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Gregor Hasler, MD; Stephen Fromm, PhD; Paul J. Carlson, MD; David A. Luckenbaugh, MA; Tracy Waldeck, PhD; Marilla Geraci, RN; Jonathan P. Roiser, PhD; Alexander Neumeister, MD; Noah Meyers, BS; Dennis S. Charney, MD; Wayne C. Drevets, MD

Arch Gen Psychiatry. 2008;65(5):521-531.

Context  The pathophysiologic mechanism of major depressive disorder (MDD) has been consistently associated with altered catecholaminergic function, especially with decreased dopamine neurotransmission, by various sources of largely indirect evidence. An instructive paradigm for more directly investigating the relationship between catecholaminergic function and depression has involved the mood response to experimental catecholamine depletion (CD).

Objectives  To determine whether catecholaminergic dysfunction represents a trait abnormality in MDD and to identify brain circuitry abnormalities involved in the pathophysiologic mechanism of MDD.

Design  Randomized, double-blind, placebo-controlled, crossover, single-site experimental trial.

Setting  Psychiatric outpatient clinic.

Participants  Fifteen unmedicated subjects with MDD in full remission (hereinafter referred to as RMDD subjects) and 13 healthy controls.

Intervention  Induction of CD by oral administration of -methylparatyrosine. Sham depletion used identical capsules containing hydrous lactose.

Main Outcome Measures  Quantitative positron emission tomography of regional cerebral glucose utilization to study the neural effects of CD and sham depletion. Behavioral assessments included the Montgomery-Asberg Depression Rating Scale and the Snaith-Hamilton Pleasure Scale (anhedonia).

Results  Depressive and anhedonic symptoms increased during CD to a greater extent in RMDD subjects than in controls. In both groups, CD increased metabolism in the anteroventral striatum and decreased metabolism in the orbital gyri. In a limbic-cortical-striatal-pallidal-thalamic network previously implicated in MDD, composed of the ventromedial frontal polar cortex, midcingulate and subgenual anterior cingulate cortex, temporopolar cortex, ventral striatum, and thalamus, metabolism increased in RMDD subjects but decreased or remained unchanged in controls. Metabolic changes induced by CD in the left ventromedial frontal polar cortex correlated positively with depressive symptoms, whereas changes in the anteroventral striatum were correlated with anhedonic symptoms.

Conclusions  This study provides direct evidence for catecholaminergic dysfunction as a trait abnormality in MDD. It demonstrates that depressive and anhedonic symptoms as a result of decreased catecholaminergic neurotransmission are related to elevated activity within the limbic-cortical-striatal-pallidal-thalamic circuitry.

Author Affiliations: Department of Psychiatry, University Hospital, Zurich, Switzerland (Dr Hasler); Mood and Anxiety Disorders Program, Section on Neuroimaging in Mood and Anxiety Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (Drs Fromm, Carlson, Waldeck, Roiser, and Drevets; Messrs Luckenbaugh and Meyers; and Ms Geraci); Molecular Imaging Program of the Clinical Neuroscience Division, Yale University School of Medicine, West Haven, Connecticut (Dr Neumeister); and Departments of Psychiatry, Neuroscience, and Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York (Dr Charney).

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