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Letter to the Editor   |    
Some Ado About a Polymorphism
MARIA NOBILE, M.D.; CECILIA MARINO, M.D., PH.D.; MASSIMO MOLTENI, M.D.; MARCO BATTAGLIA, M.D.
Am J Psychiatry 2000;157:1886-a-1887. doi:10.1176/appi.ajp.157.11.1886-a

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 longvariant 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/longhomozygotes, of significantly lower platelet 5-HT uptake (Vmax) in depressed drug-naive children and adolescents than in their nondepressed peers. Depressed heterozygote and short/short homozygote children had Vmax rates similar to those of their healthy homologues. None of several previous studies of altered Vmax 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 Vmax 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.

Benedetti F, Serretti A, Colombo C, Campori E, Barbini B, Di Bella D, Smeraldi E: Influence of a functional polymorphism within the promoter of the serotonin transporter gene on the effects of total sleep deprivation in bipolar depression. Am J Psychiatry 1999; 156:1450–  1452
 
Nobile M, Begni B, Giorda R, Frigerio A, Marino C, Molteni M, Ferrarese C, Battaglia M: Effects of serotonin transporter promoter genotype on platelet serotonin transporter functionality in depressed children and adolescents. J Am Acad Child Adolesc Psychiatry 1999; 38:1396–  1402
 
Greenberg BD, Tolliver TJ, Huang S, Li Q, Bengel D, Murphy DL: Genetic variation in the serotonin transporter promoter region affects serotonin uptake in blood platelets. Am J Med Genet  1999; 88:83–87
[PubMed]
[CrossRef]
 
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References

Benedetti F, Serretti A, Colombo C, Campori E, Barbini B, Di Bella D, Smeraldi E: Influence of a functional polymorphism within the promoter of the serotonin transporter gene on the effects of total sleep deprivation in bipolar depression. Am J Psychiatry 1999; 156:1450–  1452
 
Nobile M, Begni B, Giorda R, Frigerio A, Marino C, Molteni M, Ferrarese C, Battaglia M: Effects of serotonin transporter promoter genotype on platelet serotonin transporter functionality in depressed children and adolescents. J Am Acad Child Adolesc Psychiatry 1999; 38:1396–  1402
 
Greenberg BD, Tolliver TJ, Huang S, Li Q, Bengel D, Murphy DL: Genetic variation in the serotonin transporter promoter region affects serotonin uptake in blood platelets. Am J Med Genet  1999; 88:83–87
[PubMed]
[CrossRef]
 
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