Effects of rapid tryptophan depletion on mood and urge to drink in patients with co-morbid major depression and alcohol dependence

Rationale. Rapid tryptophan depletion (RTD) has been used to study central serotonin function and may therefore be useful in understanding co-morbid alcohol dependence (AD) and major depressive disorder (MDD). Objectives. To examine (1) the effect of RTD on mood and urge to drink among patients with AD and MDD and (2) the association of RTD effects with alleles of a functional polymorphism in the gene encoding the serotonin transporter protein. Methods. Double-blind, placebo-controlled study, in which 14 treatment responders recruited from one of two placebo-controlled trials of serotonergic antidepressants were enrolled. Patients underwent two day-long sessions, which were either a tryptophan depletion session or a sham session. During each session, mood and urge for alcohol were measured at regular intervals. Results. Five hours after RTD, plasma TRP concentrations decreased by 73.1%. There was a significant effect of session on both mood and the urge to drink. Genotype moderated the effect of session on mood, such that, during RTD, individuals homozygous for the long allele reported greater depression than did subjects with one or two copies of the S allele. Conclusions. This study provides support for the role of serotonergic neurotransmission in modulating mood and alcohol urges, and underscores the utility of these effects as a phenotype for genetic analysis. These findings may also help to identify alcoholics who are at greatest risk for MDD.