Leucine for Depression Study (L-DEP)

Depression is very common and poses a huge disease burden. About 20% of the US population suffers from depression at lease once in their lifetime. Inflammations that are hidden inside our body as a result of aging, obesity, chronic diseases, or certain treatments (e.g., interferon for hepatitis C) appear to cause depressive symptoms and even clinical depression. Individuals with such inflammations are more likely to suffer from depression and are less likely to respond to currently available antidepressant medications. This study will test leucine, an amino acid, as a new way to mitigate depressive symptoms in response to such inflammations. This study begins with a 90-minute screening session to determine whether participants are eligible to join the main study. Those who meet the eligibility criteria will then join the main study, which will consist of taking leucine or maltodextrin (i.e., oral placebo) for 2 weeks at home and an 8-hour session at the UCLA Medical Center. A brief telephone follow-up every 3 months for 2 years with questions on mood is also planned. Approximately 90 healthy adults will be recruited for participation in the study. During the course of the study, participants will take leucine or maltodextrin for 2 weeks at home and then will be injected either lipopolysaccharide (LPS) or saline (i.e., intravenous placebo) at the UCLA Medical Center. LPS is a bacterial substance that can initiate chemical reactions that are similar to those seen in individuals with mild sickness symptoms, such as a slight increase in body temperature, muscle aches, or tiredness. It is a safe way of investigating the body's response to inflammation and how these changes may alter cognitive, emotional, or neural function. It has been given thousands of times to healthy volunteers - both younger and older adults - without any serious side effects.


Eligibility Criteria:
Inclusion Criteria:

Participants will be required to be in good general health (as evaluated during the phone and in-person screening sessions) and aged 18 to 65 years.

Exclusion Criteria:

Following a structured telephone interview, prospective participants with the following conditions will not advance to the in-person screening session: presence of chronic mental or physical illness, history of allergies, autoimmune, liver, or other severe chronic diseases, current use of prescription medications such as steroids, NSAIDs, immune modifying drugs, opioid analgesics, and psychotropics, or previous history of fainting during blood draws. These inclusion and exclusion criteria will be examined in detail and confirmed in the in-person screening session by the study physician. Furthermore, any participant who has any of the following conditions will be ineligible for the study. Medical Conditions: (1) presence of co-morbid medical conditions not limited to but including maple syrup urine disease (a contraindication to leucine treatment), cardiovascular (e.g., history of acute coronary event, stroke) and neurological diseases (e.g., Parkinson's disease), as well as pain disorders; (2) presence of co-morbid inflammatory disorders such as rheumatoid arthritis or other autoimmune disorders; (3) presence of an uncontrolled medical condition that is deemed by the investigators to interfere with the proposed study procedures, or to put the study participant at undue risk; (4) presence of chronic infection, which may elevate proinflammatory cytokines; (5) presence of an acute infectious illness in the two weeks prior to the screening session. Psychiatric Disorders: (6) an Axis I psychiatric disorder as determined by the Research Version of the Structured Clinical Interview for DSM-5 (SCID-5-RV) including a current major depressive disorder (a prior history of depression is not an exclusion criterion, which will be considered for a pre-planned sensitivity analysis); (7) lifetime history of suicide attempt or inpatient psychiatric admission; (8) current suicidal ideation assessed by the Columbia Suicide Severity Rating Scale (C-SSRS); (9) current depressive symptoms assessed by the PHQ-9 (≥ 5)). Medication and Substance Use: (10) current and/or past regular use of hormone-containing medications including steroids; (11) current and/or past regular use of non-steroid anti-inflammatory drugs; (12) current and/or past regular use of immune modifying drugs that target specific immune responses such as TNF antagonists; (13) current and/or past regular use of analgesics such as opioids; (14) current and/or past regular use of psychotropic medications, including antidepressants, anxiolytics, antipsychotics, hypnotics, sedatives, and barbiturates; (15) current and/or past regular use of cardiovascular medications, including antihypertensive, antiarrhythmic, antianginal, and anticoagulant drugs; (16) current smoking or excessive caffeine use (\>600 mg/day) because of the known effects on proinflammatory cytokine levels; (17) evidence of recreational drug use from urine test. Health Factors: (18) BMI \> 35 because of the effects of obesity on proinflammatory cytokine activity and also on risk for sleep disordered breathing; or (19) any abnormalities on screening laboratory tests.