Some Ado About a Polymorphism

To the Editor: An article by Francesco Benedetti, M.D., et al. (1) reported mood improvement through total sleep deprivation in depressed carriers of the long/long genotype at the serotonin-transporter-linked polymorphic region. Although the authors hypothesized enhancement of serotonergic (5-HT) transmission by total sleep deprivation (1), no direct evidence was provided of a relationship between different genotypes at the 5-HT-transporter-linked polymorphic region and differential 5-HT transporter activity during depression.

We suggest that these results can be connected to a dysfunction of the 5-HT transporter that may be specific to the homozygote carriers of the long variant of the genotype when they become depressed, whereas heterozygotes and short/short homozygotes may have only marginally altered, or normal, 5-HT transporter function during depression. We (2) have reported a group effect, almost entirely sustained by long/long homozygotes, of significantly lower platelet 5-HT uptake (V_max) in depressed drug-naive children and adolescents than in their nondepressed peers. Depressed heterozygote and short/short homozygote children had V_max rates similar to those of their healthy homologues. None of several previous studies of altered V_max in depression had controlled for the possible effect of 5-HT transporter polymorphisms.

Thus, although 5-HT transporter function differs among individuals in the population in a fashion that can be predicted on the basis of their 5-HT-transporter-linked polymorphic region genotype (2, 3), appreciable intra-individual variation in the course of a depressive episode may be limited to the subgroup of individuals with long/long homozygotes. Since the latter constitute about 30% of the population, their presence among depressed individuals may explain a sizable proportion of the group effect in the V_max rate that was found in several studies. The appreciable differences in the effectiveness of selective serotonin reuptake inhibitors in depressed patients according to their genetic setup at the 5-HT-transporter-linked polymorphic region (cited in reference 1) closely parallel our own findings with the three subgroups of the 5-HT-transporter-linked polymorphic region (2). As far as the extent to which total sleep deprivation exerts its action through activation of serotonergic transmission, we suggest that the data by Dr. Benedetti et al. (1) offer a further hint for considering differences at the 5-HT-transporter-linked polymorphic region as a tool for discriminating among individuals with potentially different degrees of 5-HT transporter dysfunction during depressive episodes.

These findings taken together encourage studies of the epigenetic and epistatic factors that may affect 5-HT uptake specifically in patients with long/long homozygotes when they become depressed, follow-up studies of 5-HT transporter function in euthymia, and careful consideration of differences at the 5-HT-transporter-linked polymorphic region when groups of depressed patients are compared to unaffected subjects in clinical studies.