Function of Catecholamines in the Brain During Depression
Condition: Depression; Involutional
MeSH terms: Depression; Depressive Disorder
Study type: Observational

Summary: 
      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 this process.

        -  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.
    

Detailed description: 
      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
      the disorder.

      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 detail).

      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.
    

Keywords: Depression; PET; fMRI; Dopamine; Norepinephrine Depletion; Emotional Stimuli; Anhedonia; Norepinephrine; Dopamine Depletion; Major Depressive Disorder; MDD; Healthy Volunteer; HV