Personalized Pharmaco-Lifestyle Interventions for Severe Mental Illnesses (LIFETRAIN) (LIFETRAIN)

Personalised Pharmaco-Lifestyle Interventions for Severe Mental Illnesses Enhanced by Digital Health and Immersive Technologies

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Schizophrenia; Severe Mental Illness; Bipolar Disorder (BD); Depression / Major Depressive Disorder
• Intervention / Treatment: Drug: Semaglutide (SEMA); Behavioral: Exercise module; Behavioral: Anti-inflammatory diet module; Behavioral: Sleep intervention module; Behavioral: Social prescribing module; Device: Closed-loop transcranial alternating current stimulation (CL-tACS); Behavioral: Structured lifestyle psychoeducation; Device: Sham CL-tACS

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Peter Falkai, MD; Phone Number: +49 89 4400 - 55501; Email: peter.falkai@med.uni-muenchen.de

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna
• Germany
  • Mannheim, Germany, 68159
    • Central Institute of Mental Health
  • München, Germany, 80336
    • Department of Psychiatry and Psychotherapy, LMU Klinikum
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • University Medical Center Groningen
  • Utrecht, Netherlands, 3584 CX
    • University Medical Center Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Personalized pharmaco-lifestyle intervention; Participants receive one or more individualized intervention modules selected according to predefined eligibility criteria, digital guidance, and shared decision-making. Modules may include exercise, anti-inflammatory diet, sleep intervention, social prescribing, semaglutide, and optional closed-loop transcranial alternating current stimulation for participants with prominent depressive symptoms. Weekly guided support is provided through Month 3, followed by self-directed continuation with digital support through Month 6.	Drug: Semaglutide (SEMA); 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.; Behavioral: Exercise 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.; Behavioral: Anti-inflammatory diet module; Structured anti-inflammatory dietary intervention based on the Brain Anti-Inflammatory Nutrition (BrAIN) diet, supported by coaching, recipes, and digital materials.; Behavioral: Sleep intervention module; Adapted cognitive behavioral therapy for insomnia (SLEEPexpert) including a structured introduction and supported self-management.; Behavioral: Social prescribing module; Structured intervention to increase social participation, community engagement, and behavioral activation.; Device: Closed-loop transcranial alternating current stimulation (CL-tACS); Optional adjunctive bifrontal closed-loop transcranial alternating current stimulation for participants with prominent depressive symptoms.
Active Comparator: Structured lifestyle psychoeducation control; Participants receive structured psychoeducation and counseling on exercise, diet, sleep, and social contact approximately every four weeks through Month 3, followed by self-guided continuation through Month 6. Participants with prominent depressive symptoms may receive sham closed-loop transcranial alternating current stimulation.	Behavioral: Structured lifestyle psychoeducation; Control intervention consisting of psychoeducation and counseling on lifestyle domains with self-guided continuation.; Device: Sham CL-tACS; Sham closed-loop transcranial alternating current stimulation in the control arm for eligible participants with prominent depressive symptoms.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Short Form 36 Health Survey (SF-36) Mental Component Summary (MCS) score	Change from baseline in the SF-36 Mental Component Summary score.	Baseline to Month 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Weight and height will be combined to report BMI in kg/m^2	Baseline to Month 3 and Month 6
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

Collaborators and Investigators

• Sponsor: Ludwig-Maximilians - University of Munich

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2028
• Primary Completion (Estimated): July 1, 2030
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: April 9, 2026
• First Submitted That Met QC Criteria: May 7, 2026
• First Posted (Actual): May 14, 2026

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bipolar and Related Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Behavioral Symptoms; Mood Disorders; Depressive Disorder; Behavior; Schizophrenia; Depression; Bipolar Disorder; Mental Disorders; Depressive Disorder, Major; semaglutide
• Other Study ID Numbers: LIFETRAIN; U1111-1340-3272 (Other Identifier: Universal Trial Number (UTN))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No