Effects of Tirzepatide on Alcohol Intake in Patients Diagnosed With Schizophrenia and Alcohol Use Disorder

The study is a randomised (1:1), double-blinded, placebo-controlled clinical trial including 26 weeks of treatment investigating whether tirzepatide vs placebo can reduce the number of heavy drinking days in patients with comorbid diagnoses of schizophrenia and AUD. The primary endpoint will be evaluated after 16 weeks of treatment. The study will conclude after a post-intervention follow-up 14 weeks after last treatment at week 40 of the study.

108 participants will be included. Alcohol consumption and secondary endpoints will be assessed at weeks 0, 4, 8, 12, 16, 20, 26, and 40, and all patients will be offered 6 sessions of supportive therapy, while participating in the study.

The randomisation and administration of the weekly injections (tirzepatide/placebo) will be administered by an unblinded staff not involved in other trial activities. All patients will be blindfolded when receiving the injections. Eligible patients (n=50) will have an fMRI brain scan performed at baseline and in week 16. Blood tests for safety measures and secondary endpoint-measures will be performed at weeks 0, 16, 26, and 40.

Inclusion criteria

• Informed Consent: The patient must provide both oral and written informed consent.
• Diagnosis:

• Diagnosed with alcohol dependence according to the International Classification of Diseases, 10th Edition (ICD-10), and alcohol use disorder as per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).
• Diagnosed with schizophrenia spectrum disorder according to ICD-10 and DSM-5
• AUDIT Score: Alcohol Use Disorder Identification Test (AUDIT) score greater than 15.
• Body Mass Index (BMI): BMI of 23 kg/m² or higher.
• Age Range: Between 18 and 70 years old (inclusive).
• Heavy Alcohol Consumption: Defined as 4 or more heavy drinking days within a consecutive 21-day period during the 28 days preceding the baseline evaluation. The 21-day period will be selected based on the largest total alcohol consumption and the greatest number of heavy drinking days within the 28-day timeframe. This will be assessed using the Timeline Followback (TLFB) method. Heavy drinking days are defined as days with an alcohol intake of 4 or more units (48 g of alcohol) for women and 5 or more units (60 g of alcohol) for men.

Exclusion criteria

• Intellectual Disability: individuals with a diagnosis of intellectual disability.
• Acute Psychosis: Acute exacerbation of psychosis, as indicated by a score of 6 or 7 on the Clinical Global Impression-Severity (CGI-S) scale.
• Coercive Measures: Current use of coercive measures, which includes individuals sentenced to treatment ('dom til behandling').
• Suicidal Behaviour: Evidence of current severe suicidal behaviour, as assessed by the investigator during clinical evaluation.
• History of Severe Alcohol Withdrawal: History of delirium tremens or alcohol withdrawal seizures.
• Severe Withdrawal Symptoms: Clinical Institute Withdrawal Assessment of Alcohol Scale, revised (CIWA-Ar) score greater than 9 at baseline examination.
• Severe Neurological Conditions: Presence of severe neurological diseases, including severe traumatic brain injury.
• Diabetes: Type 1 or 2 diabetes
• Pregnant or Potentially Pregnant Women: WOCBP who are pregnant, breastfeeding, intend to become pregnant within the next 6 months (including 16 weeks of treatment plus two months after discontinuation of semaglutide), or are not using a highly effective contraceptive method throughout the study period. Highly effective methods include combined hormonal contraception (oral, intravaginal, transdermal), progestogen-only hormonal contraception (oral, injectable, implantable), intrauterine device (IUD), intrauterine system (IUS), bilateral tubal occlusion, vasectomised partner, or sexual abstinence. WOCBP with a measured serum human chorionic gonadotropin (hCG) level greater than 3 U/L at inclusion will also be excluded.
• Liver Function: Impaired hepatic function, defined as liver transaminases greater than three times the upper limit of normal.
• Renal Function: Impaired renal function, indicated by an estimated glomerular filtration rate (eGFR) below 50 mL/min and/or plasma creatinine above 150 μmol/L.
• Pancreatic Function: History of acute or chronic pancreatitis or amylase levels more than twice the upper limit of normal.
• Thyroid Conditions: Previous medullary thyroid carcinoma (MTC) or a family history of MTC and/or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
• Cardiac Issues: Decompensated heart failure (NYHA class III or IV), unstable angina pectoris, or myocardial infarction within the past 12 months.
• Uncontrolled Hypertension: Systolic blood pressure above 180 mmHg or diastolic blood pressure above 110 mmHg.
• Alcohol Use Disorder Medication: Use of medications for alcohol use disorder (e.g., disulfiram, naltrexone, acamprosate, nalmefene) within the 28 days prior to inclusion as recorded in the Timeline Followback (TLFB) schedule.
• Investigational Drugs: Receipt of any investigational drug within the past three months.
• Weight-Lowering Medications: Use of other weight-lowering pharmacotherapy in the past three months.
• Allergic Reactions: Hypersensitivity to the active substance or any of the excipients.
• Language Barriers: Inability to speak and/or understand Danish.
• Other Conditions: Any other condition that, in the investigator's opinion, may interfere with participation in the trial.

For the subgroup of participants undergoing brain scans:

• MRI Contraindications: any contraindications for MRI (e.g., magnetic implants, pacemaker, claustrophobia).
• Benzodiazepine Use: Intermittent use of benzodiazepines within 12 days prior to the scanning session is not allowed. However, regular use of a stable dose of benzodiazepines is permitted.