Background. Acute tryptophan depletion (ATD), a means of reducing brain serotonin synthesis, lowers mood in normal males with a multi-generational family history of major affective disorder (MAD) and in normal women devoid of any family history of psychiatric illness. As both a family history of MAD and female sex are factors predisposing to depression, the hypothesis that a mood lowering response to ATD may reflect a susceptibility to depression was further investigated in young women with an extensive, multi-generational family history of MAD. In addition, the temporal stability of mood change following repeated trials of ATD was also assessed in this study.

Methods. To deplete tryptophan, a tryptophan deficient amino acid mixture was ingested on two separate occasions. The control treatment, administered on a third occasion, was a nutritionally balanced amino acid mixture containing tryptophan.

Results. A marked lowering of plasma tryptophan (85–90%) was achieved by both depletions. In comparison to the balanced condition, family history positive (FH+) women showed no lowering of mood to either the first or second ATD (N=13) and N=12, respectively). Mood change between the two ATD trials (N=13) exhibited poor temporal stability.

Conclusions. These results may indicate that serotonin responsiveness is not an important characteristic of vulnerability to depression in these women. Alternately, these negative results may be due to the exclusion of a large number of FH+ women who had already experienced an episode of depression, resulting in the selection of a biased FH+ sample who are resistant to the mood lowering effects of ATD.