Bipolar Disorder (BD), Depression / Major Depressive Disorder, Schizophrenia, Severe Mental Illness
Conditions
Brief summary
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.
Interventions
Once-weekly subcutaneous semaglutide for eligible participants with overweight or obesity and metabolic risk, titrated according to protocol up to 2.4 mg/week as tolerated, followed by tapering after Month 6.
BEHAVIORALExercise module
Personalized moderate-intensity exercise intervention with supervised sessions during the structured phase and supported maintenance, targeting at least 150 minutes of moderate physical activity per week.
BEHAVIORALAnti-inflammatory diet module
Structured anti-inflammatory dietary intervention based on the Brain Anti-Inflammatory Nutrition (BrAIN) diet, supported by coaching, recipes, and digital materials.
BEHAVIORALSleep intervention module
Adapted cognitive behavioral therapy for insomnia (SLEEPexpert) including a structured introduction and supported self-management.
BEHAVIORALSocial prescribing module
Structured intervention to increase social participation, community engagement, and behavioral activation.
DEVICEClosed-loop transcranial alternating current stimulation (CL-tACS)
Optional adjunctive bifrontal closed-loop transcranial alternating current stimulation for participants with prominent depressive symptoms.
BEHAVIORALStructured lifestyle psychoeducation
Control intervention consisting of psychoeducation and counseling on lifestyle domains with self-guided continuation.
DEVICESham CL-tACS
Sham closed-loop transcranial alternating current stimulation in the control arm for eligible participants with prominent depressive symptoms.
Sponsors
Ludwig-Maximilians - University of Munich
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
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.
Intervention model description
Participants are randomized in a parallel 1:1 design to either an individualized personalized intervention arm or an active control arm. Within the individualized intervention arm, participants may receive one or more intervention modules according to predefined eligibility criteria, digital decision support, and shared decision-making with the treating clinician.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Short Form 36 Health Survey (SF-36) Mental Component Summary (MCS) score | Baseline to Month 3 | Change from baseline in the SF-36 Mental Component Summary score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Short Form 36 Health Survey (SF-36) Mental Component Summary score (MCS) at Month 6 | Baseline to Month 6 | — |
| Change in Short Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score | Baseline to Month 3 and Month 6 | — |
| Change in Short Form 36 Health Survey (SF-36) total score | Baseline to Month 3 and Month 6 | — |
| Change in MATRICS Consensus Cognitive Battery | Baseline to Month 3 and Month 6 | — |
| Change in Insomnia Severity Index (ISI) | Baseline to Month 3 and Month 6 | — |
| Change in UCLA Loneliness Scale score | Baseline to Month 3 and Month 6 | — |
| Change in International Physical Activity Questionnaire | Baseline to Month 3 and Month 6 | — |
| Change in EQ-5D-3L score | Baseline to Month 3 and Month 6 | — |
| Incidence of adverse events and serious adverse events | Baseline through day 240-243 | — |
| Change in Brief Psychiatric Rating Scale (BPRS) psychotic symptoms | Baseline to Month 3 and Month 6 | — |
| Change in Montgomery-Åsberg Depression Rating Scale (MADRS) | Baseline to Month 3 and Month 6 | — |
| Change in Young Mania Rating Scale (YMRS) | Baseline to Month 3 and Month 6 | — |
| Change in Pittsburgh Sleep Quality Index (PSQI) scores | Baseline to Month 3 and Month 6 | — |
| Change in step aerobic test performance | Baseline to Month 3 and Month 6 | — |
| Change in grip strength | Baseline to Month 3 and Month 6 | — |
| Change in body weight | Baseline to Month 3 and Month 6 | — |
| Change in body mass index (BMI) | Baseline to Month 3 and Month 6 | Weight and height will be combined to report BMI in kg/m\^2 |
| Change in waist-to-hip ratio | Baseline to Month 3 and Month 6 | — |
| Chage in blood pressure | Baseline to Month 3 and Month 6 | — |
| Change in lean mass | Baseline to Month 3 and Month 6 | — |
| Change in fat mass | Baseline to Month 3 and Month 6 | — |
Countries
Austria, Germany, Netherlands
Contacts
CONTACTPeter Falkai, MD
Outcome results
None listed