicationsfor disorders that are improved through this treatmentmodality (e.g. chronic pain, smoking cessation). While not astudy of a formal psychotherapy, a recent study examining thecombination of oxytocin with social support found evidencethat this combination exerted a more beneficial effect oncortisol responses to social stress than either interventionadministered individually (Heinrichs et al., 2003). However,these studies have several limitations: 1) No study hascombined oxytocin with an evidence-based psychotherapyfor the treatment of depression or bipolar disorder; 2) Nostudies of therapy plus oxytocin have examined the effect ofsustained treatment with daily oxytocin doses; and 3) Nostudies have measured oxytocin plus psychotherapy effects onsocial cognition using a standardized, validated assessment of

Table 2 Studies examining combination treatment with oxyto

Study Population N Intervention ResuPlace

Macdonaldet al.(2013)

Majordepressivedisorder

18 Single 20-min psychotherapysession+pretreatment withdouble-blind intranasaloxytocin (40IU) vs. placebo

Greacognin threducbehacontadurin

Guastellaet al.(2009)

Socialanxietydisorder

25 5 weekly sessions of groupexposure therapy+pretreatment with double-blind intranasal oxytocin(24IU) vs. placebo

Oxytimprperfodurin(speediffebetw

Bryant andHung(2013)

Healthyvolunteers

28 Single session of hypnosis+ intranasal oxytocin (24IU)vs. placebo

Greafollow


complex social interactions using real-life naturalistic socialcognition tasks before and after treatment. Comprehensivestudies combining oxytocin and psychotherapy are needed inorder to identify effects of treatments individually and incombination, and to explore the possible neural mechanismsunderlying clinical change.

4. Social cognitive remediation inschizophrenia and affective disorders

Non-pharmacological interventions for social cognitive def-icits have been developed and tested over many years inpatients with SZ, with far fewer studies in MDD and BD.Social cognitive remediation treatments have sought totarget the social cognitive deficits in SZ, namely emotionperception, ToM, and attributional style. Meta-analyticfindings from an examination of 19 studies with a total of692 participants found moderate to large effects of socialcognitive remediation on facial affect recognition, small tomoderate effects on ToM, and non-significant effects onsocial cue perception and attributional bias (Kurtz andRichardson, 2012). Social Cognition and Interaction Training(SCIT; Penn et al., 2005) is a relatively recently developedmanualized group treatment for social cognition in SZ andhas had generally positive findings (Combs et al., 2007;Roberts and Penn, 2009; Chan et al., 2010; Wang et al.,2013; Roberts et al., 2014). SCITcontains both skills trainingand an integration phase for practicing the skill set.

Overall, although social cognitive remediation is bene-ficial and appears to improve many important social cogni-tive domains in SZ, the skills generated may not generalizeto real-world situations. In order for the trainings to be ofclinical utility, they will need to also demonstrate sustain-ability over time and translate into functional improvementoutside the laboratory (Henderson, 2013). More recently,oxytocin has been used as an augmentation for socialcognitive training in SZ (Davis et al., 2014). Participants

cin with psychotherapy.

lts: Oxytocin effect vs.bo

Limitations

ter improvement in socialition on “reading the minde eyes test”, greatertion in non-verbalviors that cut off socialct, but increased anxietyg psychotherapy session.

Single-dose oxytocin (vssustained use). Therapistsinstructed to provide “minimalor neutral interaction with thesubjects.”

ocin yielded greaterovements in self-perceivedrmance and appearanceg social performancech) than placebo. Norence in anxiety outcomeseen groups.

Single-dose oxytocin(vs sustained use).

ter hypnotizability observeding oxytocin than placebo

Single-dose, single-session. Nota clinical population, hypnosisnot for therapeutic purposes.






underwent 12 sessions of social cognitive remediation over6 weeks; oxytocin (40 IU) or placebo was administered30 min before each training session. Participants whoreceived oxytocin demonstrated significant improvementsin empathic accuracy compared to the placebo condition atthe end of treatment and one month after treatment; noother social cognitive or neurocognitive variables differedbetween the placebo and treatment groups. Empathicaccuracy has been traditionally difficult to improve in SZ;thus, these results suggest that combining oxytocin withsocial cognitive remediation may lead to improved out-comes compared with either treatment alone.

Social cognitive remediation has not been well-studied inaffective disorders. A recent trial of SCIT for outpatientswith BD demonstrated that this treatment is efficacious inimproving ToM, emotion perception, and depressive symp-toms and has smaller but still significant effects in reducinghostile attributional biases (Lahera et al., 2013). To date, norandomized controlled trials of social cognitive remediationhave been conducted in MDD.

5. Limitations, challenges, and futuredirections

Current challenges in the assessment of exogenousoxytocin's effect on social cognition include the lack ofstandardized social cognition measures; the incompletecharacterization of the human central oxytocin receptor( e.g., lack of quantification of the oxytocin receptor in theliving brain, limited data regarding its distribution in thehuman brain and scarce genetic association data [Smithet al., 2013]) and neural circuitry of oxytocinergic networks(Churchland and Winkielman, 2012; Millan et al., 2014); anda lack of clarity regarding the intranasal formulation ofoxytocin (Guastella et al., 2013) and its absorption intorelevant brain areas (Born et al., 2002; Neumann et al.,2013). The development of a PET ligand would represent asignificant advance in this area of research (Smith et al.,2012, 2013).

Efforts to examine associations between oxytocin levelsand neural/behavioral effects and clinical symptoms arelimited by the challenges of accurate, reliable peripheralquantification of oxytocin (Apter-Levy et al., 2013; Keri andKiss, 2011; Kim et al., in press). Moreover, it is unknownwhether peripheral oxytocin levels are correlated withcentral (brain or CSF) levels in humans. Further work isrequired to understand the relationship between peripheraloxytocin and central levels.

None of the clinical trials of intranasal oxytocin admin-istration described above have investigated the mechanismby which oxytocin enhances social cognition, and thus thetwo models (optimizing and interactionist) remain untestedin SZ, MDD and BD. This is critically important work, as it isunclear whether oxytocin may help or hinder social cogni-tive functioning in patients with affective disorders. Futurework is sorely needed to investigate which specific socialcognitive domains are affected by oxytocin and in whichpopulations, as well as the nature and mechanism ofthis effect. The evidence to date suggests that oxytocinhas subtle and extremely person- and context-dependent


effects; clarification of who may benefit and under whatcircumstances is a promising and important next step.

Role of funding source

This research is supported by the Department of Veterans AffairsOffice of Academic Affiliations Advanced Fellowship Program inMental Illness Research and Treatment, the Medical ResearchService of the Veterans Affairs James J Peters VAMC; the Depart-ment of Veterans Affairs NY/NJ (VISN3) Mental Illness Research,Education, and Clinical Center (MIRECC); a Brain and BehaviorResearch Foundation NARSAD Young Investigator Award to Dr. PerezRodriguez, and the NIMH (R01 MH100125 to Dr. Burdick, CTSA grantUL1TR000067 awarded to the Mt. Sinai School of Medicine).

The funding sources had no further role in study design; in thecollection, analysis and interpretation of data; in the writing of thereport; and in the decision to submit the paper for publication. Thecontents are solely the responsibility of the authors and do notnecessarily represent the official views of the VA MIRECC.

Contributors

Authors MMPR, MR, AKU and KM managed the literature searches;MMPR, MR, KM, AKU and KEB wrote the initial draft, MMPR, MR, AKUand KM addressed the reviewers’ comments, and KEB and MMPRrevised the final manuscript critically.

All authors contributed to and have approved the finalmanuscript.

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgments

This research is supported by the Department of Veterans AffairsOffice of Academic Affiliations Advanced Fellowship Program inMental Illness Research and Treatment, the Medical ResearchService of the Veterans Affairs James J Peters VAMC; the Depart-ment of Veterans Affairs NY/NJ (VISN3) Mental Illness Research,Education, and Clinical Center (MIRECC); a Brain and BehaviorResearch Foundation NARSAD Young Investigator Award (20684) toDr. Perez Rodriguez, and the National Institute of Mental Health(NIMH) (R01 MH100125 to Dr. Burdick, CTSA Grant UL1TR000067awarded to the Mt. Sinai School of Medicine).

References

Aakre, J.M., Seghers, J.P., St-Hilaire, A., Docherty, N., 2009.Attributional style in delusional patients: a comparison ofremitted paranoid, remitted nonparanoid, and current paranoidpatients with nonpsychiatric controls. Schizophr. Bull. 35,994–1002.

Achim, A.M., Ouellet, R., Roy, M.A., Jackson, P.L., 2011. Assess-ment of empathy in first-episode psychosis and meta-analyticcomparison with previous studies in schizophrenia. PsychiatryRes. 190, 3–8.

Addington, J., Addington, D., 1998. Facial affect recognition andinformation processing in schizophrenia and bipolar disorder.Schizophr. Res. 32, 171–181.

Addington, J., Piskulic, D., Perkins, D., Woods, S.W., Liu, L., Penn, D.L.,2012. Affect recognition in people at clinical high risk of psychosis.Schizophr. Res. 140, 87–92.


http://refhub.elsevier.com/S0924-977X(14)00212-0/sbref1





http://refhub.elsevier.com/S0924-977X(14)00212-0/ssbib3














Alloy, L.B., Lipman, A.J., Abramson, L.Y., 1992. Attributional styleas a vulnerability factor for depression: validation by pasthistory of mood disorders. Cognit. Ther. Res. 16, 391–407.

Amminger, G.P., Schäfer, M.R., Papageorgiou, K., Klier, C.M., Schlögel-hofer, M., Mossaheb, N., Werneck-Rohrer, S., Nelson, B., McGorry,P.D., 2012. Emotion recognition in individuals at clinical high-risk forschizophrenia. Schizophr. Bull. 38, 1030–1039.

Andero, R., Ressler, K.J., 2012. Fear extinction and BDNF: translat-ing animal models of PTSD to the clinic. Genes Brain Behav. 11,503–512.

Apter-Levy, Y., Feldman, M., Vakart, A., Ebstein, R.P., Feldman, R.,2013. Impact of maternal depression across the first 6 years oflife on the child's mental health, social engagement, andempathy: the moderating role of oxytocin. Am. J. Psychiatry170, 1161–1168.

Averbeck, B.B., Bobin, T., Evans, S., Shergill, S.S., 2012. Emotionrecognition and oxytocin in patients with schizophrenia. Psy-chol. Med. 42, 259–266.

Bakermans-Kranenburg, M.J., van, I.J.M.H., 2013. Sniffing aroundoxytocin: review and meta-analyses of trials in healthy andclinical groups with implications for pharmacotherapy. Transl.Psychiatry 3, e258.

Ball, H.A., McGuffin, P., Farmer, A.E., 2008. Attributional style anddepression. Br. J. Psychiatry 192, 275–278.

Baron-Cohen, S., Wheelwright, S., Hill, J., Raste, Y., Plumb, I.,2001. The “Reading the Mind in the Eyes” test revised version: astudy with normal adults, and adults with Asperger syndrome orhigh-functioning autism. J. Child Psychol. Psychiatry 42,241–251.

Bartz, J., Simeon, D., Hamilton, H., Kim, S., Crystal, S., Braun, A.,Vicens, V., Hollander, E., 2011a. Oxytocin can hinder trust andcooperation in borderline personality disorder. Soc. Cognit.Affect. Neurosci. 6, 556–563.

Bartz, J.A., Zaki, J., Bolger, N., Hollander, E., Ludwig, N.N.,Kolevzon, A., Ochsner, K.N., 2010. Oxytocin selectivelyimproves empathic accuracy. Psychol. Sci. 21, 1426–1428.

Bartz, J.A., Zaki, J., Bolger, N., Ochsner, K.N., 2011b. Socialeffects of oxytocin in humans: context and person matter.Trends Cognit. Sci. 15, 301–309.

Bazin, N., Brunet-Gouet, E., Bourdet, C., Kayser, N., Falissard, B.,Hardy-Baylé, M.-C., Passerieux, C., 2009. Quantitative assess-ment of attribution of intentions to others in schizophrenia usingan ecological video-based task: a comparison with manic anddepressed patients. Psychiatry Res. 167, 28–35.

Bentall, R.P., Corcoran, R., Howard, R., Blackwood, N., Kinderman, P.,2001. Persecutory delusions: a review and theoretical integration.Clin. Psychol. Rev. 21, 1143–1192.

Bertrand, M.C., Sutton, H., Achim, A.M., Malla, A.K., Lepage, M.,2007. Social cognitive impairments in first episode psychosis.Schizophr. Res. 95, 124–133.

Bertsch, K., Gamer, M., Schmidt, B., Schmidinger, I., Walther, S.,Kastel, T., Schnell, K., Buchel, C., Domes, G., Herpertz, S.C.,2013. Oxytocin and reduction of social threat hypersensitivity inwomen with borderline personality disorder. Am. J. Psychiatry170, 1169–1177.

Bielsky, I.F., Young, L.J., 2004. Oxytocin, vasopressin, and socialrecognition in mammals. Peptides 25, 1565–1574.

Billeke, P., Aboitiz, F., 2013. Social cognition in schizophrenia: fromsocial stimuli processing to social engagement. Front Psychiatry 4, 4.

Bora, E., Vahip, S., Gonul, A.S., Akdeniz, F., Alkan, M., Ogut, M.,Eryavuz, A., 2005. Evidence for theory of mind deficits in euthymicpatients with bipolar disorder. Acta Psychiatr. Scand. 112, 110–116.

Bora, E., Yucel, M., Pantelis, C., 2009a. Cognitive endophenotypesof bipolar disorder: a meta-analysis of neuropsychologicaldeficits in euthymic patients and their first-degree relatives.J. Affect. Disord. 113, 1–20.

Bora, E., Yucel, M., Pantelis, C., 2009b. Theory of mind impairmentin schizophrenia: meta-analysis. Schizophr. Res. 109, 1–9.


Born, J., Lange, T., Kern, W., McGregor, G.P., Bickel, U., Fehm, H.L.,2002. Sniffing neuropeptides: a transnasal approach to the humanbrain. Nat. Neurosci. 5, 514–516.

Bos, P.A., Panksepp, J., Bluthe, R.M., van Honk, J., 2012. Acuteeffects of steroid hormones and neuropeptides on human social-emotional behavior: a review of single administration studies.Front. Neuroendocrinol. 33, 17–35.

Bourke, C., Douglas, K., Porter, R., 2010. Processing of facialemotion expression in major depression: a review. Aust. N. Z.J. Psychiatry 44, 681–696.

Bozikas, V.P., Kosmidis, M.H., Anezoulaki, D., Giannakou, M.,Karavatos, A., 2004. Relationship of affect recognition withpsychopathology and cognitive performance in schizophrenia.J. Int. Neuropsychol. Soc. 10, 549–558.

Brüne, M., 2005. Emotion recognition, ‘theory of mind,’ and socialbehavior in schizophrenia. Psychiatry Res. 133, 135–147.

Brune, M., Abdel-Hamid, M., Lehmkamper, C., Sonntag, C., 2007.Mental state attribution, neurocognitive functioning, and psy-chopathology: what predicts poor social competence in schizo-phrenia best? Schizophr. Res. 92, 151–159.

Brune, M., Ebert, A., Kolb, M., Tas, C., Edel, M.A., Roser, P., 2013.Oxytocin influences avoidant reactions to social threat in adultswith borderline personality disorder. Hum. Psychopharmacol.28, 552–561.

Bryant, R.A., Hung, L., 2013. Oxytocin enhances social persuasionduring hypnosis. PloS One 8, e60711.

Chan, R.C., Li, H., Cheung, E.F., Gong, Q.Y., 2010. Impaired facialemotion perception in schizophrenia: a meta-analysis. Psychia-try Res. 178, 381–390.

Churchland, P.S., Winkielman, P., 2012. Modulating social behaviorwith oxytocin: how does it work? What does it mean?. Horm.Behav. 61, 392–399.

Combs, D.R., Adams, S.D., Penn, D.L., Roberts, D., Tiegreen, J.,Stem, P., 2007. Social Cognition and Interaction Training (SCIT)for inpatients with schizophrenia spectrum disorders: prelimin-ary findings. Schizophr. Res. 91, 112–116.

Corcoran, R., Frith, C.D., 2003. Autobiographical memory andtheory of mind: evidence of a relationship in schizophrenia.Psychol Med. 33, 897–905.

Corcoran, R., Mercer, G., Frith, C.D., 1995. Schizophrenia, symp-tomatology and social inference: investigating “theory of mind”in people with schizophrenia. Schizophr. Res. 17, 5–13.

Couture, S.M., Penn, D.L., Roberts, D.L., 2006. The functionalsignificance of social cognition in schizophrenia: a review.Schizophr. Bull. 32 (Suppl 1), S44–S63.

Cusi, A.M., Nazarov, A., Macqueen, G.M., McKinnon, M.C., 2013.Theory of mind deficits in patients with mild symptoms of majordepressive disorder. Psychiatry Res. 210, 672–674.

Cyranowski, J.M., Hofkens, T.L., Frank, E., Seltman, H., Cai, H.-M.,Amico, J.A., 2008. Evidence of dysregulated peripheral oxytocinrelease among depressed women. Psychosom. Med. 70, 967–975.

Davis, M.H., 1983. Measuring individual differences in empathy:evidence for a multidimensional approach. J. Personal. Soc.Psychol. 44, 113–126.

Davis, M.C., Green, M.F., Lee, J., Horan, W.P., Senturk, D., Clarke,A.D., Marder, S.R., 2014. Oxytocin-augmented social cognitiveskills training in schizophrenia. Neuropsychopharmacol. 39,2070–2077.

Derntl, B., Finkelmeyer, A., Toygar, T.K., Hülsmann, A., Schneider, F.,Falkenberg, D.I., Habel, U., 2009. Generalized deficit in all corecomponents of empathy in schizophrenia. Schizophr. Res. 108,197–206.

Devylder, J.E., Ben-David, S., Kimhy, D., Corcoran, C.M., 2013.Attributional style among youth at clinical risk for psychosis.Early Interv. Psychiatry 7, 84–88.

Ditzen, B., Schaer, M., Gabriel, B., Bodenmann, G., Ehlert, U.,Heinrichs, M., 2009. Intranasal oxytocin increases positive













































































































































communication and reduces cortisol levels during couple con-flict. Biol. Psychiatry 65, 728–731.

Domes, G., Lischke, A., Berger, C., Grossmann, A., Hauenstein, K.,Heinrichs, M., Herpertz, S.C., 2010. Effects of intranasaloxytocin on emotional face processing in women. Psychoneur-oendocrinology 35, 83–93.

Domes, G., Sibold, M., Schulze, L., Lischke, A., Herpertz, S.C.,Heinrichs, M., 2013. Intranasal oxytocin increases covert atten-tion to positive social cues. Psychol. Med. 43, 1747–1753.

Doop, M.L., Park, S., 2009. Facial expression and face orientationprocessing in schizophrenia. Psychiatry Res. 170, 103–107.

Drury, V.M., Robinson, E.J., Birchwood, M., 1998. 'Theory of mind’skills during an acute episode of psychosis and followingrecovery. Psychol. Med. 28, 1101–1112.

Dziobek, I., Fleck, S., Kalbe, E., Rogers, K., Hassenstab, J., Brand, M.,Convit, A., 2006. Introducing MASC: a movie for the assessment ofsocial cognition. J. Autism Dev. Disord. 36, 623–636.

Ebert, A., Kolb, M., Heller, J., Edel, M.A., Roser, P., Brune, M.,2013. Modulation of interpersonal trust in borderline personalitydisorder by intranasal oxytocin and childhood trauma. Soc.Neurosci. 8, 305–313.

Edwards, J., Pattison, P.E., Jackson, H.J., Wales, R.J., 2001. Facialaffect and affective prosody recognition in first-episode schizo-phrenia. Schizophr. Res. 48, 235–253.

Eisenberg, N., Miller, P.A., 1987. The relation of empathy toprosocial and related behaviors. Psychol. Bull. 101, 91–119.

Ellenbogen, M.A., Linnen, A.-M., Cardoso, C., Joober, R., 2013.Intranasal oxytocin impedes the ability to ignore task-irrelevantfacial expressions of sadness in students with depressive symp-toms. Psychoneuroendocrinology 38, 387–398.

Elvevåg, B., Goldberg, T.E., 2000. Cognitive impairment in schizo-phrenia is the core of the disorder. Crit. Rev. Neurobiol. 14, 1–21.

Feifel, D., Macdonald, K., Cobb, P., Minassian, A., 2012. Adjunctiveintranasal oxytocin improves verbal memory in people withschizophrenia. Schizophr. Res. 139, 207–210.

Feifel, D., Macdonald, K., Nguyen, A., Cobb, P., Warlan, H.,Galangue, B., Minassian, A., Becker, O., Cooper, J., Perry, W.,Lefebvre, M., Gonzales, J., Hadley, A., 2010. Adjunctiveintranasal oxytocin reduces symptoms in schizophrenia patients.Biol. Psychiatry 68, 678–680.

Fett, A.K., Viechtbauer, W., Dominguez, M.D., Penn, D.L., van Os, J.,Krabbendam, L., 2011. The relationship between neurocognitionand social cognition with functional outcomes in schizophrenia: ameta-analysis. Neurosci. Biobehav. Rev. 35, 573–588.

Fioravanti, M., Carlone, O., Vitale, B., Cinti, M.E., Clare, L., 2005.A meta-analysis of cognitive deficits in adults with a diagnosis ofschizophrenia. Neuropsychol. Rev. 15, 73–95.

Fischer-Shofty, M., Brüne, M., Ebert, A., Shefet, D., Levkovitz, Y.,Shamay-Tsoory, S.G., 2013a. Improving social perception in schizo-phrenia: the role of oxytocin. Schizophr. Res. 146, 357–362.

Fischer-Shofty, M., Shamay-Tsoory, S.G., Levkovitz, Y., 2013b.Characterization of the effects of oxytocin on fear recognitionin patients with schizophrenia and in healthy controls. Front.Neurosci. 7, 127.

Frith, C.D., 2008. Social cognition. Philos. Trans. R. Soc. Lond. B363, 2033–2039.

Fyfe, S., Williams, C., Mason, O.J., Pickup, G.J., 2008. Apophenia,theory of mind and schizotypy: perceiving meaning and inten-tionality in randomness. Cortex 44, 1316–1325.

Gaebel, W., Wölwer, W., 1992. Facial expression and emotionalface recognition in schizophrenia and depression. Eur. Arch.Psychiatry Clin. Neurosci. 242, 46–52.

Garety, P.A., Freeman, D., 1999. Cognitive approaches to delusions: acritical review of theories and evidence. Br. J. Clin. Psychol. 38,113–154.

Goldberg, T.E., Goldman, R.S., Burdick, K.E., Malhotra, A.K.,Lencz, T., Patel, R.C., Woerner, M.G., Schooler, N.R.,Kane, J.M., Robinson, D.G., 2007. Cognitive improvement after


treatment with second-generation antipsychotic medications infirst-episode schizophrenia: is it a practice effect? Arch. Gen.Psychiatry 64, 1115–1122.

Goldman, M.B., Gomes, A.M., Carter, C.S., Lee, R., 2011. Divergenteffects of two different doses of intranasal oxytocin on facialaffect discrimination in schizophrenic patients with and withoutpolydipsia. Psychopharmacology 216, 101–110.

Gollan, J.K., Pane, H.T., McCloskey, M.S., Coccaro, E.F., 2008.Identifying differences in biased affective information proces-sing in major depression. Psychiatry Res. 159, 18–24.

Gooding, D.C., Pflum, M.J., 2011. Theory of mind and psychometricschizotypy. Psychiatry Res. 188, 217–223.

Gordon, I., Zagoory-Sharon, O., Schneiderman, I., Leckman, J.F.,Weller, A., Feldman, R., 2008. Oxytocin and cortisol in roman-tically unattached young adults: associations with bonding andpsychological distress. Psychophysiology 45, 349–352.

Green, M.F., 2006. Cognitive impairment and functional outcome inschizophrenia and bipolar disorder. J. Clin. Psychiatry 67, e12.

Green, M.F., Bearden, C.E., Cannon, T.D., Fiske, A.P., Hellemann, G.S.,Horan, W.P., Kee, K., Kern, R.S., Lee, J., Sergi, M.J., Subotnik, K.L.,Sugar, C.A., Ventura, J., Yee, C.M., Nuechterlein, K.H., 2012. Socialcognition in schizophrenia, Part 1: performance across phase ofillness. Schizophr. Bull. 38, 854–864.

Green, M.F., Leitman, D.I., 2008. Social cognition in schizophrenia.Schizophr. Bull. 34, 670–672.

Groppe, S.E., Gossen, A., Rademacher, L., Hahn, A., Westphal, L.,Grunder, G., Spreckelmeyer, K.N., 2013. Oxytocin influencesprocessing of socially relevant cues in the ventral tegmentalarea of the human brain. Biol. Psychiatry 74, 172–179.

Guastella, A.J., Hickie, I.B., McGuinness, M.M., Otis, M., Woods, E.A.,Disinger, H.M., Chan, H.K., Chen, T.F., Banati, R.B., 2013. Recom-mendations for the standardisation of oxytocin nasal administrationand guidelines for its reporting in human research. Psychoneuroen-docrinology 38, 612–625.

Guastella, A.J., Howard, A.L., Dadds, M.R., Mitchell, P., Carson, D.S.,2009. A randomized controlled trial of intranasal oxytocin as anadjunct to exposure therapy for social anxiety disorder. Psychoneur-oendocrinology 34, 917–923.

Gumley, A., Braehler, C., Macbeth, A., 2014. A meta-analysis andtheoretical critique of oxytocin and psychosis: prospects forattachment and compassion in promoting recovery. Br. J. Clin.Psychol. 53, 42–61.

Happé, F.G., 1994. An advanced test of theory of mind: under-standing of story characters’ thoughts and feelings by ableautistic, mentally handicapped, and normal children and adults.J. Autism Dev. Disord. 24, 129–154.

Harvey, P.D., Bowie, C.R., 2012. Cognitive enhancement in schizophre-nia: pharmacological and cognitive remediation approaches.Psychiatr. Clin. N. Am. 35, 683–698.

Heinrichs, M., Baumgartner, T., Kirschbaum, C., Ehlert, U., 2003.Social support and oxytocin interact to suppress cortisol andsubjective responses to psychosocial stress. Biol. Psychiatry 54,1389–1398.

Heinrichs, R.W., Zakzanis, K.K., 1998. Neurocognitive deficit inschizophrenia: a quantitative review of the evidence. Neurop-sychology 12, 426–445.

Henderson, A.R., 2013. The impact of social cognition training onrecovery from psychosis. Curr. Opin. Psychiatry 26, 429–432.

Hirschfeld, R.M., Montgomery, S.A., Keller, M.B., Kasper, S.,Schatzberg, A.F., Möller, H.J., Bourgeois, M., 2000. Socialfunctioning in depression: a review. J. Clin. Psychiatry 61,268–275.

Hoekert, M., Kahn, R.S., Pijnenborg, M., Aleman, A., 2007.Impaired recognition and expression of emotional prosody inschizophrenia: review and meta-analysis. Schizophr. Res. 96,135–145.












































































































































Hooker, C., Park, S., 2002. Emotion processing and its relationshipto social functioning in schizophrenia patients. Psychiatry Res.112, 41–50.

Inoue, Y., Tonooka, Y., Yamada, K., Kanba, S., 2004. Deficiency oftheory of mind in patients with remitted mood disorder. J.Affect. Disord. 82, 403–409.

Inoue, Y., Yamada, K., Kanba, S., 2006. Deficit in theory of mind is arisk for relapse of major depression. J. Affect. Disord. 95,125–127.

Insel, T., Cuthbert, B., Garvey, M., Heinssen, R., Pine, D.S., Quinn, K.,Sanislow, C., Wang, P., 2010. Research domain criteria (RDoC):toward a new classification framework for research on mentaldisorders. Am. J. Psychiatry 167, 748–751.

Kaney, S., Bentall, R.P., 1989. Persecutory delusions and attribu-tional style. Br. J. Med. Psychol. 62, 191–198.

Keri, S., Kiss, I., 2011. Oxytocin response in a trust game andhabituation of arousal. Physiol. Behav. 102, 221–224.

Kerr, N., Dunbar, R.I.M., Bentall, R.P., 2003. Theory of mind deficitsin bipolar affective disorder. J. Affect. Disord. 73, 253–259.

Kettle, J.W., O’Brien-Simpson, L., Allen, N.B., 2008. Impaired theory ofmind in first-episode schizophrenia: comparison with community,university and depressed controls. Schizophr. Res. 99, 96–102.

Kim, S., Fonagy, P., Koos, O., Michael, K., Strathearn, L., Maternaloxytocin response predicts mother-to-infant gaze. Brain Res.http://dx.doi.org/10.1016/j.brainres.2013.10.050, in press.

Koelkebeck, K., Pedersen, A., Suslow, T., Kueppers, K.A., Arolt, V.,Ohrmann, P., 2010. Theory of mind in first-episode schizophreniapatients: correlations with cognition and personality traits.Schizophr. Res. 119, 115–123.

Kohler, C.G., Hoffman, L.J., Eastman, L.B., Healey, K., Moberg, P.J.,2011. Facial emotion perception in depression and bipolar disorder:a quantitative review. Psychiatry Res. 188, 303–309.

Kohler, C.G., Walker, J.B., Martin, E.A., Healey, K.M., Moberg, P.J.,2010. Facial emotion perception in schizophrenia: a meta-analytic review. Schizophr. Bull. 36, 1009–1019.

Kraepelin, E., 1921. In: Robertson, George M (Ed.), Manic Depres-sive Insanity and Paranoia. E.& S. Livingston, Edinburgh.

Krstev, H., Jackson, H., Maude, D., 1999. An investigation ofattributional style in first-episode psychosis. Br. J. Clin. Psychol.38, 181–194.

Kurtz, M.M., Richardson, C.L., 2012. Social cognitive training forschizophrenia: a meta-analytic investigation of controlledresearch. Schizoph. Bull. 38, 1092–1104.

Ladegaard, N., Larsen, E.R., Videbech, P., Lysaker, P.H., 2013.Higher-order social cognition in first-episode major depression.Psychiatry Res. 216, 37–43.

Lahera, G., Montes, J.M., Benito, A., Valdivia, M., Medina, E.,Mirapeix, I., Saiz-Ruiz, J., 2008. Theory of mind deficit in bipolardisorder: is it related to a previous history of psychoticsymptoms? Psychiatry Res. 161, 309–317.

Lahera, G., Benito, A., Montes, J.M., Fernández-Liria, A., Olbert,C.M., Penn, D.L., 2013. Social cognition and interaction training(SCIT) for outpatients with bipolar disorder. J. Affect. Disord.146, 132–136.

Lee, L., Harkness, K.L., Sabbagh, M.A., Jacobson, J.A., 2005.Mental state decoding abilities in clinical depression. J. Affect.Disord. 86, 247–258.

Lee, M.R., Wehring, H.J., McMahon, R.P., Linthicum, J., Cascella, N.,Liu, F., Bellack, A., Buchanan, R.W., Strauss, G.P., Contoreggi, C.,Kelly, D.L., 2013. Effects of adjunctive intranasal oxytocin onolfactory identification and clinical symptoms in schizophrenia:results from a randomized double blind placebo controlled pilotstudy. Schizophr. Res. 145, 110–115.

Leknes, S., Wessberg, J., Ellingsen, D.M., Chelnokova, O., Olausson, H.,Laeng, B., 2013. Oxytocin enhances pupil dilation and sensitivity to‘hidden’ emotional expressions. Soc. Cognit. Affect. Neurosci. 8,741–749.


Lembke, A., Ketter, T.A., 2002. Impaired recognition of facialemotion in mania. Am. J. Psychiatry 152, 302–304.

Leppänen, J.M., Milders, M., Bell, J.S., Terriere, E., Hietanen, J.K.,2004. Depression biases the recognition of emotionally neutralfaces. Psychiatry Res. 128, 123–133.

Leppänen, J.M., 2006. Emotional information processing in mooddisorders: a review of behavioral and neuroimaging findings.Curr. Opin. Psychiatry 19, 34–39.

Li, H., Chan, R.C., McAlonan, G.M., Gong, Q.Y., 2010. Facialemotion processing in schizophrenia: a meta-analysis of func-tional neuroimaging data. Schizophr. Bull. 36, 1029–1039.

Lincoln, T.M., Lange, J., Burau, J., Exner, C., Moritz, S., 2010. Theeffect of state anxiety on paranoid ideation and jumping toconclusions. An experimental investigation. Schizophr. Bull. 36,1140–1148.

Loughland, C.M., Williams, L.M., Gordon, E., 2002. Schizophreniaand affective disorder show different visual scanning behaviorfor faces: a trait versus state-based distinction? Biol. Psychiatry52, 338–348.

Love, T.M., 2014. Oxytocin, motivation and the role of dopamine.Pharmacol. Biochem. Behav. 119C, 49–60.

Maat, A., Cahn, W., Gijsman, H.J., Hovens, J.E., Kahn, R.S.,Aleman, A., 2014. Open, randomized trial of the effects ofaripiprazole versus risperidone on social cognition in schizo-phrenia. Eur Neuropsychopharmacol. 24, 575–584.

Macdonald, K., Feifel, D., 2012. Oxytocin in schizophrenia: a reviewof evidence for its therapeutic effects. Acta Neuropsychiatr. 24,130–146.

Macdonald, K., Macdonald, T.M., 2010. The peptide that binds: asystematic review of oxytocin and its prosocial effects inhumans. Harv. Rev. Psychiatry 18, 1–21.

MacDonald, K., MacDonald, T.M., Brune, M., Lamb, K., Wilson, M.P.,Golshan, S., Feifel, D., 2013. Oxytocin and psychotherapy: a pilotstudy of its physiological, behavioral and subjective effects in maleswith depression. Psychoneuroendocrinology 38, 2831–2843.

Mah, B.L., Bakermans-Kranenburg, M.J., Van Ijzendoorn, M.H.,Smith, R., 2014. Oxytocin promotes protective behavior indepressed mothers: a pilot study with the enthusiastic strangerparadigm. Depress. Anxiety. http://dx.doi.org/10.1002/da.22245,in press.

Mah, B.L., Van Ijzendoorn, M.H., Smith, R., Bakermans-Kranenburg,M.J., 2013. Oxytocin in postnatally depressed mothers: itsinfluence on mood and expressed emotion. Prog. Neuropsycho-pharmacol. Biol. Psychiatry 40, 267–272.

Malaspina, D., Coleman, E., 2003. Olfaction and social drive inschizophrenia. Arch. Gen. Psychiatry 60, 578–584.

Mancuso, F., Horan, W.P., Kern, R.S., Green, M.F., 2011. Socialcognition in psychosis: multidimensional structure, clinicalcorrelates, and relationship with functional outcome. Schizo-phrenia Research 125, 143–151.

Martínez-Arán, A., Penadés, R., Vieta, E., Colom, F., Reinares, M.,Benabarre, A., Salamero, M., Gastó, C., 2002. Executive func-tion in patients with remitted bipolar disorder and schizophreniaand its relationship with functional outcome. Psychother. Psy-chosom. 71, 39–46.

Martino, D.J., Strejilevich, S.A., Fassi, G., Marengo, E., Igoa, A.,2011. Theory of mind and facial emotion recognition in euthymicbipolar I and bipolar II disorders. Psychiatry Res. 189, 379–384.

Mazza, M., De Risio, A., Surian, L., Roncone, R., Casacchia, M.,2001. Selective impairments of theory of mind in people withschizophrenia. Schizophr. Res. 47, 299–308.

McDonald, S., Bornhofen, C., Shum, D., Long, E., Saunders, C.,Neulinger, K., 2006. Reliability and validity of The Awareness ofSocial Inference Test (TASIT): a clinical test of social perception.Disabil. Rehabil. 28, 1529–1542.

McKinnon, M.C., Cusi, A.M., Macqueen, G.M., 2010. Impaired theoryof mind performance in patients with recurrent bipolar disorder:
























dx.doi.org/10.1521/pedi.2013.27.1.3















































































dx.doi.org/10.1002/da.22245

dx.doi.org/10.1002/da.22245

dx.doi.org/10.1002/da.22245
































moderating effect of cognitive load. Psychiatry Res. 177,261–262.

Meyer-Lindenberg, A., Domes, G., Kirsch, P., Heinrichs, M., 2011.Oxytocin and vasopressin in the human brain: social neuropep-tides for translational medicine. Nat. Rev. Neurosci. 12,524–538.

Meyer-Lindenberg, A., Tost, H., 2012. Neural mechanisms of socialrisk for psychiatric disorders. Nat. Neurosci. 15, 663–668.

Miklowitz, D.J., 2011. Functional impairment, stress, and psycho-social intervention in bipolar disorder. Curr. Psychiatry Rep. 13,504–512.

Millan, M.J., Bales, K.L., 2013. Towards improved animal models forevaluating social cognition and its disruption in schizophrenia:the CNTRICS initiative. Neurosci. Biobehav. Rev. 37, 2166–2180.

Millan, M.J., Fone, K., Steckler, T., Horan, W.P., 2014. Negativesymptoms of schizophrenia: clinical characteristics, pathophy-siological substrates, experimental models and prospects forimproved treatment. Eur. Neuropsychopharmacol. 24, 645–692.

Miller, D., Ross, M., 1975. Self-serving Biases in the Attribution ofCausality: Fact or Fiction? Psychol Bull. 82, 213–225.

Mitchley, N.J., Barber, J., Gray, Y.M., Brooks, N., Livingston, M.G.,1998. Comprehension of irony in schizophrenia. Cognit. Neurop-sychiatry 3, 127–138.

Modabbernia, A., Rezaei, F., Salehi, B., Jafarinia, M., Ashrafi, M.,Tabrizi, M., Hosseini, S.M., Tajdini, M., Ghaleiha, A.,Akhondzadeh, S., 2013. Intranasal oxytocin as an adjunct torisperidone in patients with schizophrenia: an 8-week, randomized,double-blind, placebo-controlled study. CNS Drugs 27, 57–65.

Montag, C., Dziobek, I., Richter, I.S., Neuhaus, K., Lehmann, A.,Sylla, R., Heekeren, H.R., Heinz, A., Gallinat, J., 2011. Differ-ent aspects of theory of mind in paranoid schizophrenia:evidence from a video-based assessment. Psychiatry Res. 186,203–209.

Montag, C., Ehrlich, A., Neuhaus, K., Dziobek, I., Heekeren, H.R.,Heinz, A., Gallinat, J., 2010. Theory of mind impairments ineuthymic bipolar patients. J. Affect. Disord. 123, 264–269.

Neumann, I.D., Landgraf, R., 2012. Balance of brain oxytocin andvasopressin: implications for anxiety, depression, and socialbehaviors. Trends Neurosci. 35, 649–659.

Neumann, I.D., Maloumby, R., Beiderbeck, D.I., Lukas, M., Land-graf, R., 2013. Increased brain and plasma oxytocin after nasaland peripheral administration in rats and mice. Psychoneuroen-docrinology 38, 1985–1993.

Nuechterlein, K.H., Barch, D.M., Gold, J.M., Goldberg, T.E.,Green, M.F., Heaton, R.K., 2004. Identification of separable cogni-tive factors in schizophrenia. Schizophr. Res. 72, 29–39.

Ochsner, K.N., 2008. The social-emotional processing stream: fivecore constructs and their translational potential for schizophre-nia and beyond. Biol Psychiatry 64, 48–61.

Pedersen, C.A., Gibson, C.M., Rau, S.W., Salimi, K., Smedley, K.L.,Casey, R.L., Leserman, J., Jarskog, L.F., Penn, D.L., 2011.Intranasal oxytocin reduces psychotic symptoms and improvesTheory of Mind and social perception in schizophrenia. Schi-zophr. Res. 132, 50–53.

Penn, D.L., Corrigan, P.W., Bentall, R.P., Racenstein, J.M., New-man, L., 1997. Social cognition in schizophrenia. Psychol. Bull.121, 114–132.

Penn, D., Ritchie, M., Francis, J., Combs, D., Martin, J., 2002.Social perception in schizophrenia: the role of context. Psychia-try Res. 109, 149–159.

Penn, D., Roberts, D.L., Munt, E.D., Silverstein, E., Jones, N.,Sheitman, B., 2005. A pilot study of social cognition andinteraction training (SCIT) for schizophrenia. Schizophr. Res.80, 357–359.

Penn, D.L., Sanna, L.J., Roberts, D.L., 2008. Social cognition inschizophrenia: an overview. Schizophr. Bull. 34, 408–411.


Perlick, D., Stastny, P., Mattis, S., Teresi, J., 1992. Contribution offamily, cognitive and clinical dimensions to long-term outcomein schizophrenia. Schizophr. Res. 6, 257–265.

Perry, A., Bentin, S., Shalev, I., Israel, S., Uzefovsky, F., Bar-On, D.,Ebstein, R.P., 2010. Intranasal oxytocin modulates EEG mu/alpha and beta rhythms during perception of biological motion.Psychoneuroendocrinology 35, 1446–1453.

Pflum, M.J., Gooding, D.C., White, H.J., 2013. Hint, hint: theory ofmind performance in schizotypal individuals. J. Nerv. Ment. Dis.201, 394–399.

Pinkham, A.E., Hopfinger, J.B., Ruparel, K., Penn, D.L., 2008. Aninvestigation of the relationship between activation of a socialcognitive neural network and social functioning. Schizophr. Bull.34, 688–697.

Pinkham, A.E., Loughead, J., Ruparel, K., Overton, E., Gur, R.E.,Gur, R.C., 2011. Abnormal modulation of amygdala activity inschizophrenia in response to direct- and averted-gaze threat-related facial expressions. Am. J. Psychiatry 168, 293–301.

Pinkham, A.E., Penn, D.L., Perkins, D.O., Graham, K.A., Siegel, M.,2007. Emotion perception and social skill over the course ofpsychosis: a comparison of individuals “at-risk” for psychosis andindividuals with early and chronic schizophrenia spectrum ill-ness. Cognit. Neuropsychiatry 12, 198–212.

Prehn, K., Kazzer, P., Lischke, A., Heinrichs, M., Herpertz, S.C.,Domes, G., 2013. Effects of intranasal oxytocin on pupil dilationindicate increased salience of socioaffective stimuli. Psychophy-siology 50, 528–537.

Quirin, M., Kuhl, J., Dusing, R., 2011. Oxytocin buffers cortisolresponses to stress in individuals with impaired emotion regula-tion abilities. Psychoneuroendocrinology 36, 898–904.

Reichenberg, A., Harvey, P.D., Bowie, C.R., Mojtabai, R.,Rabinowitz, J., Heaton, R.K., Bromet, E., 2009. Neuropsychologicalfunction and dysfunction in schizophrenia and psychotic affectivedisorders. Schizophr. Bull. 35, 1022–1029.

Riem, M.M., Bakermans-Kranenburg, M.J., Pieper, S., Tops, M.,Boksem, M.A., Vermeiren, R.R., van Ijzendoorn, M.H., Romb-outs, S.A., 2011. Oxytocin modulates amygdala, insula, andinferior frontal gyrus responses to infant crying: a randomizedcontrolled trial. Biol. Psychiatry 70, 291–297.

Riem, M.M., van IJzendoorn, M.H., Tops, M., Boksem, M.A.,Rombouts, S.A., Bakermans-Kranenburg, M.J., 2013. Oxytocineffects on complex brain networks are moderated by experiencesof maternal love withdrawal. Eur. Neuropsychopharmacol. 23,1288–1295.

Ripoll, L.H., Zaki, J., Perez-Rodriguez, M.M., Snyder, R., Strike, K.S.,Boussi, A., Bartz, J.A., Ochsner, K.N., Siever, L.J., New, A.S., 2013.Empathic accuracy and cognition in schizotypal personality disorder.Psychiatry Res. 210, 232–241.

Roberts, D.L., Penn, D.L., 2009. Social cognition and interactiontraining (SCIT) for outpatients with schizophrenia: a preliminarystudy. Psychiatry Res. 166, 141–147.

Roberts, D.L., Combs, D.R., Willoughby, M., Mintz, J., Gibson, C.,Rupp, B., Penn, D.L., 2014. A randomized, controlled trial ofSocial Cognition and Interaction Training (SCIT) for outpatientswith schizophrenia spectrum disorders. Br. J. Clin. Psychol. 53,281–298.

Roncone, R., Falloon, I.R., Mazza, M., De Risio, A., Pollice, R.,Necozione, S., Morosini, P., Casacchia, M., 2002. Is theory ofmind in schizophrenia more strongly associated with clinical andsocial functioning than with neurocognitive deficits? Psycho-pathology 35, 280–288.

Sabatinelli, D., Fortune, E.E., Li, Q., Siddiqui, A., Krafft, C., Oliver,W.T., Jeffries, J., 2011. Emotional perception: meta-analyses offace and natural scene processing. Neuroimage 54, 2524–2533.

Samamé, C., Martino, D.J., Strejilevich, S.A., 2012. Social cognitionin euthymic bipolar disorder: systematic review and meta-analytic approach. Acta Psychiatr. Scand. 125, 266–280.




















http://refhub.elsevier.com/S0924-977X(14)00212-0/sssbib1009

http://refhub.elsevier.com/S0924-977X(14)00212-0/sssbib1009






















































































































Sarfati, Y., Hardy-Baylé, M.C., Brunet, E., Widlöcher, D., 1999.Investigating theory of mind in schizophrenia: influence ofverbalization in disorganized and non-disorganized patients.Schizophr. Res. 37, 183–190.

Scantamburlo, G., Hansenne, M., Fuchs, S., Pitchot, W., Maréchal,P., Pequeux, C., Legros, J.J., 2007. Plasma oxytocin levels andanxiety in patients with major depression. Psychoneuroendocri-nology 32, 407–410.

Schreiter, S., Pijnenborg, G.H.M., Rot, M., Aan Het, 2013. Empathyin adults with clinical or subclinical depressive symptoms. J.Affect. Disord. 150, 1–16.

Sharp, C., Ha, C., Carbone, C., Kim, S., Perry, K., Williams, L.,Fonagy, P., 2013. Hypermentalizing in adolescent inpatients:treatment effects and association with borderline traits. J. Pers.Disord. 27, 3–18. http://dx.doi.org/10.1521/pedi.2013.27.1.3.

Sharp, C., Pane, H., Ha, C., Venta, A., Patel, A.B., Sturek, J.,Fonagy, P., 2011. Theory of mind and emotion regulationdifficulties in adolescents with borderline traits. J. Am. Acad.Child Adolesc. Psychiatry 50, 563–573 (e561).

Shea, T.L., Sergejew, A.A., Burnham, D., Jones, C., Rossell, S.L.,Copolov, D.L., Egan, G.F., 2007. Emotional prosodic processingin auditory hallucinations. Schizophr. Res. 90, 214–220.

Simeon, D., Bartz, J., Hamilton, H., Crystal, S., Braun, A., Ketay,S., Hollander, E., 2011. Oxytocin administration attenuatesstress reactivity in borderline personality disorder: a pilot study.Psychoneuroendocrinology 36, 1418–1421.

Smith, A.L., Freeman, S.M., Stehouwer, J.S., Inoue, K., Voll, R.J.,Young, L.J., Goodman, M.M., 2012. Synthesis and evaluation ofC-11, F-18 and I-125 small molecule radioligands for detectingoxytocin receptors. Bioorg. Med. Chem. 20, 2721–2738.

Smith, A.L., Freeman, S.M., Voll, R.J., Young, L.J., Goodman, M.M.,2013. Investigation of an F-18 oxytocin receptor selectiveligand via PET imaging. Bioorg. Med. Chem. Lett. 235415–5420

Sprong, M., Schothorst, P., Vos, E., Hox, J., van Engeland, H., 2007.Theory of mind in schizophrenia: meta-analysis. Br. J. Psychiatry191, 5–13.

Sripada, C.S., Phan, K.L., Labuschagne, I., Welsh, R., Nathan, P.J.,Wood, A.G., 2013. Oxytocin enhances resting-state connectivitybetween amygdala and medial frontal cortex. Int. J. Neuropsy-chopharmacol. 16, 255–260.

Stange, J.P., Sylvia, L.G., Magalhães, P.V., da, S., Frank, E., Otto, M.W.,Miklowitz, D.J., Deckersbach, T., 2013. Extreme attributions predicttransition from depression to mania or hypomania in bipolardisorder. J. Psychiatr. Res. 47, 1329–1336.

Stavropoulos, K.K., Carver, L.J., 2013. Research review: socialmotivation and oxytocin in autism–implications for joint atten-tion development and intervention. J. Child Psychol. Psychiatry54, 603–618.

Streit, M., Wölwer, W., Gaebel, W., 1997. Facial-affect recognitionand visual scanning behaviour in the course of schizophrenia.Schizophr. Res. 24, 311–317.

Sweeney, P.D., Anderson, K., Bailey, S., 1986. Attributional style indepression: a meta-analytic review. J. Personal. Soc. Psychol.50, 974–991.

Tollenaar, M.S., Chatzimanoli, M., van der Wee, N.J., Putman, P.,2013. Enhanced orienting of attention in response to emotionalgaze cues after oxytocin administration in healthy young men.Psychoneuroendocrinology 38, 1797–1802.


Tomasello, M., Carpenter, M., Call, J., Behne, T., Moll, H., 2005.Understanding and sharing intentions: the origins of culturalcognition. Behav. Brain Sci. 28, 675–691 (discussion 691-735).

Toomey, R., Schuldberg, D., Corrigan, P., Green, M.F., 2002.Nonverbal social perception and symptomatology in schizophre-nia. Schizophr Res. 53, 83–91.

Tracy, A., Bauwens, F., Martin, F., Pardoen, D., Mendlewicz, J.,1992. Attributional style and depression: a controlled compar-ison of remitted unipolar and bipolar patients. Br. J. Clin.Psychol. 31, 83–84.

Tseng, H.H., Chen, S.H., Liu, C.M., Howes, O., Huang, Y.L., Hsieh,M.H., Liu, C.C., Shan, J.C., Lin, Y.T., Hwu, H.G., 2013. Facialand prosodic emotion recognition deficits associate with specificclusters of psychotic symptoms in schizophrenia. PLoS One 8,e66571.

Turan, T., Uysal, C., Asdemir, A., Kılıç, E., 2013. oxytocin be a traitmarker for bipolar disorder? Psychoneuroendocrinology 38,2890–2896.

Uekermann, J., Channon, S., Lehmkämper, C., Abdel-Hamid, M.,Vollmoeller, W., Daum, I., 2008. Executive function, mentalizingand humor in major depression. J. Int. Neuropsychol. Soc. 14,55–62.

van Hooren, S., Versmissen, D., Janssen, I., Myin-Germeys, I.,à Campo, J., Mengelers, R., van Os, J., Krabbendam, L., 2008.Social cognition and neurocognition as independent domains inpsychosis. Schizophr Res., 257–265.

Van Rheenen, T.E., Rossell, S.L., 2014. Phenomenological predictorsof psychosocial function in bipolar disorder: is there evidencethat social cognitive and emotion regulation abnormalitiescontribute? Aust. N. Z. J. Psychiatry 48, 26–35.

Ventura, J., Wood, R.C., Hellemann, G.S., 2013. Symptom domainsand neurocognitive functioning can help differentiate socialcognitive processes in schizophrenia: a meta-analysis. Schizophr.Bull. 39, 102–111.

Wang, Y.G., Wang, Y.Q., Chen, S.L., Zhu, C.Y., Wang, K., 2008.Theory of mind disability in major depression with or withoutpsychotic symptoms: a componential view. Psychiatry Res. 161,153–161.

Wang, Y., Roberts, D.L., Xu, B., Cao, R., Yan, M., Jiang, Q., 2013.Social cognition and interaction training for patients with stableschizophrenia in Chinese community settings. Psychiatry Res.210, 751–755.

Wilbertz, G., Brakemeier, E.-L., Zobel, I., Härter, M., Schramm, E.,2010. Exploring preoperational features in chronic depression.J. Affect. Disord. 124, 262–269.

Wolf, F., Brüne, M., Assion, H.-J., 2010. Theory of mind andneurocognitive functioning in patients with bipolar disorder.Bipolar Disord. 12, 657–666.

Wolkenstein, L., Schonenberg, M., Schirm, E., Hautzinger, M.,2011. I can see what you feel, but I can't deal with it: impairedtheory of mind in depression. J. Affect. Disord. 132, 104–111.

Wölwer, W., Streit, M., Polzer, U., Gaebel, W., 1996. Facial affectrecognition in the course of schizophrenia. Eur. Arch. PsychiatryClin. Neurosci. 246, 165–170.

Zink, C.F., Meyer-Lindenberg, A., 2012. Human neuroimaging ofoxytocin and vasopressin in social cognition. Horm. Behav. 61,400–409.













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Oxytocin and social cognition in affective and psychotic disorders