Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls.
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.