RELAPSE OF DEPRESSION AFTER RAPID DEPLETION OF TRYPTOPHAN

Background Major depression is a common disorder but. the pathophysiol ogy is poorly understood. Current hypotheses implicate deficient funct ion of brain serotonin pathways because drugs that selectively increas e brain serotonin activity are effective antidepressants. However, the re is no direct evidence that lowered serotonin function causes major depression. We aimed to assess whether lowering of brain serotonin act ivity by depletion of its aminoacid precursor, tryptophan, could provo ke a short-term relapse of clinically significant symptoms in women vu lnerable 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 iden tical except it contained no tryptophan. Participants were scored on t he Hamilton rating scale for depression (HAM-D) before and 7 h after d rinking each mixture. They also completed hourly self-rated measures o f mood during this period. Blood samples were also taken at baseline a nd 7 h for measurement of plasma tryptophan. Findings The tryptophan-f ree mixture produced a 75% reduction in plasma tryptophan concentratio n. After drinking the tryptophan-free mixture, ten of the 15 women exp erienced temporary but clinically significant depressive symptoms. The mean difference in total HAM-D scores (7 h minus baseline) were signi ficantly higher after the tryptophan-free mixture than after the nutri tionally 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 mixt ure. Interpretation We conclude that rapid lowering of brain serotonin function can precipitate clinical depressive symptoms in well, untrea ted individuals who are Vulnerable to major depressive disorder. The f indings support a hey role for deficient serotonin function in the aet iology of depression.