Popp J, Leucht S, Heres S, Steimer W: Serotonin transporter polymorphisms and side effects in antidepressant therapy – a pilot study.Pharmacogenomics 7(2), 159–166 (2006); http://www.tandfonline.com/doi/pdf/10.2217/14622416.7.2.159.
In our paper, published in 2006, we reported a strong association between the HTTVNTR, the HTTLPR polymorphism and a combination of both polymorphisms in depressive in-patients treated with hydroxytryptamine transporter (HTT)-blocking antidepressants. No association was found in patients treated with mirtazapine, an antidepressant that does not work via HTT-blocking. However, owing to an internal laboratory audit, we recently discovered that the coding of the HTTVNTR polymorphism was performed incorrectly. In our population, we originally found 37.6% of the patients to be homozygous for the 2.10 allele (2.10/2.10), 45.9% to be heterozygous (2.10/2.12) and 16.5% to be homozygous for the 2.12 allele (2.12/2.12; no deviation from Hardy–Weinberg equilibrium). Unfortunately, the coding for statistical evaluation of the 2.10 and 2.12 alleles was unintentionally interchanged. Therefore, the correct genotypes are as follows: 16.5% of the patients are homozygous for the 2.10 allele, 45.9% are heterozygous (2.10/2.12) and 37.6% are homozygous for the 2.12 allele. This has a major impact on the results concerning the HTTVNTR polymorphism. In contrast to our results concerning the HTTLPR polymorphism, the correct statistical evaluation shows that patients with a putative lower expression genotype (2.10/2.10) concerning the HTTVNTR polymorphism have fewer side effects than patients with higher expression genotypes .
In our original paper, we further defined high-, medium- and low-risk groups for antidepressant side effects based on the influence of both polymorphisms on the expression of HTT. With the correctly coded genotypes, no correlation between the predefined risk groups and side effects in depressive in-patients treated predominantly with HTT-blocking antidepressants, could be found. Therefore, our pharmacological-based approach of risk groups (low expression genotypes may predispose to a higher incidence of [serotonin related] side effects because of easier blocking of the HTT by the same amount of antidepressant) does not appear to be suitable in predicting patient-risk for side effects of antidepressant therapy. The results concerning the HTTVNTR and HTTLPR polymorphisms contradict each other from this pharmacological point of view. Nevertheless, a combination of risk groups as performed in our original publication is still possible (with the same significant results), but to date, no reasonable pathophysiological explanation is available. According to a Medline search using the search terms ‘HTTVNTR‘, ‘STin2‘, ‘HTTLPR‘, ‘side effects‘ and ‘antidepressants‘ (limits: publication date from January 2006 to August 2010) only one pharmacogenetic study addressed the influence of the HTTVNTR (STin2) polymorphism on antidepressant side effects in depressive patients, but the results were inconsistent and observed associations were weak and statistically not significant Citation[1]. However, papers published within this timeframe support a possible influence of the HTTLPR polymorphism on antidepressant side effects. Maron E et al. showed that patients with major depression carrying the S allele of 5-HTTLPR may have an increased risk for some side effects, including headache, induced by escitalopram medication Citation[2]. This is in accordance with the results published by Smits et al.Citation[1]. Patients with the 5-HTTLPR s/s or s/l genotype appeared to have an increased risk of adverse events, especially general adverse events (dermatologic reactions, weight change and fatigue). In addition Hu et al. detected a significant association between a lesser adverse effect burden resulting from citalopram treatment and the high expression, gain of function LA allele in a large representative sample Citation[3]. By contrast, Kroneberg et al. reported no effect of the HTTLPR genotype on side effects in children treated with citalopram except for lower rates of agitation in those with the 5-HTTLPR ss genotype as compared to those with sl/ll (borderline significance: p = 0.05) Citation[4]. The authors apologize for any inconvenience or confusion our error may have caused.
Table 1. Corrected statistical validation of response and side effects in relation to HTTVNTR
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