Leucine for Depression Study (L-DEP)

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
An Experimental Treatment Approach for Inflammation-Induced Depression

Conditions
-----------------
Depression

Intervention / Treatment
-----------------
* Dietary Supplement: leucine
* Other: PO placebo
* Biological: lipopolysaccharide (LPS)
* Other: IV placebo


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PO leucine & IV LPS<br>Oral (PO) leucine 6 g twice a day for 2 weeks followed by a single intravenous (IV) bolus of lipopolysaccharide (LPS) 0.8 ng/kg of body weight | Dietary Supplement: leucine<br>* amino acid leucine in powder<br>Biological: lipopolysaccharide (LPS)<br>* purified bacterial wall component as an inflammatory challenge<br>|
| Experimental: PO placebo & IV LPS<br>PO maltodextrin (placebo) twice a day for 2 weeks followed by a single IV bolus of LPS 0.8 ng/kg of body weight | Other: PO placebo<br>* maltodextrin<br>Biological: lipopolysaccharide (LPS)<br>* purified bacterial wall component as an inflammatory challenge<br>|
| Experimental: PO leucine & IV placebo<br>PO leucine 6 g twice a day for 2 weeks followed by a single IV bolus of 0.9% saline | Dietary Supplement: leucine<br>* amino acid leucine in powder<br>Other: IV placebo<br>* 0.9% saline<br>|
| Placebo Comparator: PO placebo & IV placebo<br>PO maltodextrin (placebo) twice a day for 2 weeks followed by a single IV bolus of 0.9% saline | Other: PO placebo<br>* maltodextrin<br>Other: IV placebo<br>* 0.9% saline<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Depressed Mood From Baseline | Depression Subscale of the Short Form of the Profile of Mood States (POMS-SF): total score ranges from 0 to 32; higher values represent worse outcome, i.e., more severe depressed mood; the absolute values at each time point are presented here rather than change of values between time points; zero (0) in mean and standard deviation reflect measured data and not placeholder values. | At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Non-memory Domains of Cognitive Function From Baseline | Non-memory domains of cognitive function were measured using the computerized tests from CNS Vital Signs™: executive function using Stroop Test (average reaction time in milliseconds thus ranging from 0 to infinite; shorter reaction time means a better outcome); and attention using Shifting Attention Test (average reaction time for correct responses in milliseconds thus ranging from 0 to infinite; shorter reaction time means a better outcome) and Continuous Performance Test (average reaction time for correct responses in milliseconds thus ranging from 0 to infinite; shorter reaction time means a better outcome). The absolute values at each time point are presented. | At baseline and then 3 hours after LPS (or saline) administration | 
| Change in Depressive Symptoms From Baseline | Montgomery-Asberg Depression Rating Scale (MADRS): a clinician-rated questionnaire of depressive symptoms with scores ranging from 0 to 60, with higher scores indicating more severe depressive symptoms. | At baseline and then at 2 and 4 hours after LPS (or saline) administration | 
| Change in Feelings of Social Disconnection From Baseline | Feelings of Social Disconnection Scale: a self-report questionnaire of feelings of social disconnection with scores ranging from 0 to 28, with higher scores indicating more severe feelings of social disconnection. | At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration | 
| Change in Fatigue From Baseline | Fatigue Subscale of the Short Form of the Profile of Mood States (POMS-SF): total score ranges from 0 to 20; higher values represent worse outcome, i.e., more severe fatigue; the absolute values at each time point are presented here rather than change of values between time points. | At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration | 
| Change in Confusion From Baseline | Confusion Subscale of the Short Form of the Profile of Mood States (POMS-SF): total score ranges from 0 to 20; higher values represent worse outcome, i.e., more severe confusion; the absolute values at each time point are presented here rather than change of values between time points; zero (0) in mean and standard deviation reflect measured data and not placeholder values. | At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration | 
| Change in Memory Domains of Cognitive Function From Baseline | Memory domains of cognitive function were measured using the computerized tests from CNS Vital Signs™: verbal memory using Verbal Memory Test (total scores ranging from 0 to 60; higher scores mean a better outcome); and visual memory using Visual Memory Test (total scores ranging from 0 to 60; higher scores mean a better outcome). The absolute values at each time point are presented. | At baseline and then 3 hours after LPS (or saline) administration |