The serotonin transporter linked polymorphic region (5-HTTLPR) is an important genetic variation that has been studied in relation to both efficacy and adverse effects of serotonergic antidepressants. Before continuing to read this page, please read the basics on the following page: serotonin transporter linked polymorphic region (5-HTTLPR)
A key point is that studies that look at one side effect at a time would need to have a very large number of patients. Therefore, let’s look only at studies that looked at all (or a large group) of side effects together. This can be done by looking at:
– some type of overall score for severity or burden of side effects, or
– discontinuation of the medication due to side effects.
Study no. 1
Polymorphisms of 5-HTTLPR were evaluated in 1775 patients in the large STAR*D study (Hu et al., 2007). In this analysis, patients with low-expression alleles (either short or long with A-G substitution, i.e., LG) were compared to patients with the high-expression allele (LA or the long allele without the A-G substitution).
Main finding: The burden of adverse effects was statistically significantly less in those with theLA allele, and especially in those who were homozygous (i.e., LA/LA).
This was also true when the analysis was limited to Caucasian patients.
But it was not true if those with L alleles (not distinguishing between LA and LG) were compared to those with S alleles. This showed that in evaluating the association between 5-HTTLPR and a phenotype, it is important to group alleles based on gene expression and not just based on long versus short forms.
But how much of a difference did this make? Based on the definition of high burden of side effects used in the study, 7% of those who were homozygous for theLA allele, i.e., LA/ LA had a high burden of side effects while 13% of those without any LA allele had a high burden of side effects. This means that the risk of having a significant burden of side effects increased by 6%, which amounted to almost doubling of the risk.
Study no. 2
In 246 older patients with major depression (Murphy et al., 2004), 5-HTTLPR polymorphism had a small effect on efficacy but a “dramatic” effect on side effects.
In patients treated with paroxetine, those with the S allele had more severe adverse events during the study, reached significantly lower final daily doses, and were more likely to discontinue the medication (Murphy et al., 2004).
How much of a difference? The mean final dose of paroxetine was 23.2 mg/day with the S/S genotype and 32.1 mg/day with the L/L genotype. Of those with an S/S genotype and on paroxetine, 50% (12 of 24 patients) discontinued the paroxetine due to adverse events compared to 12.5% (5 of 40 patients) of those with the L/L genotype. The hazard ratio for discontinuation of paroxetine was 2.6 for those with S/S genotype. That is, persons with an S/S genotype were 2.6 times more likely to discontinue paroxetine than those with other genotypes, even though they were taking higher doses and higher plasma concentrations of paroxetine.
Which adverse events led to discontinuation of paroxetine in persons with the S allele? Gastrointestinal complaints, fatigue, agitation, sweating, and dizziness.
Another important finding was that 5-HTTLPR and the HTR2A T102C polymorphism had additive rather than interactive effects on discontinuation of paroxetine (Murphy et al., 2004).
On the other hand, in patients treated with mirtazapine, those with the S allele had less severe side effects, were able to reach higher final daily doses, and were less likely to discontinue the medication (Murphy et al., 2004).
How much of a difference? With mirtazapine, the mean final dose was 36.0 mg/day in those with the S/S genotype versus 28.7 mg/day in those with the L/L genotype. Of those with the S/S genotype, 6.5% (2 of 31 patients) discontinued due to adverse events, versus 26.3% (10 of 38 patients) with the L/L genotype.
The authors made the important observation that in this study, the major effect of the S allele of 5-HTTLPR was on the tolerability of the antidepressants used rather than their efficacy.
Study no. 3
In 214 patients with major depression, 18 to 64-years-old, who were treated with an SSRI for at least six weeks, those with an S/S or S/L genotype had an increased risk of adverse events (odds ratio 1.8 to 2.4; Smits et al., 2007).
This was especially true for “general” adverse events (skin reactions, weight change, fatigue).
Study no. 4
In 109 depressed inpatients treated with a serotonergic antidepressant (n=44) or mirtazapine (n=65), 50.0% of patients on a serotonergic antidepressant had side effects compared to 40% who with the S/L genotype, and 0% with the L/L genotype (Popp et al., 2006).
Studies of one side effect at a time
A few studies have also looked at the association between 5-HTTLPR polymorphisms and other specific side effects and the results are not clear cut. For example:
In a small study (Perlis et al., 2003), there was a much higher incidence of agitation in those patients treated with open-label fluoxetine who were homozygous for the short allele of 5-HTTLPR (i.e., S/S) compared to other patients (67% versus 7%).
But lower rates of agitation (6.3% versus 32.8%) were reported with S/S in children/adolescents (Kronenberg et al., 2007)
In a small study of only 43 patients, no association was found between 5-HTTLPR S/S genotype and bleeding tendency as measured by PFA-closure time (a measure of platelet function), frequency of bruising, or spontaneous bleeding (Hougardy et al., 2008).
However, in another study of 19 patients (Abdelmalik et al., 2008), bleeding times significantly increased in those with at least one low-expression allele (S or LG) <2L(A)-allele carriers (2.3 min; 95% CI 0.5 to 4.07; P = 0.032). Platelet serotonin decreases were larger in patients without L(A)-alleles (868 ng 10(-9) platelets; IQR 585 to 1213) than in > or =1 L(A)-allele carriers (457 ng 10(-9) platelets; IQR 392 to 598; P = 0.035). PFA closure time and PF4 increased significantly in patients without L(A)-alleles.
Persons with the S allele have been found to have a higher incidence of severe headaches on increasing the dose of citalopram to escitalopram (Maron et al., 2009).
In a small study (Perlis et al., 2003), there was a much higher incidence of new or worsening insomnia in those patients treated with open-label fluoxetine who were homozygous for the short allele of 5-HTTLPR (i.e., S/S) compared to other patients (78% versus 22%).
The study by Takahashi et al. (2002) had a total of only 66 patients, not all of whom developed nausea. Therefore, their finding that 5-HTTLPR polymorphisms did not predict the incidence of nausea cannot be accepted with any confidence.
Abdelmalik N, Ruhé HG, Barwari K, van den Dool EJ, Meijers JC, Middeldorp S, Büller HR, Schene AH, Kamphuisen PW. Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism. J Thromb Haemost. 2008 Dec;6(12):2168-74. PubMed PMID: 18983505.
Hougardy DM, Egberts TC, van der Graaf F, Brenninkmeijer VJ, Derijks LJ. Serotonin transporter polymorphism and bleeding time during SSRI therapy. Br J Clin Pharmacol. 2008 May;65(5):761-6. PubMed PMID: 18279474; PubMed Central PMCID: PMC2432488.
Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, Xu K, Arnold PD, Richter MA, Kennedy JL, Murphy DL, Goldman D. Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet. 2006 May;78(5):815-26. PubMed PMID: 16642437; PubMed Central PMCID: PMC1474042.
Hu XZ, Rush AJ, Charney D, Wilson AF, Sorant AJ, Papanicolaou GJ, Fava M, Trivedi MH, Wisniewski SR, Laje G, Paddock S, McMahon FJ, Manji H, Lipsky RH. Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression. Arch Gen Psychiatry. 2007;64(7):783-92.
Kronenberg S, Apter A, Brent D, Schirman S, Melhem N, Pick N, Gothelf D, Carmel M, Frisch A, Weizman A. Serotonin transporter polymorphism (5-HTTLPR) and citalopram effectiveness and side effects in children with depression and/or anxiety disorders. J Child Adolesc Psychopharmacol. 2007 Dec;17(6):741-50. PubMed PMID: 18315446.
Maron E, Tammiste A, Kallassalu K, Eller T, Vasar V, Nutt DJ, Metspalu A. Serotonin transporter promoter region polymorphisms do not influence treatment response to escitalopram in patients with major depression. Eur Neuropsychopharmacol. 2009 Jun;19(6):451-6. PubMed PMID: 19272758.
Murphy GM Jr, Hollander SB, Rodrigues HE, Kremer C, Schatzberg AF. Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. Arch Gen Psychiatry. 2004 Nov;61(11):1163-9. PubMed PMID: 15520364.
Oliver KH, Duvernay MT, Hamm HE, Carneiro AM. Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor. J Biol Chem. 2016 Sep 16;291(38):20210-9. PubMed PMID: 27422820; PubMed Central PMCID: PMC5025703.
Perlis RH, Mischoulon D, Smoller JW, Wan YJ, Lamon-Fava S, Lin KM, Rosenbaum JF, Fava M. Serotonin transporter polymorphisms and adverse effects with fluoxetine treatment. Biol Psychiatry. 2003 Nov 1;54(9):879-83. PubMed PMID: 14573314.
Popp J, Leucht S, Heres S, Steimer W. Serotonin transporter polymorphisms and side effects in antidepressant therapy–a pilot study. Pharmacogenomics. 2006 Mar;7(2):159-66. Erratum in: Pharmacogenomics. 2010 Oct;11(10):1504. PubMed PMID: 16515395.
Smits K, Smits L, Peeters F, Schouten J, Janssen R, Smeets H, van Os J, Prins M. Serotonin transporter polymorphisms and the occurrence of adverse events during treatment with selective serotonin reuptake inhibitors. Int Clin Psychopharmacol. 2007 May;22(3):137-43. PubMed PMID: 17414739.
Takahashi H, Yoshida K, Ito K, Sato K, Kamata M, Higuchi H, Shimizu T, Ito K, Inoue K, Tezuka T, Suzuki T, Ohkubo T, Sugawara K. No association between the serotonergic polymorphisms and incidence of nausea induced by fluvoxamine treatment. Eur Neuropsychopharmacol. 2002 Oct;12(5):477-81. PubMed PMID: 12208565.
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