e-mail: ns@mblcommunications.com


Dr. Sussman is editor of Primary Psychiatry as well as professor of psychiatry and interim chairman in the Department of Psychiatry at the New York University School of Medicine in New York City.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest.


In last month’s issue, 1 I commented on recent research that the gene responsible for expression of the serotonin transporter (5-HTT) modulates the effect of life stressors and the development of major depressive disorder. Caspi and colleagues2 cited a polymorphism in the 5-HTT-linked polymorphic region (5-HTTLPR), that results in two common alleles, termed “short”(s) and “long’”(l). The “s” allele was found to be associated with increased risk for depression, especially when exposed to loss or environmental stress. I also pointed out that a new study3 found that the 5-HTTLPR gene may not be as critical as believed, since the original finding had not been consistently replicated. The authors found no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined. Yet, here we are a month later and two new articles published in the July British Journal of Psychiatry4,5 brings us back to 5-HTTLPR as a focal point of research on the prediction of who will develop depression and the prediction of antidepressant response. 

Huezo-Diaz and colleagues4 looked at the conflicting reports on whether the length polymorphism—“s” or “l”—in the promoter of the 5-HTTLPR moderates the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs). Participants included 296 men and 514 women between 19–72 years of age. They hypothesized that the pharmacogenetic effect of 5-HTTLPR is modulated by gender, age, and other variants in the serotonin transporter gene. They tested the hypothesis that the 5-HTTLPR differently influences response to escitalopram (an SSRI) compared with nortriptyline (a norepinephrine reuptake inhibitor), and found that 5-HTTLPR moderated the response to escitalopram, with long-allele carriers improving more than short-allele homozygotes. They reported that “a significant three-way interaction between 5-HTTLPR, drug and gender indicated that the effect was concentrated in males treated with escitalopram.”4 The effect of 5-HTTLPR on antidepressant response is SSRI specific (not being seen with nortripyline), conditional on gender, and modulated by another polymorphism at the 5’ end of the serotonin transporter gene—the single-nucleotide polymorphism rs2020933.

Among men treated with escitalopram, the 5-HTTLPR polymorphism was associated with a five-point difference on the Montgomery Åsberg Depression Rating Scale between short-allele homozygotes and long-allele carriers. The authors speculated that this may reflect a biologic interaction between the serotonergic system and ovarian hormones. Specifically, they hypothesized “that through the estrogen alpha receptor, estrogens stimulate the production of the 5-HT1A receptor that is involved in the regulation of serotonin release and is down-regulated in response to serotonin reuptake inhibitors.” This is the largest study to date to compare a tricyclic antidepressant with an SSRI and is the second largest sample with pharmacogenetic data on antidepressant treatment outcome.

Caspi and colleagues2 found that the “s” allele of the serotonin transporter gene promoter (5-HTTLPR) may be associated with exposure to social adversities and the subsequent onset of depressive illness in adulthood. They studied adolescents at high risk for depression to see whether the “s” allele is associated with levels of morning cortisol and the subsequent onset of a depressive episode. These adolescents were genotyped for 5-HTTLPR. Salivary samples were obtained on four consecutive school days within 1 hour of waking from 393 (97.5%) individuals, and 367 (91%) underwent a mental state reassessment at 12 months. Analysis revealed “higher levels of salivary cortisol in short allele carriers (s/s>s/l>l/l). A subsequent episode of depression was increased in those with higher cortisol and the ‘s’ allele, and independently by depressive symptoms at entry, in both genders.” They concluded  that “the short allele of 5-HTTLPR may moderate the association between morning cortisol and the subsequent onset of a depressive episode.”2

This was true for both genders and supports the notion that there is an increase in hypothalamic-pituitary-adrenal axis activity in “s” carriers compared with those homozygous for the l/l form of the 5-HTTLPR gene. It also supports the notion that this polymorphism moderates the association between higher cortisol and subsequent depression. This association might be a component of a biologic pathway linking 5-HTTLPR with subsequent depression. PP


1. Sussman N. Why replication matters. Primary Psychiatry. 2009;16(7):14-15.
2. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301(5631):386-389.
3. Risch N, Herrell R, Lehner T, et al. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA. 2009;301(23):2462-2471.
4. Huezo-Diaz P, Uher R, Smith R, et al. Moderation of antidepressant response by the serotonin transporter gene. Br J Psychiatry. 2009;195(1):30-38.
5. Goodyer IM, Bacon A, Ban M, Croudace T. Serotonin transporter genotype, morning cortisol and subsequent depression in adolescents. Br J Psychiatry. 2009;195(1):39-45.