Rapid Antidepressant Effects of Leucine

This is a pilot phase II clinical trial of L-leucine to test its efficacy in reducing
depressive symptoms in MDD patients, especially those who exhibit increased inflammation. The
determination of increased inflammation will be done post-hoc. During the screening visit,
all study participants will provide demographic information and complete self-report
assessments and clinician evaluations and examinations. Blood and urine tests will also be
performed. All participants who meet eligibility criteria and are willing to proceed with the
study will enter this 6-week study after being randomized to two-week course of either
L-leucine or placebo. In this cross-over study, participants will be crossed over to the
second treatment after 2 weeks of washout. The study period will last 42 days (6 weeks) from
the baseline visit. Both L-leucine and placebo will be provided as an effervescent mixture
powder. Investigators hypothesize that MDD subjects will have greater reduction in depression
severity on leucine as compared to placebo.

Inclusion Criteria:

- Current primary diagnosis of nonpsychotic major depressive disorder.

- Stable antidepressant dose of no more than one antidepressant medication for 4 weeks
and no anticipated changes during the study period.

- Stable doses of all concomitant medications for over 6 weeks.

- No more than two failed antidepressant trials of adequate dose and duration, as
defined by ATRQ, in the current episode.

Exclusion Criteria:

- Psychiatric co-morbidity posing safety risk.

- Pregnant or breastfeeding or plan to become pregnant over the ensuing 2 months
following study entry or are sexually active and not using adequate contraception

- Exclusionary psychiatric conditions (such as substance dependence in the last 6
months, substance abuse in the last 2 months, or lifetime history of psychotic
disorders.

- Unstable or terminal general medical condition (GMC).

- Concomitant medications that interact with L-leucine (e.g. sildenafil).

- Vagus nerve stimulation, ECT, or rTMS, or other somatic antidepressant treatment
during current episode

- Inadequately controlled hypothyroidism.

- Therapy that is depression specific, such as CBT or Interpersonal Psychotherapy of
Depression.

- Hypersensitivity to L-leucine

- Have Maple Syrup Urine Disease.