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.
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.
Randomized double-blind crossover study.
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).
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
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
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.
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.