Oxytocin as Adjunctive Treatment of Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 2

Summary: 
      The focus of the current project is to advance our understanding of the effects of oxytocin
      (OT) on components of social cognition in schizophrenia (SCZ). Despite the rapid increase in
      our understanding of the role of OT in rodent models of social behavior and an explosion of
      interest in the prosocial effects of OT in healthy controls, little work has been done to
      dissect the potential effects of OT on SCZ subjects with social deficits. Social deficits are
      a crucial aspect of the functional impairments that limit the rehabilitation of patients with
      SCZ. In particular, SCZ patients with enduring negative symptoms (deficit syndrome,
      Kirkpatrick et al. 1989) have prominent social deficits as a core feature of this subtype of
      the illness. Our currently available medications do very little to improve these social
      deficits. Hence it is of utmost public health importance to address the knowledge gap
      regarding the potential of OT to improve social function in this illness. Intact social
      function depends on the competent functioning of several cognitive domains that subserve
      perception of social cues and the generation of motivated social behavior. We propose to
      conduct a pharmacological challenge study of OT vs. placebo administration to study the
      effects of OT on specific components of social cognition in male deficit syndrome SCZ
      subjects.

      Primary Hypothesis: Intranasal OT will improve social cognition in subjects with deficit
      syndrome SCZ.
    

Detailed description: 
      Specific Aim 1: Administer OT intranasally vs. placebo in a parallel group double-blind
      design to 40 deficit syndrome SCZ subjects. Following OT or placebo (PBO) dosing, components
      of social cognition will be assessed as follows.

        1. Evaluate the salience of social cues by the measurement of visual scan paths during gaze
           at pictures of faces.

        2. Evaluate sensitivity to social reward by means of a computerized social reward
           ball-tossing task that assays social interactions in response to social reward.

        3. Evaluate social cognition by means of testing the ability to correctly identify emotion
           from pictures of faces (Facial Emotion Identification Test, FEIT).

      BACKGROUND

      Impaired social functioning is an important symptom in SCZ SCZ is a chronic severe psychotic
      illness that affects two to three million Americans, over 100,000 of whom are veterans (Owen
      et al. 2004). There are several key symptom domains that characterize the illness. Positive
      symptoms (such as hallucinations and delusions) are at least somewhat responsive to
      antipsychotic medication in a majority of patients. Negative symptoms such as poor
      motivation, anhedonia, poor social function, and poor occupational function are poorly
      responsive to medication or other currently available treatments. The deficit syndrome has
      been defined as a complex of these negative symptoms that endure throughout the course of a
      schizophrenia patient's disease (Kirkpatrick et al. 1989). The social impairments seen in
      these patients are core deficits that have been linked to poor functional outcomes (Couture
      et al. 2006; Fett et al. 2011). Furthermore, deficits in social cognition have been proposed
      to underlie and contribute significantly to impaired social functioning (Kern et al. 2008;
      Green et al. 2008). An underlying hypothesis of this work is that if social cognition could
      be effectively treated, these patients would improve their social and functional outcomes,
      potentially enabling them to achieve occupational competence, sustain stable independent
      living, and lead more fulfilling independent lives. Thus our understanding and treatment of
      the social impairments of SCZ is very important from a public health perspective.

      OT effects on social cognition and behavior Studies in rodents demonstrate a critical role
      for the neuropeptide OT in social bonding (Young et al. 2005). A large and rapidly growing
      translational literature indicates that this neuropeptide may also play a prosocial role in
      human behavior. The prosocial effects of OT administration have already been extensively
      reviewed in the literature (Striepens N et al., 2011). In the area of trust and altruism,
      studies utilizing a variety of economic and cooperation paradigms indicate that OT enhances
      trusting and social cooperation (Baumgartner T et al., 2008; De Dreu CK et al., 2010;
      Declerck CH et al., 2010; Kosfeld M et al., 2005; Mikolajczak M et al., 2010; Zak PJ et al.,
      2007). Feelings of empathy to others were enhanced with OT in three studies (Domes et al.
      2007; Bartz et al. 2010; Hurlemann et al. 2010). Several studies indicate that OT increases
      the ability of healthy controls to identify emotion in faces (Di Simplicio et al. 2009;
      Fischer-Shofty et al. 2010, Marsh et al. 2010). There are reports using memory paradigms, in
      which OT administration induced enhanced recall of faces after OT (Savaskan et al. 2008;
      Rimmele et al. 2009), although an earlier study found no improvement (Ferrier et al. 1980).
      OT administration also increased recall of social words (Unkelbach et al. 2008). There is
      some indication that OT effects on recall are specific to emotional stimuli since several
      studies in healthy controls found that OT did not improve memory for nonsocial stimuli
      (Bruins J et al., 1992; Fehm-Wolfsdorf G et al., 1984; Geenen V et al., 1988; Kennett DJ et
      al., 1982).

      OT as potential treatment in SCZ Several lines of reasoning suggest that OT could be helpful
      as adjunct treatment of SCZ.

        1. Patients with SCZ have altered OT levels compared to healthy controls (Linkowski et al.
           1984; Beckmann et al. 1985; Legros et al. 1992; Goldman et al. 2008; Keri et al. 2009).

        2. fMRI in concert with intranasal OT administration was associated with reduced
           blood-oxygen-level-dependent (BOLD) activation in the amygdala during presentation of
           fearful/threatening faces and scenes (Kirsch et al. 2005). This study gives indirect
           support to the idea that OT may ameliorate paranoia in patients with SCZ.

        3. The negative symptoms of SCZ include social isolation, autism, and amotivation for
           social engagement. There is face validity to the notion that OT could help with these
           symptoms in virtue of its pro-social action.

        4. To date there are three published placebo controlled trials of OT in SCZ. In the first
           study, OT was given in a placebo-controlled double-blind randomized crossover design
           (Feifel et al. 2010). In this study of fifteen completers, the Positive and Negative
           Symptom Scale (PANSS) and the Clinical Global Impressions scale (CGI) were used as
           outcome measures. OT added to antipsychotic treatment resulted in a significant
           improvement in positive symptoms, as measured by the PANSS total score, PANSS positive
           symptom subscale, PANSS negative symptom subscale, and the CGI. The effect size for
           these changes ranged from 0.40 for PANSS positive symptoms to 0.74 for the CGI.
           Furthermore, treatment with OT was well tolerated, with no significant differences
           between OT and placebo in rates of adverse effects nor in blood chemistry (Feifel et al.
           2010). This same group published a second paper indicating an improvement in verbal
           memory in SCZ subjects following three weeks of twice daily OT (Feifel et al. 2012). The
           third study reports that two weeks of OT reduced psychotic symptoms and improved
           performance in a Theory of Mind task (Pedersen et al. 2011).

      Dissecting components of social impairment in SCZ Intact social competence depends on
      adequate function in several cognitive domains that subserve perception of social cues and
      motivated social behavior. We propose to interrogate these composite domains after
      administration of OT vs. placebo in this project.

      i. Eye tracking. Relevant social cues must be of sufficient salience to command attention.
      This aspect of social cognition has been investigated by means of visual scan path paradigms
      that quantify the amount of time a subjects spends looking at the eyes and mouth regions of
      pictures of faces presented while the position of the eyes is tracked. The amount of eye gaze
      is predictive of a subject's ability to correctly identify emotions and meaning in others
      (Haxby et al. 2002). A single dose of OT significantly increases the amount of eye gaze in
      healthy controls (Guastella et al. 2008a) and in high functioning subjects with autism
      spectrum disorders (Andari et al. 2010). SCZ subjects have abnormalities in visual scan paths
      while viewing pictures of faces (Phillips and David 1997; Loughland et al. 2002a). Thus we
      hypothesize that OT will increase gaze at the eyes in subjects with deficit syndrome SCZ
      (Specific Aim 2a).

      ii. Social Reward Ball-Tossing Task. Social stimuli must be sufficiently rewarding to
      motivate decision-making and behavior. This aspect of social function has been investigated
      with a computerized social interaction game that assays the effects of social reinforcement
      on decision-making. In a task developed by Andari et al. (2010) that was derived from an
      earlier task by Williams et al. (2000), subjects engage in a computerized version of a
      ball-toss game in which three fictional partners vary the proportion of times they throw the
      ball back to the subject. The outcome measure of interest was the choices made by the subject
      regarding to which fictional player they would throw the ball. In a study of high functioning
      autism spectrum subjects, OT administration selectively enhanced return of the ball to the
      most socially cooperative fictional partner (Andari et al. 2010). This result was interpreted
      as evidence that OT enhances appropriate behavioral responses to the social reward of
      reciprocity. We hypothesize that OT administration will enhance socially reinforced behavior
      in subjects with deficit syndrome SCZ (Specific Aim 2b).

      iii. Facial Emotion Identification Task (FEIT). The socially competent person must be able to
      correctly identify the emotions in others in order to respond appropriately during social
      communication. The correct identification of emotions in others is a key aspect of social
      cognition that has been linked to functional outcomes in SCZ (Couture et al. 2006). This
      aspect of social cognition has been investigated in paradigms that query the subjects on
      identifying emotions displayed in pictures. Most studies in the literature report that
      patients with SCZ are deficient in the correct identification of emotions displayed in
      pictures of faces (Addington et al. 2006; Bigelow et al. 2006; van't Wout et al. 2007;
      Averbeck et al. 2012 and see review in Couture et al. 2006), although not all studies have
      found such impairments (de Achaval et al. 2010). The classic series of pictures of faces
      introduced by Eckman and Friesen (1976) have been used in many studies of affect recognition,
      but other series of pictures have also been utilized (Erwin et al. 1992; Kerr and Neale
      1993). OT administration has been shown in two studies to increase the correct identification
      of emotions in faces in subjects with SCZ (Goldman et al. 2011; Averbeck et al. 2012). We
      hypothesize that deficit syndrome SCZ subjects will exhibit improvement in facial emotion
      recognition after administration of OT (Specific Aim 2c).
    

Intervention name(s): Oxytocin; Placebo; Control
Intervention type(s): Drug; Drug; Other
Intervention description(s): OT intervention will be administration of OT intranasally at a dose of three 4 IU puffs per nostril for a total dose of 24 IU. This dose has been used in a number of other similarly designed challenge studies examining the effects of a single dose of OT (Kirsch et al. 2005; Kosfeld et al. 2005; Guastella et al. 2008a; Guastella et al. 2008b; Rimmele et al. 2009; Andari et al. 2010).; The PBO/control will consist of the OT vehicle only delivered as 3 puffs of saline per nostril for a total of 6 puffs. Each puff contains 0.1 ml in volume, so the total delivered will be 0.6 ml intranasally.; Participants who have no psychiatric diagnosis and will be controls for this project. These controls will NOT receive oxytocin or PBO. They will only receive psychiatric screening interview, MCCB Consensus Cogntive Battery assessment, urine drug screen, vision testing, and the three social cognition tasks.
Other intervention name(s): Syntocinon; Inactive vehicle
Intervention MeSH terms: Oxytocin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment