Leucine in Midlife Depression

Eligibility Criteria

• * Able and willing to provide informed consent
• * Diagnosis of major depression per Structured Interview for DSM-V (SCID-V)
• * Moderate to severe depression- Inventory of Depressive Symptoms - Self Reported (IDS-SR score \>34).
• * SHAPS score \>30 on the 0-56 scale
• * Body mass index (BMI) between 20-35 kg/m2
• * Plasma CRP \>1 mg/L
• * No contraindications to MRI
• * Availability of friends or family for transportation after lumbar puncture procedure
• * Clinically significant findings on EKG
• * Patient Health Questionnaire (PHQ-9) score greater than 10
• * Willingness to adopt contraceptive measures. Persons exempt from contraception requirements are:
• * Persons assigned male at birth
• * Persons assigned female at birth who:
• * have undergone a hysterectomy or bilateral oophorectomy; or
• * have been naturally postmenopausal for at least 24 consecutive months (i.e., has NOT had menses at any time in the preceding 24 consecutive months)
• * Leucine-Specific:
• * History of maple syrup urine disease
• * Risk of hypoglycemia (unstable diabetes)
• * History of vitamin B6 deficiency, relative
• * Lysine-Specific:
• * On calcium supplements, relative
• * History of renal/gall stones (could cleared by a primary care provider)
• * Cognitive:
• * Psychiatric Disorders:
• * Lifetime diagnosis of psychotic disorders.
• * Current mania/hypomania.
• * Substance use disorder in the last 6 months.
• * Active suicidal ideation:
• * Psychiatric hospitalization in the past year.
• * Suicide attempts within the last five years.
• * Scores \>3 on the Columbia Suicide Severity Rating Scale (C-SSRS)
• * Binge eating in the absence of mood symptoms increases.
• * Primary diagnosis of severe DSM-V79 anxiety disorders.
• * Primary diagnosis of DSM-V PTSD (if severity exceeds major depression).
• * Primary diagnosis of DSM-V obsessive-compulsive disorders.
• * Significant personality disorders with multiple hospitalizations or suicide attempts.
• * Developmental disorders (e.g., ADHD).
• * Concomitant medications:
• * Immune-active medications (e.g., non-steroidal anti-inflammatory agents).
• * Antibiotics and immunizations in the past 2 weeks.
• * Topical or inhaled steroids within the past week.
• * Oral/parenteral steroids in the last 6 months.
• * Supplements that impact the immune system (e.g., omega-3, probiotics) within the past 2 weeks.
• * Psychotropic medications within the last 4 weeks (8 weeks for fluoxetine).
• * Daily use of sedative-hypnotics, benzodiazepines, and opiates.
• * Medical Disorders:
• * Unstable medical disorders (frequent provider or medication changes).
• * Lifetime diagnosis/treatment of cancers (excluding basal cell carcinoma).
• * Lifetime diagnosis/treatment of autoimmune disorders.
• * Lifetime exposure to chemotherapeutic agents.
• * MRI Considerations:
• * Concomitant Treatment for Depression:
• * Treatment for General Medical Conditions (GMCs):
• * Stabilized medications are allowed if maintained at the same dose during the trial.
• * Multiple recent changes in concomitant medications reviewed by the study PI
• * Population
• * Pregnant women.
• * Children.
• * Prisoners.
• * Individuals unable to consent