A Pharmaco-imaging Approach to Predicting Social Functioning and Clinical Responses to Oxytocin Administration in Schizophrenia

Schizophrenia has a devastating and disproportionate effect on veterans compared to the general US population. Some of the most disabling symptoms, such as low motivation, difficulty expressing emotions, and decreased ability to infer the mental states of others, cause poor social functioning. This means that veterans with schizophrenia have trouble navigating interpersonal interactions and building meaningful relationships in the community. Unfortunately, current antipsychotic medications typically only improve positive symptoms but fail to improve social functioning deficits, which are strong predictors of poor quality of life and functional outcomes. Oxytocin, a peptide found in the brain, plays an important role in social behavior and is known to moderate affiliation, stress, and learning across taxa. In this study, the investigators will test whether oxytocin could be an effective treatment for social functioning deficits in schizophrenia. The investigators will examine changes in brain activation to understand how oxytocin affects behavior and to predict which individuals may benefit from oxytocin treatment.

The study uses a combined within- and between-subject placebo-controlled study design. After screening, participants will be randomized into two study arms for the fMRI phase of the study. In each study arm, participants will complete a placebo-controlled, within-subject, pharmaco-fMRI paradigm with one of two possible dosages of oxytocin (20 or 40IU) and placebo. In the fMRI scanner, they will complete two well-validated theory of mind tasks: the false belief task and the person description task. Following the fMRI phase of the study, participants will be randomized to receive the same dosage of oxytocin the participant received in the fMRI phase, or placebo, twice daily for 3 weeks. Before and after the three weeks of drug administration, participants will be assessed for social functioning, social ability, negative symptoms, and theory of mind. More participants will be randomized to receive chronically administered oxytocin than placebo to maximize the study's power to test the investigators' hypothesis that acute oxytocin-induced increases in right temporo-parietal junction activity will be positively correlated with improvements in social functioning (primary outcome), social ability, negative symptoms, and theory of mind over three weeks of oxytocin administration.

Eligibility Criteria:
Inclusion Criteria:

* Veteran
* age 18-70
* a diagnosis of schizophrenia, schizophreniform, schizoaffective, or brief psychotic disorder determined by the Structured Clinical Interview for DSM-5
* no medication changes or psychiatric hospitalizations in the past month
* SFS modified raw score of no more than 75

Exclusion Criteria:

* substance use disorder in the past month, except mild to moderate cannabis use disorder
* illness affecting the nasal passages
* significant neurological/medical disorder
* pacemakers
* extensive dental work
* claustrophobia
* deafness
* inability to read
* currently participating in a psychosocial intervention targeting social functioning deficits
* currently taking high dose testosterone or estrogen/progesterone
* inability to complete VOT