This randomized, rater-blind, multicenter clinical trial will evaluate whether a personalized pharmaco-lifestyle intervention improves mental functioning in adults with severe mental illness, including schizophrenia, bipolar disorder, or major depressive disorder. Participants will be randomized to either a modular individualized intervention program or a structured psychoeducation control condition. The individualized intervention may include physical exercise, an anti-inflammatory diet, sleep intervention, social prescribing, semaglutide for eligible participants with overweight or obesity, and optional closed-loop transcranial alternating current stimulation for participants with prominent depressive symptoms. The primary outcome is change in the SF-36 Mental Component Summary score from baseline to Month 3.

Inclusion Criteria:

• Age 18 to 65 years
• Able and willing to provide written informed consent
• Diagnosis of schizophrenia, bipolar disorder, or major depressive disorder according to DSM-5-TR, confirmed by M.I.N.I.
• Female participants of childbearing potential must agree to use an effective method of contraception
• Stable psychopathology defined as BPRS less than or equal to 41, MADRS less than or equal to 34, and YMRS less than or equal to 25, with stable psychopharmacological treatment for at least 2 weeks
• Reduced functioning at screening defined as SF-36 score less than or equal to 40
• If using benzodiazepines, dose less than or equal to 2 mg lorazepam equivalent per day
• Stable somatic condition for at least 4 weeks
• For semaglutide treatment: overweight with BMI at least 27 and less than 30 kg/m² plus at least one weight-related risk condition, or obesity with BMI at least 30 kg/m²
• For optional adaptive neurostimulation: MADRS score at least 19
• Expected ability to comply with study procedures in the investigator's judgment

Exclusion Criteria:

• Unable to provide informed consent
• Current or past neurological disorder or structural brain pathology that may affect study procedures
• Known intolerance or hypersensitivity to semaglutide
• Pregnancy or lactation
• Serious suicidal risk
• Substance dependence within the last 3 months
• BMI less than 18.5 kg/m²
• eGFR less than 30 mL/min/1.73 m²
• Type 1 diabetes, diabetic ketoacidosis, diabetic retinopathy, or poorly controlled diabetes with recurrent hypoglycemic episodes
• Pancreatitis, history of pancreatitis, or pancreatic cancer
• Multiple endocrine neoplasia type 2 or personal/family history of medullary thyroid cancer
• Pre-existing significant gastrointestinal conditions such as inflammatory bowel disease or gastroparesis
• Need for acute surgery
• Other medical condition that may affect study procedures or participant safety
• For optional adaptive neurostimulation: nonremovable metal in or around the head, known increased intracranial pressure due to infarcts or trauma, professional metal work or prior ocular metal injury, history of rTMS or ECT, or current (es)ketamine treatment

Due to the nature of the behavioral and pharmacological interventions, participants and treating clinicians are not blinded to study arm assignment. Outcome assessors are blinded to treatment allocation. In the subgroup with prominent depressive symptoms, sham closed-loop transcranial alternating current stimulation is used in the control arm to reduce nonspecific procedural effects.