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 contraceptionrequirements 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 consecutivemonths)

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 suicideattempts.

• 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) withinthe 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 thetrial.

• Multiple recent changes in concomitant medications reviewed by the study PI

• Population

• Pregnant women.

• Children.

• Prisoners.

• Individuals unable to consent