Investigating the Role of Serotonin in Emotional Processing Through the Use of Tryptophan Depletion
Condition: Healthy
Study type: Observational

Summary: 
      This study will examine the role of serotonin function in the brain. Serotonin, one of the
      brain's natural chemicals, connects with receptors on brain cells to regulate emotion,
      anxiety, sleep, stress hormones, and other body functions that are disturbed in various mood
      and anxiety disorders. Also, the research will look at the function of particular brain
      areas, how they are involved in regulating emotions, and how serotonin is involved in the
      regulation of their function. The procedures entailed are tryptophan depletion and magnetic
      resonance imagining (MRI). Also, researchers' understanding of the genetic causes of mood and
      anxiety disorders will increase through examination of participants' DNA.

      Adults in good health, ages 20 through 50, may be eligible for this study. Among those not
      eligible are females who are pregnant or breast feeding, patients with psychiatric or central
      nervous system disease, and those taking medications that would interfere with study results.

      At the first visit, patients will be asked about their general mood, degree of nervousness,
      thinking skills, and behavior. The session will last from 1.5 to 2.0 hours. A blood sample of
      about 2 tablespoons will be drawn, for DNA study.

      Participants will undergo the following procedures and tests:

        -  Physical examination.

        -  Test of vital signs, lying and standing.

        -  Electrocardiogram.

        -  Collection of blood for chemistry and hematology.

        -  Urinalysis.

        -  HIV, urine drug, and hepatitis screening.

        -  Psychiatric screening.

        -  (SqrRoot) -HCG pregnancy test, if applicable.

      At the second visit, patients will receive either tryptophan depletion or placebo, and 5
      hours later, the study will begin, to last up to 2 additional hours. Patients will be asked
      periodically about their emotional state or changes in their well-being. The MRI system will
      create images of the brain's blood flow and measure glucose metabolism as a measure of brain
      activity. During the MRI scan, patients will hear knocking or beeping sounds, and they will
      wear earplugs to reduce the noise. Patients will be able to communicate with the MRI staff at
      all times during the scan, and they may ask to be moved out of the machine at any time. The
      MRI session lasts up to 1.5 hours.

      Results of any medical tests or other information will not be provided to participants,
      because further research may be needed before such results are meaningful. But if meaningful
      information develops from this study that may be important for a participant's health, he or
      she will be notified about it when it becomes available.
    

Detailed description: 
      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
    

Keywords: Emotional Learning; Neurotransmitter; Neural Systems; Response Control; Orbitofrontal Cortex; Amygdala; Serotonin; Healthy Volunteer; HV