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Polymorphisms in the SLC6A4 and HTR2A Genes Influence Treatment Outcome Following Antidepressant Therapy

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Polymorphisms in the SLC6A4 and HTR2A Genes Influence Treatment Outcome Following Antidepressant Therapy The Pharmacogenomics Journal (2009) 9, 61–70 & 2009 Nature Publishing Group All rights reserved 1470-269X/09 $32.00 www.nature.com/tpj ORIGINAL ARTICLE Polymorphisms in the SLC6A4 and HTR2A genes influence treatment outcome following antidepressant therapy MJV Wilkie1, G Smith1, RK Day2, The majority of antidepressant drugs act by increasing synaptic serotonin 2 3 levels in the brain. Genetic variation in serotonin-related genes may therefore K Matthews , D Smith , influence antidepressant efficacy. In this study, nine polymorphisms in four 3 4 D Blackwood , IC Reid serotonin receptor genes (HTR1B, HTR2A, HTR5A and HTR6) and the and CR Wolf1 serotonin transporter gene (SLC6A4) were analysed to investigate their influence on antidepressant response in a well-characterized unipolar 1Biomedical Research Centre, Ninewells Hospital depressive population (n ¼ 166) following a protocolized treatment regimen. and Medical School, University of Dundee, 5-HTTLPR short-allele homozygotes were significantly associated with Dundee, UK; 2Department of Psychiatry, Ninewells Hospital and Medical School, Dundee, both remission (odds ratios (OR) ¼ 4.00, P ¼ 0.04) and response UK; 3Division of Psychiatry, Royal Edinburgh (OR ¼ 5.06, P ¼ 0.02) following second switch treatment, with a similar Hospital, University of Edinburgh, Edinburgh, UK trend observed following initial treatment and paroxetine therapy. Following 4 and Department of Mental Health, Institute of initial treatment, unipolar patients homozygous for the SLC6A4 intron 2 Medical Sciences, Forresterhill Hospital, Aberdeen, UK repeat polymorphism were significantly associated with lack of remission (OR ¼ 0.38, P ¼ 0.02) and lack of response (OR ¼ 0.42, P ¼ 0.01). Addition- Correspondence: ally, the HTR2A C1354T polymorphism showed an association with remission Professor CR Wolf, Biomedical Research Centre, (OR ¼ 7.50, P ¼ 0.002) and response (OR ¼ 5.25, P ¼ 0.01) following Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, paroxetine therapy. These results suggest that genetically determined Scotland, UK. variation in serotonin receptor genes makes a significant contribution to E-mail: [email protected] the efficacy of commonly prescribed antidepressant drugs. The Pharmacogenomics Journal (2009) 9, 61–70; doi:10.1038/sj.tpj.6500491; published online 5 February 2008 Keywords: serotonin; depression; antidepressants; treatment response; polymorphism; pharmaco- genetics Introduction Serotonin receptors can be directly targeted by antidepressants, for example imipramine directly antagonizes the serotonin receptor 2A (HTR2A), whereas clomipramine and mianserin have been shown to target serotonin receptor 6 (HTR6).1 The majority of serotonin receptors are G-protein-coupled receptors that modulate intra-cellular levels of cAMP. The majority of studies investigating the association between genetic variations in the serotonin genes and antidepressant response have analysed polymorphisms in the serotonin transporter gene (SLC6A4), which is targeted by selective serotonin reuptake inhibitors (SSRIs) and the majority of tricyclic antidepressants (TCAs).2 The SLC6A4 gene is located on chromosome 17q11.1–q12, spans 31 kb, Received 25 April 2006; revised 18 January 3 2007; accepted 26 November 2007; published consists of 14 exons and encodes a 630 amino-acid protein. Two common online 5 February 2008 polymorphisms have been shown to affect expression of SLC6A4: a 44 bp Polymorphisms and antidepressant response MJV Wilkie et al 62 deletion/insertion polymorphism (5-HTTLPR) in the 50 remitters (w2 ¼ 5.23, P ¼ 0.07) and responders and non- flanking regulatory region of the SLC6A4 gene and a second responders (w2 ¼ 5.74, P ¼ 0.06), following initial drug variable number of tandem repeats (VNTR) polymorphism treatment (Table 1B). In both cases, the frequency of in intron 2. This VNTR polymorphism consists of 9, 10 or 12 individuals carrying two copies of the 12-copy repeat was copies of a 16–17 bp repeat element. significantly associated with lack of remission (OR ¼ 0.38, The serotonin system plays a central role in the action of P ¼ 0.02) and lack of response (OR ¼ 0.42, P ¼ 0.01) (Table 2A). antidepressant drugs. Genetic variation that may affect the No significant associations were found between ADR integrity of this system may therefore influence treatment incidence and this genotype following initial therapy response. In this study, we have investigated a number of (w2 ¼ 3.08, P ¼ 0.55). polymorphisms in a variety of serotonin receptor genes to determine whether inheritance of specific polymorphisms Second switch therapy. No significant associations were is associated with response to a variety of commonly found following second switch treatment for the SLC6A4 prescribed antidepressants. intron 2 polymorphism, although 12-copy repeat homozygote carriers were more frequent in non-remitter Results (45 vs 36%, w2 ¼ 1.67, P ¼ 0.80) and non-responder (40 vs 37%, w2 ¼ 1.49, P ¼ 0.83) groups. 5-HTTLPR Initial therapy. Following initial drug treatment, a higher frequency of 5-HTTLPR short-allele homozygotes was Paroxetine therapy. Higher frequencies of the 12 allele observed in responders compared to non-responders (29 vs homozygote genotype were also observed in non-remitters 2 19%, w2 ¼ 2.77, P ¼ 0.25), although this failed to reach (45 vs 28%, w ¼ 2.10, P ¼ 0.36) and non-responders (46 vs 2 significance. Similarly, no significant differences in 33%, w ¼ 2.94, P ¼ 0.23) to paroxetine treatment (Table 1B), genotype distribution were associated with remission although this did not reach statistical significance. (w2 ¼ 0.25, P ¼ 0.88) or adverse drug reaction (ADR) 2 incidence (w ¼ 2.52, P ¼ 0.28) (Table 1A). HTR2A T102C and C1354T Initial therapy. Two polymorphisms were analysed in the Second switch therapy. Significant differences in 5-HTTLPR HTR2A gene. HTR2A T102C genotype did not influence genotype frequencies were observed following second response to initial drug therapy, assessed in terms of switch treatment (Table 1A). Inheritance of two copies of remission (w2 ¼ 0.42, P ¼ 0.81), response (w2 ¼ 0.10, P ¼ 0.95) the 5-HTTLPR short allele was associated with both or ADR incidence (w2 ¼ 1.23, P ¼ 0.54). In addition, no remission (w2 ¼ 5.98, P ¼ 0.05) and response (w2 ¼ 7.40, associations were observed in response to initial therapy P ¼ 0.025) following longer-term treatment, while a higher correlating HTR2A C1354T genotype and remission frequency of heterozygotes was found in the non-remission (w2 ¼ 2.20, P ¼ 0.33), response (w2 ¼ 2.02, P ¼ 0.36) and ADR and non-response groups (Table 1A). These results suggest incidence (w2 ¼ 0.03, P ¼ 0.86). a recessive mode of action for the short allele, with homozygotes associated with remission (odds ratios Second switch therapy. Following second switch treatment, (OR) ¼ 4.00, P ¼ 0.04) and response (OR ¼ 5.06, P ¼ 0.02) the HTR2A T C genotype frequencies did not significantly (Table 2b). 5-HTTLPR genotype did not influence ADR 102 differ between remitters and non-remitters (w2 ¼ 1.40, incidence (w2 ¼ 0.39, P ¼ 0.82). P ¼ 0.50), responders and non-responders (w2 ¼ 0.85, P ¼ 0.65), and between ADR and non-ADR groups Paroxetine therapy. Following paroxetine treatment, the 2 (w ¼ 0.45, P ¼ 0.80). The HTR2A C1354T genotype did not 5-HTTLPR short/short genotype was more frequent in influence second switch therapy in terms of remission responders compared to non-responders (40 vs 19%, (w2 ¼ 0.03, P ¼ 0.98), response (w2 ¼ 0.69, P ¼ 0.71) and ADR w2 P ¼ 4.20, ¼ 0.12) and in remitters compared to non- incidence (w2 ¼ 3.01, P ¼ 0.22). remitters (38 vs 24%, w2 ¼ 2.24, P ¼ 0.33). However, due to lower number of patients in this group, these figures failed to reach significance. ADRs following paroxetine therapy Paroxetine therapy. HTR2A C1354T heterozygotes were were not influenced by 5-HTTLPR genotype (w2 ¼ 2.94, significantly associated with improved response to P ¼ 0.23). paroxetine therapy. There was a significantly higher frequency of heterozygotes in the remitter and response Early onset depressive population. The 5-HTTLPR short-allele groups in comparison to the non-remitter (OR ¼ 7.50, homozygotes genotype was more frequent in patients P ¼ 0.002) and non-response groups (OR ¼ 5.25, P ¼ 0.01) responding to antidepressant treatment (28 vs 14%, (Table 2C). The HTR2A C102T genotype did not influence 2 2 w2 ¼ 5.88, P ¼ 0.05) (Table 3). remission (w ¼ 0.65, P ¼ 0.72) or response (w ¼ 1.36, P ¼ 0.51) but was associated with the incidence of ADRs SLC6A4 intron 2 (w2 ¼ 9.73, P ¼ 0.008) following paroxetine treatment with Initial therapy. Genotype frequencies for the SLC6A4 intron patients inheriting the HTR2A C102C genotype associated 2 polymorphism differed between remitters and non- with the incidence of ADRs (OR ¼ 24.69, P ¼ 0.007). The Pharmacogenomics Journal Table 1 Genotype frequency distribution in response groups following initial, second switch and paroxetine therapy Response following initial therapy Response following second switch therapy Response following paroxetine therapy Remitter Non-remitter Responder Non-responder ADR Non-ADR Remitter Non-remitter Responder Non-responder ADR Non-ADR Remitter Non-remitter Responder Non-responder ADR Non-ADR (n ¼ 39) (n ¼ 124) (n ¼ 58) (n ¼ 105) (n ¼ 15) (n ¼ 148) (n ¼ 70) (n ¼ 40) (n ¼ 98) (n ¼ 30) (n ¼ 36) (n ¼ 105) (n ¼ 21) (n ¼ 55) (n ¼ 30) (n ¼ 46) (n ¼ 4) (n ¼ 72) 5-HTTLPR A Long/long 12 (30%) 40 (32%) 15 (26%) 37 (35%) 7 (46%) 45 (31%) 26 (37%) 14 (35%) 34 (35%) 9 (30%) 10 (28%) 35
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