Leucine for Major Depression in Midlife

Inclusion 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) Exclusion Criteria: * 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: --Cognitive impairment (MMSE score \<28) * 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: \-- Location and quantity of metallic objects safe to MR * Concomitant Treatment for Depression: \-- Treatments with antidepressant medications or those with antidepressant effects (dopamine supplements). * 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