Oxytocin + Non Specific Counselling Clinical Trial
Official title:
A Randomized Trial Administering Oxytocin vs Placebo as add-on to Antipsychotics in Patients With Schizophrenia and Schizo-affective Disorder
The objectives of the study are:
1. To evaluate the effect of OT compared to placebo, as add-on to anti-psychotics, on
social functioning in schizophrenia.
2. To evaluate the effect of socially oriented CBT administered to patients immediately
after they receive OT, compared to patients who receive OT with not-socially oriented
CBT, and compared to patients who receive socially oriented CBT without OT. The
investigators hypothesize that OT and socially oriented CBT will have a synergistic
effect, and will be better than OT or CBT alone.
3. Use a detailed, in depth analysis of social interaction to assess these putative
effects of OT. The investigators hypothesize that the use of this analysis will show
larger treatment effects of OT than previously shown in less sensitive assessments,
such as PANSS.
4. To assess the effect of epigenetic status on response to OT. The investigators
hypothesize that epigenetic variants associated with lower OT plasma levels will be
associated with greater response to OT treatment.
5. To assess in the relationships between levels of salivary OT and vasopressin, and
social interactions in schizophrenia.
6. To assess in the relationships between levels of salivary OT and vasopressin, and
response to OT treatment.
Social disability is a hallmark of schizophrenia, and improving social functioning in
schizophrenia should improve patients' overall functioning and quality of life. Oxytocin
(Granholm, McQuaid et al.) is a nine amino-acid neuropeptide synthesized in the
hypothalamus, has found to modulate social behaviors in mammals, including humans (Insel and
Young 2001; Kosfeld, Heinrichs et al. 2005). Among its influences on human social behavior
are increased trust (Kosfeld, Heinrichs et al. 2005), empathy (Hurlemann, Patin et al. 2010)
and eye contact (Guastella, Mitchell et al. 2008).
Impaired social behaviors are a core domain of Autism Spectrum Disorders (ASD) (Modahl,
Green et al. 1998; Bartz and Hollander 2008); studies have shown that social disabilities
have been associated with OT dysfunction in ASD, and have been improved by administration of
intranasal OT (Hollander, Bartz et al. 2007; Andari, Duhamel et al. 2010; Guastella, Einfeld
et al. 2010).
Furthermore, epigenetic changes in the genes encoding for OT have been demonstrated in
autism (Gregory, Connelly et al. 2009)
Impaired social functioning is a hallmark of schizophrenia; studies show that plasma levels
of endogenous OT are lower in schizophrenia patients compared to controls, and patients with
lower levels of plasma OT have more positive symptoms (Kéri , Kiss et al. 2009; Kיri, Kiss
et al. 2009; Rubin, Carter et al. 2010). Moreover, a recent study demonstrated a significant
genetic association between OT and Arginine Vasopressin, another peptide linked with social
behavior, and schizophrenia (Teltsh, Kanyas-Sarner et al. 2011). Only two published studies
have investigated the therapeutic potential of OT in schizophrenia; both administered OT in
addition to anti-psychotic treatment. Feifel (Feifel, Macdonald et al. 2010) reported a
decrease in positive symptoms after 3 weeks of treatment, and Pedersen (Pedersen, Gibson et
al. 2011) reported an improvement in social cognition. There is ongoing research aiming to
validate these findings.
Vasopressin is also a peptide with a putative effect on social interaction (Ebstein, Israel
et al. 2009; Heinrichs, von Dawans et al. 2009). In this proposed study we will assay
salivary levels both of OT and vasopressin.
In this proposed study we intend to administer OT in a placebo-controlled, double-blind
design to patients with schizophrenia. In addition to assessing the effect of OT on the
symptoms of schizophrenia, this proposal has four characteristics which we believe are
unique, and we hope will enable a large step forward in understanding the role of OT in
schizophrenia.
- Social functioning: will be assessed using previously validated techniques, by
video-taping interviews with schizophrenia patients. The quality of the social
interactions will then be assessed, by raters blinded to treatment status. The
assessment will , specifically focus on the gaze to the experimenter's face,
vocalization (patient's vocal output, positive/negative tone, and fluent speech) and
affect, body tone, movements, and other non-verbal signs. This technique was developed
in Prof. Feldman's lab, and has been show to accurately assess social interactions
(Feldman, Masalha et al. 2001; Feldman and Klein 2003; Feldman and Eidelman 2009;
Feldman 2010). This technique will enable meticulous quantification of the putative
effects of OT on social functioning in schizophrenia.
- Data from preclinical models of traumatic brain injury (Feeney, Gonzalez et al. 1982)
and clinical studies in stroke patients (Crisostomo, Duncan et al. 1988; Scheidtmann,
Fries et al. 2001; Taub, Uswatte et al. 2002)] suggest that new learning develops
faster, has increased magnitude and is longer lasting under a combined intervention of
drug and practice relative to learning occurring under either intervention in
isolation. Similar thoughts have been expressed regarding compounds which putatively
enhance cognition, in that patients who receive compounds which enhance cognition
should be treated with cognitive remediation at the same time. We propose to apply this
concept to OT. In this proposal, patients will be treated with cognitive-behavioral
therapy (socially oriented CBT) focused on social interactions, emphasizing eye
contact, body language, empathy, etc. Socially oriented CBT will be administered three
times/week during the time period immediately after OT administration, when OT is
active. There will be a control CBT condition addressing medication compliance and
vocational rehabilitation, without any social orientation, with somewhat analogous
demand characteristics. We hypothesize that the combined effects of OT co-administered
with socially oriented CBT will be synergistic, i.e. greater than the effect of either
alone.
- The effects of epigenetic variation on the effects of OT treatment will be examined by
assessing epigenetic status of subjects, and these will be correlated with response to
treatment. We will examine the methylation status of two CpG sites (-934 and -924) in
the OXTR promoter. The epigenetic evaluation would detect whether the exogenously
administered OT changes OXTR genes, their expression or function on OT levels and
behavior.
- Two previous studies have administered 40 international units (IU) X2/d= 80 IU/d
(Feifel, Macdonald et al. 2010) or 24 IU X2/d= 48 IU/d (Pedersen, Gibson et al. 2011),
with no adverse effects. Based on this data, we propose to administer 24 IU X3/d= 72
IU. This dose is lower than Feifel et al. and no adverse effects were seen. Therefore,
we are sure that thus dose is safe.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment