TY - JOUR

T1 - Effect of the GLP-1 receptor agonist semaglutide on metabolic disturbances in clozapine-treated or olanzapine-treated patients with a schizophrenia spectrum disorder: study protocol of a placebo-controlled, randomised clinical trial (SemaPsychiatry)

AU - Sass, Marie Reeberg

AU - Danielsen, Andreas Aalkjær

AU - Köhler-Forsberg, Ole

AU - Storgaard, Heidi

AU - Knop, Filip Krag

AU - Nielsen, Mette Ødegaard

AU - Sjödin, Anders Mikael

AU - Mors, Ole

AU - Correll, Christoph U

AU - Ekstrøm, Claus

AU - Vinberg, Maj

AU - Nielsen, Jimmi

AU - Vilsbøll, Tina

AU - Fink-Jensen, Anders

N1 - © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2023

Y1 - 2023

N2 - Introduction: Clozapine and olanzapine are some of the most effective antipsychotics, but both are associated with weight gain and relevant metabolic disturbances, including pre-diabetes and diabetes. Non-pharmacological/ behavioural interventions have had limited effects counteracting these adverse effects. Semaglutide, a glucagon-like peptide 1 receptor agonist, is approved for the treatment of type 2 diabetes and obesity. We will investigate the long-term effects of add-on treatment with semaglutide once a week versus placebo once a week on the metabolic status in pre-diabetic (glycated haemoglobin A1c (HbA1c) 35-47 mmol/mol (5.4%-6.4%) and diabetic (HbA1c 48-57 mmol/mol (6.5%-7.4%)) patients diagnosed with a schizophrenia spectrum disorder who initiated clozapine or olanzapine treatment within the last 60 months.Methods and analysis: This is a 26-week, double-blinded, randomised, placebo-controlled trial. Altogether, 104 patients diagnosed with a schizophrenia spectrum disorder, aged 18-65 years, with pre-diabetes or diabetes will be randomised to injections of 1.0 mg semaglutide once a week or placebo for 26 weeks. The primary endpoint is change from baseline in HbA1c. Secondary endpoints include changes in body weight, hip and waist circumference and plasma levels of insulin, glucagon, glucose, and C-peptide, insulin sensitivity, beta cell function, hepatic function, fibrosis-4 score, lipid profile, incretin hormones, bone markers, body composition, bone density, proteomic analyses and oxidative stress markers. Together with alcohol, tobacco and drug use, potential effects on the reward value of a sweet-fat stimulus, psychopathology, level of activity and quality of life will also be assessed.Ethics and dissemination: This study is approved by the Danish Medicines Agency and the regional scientific ethics committee of the Capital Region of Denmark (committee C, #H-20019008) and will be carried out in accordance with International Council for Harmonisation Good Clinical Practice guidelines and the Helsinki Declaration. The results will be disseminated through peer-review publications and conference presentations.Trial registration number: NCT04892199.

AB - Introduction: Clozapine and olanzapine are some of the most effective antipsychotics, but both are associated with weight gain and relevant metabolic disturbances, including pre-diabetes and diabetes. Non-pharmacological/ behavioural interventions have had limited effects counteracting these adverse effects. Semaglutide, a glucagon-like peptide 1 receptor agonist, is approved for the treatment of type 2 diabetes and obesity. We will investigate the long-term effects of add-on treatment with semaglutide once a week versus placebo once a week on the metabolic status in pre-diabetic (glycated haemoglobin A1c (HbA1c) 35-47 mmol/mol (5.4%-6.4%) and diabetic (HbA1c 48-57 mmol/mol (6.5%-7.4%)) patients diagnosed with a schizophrenia spectrum disorder who initiated clozapine or olanzapine treatment within the last 60 months.Methods and analysis: This is a 26-week, double-blinded, randomised, placebo-controlled trial. Altogether, 104 patients diagnosed with a schizophrenia spectrum disorder, aged 18-65 years, with pre-diabetes or diabetes will be randomised to injections of 1.0 mg semaglutide once a week or placebo for 26 weeks. The primary endpoint is change from baseline in HbA1c. Secondary endpoints include changes in body weight, hip and waist circumference and plasma levels of insulin, glucagon, glucose, and C-peptide, insulin sensitivity, beta cell function, hepatic function, fibrosis-4 score, lipid profile, incretin hormones, bone markers, body composition, bone density, proteomic analyses and oxidative stress markers. Together with alcohol, tobacco and drug use, potential effects on the reward value of a sweet-fat stimulus, psychopathology, level of activity and quality of life will also be assessed.Ethics and dissemination: This study is approved by the Danish Medicines Agency and the regional scientific ethics committee of the Capital Region of Denmark (committee C, #H-20019008) and will be carried out in accordance with International Council for Harmonisation Good Clinical Practice guidelines and the Helsinki Declaration. The results will be disseminated through peer-review publications and conference presentations.Trial registration number: NCT04892199.

KW - Humans

KW - Schizophrenia/drug therapy

KW - Clozapine

KW - Olanzapine/therapeutic use

KW - Glucagon-Like Peptide-1 Receptor

KW - Prediabetic state

KW - Diabetes Mellitus, Type 2

KW - Glycated Hemoglobin

KW - Proteomics

KW - Quality of life

KW - Randomized controlled trials as topic

U2 - 10.1136/bmjopen-2022-068652

DO - 10.1136/bmjopen-2022-068652

M3 - Journal article

C2 - 36720576

VL - 13

JO - BMJ Open

JF - BMJ Open

SN - 2044-6055

IS - 1

M1 - e068652

ER -