Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-free depressed patients

Arch Gen Psychiatry. 1994 Nov;51(11):865-74. doi: 10.1001/archpsyc.1994.03950110025005.


Objective: To investigate the effects of tryptophan depletion in untreated depressed patients. Rapid dietary depletion of the precursor of serotonin synthesis, tryptophan, causes a transient return of depression in 67% of patients who have had a therapeutic antidepressant response.

Method: Forty-three untreated depressed patients underwent tryptophan depletion in a double-blind, placebo-controlled cross-over study. After testing, they received open sequential antidepressant treatment.

Results: Mood did not change when tryptophan was depleted but did change on the day after the depletion test. Relative to the control test, 37% of the patients had 10-point or greater decrease in Hamilton Depression Rating Scale (Ham-D) score, while 23% had a 10-point or greater increase in Ham-D score on the day after the tryptophan depletion test. Change in mood was correlated to treatment response after testing. Patients whose condition worsened proved to be highly refractory to treatment while those who showed improvement were more likely to respond.

Conclusions: That tryptophan depletion did not rapidly worsen depression argues that serotonin function is not linearly related to the level of depression and if reduced serotonin function does cause depression, then it is either as predisposing factor or due to a postsynaptic deficit in the utilization of serotonin.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Antidepressive Agents / therapeutic use
  • Comorbidity
  • Cross-Over Studies
  • Depressive Disorder / drug therapy
  • Depressive Disorder / physiopathology*
  • Depressive Disorder / psychology
  • Diet
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Personality Disorders / diagnosis
  • Personality Disorders / psychology
  • Placebos
  • Psychiatric Status Rating Scales
  • Recurrence
  • Serotonin / blood
  • Serotonin / physiology*
  • Treatment Outcome
  • Tryptophan / administration & dosage
  • Tryptophan / blood*
  • Tryptophan / deficiency


  • Antidepressive Agents
  • Placebos
  • Serotonin
  • Tryptophan