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.
- Collection of blood for chemistry and hematology.
- 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.
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
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.
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
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
- INCLUSION CRITERIA:
Age: Participants will be males and females, 20-50 years of age.
IQ: IQ, as measured by 4 subscales from the Wechsler Adult Intelligence Scale-Revised
(WAIS-R), must be greater than 80.
Participants will be able to comprehend the purpose and procedures of the study. They will
be able to provide written, informed consent for all study procedures.
Psychiatric history: Participants will be assessed using DSM-IV criteria via standardized
psychiatric interviews conducted by trained examiners (SCID). All participants will be free
of any current or past major affective disorder, psychotic disorder, substance dependence,
anorexia nervosa or bulimia. All participants will be free of any current anxiety disorders
with the exception of specific phobias and free of current somatoform disorders. In
addition, participants with a first degree relative with major depressive disorder will be
Severe acute and chronic medical illnesses (e.g., cardiac disease, diabetes, epilepsy).
CNS disease: History of brain abnormalities (e.g., neoplasms, subarachnoid cysts),
cerebrovascular disease, infectious disease (e.g., abscess), or other neurological disease,
or history of head trauma (defined as loss of consciousness greater than 3 min).
Currently on any regular medication that would interfere with study results (with exception
of contraceptive pill).
Current use of psychotropic medication or benzodiazepine
Currently breast feeding or pregnant (as documented by pregnancy testing done within 24 hr
of the study starting)
Subjects who are lactose intolerant will be excluded as the placebo capsules contain
lactose. Also, those subjects who cannot consume the diets provided by metabolic nutrition
on the study day will be excluded.
ADDITIONAL EXCLUSION CRITERIA FOR fMRI STUDIES:
Metal or electronic objects: Metal plates, certain types of dental braces, cardiac
pacemakers, etc., that are sensitive to electromagnetic fields contraindicate MRI scans.
Claustrophobia: participants will be questioned about potential discomfort in being in an
enclosed space, such as an MRI scanner.