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Alexander Neumeister, MD; Allison C. Nugent, PhD; Tracy Waldeck, PhD; Marilla Geraci, RN; Markus Schwarz, MD; Omer Bonne, MD; Earle E. Bain, MD; David A. Luckenbaugh, MA; Peter Herscovitch, MD; Dennis S. Charney, MD; Wayne C. Drevets, MD

Arch Gen Psychiatry. 2004;61:765-773.

Context  An instructive paradigm for investigating the relationship between brain serotonin function and major depressive disorder (MDD) is the response to tryptophan depletion (TD) induced by oral loading with all essential amino acids except the serotonin precursor tryptophan.

Objective  To determine whether serotonin dysfunction represents a trait abnormality in MDD in the context of specific neural circuitry abnormalities involved in the pathogenesis of MDD.

Design  Randomized double-blind crossover study.

Setting  Outpatient clinic.

Participants  Twenty-seven medication-free patients with remitted MDD (18 women and 9 men; mean ± SD age, 39.8 ± 12.7 years) and 19 controls (10 women and 9 men; mean ± SD age, 34.4 ± 11.5 years).

Interventions  We induced TD by administering capsules containing an amino acid mixture without tryptophan. Sham depletion used identical capsules containing hydrous lactose. Fluorodeoxyglucose F 18 positron emission tomography studies were performed 6 hours after TD. Magnetic resonance images were obtained for all participants.

Main Outcome Measures  Quantitative positron emission tomography of regional cerebral glucose utilization to study the neural effects of sham depletion and TD. Behavioral assessments used a modified (24-item) version of the Hamilton Depression Rating Scale.

Results  Tryptophan depletion induced a transient return of depressive symptoms in patients with remitted MDD but not in controls (P<.001). Compared with sham depletion, TD was associated with an increase in regional cerebral glucose utilization in the orbitofrontal cortex, medial thalamus, anterior and posterior cingulate cortices, and ventral striatum in patients with remitted MDD but not in controls.

Conclusion  The pattern of TD-induced regional cerebral glucose utilization changes in patients with remitted MDD suggests that TD unmasks a disease-specific, serotonin system–related trait dysfunction and identifies a circuit that probably plays a key role in the pathogenesis of MDD.

From the Sections on Experimental Therapeutics and Pathophysiology (Drs Neumeister, Waldeck, Bonne, and Charney; Ms Geraci; and Mr Luckenbaugh) and Neuroimaging in Mood and Anxiety Disorders (Drs Nugent, Bain, and Drevets), Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, Md; the Department of Neurochemistry, University Hospital of Psychiatry, Munich, Germany (Dr Schwarz); and the PET Department, Clinical Center, National Institutes of Health, Bethesda (Dr Herscovitch). Dr Neumeister is now with the Department of Psychiatry, Yale University, New Haven, Conn.

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