Leucine in Midlife Depression

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