Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders

Arch Gen Psychiatry. 1994 Sep;51(9):687-97. doi: 10.1001/archpsyc.1994.03950090019003.


Methods: A double-blind placebo-controlled cross-over study in which plasma tryptophan was manipulated by administration of a tryptophan-deficient amino acid mixture. In the placebo condition, all subjects received a nutritionally balanced amino acid mixture that contained tryptophan. To further standardize baseline amino acids, each subject was provided with a low-protein diet the day before amino acid challenges. Subjects were euthymic, healthy men aged 18 to 30 years with either a multigenerational family history of affective illness or no family history of psychiatric illness in the present or in the two previous generations. Each subject was screened with a structured clinical interview to rule out a personal history of psychiatric illness.

Results: Plasma tryptophan was reduced by 89% 5 hours after the administration of the tryptophan-deficient amino acid mixture. Six of 20 subjects with a family history of affective illness and none of 19 subjects without a family history of psychiatric illness showed a lowering of mood of 10 or more points on the Profile of Mood States depression scale (P = .012, Fisher's Exact Test) 5 hours after tryptophan depletion. No significant mood changes were observed following the control treatment (balanced amino acid mixture) in either group.

Conclusions: Our data support the hypothesis that subjects with no prior depressive episodes but with a multigenerational family history of major affective disorder show a greater reduction in mood after tryptophan depletion. They are also consistent with theories that implicate deficient serotonergic function as one possible etiological factor in major depressive disorders.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Affect* / physiology
  • Alcoholism / diagnosis
  • Alcoholism / genetics
  • Amino Acids / administration & dosage
  • Amino Acids / metabolism
  • Depressive Disorder / diagnosis
  • Depressive Disorder / genetics*
  • Depressive Disorder / physiopathology
  • Double-Blind Method
  • Family
  • Genetic Markers
  • Humans
  • Male
  • Phenotype
  • Placebos
  • Psychiatric Status Rating Scales
  • Serotonin / biosynthesis
  • Serotonin / physiology
  • Substance-Related Disorders / diagnosis
  • Tryptophan / blood*
  • Tryptophan / deficiency
  • Tryptophan / metabolism


  • Amino Acids
  • Genetic Markers
  • Placebos
  • Serotonin
  • Tryptophan