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

• ClinicalTrials.gov Identifier: NCT03900754
• Recruitment Status: Not yet recruiting
• First Posted: April 3, 2019
• Last Update Posted: December 13, 2019
• Sponsor: VA Office of Research and Development
• Collaborator: University of California, San Francisco
• Information provided by (Responsible Party): VA Office of Research and Development

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Schizophrenia	Drug: Oxytocin; Drug: Placebo	Phase 2

Detailed Description:

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. 75 participants will be randomized to receive 20IU oxytocin and placebo and 75 will be randomized to receive 40IU oxytocin and placebo, with the order of administration randomized and separated by two weeks. 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 (55 from each cohort of 75) 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 188 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: 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. 75 participants will be randomized to receive 20IU oxytocin and placebo and 75 will be randomized to receive 40IU oxytocin and placebo, with the order of administration randomized and separated by two weeks. 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.
• Masking: Double (Participant, Investigator)
• Masking Description: Double Blind
• Primary Purpose: Treatment
• Official Title: A Pharmaco-imaging Approach to Predicting Social Functioning and Clinical Responses to Oxytocin Administration in Schizophrenia
• Estimated Study Start Date: January 6, 2020
• Estimated Primary Completion Date: September 30, 2024
• Estimated Study Completion Date: September 30, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Intranasal Oxytocin; Dosages of oxytocin: 20IU or 40IU.	Drug: Oxytocin; Intranasal administration of oxytocin; Other Name: Syntocinon
Placebo Comparator: Placebo; Saline	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures :

1. Social Functioning Score [ Time Frame: From the baseline visit in the chronic OT administration portion of the study design to after three weeks of oxytocin administration ]
   The Social Functioning Scale is a 79-item semi-structured interview based assessment that includes [a global summary score (primary outcome) as well as seven subscales (secondary outcomes): social engagement, interpersonal communication, independence, competence, recreation, prosocial, and employment.] A mean of the subscale scores provides overall score of social functioning. Each subscale score is transformed into a standard distribution with a mean of 100 and standard deviation of 15 for comparability and interpretation. Higher scores indicates a high level of functioning.

Secondary Outcome Measures :

1. SSPA score (social skills performance assessment) [ Time Frame: From the baseline visit in the chronic OT administration portion of the study design to after three weeks of oxytocin administration ]
   Social skills will be assessed using the Social Skills Performance Assessment (SSPA), which consists of three role-plays in which the participant is assigned a role and interacts with an assessor for three minutes. The SSPA has established convergent and divergent validity. In order to evaluate empathy in social situations, the investigators will also include a fourth role-play in which participants attempt to console an upset friend played by the assessor. Role-plays will be video-recorded and rated on interest, fluency, clarity, focus, affect, overall conversation/argument, grooming, social appropriateness, and possibly submissiveness/persistence on a scale from 1 very poor to 5 very good. In addition, the investigators will code participant's verbal content and prosody, and facial expressivity using standardized coding systems. The total scores range 8-40 or 9-45 dependent on role-play (higher scores indicate appropriate social skills).
2. TASIT III Scores (the awareness of social inference test) [ Time Frame: From the baseline visit in the chronic OT administration portion of the study design to after three weeks of oxytocin administration ]
   Theory of Mind (ToM) will be assessed using The Awareness of Social Interference Test (TASIT) III, a well-validated audiovisual tool participants make social inferences after viewing 16 video vignettes of actors engaging in social scenarios. In half of the videos, one character depicts a white lie and the other half of the videos consists of a speaker using complex sarcasm. The ability to interpret the vignettes correctly was assessed via a set of 4 yes/no questions for each vignette that focused on the speaker's belief, intention, what the speaker intended the listener to comprehend, and the speaker's emotional state. TASIT III performance has been linked to social functioning in SZ, and the investigators have previously captured OT effects in SZ using this tool. In TASIT III, validated alternate forms of will be counterbalanced across testing days. Higher scores indicate normative social perception.
3. CAINS Score (clinical assessment interview for negative symptoms) [ Time Frame: From the baseline visit in the chronic OT administration portion of the study design to after three weeks of oxytocin administration ]
   Negative symptoms will be assessed with the CAINS, comprising two subscales reflecting the negative symptom factors: The 9-item Motivation and Pleasure subscale (each item is scored from 0 no impairments to 4 severe deficit) captures experiential negative symptoms by assessing motivation, behavior, and pleasure derived from social, vocational, and recreational activities over the past week. The MAP total score therefore ranges from 0-36. The 4-item Expression subscale (each item is scored from 0 no impairment to 4 severe deficit) captures both non-verbal (face, posture) and verbal expressivity (output, prosody). The EXP total score ranges from 0 to 16 (higher scores indicate greater severity of symptoms). The CAINS has excellent convergent and divergent validity.
4. CAMS (Computerized Assessment of Mental Status) [ Time Frame: From the baseline visit in the chronic OT administration portion of the study design to after three weeks of oxytocin administration ]
   Participants will watch 5 short (~90s) videos previously shown to induce strong emotional responses (joy, sadness, fear, disgust, pain) in healthy people. Facial expressivity including valence (positive, negative) and intensity, during video viewing will be coded by trained and calibrated raters using the validated Facial Expression Coding System.

Other Outcome Measures:

1. Brief-IPSAQ (internal, personal, and situational attributions questionnaire) [ Time Frame: From the baseline visit in the chronic OT administration portion of the study design to after three weeks of oxytocin administration ]
   Attributional bias will be assessed with the brief-IPSAQ (Internal, Personal, and Situational Attributions Questionnaire, which presents hypothetical events (8 positive, 8 negative) involving a friend. For each event, participants determine the most likely cause of the situation and decide if the cause is linked to the participant, the participant's friend, or the situation. Two cognitive bias scores are derived: externalizing (EB) (i.e., the number of internal attributions for positive events minus internal attributions for negative events) and personalizing (PB) (i.e., the number of personal external attributions for negative events divided by the number of personal plus situational external attributions for negative events).] Positive EB indicates strong self-serving biases, PB score > 0.5 indicates tendency to use personal rather than situational external attributions for negative events.
2. QLS Scale (quality of life) [ Time Frame: From the baseline visit in the chronic OT administration portion of the study design to after three weeks of oxytocin administration ]
   Quality of Life will be assessed with the Quality of Life Scale (QLS), a 9-item assessment that measures domains such as interpersonal relations, occupation role functioning, and intrapsychic foundations. Each item is rated from 0 to 6 with the lower values indicating greater severity of symptoms. As such, the total score ranges from 0-54 (higher scores indicate good quality of life).
3. SAPS Scale (Scale for Assessment of Positive Symptoms) [ Time Frame: From the baseline visit in the chronic OT administration portion of the study design to after three weeks of oxytocin administration ]
   Positive symptoms will be assessed with the Scale for Assessment of Positive Symptoms (SAPS), a 34-item interview-based assessment that focuses on four sub-scales, which are hallucinations, delusions, disorganized behavior, and thought disorder. There are thirty individual symptom ratings (from 0 none to 5 severe) and four global symptom severity scores.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Veteran
• age 18-65
• a diagnosis of schizophrenia determined by the Structured Clinical Interview for DSM-V
• no medication changes or psychiatric hospitalizations in the past month
• SFS raw score of no more than 115
• CAINS Motivation and Pleasure subscale score of at least 18
• CAINS Experience subscale score of at least 8.

Exclusion Criteria:

• substance use disorder in the past month
• 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 or 5HT1a agonists/antagonists
• inability to complete VOT

Contacts and Locations

Contacts

Contact: Josh Woolley, BS; (415) 221-4810 ext 4117; Josh.Woolley@ucsf.edu

Contact: Lisa Lin, BA; (415) 221-4810 ext 23318; lisa.lin@ucsf.edu

Locations

United States, California

San Francisco VA Medical Center, San Francisco, CA; Not yet recruiting

San Francisco, California, United States, 94121

Contact: Lisa Lin, BA 415-221-4810 ext 23318 lisa.lin@ucsf.edu

Principal Investigator: Josh Woolley, BS

Sponsors and Collaborators

VA Office of Research and Development

University of California, San Francisco

Investigators

• Principal Investigator: Josh Woolley, BS; San Francisco VA Medical Center, San Francisco, CA

More Information

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT03900754 History of Changes
• Other Study ID Numbers: MHBB-011-18F; 19-27265 ( Other Identifier: University of California, San Francisco )
• First Posted: April 3, 2019
• Last Update Posted: December 13, 2019
• Last Verified: December 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by VA Office of Research and Development:

Oxytocin

Additional relevant MeSH terms:

Schizophrenia; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Oxytocin; Oxytocics; Reproductive Control Agents; Physiological Effects of Drugs