Semaglutide for the Treatment of Cognitive Dysfunction in Major Depressive Disorder

This is a 16-week, placebo-controlled, randomized, double-blind, clinical trial, involving 60 overweight individuals with MDD and pre-treatment cognitive dysfunction. Study participants will receive one of the following study interventions in addition to 'standard of care' treatment: once-daily semaglutide, initiated at 3 mg/day for 4 weeks, increased to 7 mg/day for 4 more weeks and titrated to 14 mg/day for the subsequent 8 weeks; or matching placebo. Participants will be assessed to examine the effect of semaglutide on their cognitive function.

Inclusion criteria

• Informed consent before study-related activity
• Individuals between the ages of 18 and 60 who meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for MDD
• Overweight (i.e. BMI ≥ 25 kg/m2)
• Below-average (i.e. >1 SD below norm) performance in the Trail Making Test-B (TMTB)

Exclusion criteria

• Current, or in the past 4 weeks, treatment with other oral hypoglycemic agents and/or insulin
• Diagnosis of possible or probable Alzheimer's Disease, Mild Cognitive Impairment, or any other dementia
• History of neurological disorder, or evidence of neurologic or other physical illness that could produce cognitive deterioration
• Severe mood episode, defined as a Hamilton Depression Rating Scale (HAMD-17) score of >23
• Actively suicidal or evaluated as being a suicide risk (operationalized as a score of ≥3 on HAMD-17 suicide item and/or by clinical assessment).
• Substance use disorder within 3 months before screening or a positive baseline toxicology screen
• DSM-5 diagnosis of obsessive compulsive disorder, posttraumatic stress disorder (current or within the last year), or borderline personality disorder as assessed by a study investigator
• Presence of absolute or relative contraindication to semaglutide (e.g. hypersensitivity to semaglutide, hepatic impairment, renal impairment with chronic kidney disease stage 3 and above, personal or familial history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2)
• History of diabetic retinopathy
• History of pancreatitis or pancreatic cancer
• Presence of clinically unstable general medical illness
• Pregnancy or breastfeeding women