Individuals who suffer from schizophrenia often show a marked and stable deficit in many aspects of social cognition, such as emotion recognition, social perception, and empathy (Brune, 2005; Green et al., 2005, 2012; Derntl et al., 2009; Kohler et al., 2010; Achim et al., 2011). These deficient abilities are consistent over time, apparent in the prodrome to psychosis (Amminger et al., 2012a,b; Thompson et al., 2011, 2012) and seriously impede social competence (Brune et al., 2007; Smith et al., 2012). Indeed, they have a tremendous impact on overall proficiency and rehabilitation results, leading Wible (2012) to define this illness as one of “social communication.” Furthermore, social cognition has been suggested as a mediator between neurocognition and functional outcome, demonstrating once more this domain's prominent role in this disease (Green et al., 2012).

Numerous studies of schizophrenic patients over the last decades have shown a consistent and marked impairment in emotion recognition via facial expression (Pinkham et al., 2007; Kohler et al., 2010), prosody (Edwards et al., 2001, 2002; Hoekert et al., 2007; Roux et al., 2010; Jahshan et al., 2013), and whole body movements (Singh et al., 2011). Furthermore, impairments in emotion recognition have been shown to predict functional outcome for schizophrenic patients (Irani et al., 2012).

Facial emotion recognition has been widely investigated in the context of schizophrenia, due to its correlation with global functioning, as well as the fact that patients with schizophrenia show a consistent impairment in this domain. Furthermore, previous studies have suggested that compared with the recognition of other emotions (i.e., happiness), patients with schizophrenia may have a selective dysfunction in the perception of negative emotions such as fear (Kohler et al., 2003; Hofer et al., 2009; Huang et al., 2011; Amminger et al., 2012a,b; Chen et al., 2012). For example, Chen et al. (2012) reported a deficit in fear discrimination in patients with schizophrenia compared to healthy control subjects, as well as a significant correlation between fear discrimination and Positive and Negative Symptoms of Schizophrenia (PANSS) negative symptoms scores. A specific impairment in fear recognition was also evident in a group of patients with schizophrenia (Leung et al., 2011), as well as in the studies of Norton et al. (2009) and Amminger et al. (2012a,b). These findings suggest that while fear recognition may not encompass the whole social cognition deficit shown by patients with schizophrenia, it might have a considerable importance with respect to this disorder. Impaired fear recognition has been associated with maladaptive aggressive behavior in schizophrenia (Weiss et al., 2007), as well as in other socially impaired populations (Marsh and Blair, 2008). Earlier, Marsh et al. (2007) showed evidence to support that fear recognition in healthy participants is strongly associated with prosocial behavior. Thus, it is possible that improving fear recognition in schizophrenia may be valuable in diminishing their levels of social impairment and improve their daily interactions.

We have recently developed a novel explanatory model of social impairments in schizophrenia that focuses on dysfunction in the oxytocinergic system (Fischer-Shofty et al., 2013). Oxytocin (OT) has repeatedly been shown to improve different facets of social cognition, such as emotion recognition (Fischer-Shofty et al., 2010; Marsh et al., 2010; Lischke et al., 2012a,b; Van and Bakermans-Kranenburg, 2012), empathy (Domes et al., 2007a,b; Bartz et al., 2010; Krueger et al., 2013), and trust (Kosfeld et al., 2005; Theodoridou et al., 2009). Recently, Lischke et al. (2012a,b) reported that intranasal administration of OT (IN OT) increased participants' ability to detect emotion in facial expressions, as compared to a placebo group. Schulze et al. (2011) demonstrated a similar effect of enhanced emotion detection following IN OT administration, as expressed in more accurate performance on tasks involving emotion recognition of masked facial expressions. Consistent with these studies, we previously reported that intranasal administration of OT specifically improved accurate recognition of fearful facial expressions (Fischer-Shofty et al., 2010). An improvement in emotion recognition, and that of fear in particular, following OT administration was also evident in the recent meta-analysis of Shahrestani et al. (2013), adding further evidence for the possible role of OT in fear recognition.

Thus, the oxytocinergic system is a promising neuromodulator of emotion recognition that may have the potential to normalize the social dysfunction seen in schizophrenia. Indeed, studies have shown abnormal levels of OT in the plasma of patients with schizophrenia (Goldman et al., 2008), as well as in their cerebrospinal fluid (CSF) (Linkowski et al., 1984; Beckmann et al., 1985; Legros et al., 1992). Moreover, OT levels have been significantly associated with social functioning of patients (Rubin et al., 2010; Sasayama et al., 2012), and recent studies have linked variations in the OXTR gene to schizophrenia (Souza et al., 2010a,b; Montag et al., 2012a,b). In addition, previous studies suggest an antipsychotic influence of OT among individuals who suffer from schizophrenia (Bujanow, 1974; Feifel and Reza, 1999; Caldwell et al., 2009; Feifel et al., 2010; Pedersen et al., 2011; Macdonald and Feifel, 2012). Recently Feifel et al. (2012) reported a beneficial effect for IN OT on verbal memory in schizophrenia. With respect to social cognition, OT was reported to improve emotion recognition among schizophrenic patients (Averbeck et al., 2012), as well as theory of mind and social judgments (Pedersen et al., 2011).

In view of the role of OT in facial emotion recognition (especially fear recognition), as well as the established deficit of patients with schizophrenia in emotion recognition, we sought to examine the effect of IN OT on fear recognition in individuals with schizophrenia. In light of our previous research (Fischer-Shofty et al., 2010) demonstrating that a single dose of IN OT significantly improved fear recognition among healthy men, we hypothesized that patients with schizophrenia would show improved fear (but not happiness) recognition following the administration of IN OT. Second, we sought to compare the effect of IN OT on emotion recognition in patients to that of healthy control individuals. Moreover, based on earlier results exhibiting a selective effect of IN OT on less socially competent individuals (Bartz et al., 2010), we hypothesized that the effect of IN OT administration on fear recognition would be stronger among patients compared to among healthy controls.

Independent-sample t-tests were employed to identify the demographic and clinical characteristics of both groups, as well as to evaluate group differences (see Table 1).

The aim of the current study was to characterize the effect of intranasal administration of OT on fear recognition in individuals with schizophrenia and in healthy controls. In line with our previous study (Fischer-Shofty et al., 2010), our results show that indeed participants were able to detect fearful facial expressions more accurately following IN OT administration regardless of their psychiatric status (e.g., healthy vs. patients). However, it is important to note that not all studies have found a specific improvement in the recognition of fear following IN OT administration, and rather reported a general effect on emotion recognition in patients with schizophrenia (Averbeck et al., 2012) and in healthy individuals (Schulze et al., 2011; Lischke et al., 2012a,b; Van and Bakermans-Kranenburg, 2012). Furthermore, in contrast to Marsh et al. (2010), the current results did not show any effect of IN OT administration on recognition of happiness. Notwithstanding the importance of these studies, they were all limited by relying primarily on still emotional faces. The task used in the present study is highly ecologically valid as it mimics the dynamics of gradual changes in facial expressions. Thus, it is possible that the difference between previous studies and the present study is derives from the use of different tasks of emotion recognition.

A second goal of this study was to investigate whether IN OT affects differently patients and controls. In contrast with our original hypothesis, IN OT did not have a differential effect on patients and controls. While IN OT had a general effect on improving fear recognition, it did not change performance in the groups separately. In the next stage we wanted to examine the differential impact of IN OT depending on individual baseline ability of fear recognition. Our results show that IN OT improved the performance of participants whose baseline performance levels in fear recognition was below the median, while significant difference between IN OT and placebo trials was evident in the above-median subgroup. These findings are in line with the work of Bartz et al. (2010), who reported a selective enhancing effect for intranasal administration of OT on empathic accuracy. In their study, participants were rated according to the Autism Spectrum Quotient (AQ) to determine their basic social capability. While the performance of the more capable subgroup (i.e., lower AQ scores) was not affected by IN OT administration, participants with high AQ scores performed the task better following OT administration. These findings by Bartz, et al. suggest a more “circumscribed” role for IN OT's augmentation of social salience, one that preferentially benefits those with lower baseline capabilities. As mentioned by Bartz et al., these results are in line with the proposition made by Shamay-Tsoory et al. (2009) that IN OT exerts its effect by enhancing the salience of social cues, thus increasing their importance as sensory input. Therefore, it may be that IN OT will mostly benefit those who have deficits in the perception of valuable social signals, as is the case in schizophrenia and other disorders.

Numerous studies have established the dominant and crucial involvement of the amygdala in emotion recognition and particularly in fear processing (see Adolphs, 2008). More recently, increasing evidence has linked OT to the amygdala, mainly as an effect of activation reduction (Kirsch et al., 2005; Pittman and Spencer, 2005; Domes et al., 2007a,b, 2010; Baumgartner et al., 2008; Riem et al., 2012; Rupp et al., 2012), thus associating OT and fear perception. In this regard, it is worth mentioning the study by Huber et al. (2005), which reported an excitatory effect for OT in a distinct part of the amygdala (central and capsular division of the central amygdala). Findings like these suggest a neuromodulatory role for OT in amygdala and brainstem circuits (see Stoop, 2012 for recent review) which may underlie OT's ability to increase the accurate perception and interpretation of survival-related social cues (i.e., facial expressions of fear) (Fischer-Shofty et al., 2010; Labuschagne et al., 2010; Lischke et al., 2012a,b). While OT seems to be useful in heightening one's attention to social cues (Shamay-Tsoory et al., 2009), which might be helpful for individuals who exhibit impaired social attention, it is also worth considering the ramifications of exaggerated social salience. These latter effects may be important in individuals with a maladaptive, hypervigilant social perception system, as can be seen in Borderline personality disorder (Fertuck et al., 2009; Bartz et al., 2011; Frick et al., 2012). Our results are linked to previous data indicating the beneficial effect of IN OT administration on social cognition in schizophrenia. They are also in line with previous studies that reported an association between endogenous levels of OT and social cognition in schizophrenia (Goldman et al., 2008; Rubin et al., 2010; Sasayama et al., 2012), those reporting links between OXTR genes and schizophrenia (Souza et al., 2010a,b; Montag et al., 2012a,b), as well as studies examining the effect of intranasal administration of OT on social cognition in schizophrenia as a single dosage (Averbeck et al., 2012; Goldman et al., 2011) or as a more long-term treatment (Feifel et al., 2010; Pedersen et al., 2011; Modabbernia et al., 2013). These findings further reinforce the hypothetical role of the oxytocinergic system in the epidemiology of this disorder and suggest OT as a possible therapeutic target in schizophrenia.

It is important to note that recent studies suggest a dissociable role for IN OT in males and females. Domes et al. (2010) reported a different neural activation pattern, including the amygdala, following IN OT administration in women, as opposed to men. Similarly, Lischke et al. (2012a,b) have found an increased activation response of women's amygdala following IN OT administration, as opposed to the known reduced activation of the amygdala in men (Kirsch et al., 2005). The sample in the current study included both men and women (with the majority of men), and while our reanalysis of the data using only male participants remained marginally-significant, future studies should use larger samples of women and men and take into consideration sex differences in the context IN OT.

The study has some limitations that should be taking into consideration. One relates to sample size and sample composition. The participants in the current study were healthy individuals and patients with schizophrenia, while other psychiatric populations were not represented in our cohort. Therefore, general implications regarding the effects of intranasal administration of OT on fear recognition should be made with caution. Moreover, our power analysis suggests that a larger sample (more than 150 participants) could provide significant results regarding the contribution of psychiatric status to the reported results. Thus, future studies may examine the study hypotheses using larger samples in order to provide the basis for stronger conclusions. Our results show a general effect of IN OT on fear recognition, while no significant effect was evident in either the patients group or in the healthy control group alone. Therefore it is impossible to infer whether the effect of oxytocin is driven by the patients or by the healthy controls. Moreover, as our regression model indicates, it cannot be concluded which of the groups (i.e., patients or healthy controls) is responsible for these results. In view of the fact that several psychiatric disorders show meaningful deficits in emotion recognition, future studies should further examine this possible effect in larger groups, as well as for other types of social inadequacy seen in mental illnesses such as anxiety, depression, and autism spectrum disorders. In regard to study cohort, future studies should address important issues in the context of schizophrenia, such as illness stage, medication type, and comorbidity, which could potentially affect the results. Finally, it should be noted that in the current study we used only two basic emotions, happiness, and fear. Therefore, any generalization of the effect of IN OT on emotion recognition, other than those who were evaluated in the study must be also done with caution. Moreover, it has been suggested that fearful facial expressions are better recognized in masked faces that lack the mouth region, as opposed to facial expressions of happiness. Thus, we cannot rule out the effect of the masked stimuli used in the current study, which could have had an effect on our results. Another aspect of the study design that could affect our results involves the use of performance following placebo administration as baseline performance. While the use of placebo trials has been reported in previous studies of different drugs and cognition (Farah et al., 2009), the design could be improved by having a second measure of performance following placebo to prevent the use of our predictor variable in calculating the drug effect. Moreover, differences between patients and healthy control participants in education level, as well as intelligence level as assessed by the Shipley test, may also serve as study limitations. Although our controlled analysis did not blemish the original result of interaction between treatment and emotion recognition, nonetheless, future studies which will control for these factors a priori could have stronger results. Therefore, we cannot confidently conclude that IN OT is solely responsible for the apparent difference in emotion recognition. Future studies should rule out the effect of education and intelligence levels on these abilities by employing a matched-group design regarding these factors.