Relapse of depression after rapid depletion of tryptophan

Summary

Background

Major depression is a common disorder but the pathophysiology is poorly understood. Current hypotheses implicate deficient function of brain serotonin pathways because drugs that selectively increase brain serotonin activity are effective antidepressants. However, there is no direct evidence that lowered serotonin function causes major depression. We aimed to assess whether lowering of brain serotonin activity by depletion of its aminoacid precursor, tryptophan, could provoke a short-term relapse of clinically significant symptoms in women vulnerable to major depressive disorder.

Methods

We studied 15 women who had suffered recurrent episodes of major depression but had recovered and were no longer on drug treatment. Patients received two aminoacid mixtures in a double-blind crossover design. One of the mixtures was nutritionally balanced and contained tryptophan and the other was identical except it contained no tryptophan. Participants were scored on the Hamilton rating scale for depression (HAM-D) before and 7 h after drinking each mixture. They also completed hourly self-rated measures of mood during this period. Blood samples were also taken at baseline and 7 h for measurement of plasma tryptophan.

Findings

The tryptophan-free mixture produced a 75% reduction in plasma tryptophan concentration. After drinking the tryptophan-free mixture, ten of the 15 women experienced temporary but clinically significant depressive symptoms. The mean difference in total HAM-D scores (7 h minus baseline) were significantly higher after the tryptophan-free mixture than after the nutritionally balanced mixture (7·3 vs 0·15 [95% CI 4·5-9-9]; p<0·001). No changes in mood were seen after taking the nutritionally balanced mixture.

Interpretation

We conclude that rapid lowering of brain serotonin function can precipitate clinical depressive symptoms in well, untreated individuals who are vulnerable to major depressive disorder. The findings support a key role for deficient serotonin function in the aetiology of depression.

Introduction

Major depressive disorder is common and is characterised by cognitive, behavioural, and somatic symptoms.¹ Although much is known about the social and personal antecedents of depression, the neurobiological basis of the clinical syndrome remains poorly understood.2, 3 Evidence suggests a role for the neurotransmitter serotonin because depressed patients have altered brain serotonin activity3, 4 and drugs that selectively increase serotonin neurotransmission are effective antidepressants.⁵ is not clear, however, whether impaired serotonin function is responsible for the clinical signs of major depressive disorder.4, 5, 6

The synthesis of serotonin in the brain is dependent on the availability of its aminoacid precursor tryptophan from plasma.⁷ It is possible to produce a rapid lowering of tryptophan availability to the brain by replacing a normal balanced diet with an aminoacid mixture that lacks tryptophan. This lowers the concentration of tryptophan in plasma and inhibits transport across the blood-brain barrier.8, 9 As a result, brain serotonin synthesis and release decrease.8, 10, 11

If impaired serotonin function plays an important part in the pathophysiology of major depressive disorder, one would expect that a rapid lowering of tryptophan in the plasma of people who are vulnerable to major depression might lead to clinically significant depressive symptoms. Patients who have had episodes of major depression are known to be vulnerable to the development of subsequent episodes.¹² We studied the effect of a tryptophan-free aminoacid mixture on women with a history of recurrent depression but who had recovered and were not taking antidepressant medication.