This study will explore brain function related to depressive symptoms and will examine DNA
for genes that may be involved in depressive disorders, particularly genes that regulate
synthesis and metabolism of the brain neurotransmitter catecholamine. It will compare
findings in patients with major depressive disorders who are in remission with those in
normal, healthy volunteers.
Patients with remitted major depressive disorders and healthy normal volunteers between 18
and 60 years of age may be eligible for this study. Candidates are screened with a
psychiatric and medical history, physical examination, electrocardiogram, and blood and
urine tests. Participants undergo the following tests and procedures in up to eight visits
to the NIH Clinical Center:
Memory Tasks and Problem Solving and Brain Imaging
Subjects are tested with measurements of intelligence or memory ability. They also undergo
magnetic resonance imaging (MRI), a test that uses a magnetic field and radio waves to
produce images of the brain. For this procedure, the patient lies on a table that is moved
into the scanner (a narrow cylinder), and wears earplugs to muffle loud knocking and
thumping sounds that occur during the scanning process. The MRI lasts about 60 minutes.
Catecholamine Depletion Study
For this study, subjects take capsules containing either AMPT (a drug that temporarily
reduces brain catecholamine activity) or a placebo (lactose capsules, which do not affect
brain catecholamine activity) at 9 a.m., 2 p.m., and 7 p.m. on one visit and return the next
day to take additional capsules at 7 a.m. and noon. In addition to the study medication,
subjects keep a low-monoamine diet (e.g., no chocolate, cheese, smoked meats, and various
other foods that will be enumerated) and do not smoke, drink alcohol, or take in food or
drink containing caffeine. After taking all the study capsules, the subjects have positron
emission tomography (PET) and functional MRI (fMRI) scans, as follows:
- fMRI: While lying in the MRI scanner, the subject performs a monetary reward task that
is somewhat like playing a computer video game for money. The amount of cash the
subject can win depends on his or her performance. It is possible to lose money that
was previously won, if performance declines. This portion of the study provides
information on how the brain processes reward and about the role of catecholamines in
- PET: The subject is injected in the arm with a glucose solution that has a radioactive
substance attached that can be detected by the PET scanner. During the scan, the
subject looks at photographs of faces on a computer screen and is asked to tell the
gender of the persons. This test shows brain blood flow and measures brain glucose
(sugar) metabolism, which reflects brain activity. At the end of the scan, subjects are
asked about their mood and general well being. They return to the Clinical Center the
following day for and evaluation of their emotional state.
The catecholamine depletion study is repeated a second time 14 days or more after the first.
Subjects who received AMPT capsules for the first study take lactose capsules for the second
study, and vice-versa.
The depressive and anhedonic response precipitated by CD raises the possibility that
dysfunction of the dopamine system is a stable, sometimes latent characteristic of MDD.
Following this line of reasoning, central catecholamine dysfunction as evinced by CD may be
equally salient in a subset of unaffected relatives who are at genetic risk for developing
We plan to extend the phase I project to unaffected relatives of BD and MDD patients in
order to evaluate sensitivity to CD as an endophenotype of MDD and BD. In order to maximize
our statistical power, we will be recruiting equal numbers healthy low and high-risk
relatives. Here, risk is defined on the basis of chronological age (see below for more
Furthermore, it has recently become feasible to conduct genome-wide association studies and
quantify the burden of risk alleles carried by an individual. Certainly, the identity of
these risk alleles remains unknown or unproven. Nevertheless, Francis McMahon's group, with
whom we are collaborating, have identified upwards of 20 common risk variants in two
independent samples. Individuals carrying 19 or more of these risk alleles were found to be
4 times more likely to be cases than controls. This approach may provide us with another
method of quantifying genetic risk.
The endophenotypic status of sensitivity to CD will be evaluated with psychometric
instruments, FDG PET, and an fMRI-coupled appetitive learning task. We now have access to a
high resolution PET scanner (High Resolution Research Tomograph) that will enable us to
study hitherto irresolvable structures of importance such as the habenula and
peri-aqueductal gray matter (PAG) in addition to previously implicated regions such as the
ventral striatum and OFC. Analysis of the metabolic activity of these regions under sham and
CD conditions in both remitted MDD and relatives of BD and MDD patients is of great
theoretical import. So to is identifying regions of the brain involved in reward response
that are selectively impacted by CD, a question that we hope to answer through the use of
the fMRI-coupled appetitive learning task.
- INCLUSION CRITERIA:
MDD Sample: 40 subjects (ages 18-45) with remitted MDD will be selected. MDD is defined by
the DSM-IV criteria, and one of the following additional criteria:
1. history of two or more major depressive episodes, or
2. history of one major depressive episode and a family history for major depression.
Remission is defined as a period of at least three months during which the subject
has not taken any antidepressant agents, with the Hamilton Depression Rating Scale
(HDRS; 21-item) scores in the non-depressed range (less than 8), and with no more
than one clinically significant depressive symptom.
Unaffected MDD Relative Sample:
40 healthy relatives of MDD probands (ages 18-45) will be recruited. Subjects will be
screened to ensure that they have no history of psychiatric illness.
Unaffected BD Relative Sample:
Healthy relatives of BD probands (ages 18-45) will be recruited. Subjects will be screened
to ensure that they have no history of psychiatric illness.
Healthy Control Samples:
-Healthy subjects (ages 18-45) without a known personal or first-degree family history of
psychiatric disorders in first-degree relatives will be selected.
- Any subject who appears incapable of providing informed consent will be excluded from
- Subjects who take effective antidepressant medication
- Subjects must not have taken antidepressant or other medications likely to alter
monoamine neurochemistry or cerebrovascular and cardiovascular function for at least
3 months prior to the studies.
- Subjects who have:
1. psychosis to the extent that the ability to provide informed consent is in doubt
2. medical or neurological illnesses likely to affect physiology or anatomy, i.e.
hypertension, cardiovascular disorders
3. a history of drug (including benzodiazepines [BZD]) or alcohol abuse within 1
year or a lifetime history of alcohol or drug dependence (DSM IV criteria)
longer than 2 years
4. current pregnancy (as documented by pregnancy testing at screening or at days of
the challenge studies)
5. current breast feeding
7. serious suicidal ideation or behavior
8. general MRI exclusion criteria (e.g., subjects with metallic implants that are
ferromagnetic will be excluded from the fMRI scanning). Subjects must exhibit no
or only moderate alcohol use. Subjects with current excessive use of alcohol
(greater than 4 ounces/day for men and greater than 3 ounces/day for women) are
ineligible for participation, as such drug use confounds the results
9. smokers are ineligible because of the evidence for interactions between nicotine
and depression, and the possibility of withdrawal symptoms that may affect
behavioral and neural responses to CD
10. history of suicidality and other axis I diagnoses beside major depressive
11. lactose intolerance
12. women not using a reliable contraception method. Finally subjects who have had
an upper respiratory tract infection in the last week will be excluded as this
may impact sense of smell.
- Subjects beyond age 45
- Individuals whose first major depressive episodes arose after other medical or
- Subjects showing significant side effects during AMPT depletion such as dystonic
reactions will receive adequate treatment and will be excluded from the study