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

Arch Gen Psychiatry. 2004 Aug;61(8):765-73. doi: 10.1001/archpsyc.61.8.765.


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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Amino Acids, Essential / administration & dosage
  • Amino Acids, Essential / metabolism
  • Brain / metabolism
  • Brain / physiopathology*
  • Brain Mapping
  • Cross-Over Studies
  • Depressive Disorder / diagnosis
  • Depressive Disorder / physiopathology*
  • Depressive Disorder / therapy*
  • Double-Blind Method
  • Female
  • Fluorodeoxyglucose F18
  • Genetic Markers
  • Glucose / metabolism
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Neural Pathways / metabolism
  • Neural Pathways / physiopathology
  • Recurrence
  • Serotonin / biosynthesis
  • Serotonin / physiology*
  • Tomography, Emission-Computed
  • Treatment Outcome
  • Tryptophan / blood
  • Tryptophan / deficiency*


  • Amino Acids, Essential
  • Genetic Markers
  • Fluorodeoxyglucose F18
  • Serotonin
  • Tryptophan
  • Glucose