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