Oxytocin Treatment of Social Cognitive and Functional Deficits in Schizophrenia

Overview of Procedures: All procedures will be conducted at the UNC Hospitals Clinical and Translational Research Center (CTRC) outpatient clinic or at the outpatient North Carolina Psychiatric Research Center (NCPRC), a specialized program of the University of North Carolina Center for Excellence in Community Mental Health in Raleigh, NC. Except for Screening, all clinic visits will begin between 0800-1000 hours and subjects will have fasted since midnight. Approximately 10 minutes after checking into the clinic, subjects' weight and vital signs will be measured followed by blood and urine sample collection. Breakfast will then be served. At regular intervals during each clinic visit, subjects will be allowed to rest for 15-20 minutes. Lunch will also be provided for the subjects.

Screening assessment: During the initial clinic visit and after giving informed consent, prospective subjects' psychiatric and medical histories will be reviewed, physical exams conducted, EKGs run and blood and urine collected for complete blood count (CBC), electrolytes, liver/renal function tests, TSH, glucose, urinalysis (UA), pregnancy test, and urine drug screen (UDS). The Structured Clinical Interview for DSM-IV will be administered to confirm diagnoses if one not on record within the past two years. The WRAT will be administered to determine reading ability as well as the Reading the Mind in the Eyes Test (Eyes Test) to determine if subjects meet the social cognition criterion for impairment. Finally, PANSS and Calgary Depression Scale ratings will be obtained.

Baseline and Treatment Week 6 and 12 assessments: All of the primary and secondary outcome measures will be obtained during clinic visits at Baseline (occurring within 1 week after the Screening assessment) and at the end of the treatment trial (12-week time point). Some of the outcome measures will be obtained at a clinic visit at the 6-week time point during the treatment trial. Subjects will arrive at the clinic between 8:00 and 10:00 a.m. for each of these visits where they will be given breakfast. At Baseline, administration of assessments will begin 10 min after completion of breakfast. At the 6 and 12-week clinic visits, assessments will begin 50 min after intranasal administration of test treatment (which will be given before breakfast-see details below). The primary outcomes are social cognition measures (details below): emotion recognition (ER-40, Eyes Test), theory of mind (Eyes Test, Brüne test), social perception (Trustworthiness Task) and attributional style (AIHQ). The secondary outcomes (details below) are social functioning (SLOF), social skill (role plays), psychotic symptoms (PANSS), paranoia (Green Paranoia Thought Scale), empathy (IRI), non-social cognition (RBANS), anxiety (Liebowitz social anxiety scale) depression (Calgary Depression Rating Scale), social perception (IPT-15) and food cravings (Food Craving Inventory and Night Eating Questionnaire). While we ultimately want to improve social functioning, we acknowledge that this domain might be slower to improve than social cognition, thus rendering it a secondary rather than primary outcome (and for that reason, we are assessing social functioning only at baseline and week 12 (end of treatment)). We included non-social cognition in the battery to assess whether treatment effects on social cognition generalize to other domains of cognition. A similar sentiment underlies our inclusion of symptoms (both psychotic and general) in the battery, as the value of OT may be enhanced if it can impact symptoms that might ultimately interfere with treatment engagement. Finally, we included empathy because of the relationship with theory of mind.

Test substance administration and other procedures during the treatment trial: During the treatment trial, subjects will self-administer test treatments twice daily; before breakfast and before dinner. Each treatment consists of 6 insufflations (each 0.1 ml) of Syntocinon Spray (Novartis), which contains 24 international units of OT, or placebo solution containing all of the ingredients in Syntocinon Spray except OT. Blind-labeled test treatment vials will be dispensed following a randomization scheme permuted in blocks of 4, stratified by gender, as oxytocin often has different effects in males and females, in animals and in humans. Subjects will self administer test treatments from 60 ml spray vials (ejecting 0.1 ml per spray) initially containing 35 ml of test substance. Each vial contains enough solution for 3 weeks of self administration. Subjects will receive their first vial of test treatment right after assessments are complete at the Baseline clinic visit. They will be instructed in intranasal self administration and care of test vials at that time and given written instructions on these matters. They will take their first intranasal test dose under the observation of research nurses before leaving the clinic. Before leaving the clinic, subjects will be given a card with the date of their return appointment in one week.

Subjects will return to the clinic at the 2, 6, 9 and 12 week time points during the treatment period. At the 2, and 9-week visits, subjects will have a brief visit with a study clinician who will assess side effects, perform a mental status examination, administer the PANSS and CGI. Spot urine pregnancy tests will also be done at the 2 and 9 week visits. At the baseline, 6 and 12-wk time points, subjects will arrive at the clinic between 8:00 and 10:00 a.m., having fasted overnight. Before eating breakfast, weight and vital sign measurements will be obtained along with blood and urine samples. Blood collected at baseline will be used to measure serum glucose and lipids and urine will be used to screen for pregnancy in women and for drug screening in all subjects. Blood and urine samples obtained at the 6 and 12-week time points will be used for the same measures obtained at the Screening visit. EKG will also be repeated at the 6 and 12-week time points. Prior to breakfast at the 6 and 12-wk time point visits, subjects will self-administer their morning dose while observed by a research nurse to be sure the process is being done correctly. To obtain plasma for later assay of OT concentrations, blood will be drawn 40 minutes after the morning test dose into a chilled EDTA vacutainer tube which will be immediately placed in an ice bath and spun down within 20 minutes. Plasma samples will be stored at ultralow temperatures. OT levels may reflect individual variability in OT absorption and metabolism and will be a covariate in statistical analyses.