Does Acute Oxytocin Administration Enhance Social Cognition in Individuals With Schizophrenia?

Schizophrenia is characterized by the presence of positive symptoms (delusions,
hallucinations, disorganization of thought process and behavior) as well as negative
symptoms (blunted affect, alogia, and avolition), neurocognitive deficits, and impaired
social cognition. While positive symptoms can often respond well to antipsychotic
medications, the latter symptoms are more difficult to treat. In this study, we will focus
on social cognition, which is defined as the functions that are engaged during social
interactions. Social cognition has been categorized into four main domains: theory of mind,
social perception, attributional bias, and emotional processing. Social cognition in
patients with schizophrenia has been found to be critical in predicting multiple aspects of
community functioning. There are currently two broad approaches to improve social cognition
in patients with schizophrenia: pharmacological and psychosocial interventions. While
psychosocial interventions (training exercises to target improvement in domains of social
cognition) have shown some benefit, their resultant improvements have been limited in their
distribution across multiple domains as well as their generalization to improved functioning
in the community. Pharmacological trials have yielded mixed results, and there are not any
currently available medications that have been consistently found to improve social
cognition in patients with schizophrenia2. One potential future therapeutic target for
enhancing social cognition is the oxytocin system.

Oxytocin is a nine-amino acid peptide that, in addition to its role in the periphery for
regulating lactation and uterine contractions, functions centrally as a neurotransmitter
which is involved in multiple aspects of social behavior and related emotions. Specifically,
it has been found to modulate emotion recognition, trust, eye contact, empathic accuracy, as
well as envy and gloating. Given oxytocin's role in social functioning, in conjunction with
the deficits in social functioning found frequently in individuals with schizophrenia, there
have been several studies over the past three decades examining the oxytocin system in
humans with schizophrenia and in rodent experimental models.

It has been found that individuals with schizophrenia do not show the same level of increase
in oxytocin as normal controls in response to trust-related interpersonal interactions, and
low plasma oxytocin predicted negative symptoms of schizophrenia. Additionally, it has also
been found that plasma oxytocin levels predicted the ability of patients with schizophrenia
to identify facial expressions. Finally, it has been found recently that sustained regular
administration of intranasal oxytocin significantly reduced both positive and negative
symptoms of schizophrenia. Thus, there is significant evidence supporting further research
studying the effect of oxytocin on social cognition. It is not yet known if exogenous
administration of oxytocin will have acute effects on neuropsychological measures of social
cognition in individuals with schizophrenia, and this is the focus of this proposed pilot
study.

The overall hypothesis guiding this study is that acute oxytocin administration will improve
social cognition (as assessed by a composite score comprising two measures of "low level"
social cognitive processes and two measures of "high level" social cognitive processes) in
individuals with schizophrenia. Our primary goals are to assess the feasibility of this
experimental paradigm and to generate pilot data and obtain estimates of effect sizes which
can be used in planning future larger studies.

Inclusion Criteria:

- Veteran being treated in the Veterans Administration Healthcare System

- Meet DSM-IV-TR criteria for Schizophrenia

- At least 6 months since any hospitalization or substantial increase in level of care
for an acute exacerbation of psychotic symptoms

- At least 1 month since meeting the criteria for having a major depressive episode

- At least 6 months since any behaviors suggesting any potential danger to self or
others

- Adherence to the regular administration of an antipsychotic medication (e.g.,
risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone,
iloperidone, asenapine, fluphenazine, haloperidol, loxapine, molindone, perphenazine,
thiothixene, chlorpromazine, clozapine)

- Dose of antipsychotic medication not varying by more than 25% over the 3 months prior
to study participation

- No acute medical problems

- Chronic medical conditions (e.g., hypertension, diabetes, dyslipidemia) consistently
treated and stable for at least 3 months prior to study participation

- Ability to provide signed informed consent and to cooperate with study procedures

Exclusion Criteria:

- Documented history of mental retardation or severe learning disability

- History of treatment with electroconvulsive therapy within 6 months prior to study
participation

- History of neurological or neuropsychiatric condition (e.g., stroke, severe traumatic
brain injury, epilepsy, etc.)

- Documented history of persistent substance abuse or dependence within 6 months prior
to study participation

- History of hyponatremia within the past 6 months

- Allergic rhinitis or other inflammation of the nasal mucosa