Background and objective:

Clozapine and olanzapine are some of the most effective antipsychotic drugs, but unfortunately, both drugs induce weight gain and conveys a high degree of metabolic disturbances. The antipsychotic-induced side-effects cause a major clinical problem among patients diagnosed with schizophrenia receiving antipsychotic treatment. Limited effects have been demonstrated for counteracting the side-effects by the switch of antipsychotic therapy, non-pharmacological/behavioural interventions or adjunct pharmacological treatments. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA,) is approved for the treatment of type 2 diabetes worldwide. The objective of the study is to investigate effects of semaglutide once-weekly vs. semaglutide placebo once-weekly on the metabolic state in prediabetic or diabetic patients with schizophrenia, who have initiated treatment with clozapine or olanzapine.

Methods and analysis:

Trial design, intervention and participants: The study is a 26-week, double-blinded, randomized, parallel-group, placebo-controlled, good clinical practice (GCP)-monitored, clinical trial. 104 prediabetic or diabetic patients diagnosed with a schizophrenia, age 18 years and 65 years, who have initiated of clozapine- or olanzapine-treatment within 5 years will be included in the study. The patients will be randomized to receive blinded treatment in one of the two study arms; semaglutide once-weekly vs. semaglutide placebo. All participants who complete the 26 weeks of intervention, will be invited for a follow up visit 1.5 yeras after study completion.

The primary endpoint is the change from baseline in glycated haemoglobin A1c (HbA1c). Secondary endpoints include change in body weight, hip and waist circumference, vitals, and plasma levels of insulin, glucose, C-peptid, insulin sensitivity, beta cell function, glucagon, liver function, lipid profile, incretin hormones, lipid profile, bone makers, body composition, bone density and proteomic analyses. Additional endpoints include alcohol, tobacco and drug use, food preferences, psychopathology, activity and quality of life.

Inclusion Criteria:

1. Informed oral and written consent
2. Diagnosed with schizophrenia according to the criteria of ICD-10 (International Classification of Diseases, World Health Organization (WHO)) or the DSM-V (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, the American Psychiatric Association)
3. Initiating current treatment with clozapine or olanzapine within 60 months (not PRN ordinations)
4. Age 18 years to 65 years (both included)
5. Body mass index (BMI) ≥25 kg/m2
6. Diagnosed with prediabetes or type 2 diabetes, after initiation of current treatment with clozapine- or olanzapine, with the following plasma levels: Prediabetes: HbA1c 35-47 mmol/mol or fasting plasma glucose (FPG) 5.6-6.9 mM or 2-h during 75 mg OGGT 7.8-11.0 mM. The test result has to be confirmed on a different day. Type 2 diabetes: HbA1c 48-57 mmol/mol or fasting plasma glucose (FPG) 6.9-9.9 mM or 2h OGTT > 11 mM (although FPG and HbA1c might still be under the diagnostic range). The test result has to be confirmed on a different day.

Exclusion Criteria:

1. Acute worsening of psychosis based on a clinical evaluation (score of 6 or 7 on the CGI-S scale)
2. Coercive measures
3. Females of child-bearing potential who are pregnant, breast-feeding or have intention of becoming pregnant.
4. Women who are not willing to use adequate contraceptive during the full length of the study
5. Patients treated with corticosteroids or other hormone therapy (except oestrogens)
6. Any active substance abuse or dependence for the past six months (except for nicotine)
7. Impaired hepatic function (plasma liver transaminases >3 times upper normal limit)
8. Impaired renal function (serum creatinine >150 μmol/l and/or macroalbuminuria)
9. Impaired pancreatic function (acute or chronic pancreatitis and/or plasma amylase >2 times upper normal limit)
10. Cardiac problems defined as decompensated heart failure (NYHA class III/IV), unstable angina pectoris and/or myocardial infarction within the last 12 months
11. Hypertension with systolic blood pressure >180 mmHg or diastolic blood pressure >100 mmHg
12. Any condition that the investigator feels would interfere with trial participation
13. Receiving any experimental or pre-marketing drug within the last 3 months
14. Use of weight-lowering pharmacotherapy within the preceding 3 month
15. Known type 1 diabetes
16. Suicidal behavior as judged by the investigator and based on clinical evaluation. At all contact with patient attendance possible suicidality will be evaluated according to the guidelines. If the patient is evaluated as suicidal, the person will be excluded from the study and evaluated by a senior consultant in psychiatry, who will take further action.
17. Plasma HbA1c > 57 mmol/mol (tested twice) in which case the patient will be excluded from the study and transferred to general practitioner or hospital for diabetic treatment. No diabetic medication is allowed except for the trial medicin.
18. Any known contraindication towards the treatment with semaglutide.

All of the individual participant data collected during the trial, after deidentification.

Immediately following publication. No end date.

Researchers who provide a methodologically sound proposal