Association Study of Genotype by Depressive Response during Acute Tryptophan Depletion in Subjects Recovered from Major Depression

Abstract

Purpose: To study the brief and reversible mood response to acute tryptophan depletion (ATD) as a trait marker in subjects considered at risk for major depressive disorder (MDD). Procedures: ATD was administered to 64 subjects (54 European-Americans and 10 from other races) with a personal and family history of MDD. They were in remission and had been medication-free for at least 3 months. Subjects were randomly assignment to an active or sham condition in a double-blind crossover design. They were genotyped for serotonin-related candidate genes, and mood response was quantified with the Hamilton Depression Rating Scale (HDRS). Data were analyzed using Poisson regression with repeated measures and latent trajectory models. Results: Compared to the sham controls, active ATD caused modest depressive changes showing significant main effects of test condition (χ 2 = 5.14, d.f. = 1, p = 0.023) and time (χ 2 = 12.22, d.f. = 3, p = 0.007), but no significant interaction of time and test condition. Latent trajectory analysis revealed two groups, identified as depletion responders and non-responders. Those with the HTR2A rs6313 CC genotype had significantly higher HDRS scores during ATD (χ 2 = 11.72, d.f. = 1, p = 0.0006). Conclusions: ATD may help identifying the biological subtypes of MDD. These data are consistent with imaging reports implicating 5-HT 2A receptor function in ATD phenotypes.