Investigating the Role of Serotonin in Emotional Processing Through the Use of Tryptophan Depletion

Objective

The goal of this protocol is to use a targeted serotonergic manipulation [acute tryptophan depletion (ATD)] and specific neurocognitive and neuroimaging paradigms to consider the role of serotonin (5-HT) in emotional processing. In particular, we wish to evaluate claims that serotonin has a role in the effective processing of aversive signals. Additionally, we wish to examine whether tryptophan depletion will attenuate the neural response to aversive material.

Study population

Healthy human adult volunteers, ages 20-50 years old, with no DSM-IV-defined Axis I mental disease and who fulfill the remainder of the inclusion/exclusion criteria.

Design

This is a prospective, randomized, double-blind, placebo-controlled, single-dose, outpatient study in eligible, healthy volunteers. Participants will be randomly assigned in a 1:1 ratio to single doses of drug (ATD) or placebo. The National Institutes of Health (NIH) Clinical Center Pharmacy will facilitate randomization and supply the randomization code to the Clinical Center s Metabolic Nutrition Department (see below). All subjects will be monitored for adverse events. Participants will give written, informed consent prior to any assessments and procedures covered by this protocol.

The study will be conducted in the NIH Clinical Center 5SW Day Hospital and the NMRF center (for the imaging arm of the study). Subjects will arrive in the morning of the testing day and complete baseline measurements (i.e., mood and anxiety ratings and serum tryptophan levels). Participants will then receive an oral dose of ATD capsules or placebo. Participants will consume two meals during the study day; the placebo group (control subjects) will be given high-tryptophan meals and tryptophan-depleted subjects will receive low-tryptophan meals. Meals will be designed and supplied by the NIH Clinical Center Metabolic Nutrition Department. At specified times, subjects will complete primary measures [either neurocognitive or neuroimaging (fMRI) paradigms] and secondary measures (mood and anxiety ratings and serum levels of tryptophan) as detailed in the protocol. Adverse events will be monitored throughout the study day. A post-study evaluation will occur prior to discharging the participant to verify that he/she is physically and mentally well and fit to leave the Clinical Center.

Outcome Measures

Primary Outcome Measures:

• Neurocognitive Paradigms: Behavioral measures including reaction time and accuracy
• Neuroimaging Paradigms: Blood-oxygen-level-dependent (BOLD) response

Secondary Outcome Measurements:

• Serum tryptophan levels
• Mood and Anxiety Rating Scales