Randomized, Double-Blind Trial of Intranasal Oxytocin as an Adjunct to Psychosocial Treatment in Schizophrenia Spectrum Disorders

The primary objective of this clinical trial is to evaluate the efficacy of **intranasal oxytocin** compared to placebo as an add-on to psychosocial treatment for individuals with schizophrenia spectrum disorders. This objective is clinically relevant as it aims to determine whether oxytocin can enhance the effectiveness of existing psychosocial interventions, potentially leading to improved treatment outcomes for patients with these disorders.

Secondary objectives include:

• Evaluating improvements in psychopathology, social, and occupational functioning.
• Analyzing changes in neurocognition.
• Comparing changes in the cumulative dose of concomitant and rescue medication.

The clinical trial involves participants diagnosed with **schizophrenia** or other primary psychotic disorders, as defined by the ICD-11 criteria. The study population includes both male and female subjects, aged between 18 to 64 years, who are either inpatients or outpatients receiving psychosocial treatment at least twice a week. Participants must have at least one symptom of moderate severity or worse on the PANSS negative subscale. The trial does not involve a vulnerable population. Female participants must either be incapable of bearing children or use a highly effective, medically approved birth control method. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **intranasal oxytocin** compared to a placebo as an add-on to psychosocial treatment for individuals with schizophrenia or other primary psychotic disorders. This study is structured as a two-arm, double-blind, randomized clinical trial, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thereby minimizing bias. The trial is expected to span a duration of approximately four years, with recruitment starting in March 2024 and concluding by March 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and treatment history. Following successful screening, participants will be randomized to receive either the active treatment, **Syntocinon** nasal spray, or a placebo. The primary endpoint is the change in the Personal and Social Performance Scale after 12 weeks, with secondary endpoints including improvements in psychopathology, social functioning, and quality of life.

Study visits will occur regularly throughout the trial, with follow-up assessments to monitor efficacy and safety. The end-of-study visit will mark the completion of the participant's involvement, which is anticipated to last up to 12 weeks. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. The trial aims to provide valuable insights into the potential benefits of **oxytocin** as an adjunctive treatment for enhancing social skills in individuals with schizophrenia spectrum disorders.

The clinical trial involves the administration of **oxytocin** as the experimental medication. The product, marketed under the name SYNTOCINON, is formulated as a **nasal spray** solution with a concentration of 40 international units (IU) per milliliter. The active substance, **oxytocin**, is a protein of non-human origin. The maximum daily dose is set at 22.9 IU, with a total maximum dose of 1920 IU over the course of the treatment. The administration route is intranasal, and the treatment period is limited to a maximum of 12 weeks. The pharmaceutical product is manufactured by Viatris Healthcare Ltd and is authorized for use in Slovenia. The trial aims to assess the efficacy of intranasal oxytocin as an adjunct to psychosocial treatment in individuals with schizophrenia spectrum disorders.

The study also includes a **placebo** group for comparison. The placebo is designed to mimic the experimental treatment in appearance and administration method but contains no active substance. The placebo is referred to as "Oxytocin Placebo" in the trial documentation. The placebo is administered via the same nasal spray route as the active treatment, ensuring blinding of participants and investigators to the treatment allocation. The placebo serves as a control to evaluate the true efficacy of the oxytocin treatment when used as an add-on to standard psychosocial therapy.

The efficacy of intranasal **oxytocin** as an add-on to psychosocial treatment for schizophrenia spectrum disorders will be assessed through a two-arm, double-blind, randomized clinical trial. The primary endpoint for evaluating efficacy is the change in the Personal and Social Performance Scale (PSP) after 12 weeks. Secondary endpoints include improvements in psychopathology from baseline using the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression-Schizophrenia (CGI-SCH). Additionally, social and occupational functioning will be measured using the Global Assessment of Functioning (GAF), and quality of life will be assessed with the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) and The Oxford Positive Self Scale.

Further secondary endpoints involve changes from baseline in the Calgary Depression Scale for Schizophrenia (CDSS) and neurocognition assessed by the Brief Cognitive Assessment Tool for Schizophrenia (B-CATS). Other measures include all-cause discontinuation, ecological momentary assessment (EMA) and passive sensing, Drug Attitude Inventory (DAI), self-reported treatment adherence, and cumulative dose of concomitant or rescue medication. Genetic alterations in the oxytocin receptor gene and changes in biomarkers such as brain network alterations, DNA methylation, and oxytocin levels in blood and saliva will also be evaluated. Real-life social contacts and physical activity will be measured to provide additional insights into the treatment's efficacy.