Oxytocin as Adjunctive Treatment of Schizophrenia

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).

Subjects for the study will be forty male VA patients with a diagnosis of schizophrenia.
Diagnosis will be determined using the Structured Clinical Interview for DSM-IV Axis I
Disorders/SCID-P (Spitzer et al. 1992). Subjects must be categorized as having a primary
deficit syndrome on the Kirkpatrick Schedule for the Deficit Syndrome (Kirkpatrick et al.
1989).

Additional inclusion criteria:

1. Subjects must be between 18 and 55 years old at the time of study screening.

2. Subjects must demonstrate adequate decisional capacity, in the judgment of the
consenting study staff member, to make a choice about participating in this research
study.

3. Subjects must have been psychiatrically and medically stable for 8 weeks prior to
consent in the judgment of the Principal Investigator.

4. Subjects must have been maintained on a stable treatment of antipsychotics and/or
other concomitant psychotropic treatment for at least 6 weeks prior to consent.

5. Subjects must have no more than a moderate severity rating on hallucinations and
unusual thought content as shown by a score of ≤ 4 on the Positive and Negative
Symptoms Scale (PANSS).

6. Subjects must be able to validly complete the Measurement and Treatment Research to
Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB), in
the judgment of the consenting study staff person.

7. Subjects must have the visual, auditory, and motor capacity to use the computer
software in the judgment of the consenting study staff person. Visual acuity must be
at least 20/30 corrected.

8. Subjects must have a minimal level of extrapyramidal symptoms as shown by a
Simpson-Angus Scale total score of no more than 6.

9. Subjects must have a minimal level of depressive symptoms as shown by a Calgary
Depression Scale (CDSS) total score of no more than 10.

Exclusion criteria:

1. Female sex

2. History of bipolar disorder

3. Active substance dependence within the prior 30 days (cigarette smoking is allowed)

4. Has had a psychiatric hospitalization in the 8 weeks prior to consent.

5. Suicidal or homicidal ideation in the previous six months

6. Subjects who have answered 'yes' to Question 5 (Active Suicidal Ideation with Specific
Plan and Intent) on the Columbia-Suicide Severity Rating Scale, C-SSRS, or who have
answered 'yes' to any of the suicide-related behaviors (actual attempt, interrupted
attempt, aborted attempt, preparatory act or behavior) on the C-SSRS "Suicidal
Behavior" portion shall be excluded from the study if ideation or behavior occurred
within one month of consent. Subjects excluded for this reason will be referred for
appropriate treatment.

7. History of mental retardation or pervasive developmental disorder

8. History of neurological disorder (e.g., traumatic brain injury, seizure disorder,
Parkinson's Disease, dementia), loss of consciousness for more than 10 minutes due to
head trauma, known HIV infection, or AIDS

9. Treatment with a benzodiazepine in the two weeks prior to consent.