Oxytocin as Adjunctive Therapy for Schizophrenia

The Use of Oxytocin as Adjunctive Therapy for the Treatment of Schizophrenia: a Randomized, Double Blind Trial

Background: A large body of research has shown that Oxytocin (OXT) is an important prosocial peptide and there is also initial evidence that the central OXT system is altered in several mental disorders that are characterized by severe social disturbances and deficits, such as anxiety disorders with prominent social dysfunction (e.g., schizophrenia), mood disorders and borderline personality disorder. OXT may reduce psychotic symptoms and may diminish certain social cognition deficits that are not improved by current antipsychotic medications.

Aims: The project has two main aims, listed below:

1. To assess the efficacy of intranasal OXT in reducing negative symptoms in patients with schizophrenia in association with second-generation antipsychotics (SGA);
2. To use an Emotional Priming Paradigm task to assess pre- and post-treatment change in the patients general cognitive and emotional status.

Study Design: Randomized, double-blind, placebo-controlled, cross over design. Materials and methods: Patients involved in the study will be recruited in six centres in the north of Italy. Each subject (aged 18-45, with a duration of the disorder no longer than 10 years) will be enrolled after a screening phase. 80 patients will be randomly assigned to either 40 IU OXT once daily or vehicle placebo, in addition to their pre-study antipsychotic medication regimen: all reasonable attempts maintain the same SGA dosages throughout the study will be made. The study ratio is 1:1. The total study duration for each individual subject will be approximately 8 months, which includes an up to 7-day screening period, a baseline randomization visit, and a four month long cross-over treatment period. Subjects will be trained by researchers about the self-administration of intranasal OXT. A trustworthy caregiver will be trained as well. Each patient will receive every morning a SMS text message on his mobile phone as a reminder for OXT administration.

Before starting the treatment, all patients will be assessed with standardized assessment instruments and will undergo an in depth neuropsychological assessment; additional evaluations, including safety evaluations, will be performed at 4 and 8 month follow-ups.

The primary outcome measure will be the negative score in the Positive and Negative Syndrome Scale (PANSS) performed at 2,4,6 and 8 months since the start of the treatment.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Oxytocin; Drug: Placebo

Detailed Description

The project has two main aims:

1. Aims of the cross-over study To assess the efficacy of intranasal OXT in reducing negative symptoms in patients with SZ (as evaluated with PANSS), in association with standard Second Generation Antipsychotics (SGA)treatment; recruited patients will be aged 18-45 years and will have a disorder duration of no longer than 10 years.
2. Aims of the neuropsychological assessment To use an Emotional Priming Paradigm (EPP) task to assess pre- and post-treatment change in the patients general cognitive and emotional status.

The investigators aim at treating a large sample size of patients with schizophrenia, consisting exclusively of patients with a limited disorder duration and rather young age, for a sufficiently long period of time. Our rationale for employing a longer treatment period than used in previous and on-going trials is to ascertain the possibility of a positive OXT dose-response relationship, which would be observable, however, with longer treatment exposure. Moreover, only patients with a disorder onset of 10 years or less will be enrolled.

They will then be standardized in terms of AP treatment and randomized to OXT or placebo for 8 months.

OXT is a hormone that is naturally present in the human body, and recent studies have suggested that patients with SZ show low levels of this neuropeptide. It is therefore hypothesized that the treatment proposed in this project might balance apparently lower OXT levels in these patients.

Finally, another innovative aspect of this project is the attention at ameliorating patients adherence to treatment by supporting them with a reminder program (automatic SMS will be sent every morning to remind patients the daily OXT self-administration) and involving a trustworthy caregiver who will be trained in OXT administration and will be asked to monitor the patient compliance by recording each self-administration on a written form.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Brescia, Italy, 25125
    • IRCCS Fatebenefratelli
  • Desenzano, Italy, 25024
    • Department of Mental Health
  • Milan, Italy, 20129
    • Institute of Neuroscience, National Research Council
  • Padua, Italy, 35124
    • Department of Mental Health
  • Pisa, Italy, 56100
    • Psychiatric Clinic, University of Pisa
  • Udine, Italy, 33100
    • Psychiatric Clinic, University of Udine
  • Pesaro Urbino
    • Urbino, Pesaro Urbino, Italy
      • Statistical Unit, Institute of Biomathematics, University of Urbino

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with a diagnosis of SZ, according to DSM-IV criteria, for at least one year, evaluated with SCID/P
• A minimum PANSS total score of 55 (indicating moderate severity, due to ongoing AP treatment) .
• A minimum CGI-S score of 4
• Age between 18 and 45 years
• A disorder duration of no longer than 10 years
• Women of childbearing age must test negative for pregnancy at the time of enrolment.

All patients must:

• be on a therapeutic dose of a SGA (or a maximum 2 SGAs) with no major dose changes for at least 4 weeks.
• have the ability to provide informed consent
• be able to use a nasal spray
• reside in the service catchment area
• show evidence of no alcohol or substance dependence in the last year

Exclusion Criteria:

• Diagnosis of mental retardation
• Diagnosis of organic mental disorder
• History of no response to treatment with clozapine
• History of hypersensitivity to OXT or vehicle
• Alcohol or substance dependence in the last year
• Presence of, or history of clinically significant allergic rhinitis as assessed by the treating clinician
• Being pregnant or breastfeeding
• Having given birth in the past 6 months or breast-feeding in the past 3 months
• Low literacy as indicated by an inability to read and understand the consent form

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oxytocin; Each treatment will consist of 10 insufflations (5/nostril alternating between nostrils) of OXT Spray, which contains approximately 40 international units (IU) of OXT	Drug: Oxytocin; Intranasal spray with 40 IU of OXT
Placebo Comparator: Placebo vial; Each treatment will consist of 10 insufflations (5/nostril alternating between nostrils) of placebo Spray, which contains all OXT Spray ingredients except for oxytocin.	Drug: Placebo; Intranasal spray with placebo solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in PANSS negative score, as measured at T0 and at 2,4,6 and 8 months.	Using the PANSS negative score as primary end-point, the investigators expect to observe a reduction in PANSS negative subscale scores in the treated group ranging from 0.9 to 2, with an effect size Cohens d=0.45, in agreement with the results of a previous study, in which authors who observed a reduction of 1.7 with an effect size Cohens d= 0.5. The investigators also expect that OXT will have a positive influence on the patients quality of life and reduction of PANSS positive subscale score. Correlations between OXT plasma levels, symptoms, and response to treatment will be evaluated to identify respondent and non-respondent patient groups	8 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PANSS total score change.	The secondary end-point will be the PANSS total score	8 months

Other Outcome Measures

Outcome Measure	Time Frame
Brief Assessment of Cognitive deficits in Schizophrenics (BACS) score change	8 months
Reading the Mind in the Eyes Test (RMET) score change.	8 months

Collaborators and Investigators

• Sponsor: IRCCS Centro San Giovanni di Dio Fatebenefratelli
• Investigators: Principal Investigator: Giovanni de Girolamo, M.D., IRCCS Fatebenefratelli, Brescia

Publications and helpful links

General Publications

• Dagani J, Sisti D, Abelli M, Di Paolo L, Pini S, Raimondi S, Rocchi MB, Saviotti FM, Scocco P, Totaro S, Balestrieri M, de Girolamo G. Do we need oxytocin to treat schizophrenia? A randomized clinical trial. Schizophr Res. 2016 Apr;172(1-3):158-64. doi: 10.1016/j.schres.2016.02.011. Epub 2016 Feb 14.
• Lee MR, Wehring HJ, McMahon RP, Liu F, Linthicum J, Verbalis JG, Buchanan RW, Strauss GP, Rubin LH, Kelly DL. Relationship of plasma oxytocin levels to baseline symptoms and symptom changes during three weeks of daily oxytocin administration in people with schizophrenia. Schizophr Res. 2016 Apr;172(1-3):165-8. doi: 10.1016/j.schres.2016.02.014. Epub 2016 Feb 12.

Helpful Links

• This is the website of the Coordinating Centre

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: October 2, 2012
• First Submitted That Met QC Criteria: October 3, 2012
• First Posted (Estimate): October 4, 2012

Study Record Updates

• Last Update Posted (Estimate): February 24, 2016
• Last Update Submitted That Met QC Criteria: February 23, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: Schizophrenia; Oxytocin; RCT
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Reproductive Control Agents; Oxytocics; Oxytocin
• Other Study ID Numbers: RF-2010-2311148