Clinical Trial: Function of Catecholamines in the Brain During Depression

This study is currently recruiting patients.

Sponsored by: National Institute of Mental Health (NIMH)
Information provided by: Warren G Magnuson Clinical Center (CC)

Purpose

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.

Condition Treatment or Intervention
Depression
Involutional
 Drug: O-15 Water
 Drug: F-18 FDG

MedlinePlus related topics:  Depression

Study Type: Observational
Study Design: Natural History

Official Title: Neural Correlates of Depressive Symptoms and Reward Related Mechanisms Following AMPT Depletion in Remitted Depressed Patients Off Treatment and Healthy Controls

Further Study Details: 

Expected Total Enrollment:  60

Study start: April 19, 2004

Major depressive disorder (MDD) has been associated with dysregulation of central catecholaminergic systems by various types of evidence. One instructive paradigm for investigating the relationship between catecholaminergic function and depression has involved the mood response to catecholamine depletion (CD), achieved by oral administration of alpha-methyl-paratyrosine (AMPT). Previous studies have shown that AMPT administration leads to a transient exacerbation of depressive symptoms in patients who have responded to catecholaminergic antidepressants. Moreover, fully remitted, drug-free patients with a history of depressive episodes show depressive symptoms after CD. There is some data suggesting that mood changes induced by AMTP may be mediated by decreases in norepinephrine, while changes in selective attention and motivation may be mediated by dopamine.

The current study employs PET imaging of cerebral blood flow (CBF) and glucose metabolism to investigate the neural correlates of AMPT-induced depressive symptoms by comparing subjects with return of depressive symptoms to subjects without return of depressive symptoms, and to healthy controls. By comparing the result of this study to a recent study investigating the neural correlates of depressive symptoms induced by tryptophan depletion in remitted depressed subjects, we expect to identify common neural circuits involved in the development of depressive symptoms mediated by lowering of monoamines representing trait markers of MDD. Based on data suggesting that dopamine plays a role in the regulation of amygdala activity and that increased amygdala activity represents another potential trait marker of MDD, the current study will also examine the impact of lowering catecholamines on amygdala responses to emotional faces.

Impairment of reward-related behavior is a key symptom of MDD. Given the role played by dopamine in the brain reward system, the current study will investigate the effects of AMPT on reward anticipation and reward consumption using the monetary incentive delay task and examining the changes in cerebral blood flow as measured by fMRI.

As a secondary aim, the current study will obtain preliminary data regarding the associations between AMPT-induced depressive symptoms and candidate genes for MDD. The high activity allele of the monoamine oxidase A (MAO-A) gene promotor has been associated with increased risk for MDD. MAO-A metabolizes norepinephrine and is localized in noradrenergic neurons in brain areas being potentially relevant in the pathophysiology of MDD. We predict a greater degree of depressive exacerbation and different metabolic responses to AMPT in the high activity allele group relative to the low activity allele group. In addition, we will examine the role of a functional polymorphism of the dopamine beta-hydroxylase (DBH) gene that has been associated with decreased DBH activity, suggesting increased dopamine and decreased norepinephrine levels, and has been located in brain regions mediating arousal, motivation and stress.

30 unmedicated-remitted subjects with MDD and 15 healthy controls will be studied in a double-blind, placebo-controlled, randomized crossover study.

Eligibility

Genders Eligible for Study:  Both

Accepts Healthy Volunteers

Criteria

INCLUSION CRITERIA:
To assess inclusion and exclusion criteria, subjects will come in for screening and physical examination, then called back for the CD-brain imaging studies after the comparison groups are constructed.
Subjects are screened for present or past psychiatric axis I diagnoses using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, non-patient version. Family history of mental illness (mood and anxiety disorders, schizophrenia and other psychotic disorders, substance abuse disorders) will be obtained in all 1st degree relatives using the Family Interview of Genetic Studies.
MDD Sample: 30 subjects (ages 18-60) with remitted MDD will be selected. MDD is defined by the DSM-IV criteria, and one of the following additional criteria:
a) history of two or more major depressive episodes, or
b) 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.
Healthy Control Samples: 15 healthy subjects (ages 18-60) without a known personal or first-degree family history of psychiatric disorders in first-degree relatives will be selected.
EXCLUSION CRITERIA:
We will not enter subjects under age 18, however, because of ethical concerns about exposing them to ionizing radiation and because the restrictions imposed by the RSC to limit the annual radiation exposure for subjects under age 18 are below that planned for the current study.
Pregnant and lactating females will be excluded due to the unacceptable risk of radiation exposure during pregnancy or nursing.
If any subject appears incapable of providing informed consent, they will be excluded from the study.
Subjects who take effective antidepressant medication will also be excluded from the study. In addition, 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 will also be excluded if they have:
a) psychosis to the extent that the ability to provide informed consent is in doubt,
b) medical or neurological illnesses likely to affect physiology or anatomy, i.e. hypertension, cardiovascular disorders,
c) 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,
d) current pregnancy (as documented by pregnancy testing at screening or at days of the challenge studies),
e) current breast feeding,
f) smokers,
g) serious suicidal ideation or behavior,
h) 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,
i) 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,
j) history of suicidality and other axis I diagnoses beside major depressive disorder,
k) lactose intolerance,
l) women not using a reliable contraception method.
Subjects beyond age 60 are excluded to address the biological heterogeneity encompassed by the MDD criteria, since depressives whose age-at-onset is later than 60 have a far greater likelihood of having MRI correlates of cerebrovascular disease than age-matched healthy controls or age-matched early-onset depressives.
Subjects whose first major depressive episodes arose temporally after other medical or psychiatric conditions will also be excluded, since their functional imaging results generally differ from those reported in primary MDD.
Subjects showing significant side effects during AMPT depletion such as dystonic reactions will receive adequate treatment and will be excluded from the study.

Location and Contact Information


Maryland
      National Institute of Mental Health (NIMH), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting
Patient Recruitment and Public Liaison Office  1-800-411-1222    prpl@mail.cc.nih.gov 
TTY  1-866-411-1010 

More Information

Detailed Web Page

Publications

Verhoeff NP, Christensen BK, Hussey D, Lee M, Papatheodorou G, Kopala L, Rui Q, Zipursky RB, Kapur S. Effects of catecholamine depletion on D2 receptor binding, mood, and attentiveness in humans: a replication study. Pharmacol Biochem Behav. 2003 Jan;74(2):425-32.

Verhoeff NP, Kapur S, Hussey D, Lee M, Christensen B, C Psych, Papatheodorou G, Zipursky RB. A simple method to measure baseline occupancy of neostriatal dopamine D2 receptors by dopamine in vivo in healthy subjects. Neuropsychopharmacology. 2001 Aug;25(2):213-23.

Lambert G, Johansson M, Agren H, Friberg P. Reduced brain norepinephrine and dopamine release in treatment-refractory depressive illness: evidence in support of the catecholamine hypothesis of mood disorders. Arch Gen Psychiatry. 2000 Aug;57(8):787-93.

Study ID Numbers:  040160; 04-M-0160
Record last reviewed:  February 16, 2005
Last Updated:  March 29, 2005
Record first received:  April 28, 2004
ClinicalTrials.gov Identifier:  NCT00082030
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08


Source: ClinicalTrials.gov
Cache Date: April 9, 2005