Pharmacokinetic Genes Do Not Influence Response or Tolerance to Citalopram in the STAR*D Sample

Peters, Eric; Slager, Susan L.; Kraft, Jeffrey B.; Jenkins, G. Douglas; Reinalda, Megan S.; McGrath, Patrick J.; Hamilton, Steven P.

doi:10.1371/journal.pone.0001872

Cited by 148 publications

(117 citation statements)

References 41 publications

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“…The effect of genetic variation has been studied at the pharmacokinetic (eg, CYP2D6; Kirchheiner and Seeringer, 2007;Peters et al, 2008;Tomalik-Scharte et al, 2008;Uhr et al, 2008), the pharmacodynamic (Binder and Holsboer, 2006;Kato and Serretti 2008;Horstmann and Binder, 2009), and the bioavailability level (eg, ABCB1; Uhr et al, 2008). Up till now all studies were driven by hypothesis, analyzing candidate genes in the main systems currently implicated in the etiology of major depression and mechanism of action of antidepressant drugs (Holsboer, 2008).…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in GRIK4, HTR2A, and FKBP5 Show Interactive Effects in Predicting Remission to Antidepressant Treatment

Horstmann

Lucae

Menke

et al. 2009

Neuropsychopharmacol

171

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Single-nucleotide polymorphisms (SNPs) in the FKBP5, GRIK4, and HTR2A genes have been shown to be associated with response to citalopram treatment in the STAR*D sample, but only associations with FKBP5 have so far been tested in the Munich Antidepressant Response Signature (MARS) project. Response and remission of depressive symptoms after 5 weeks of antidepressant treatment were tested against 82 GRIK4 and 37 HTR2A SNPs. Association analysis was conducted in about 300 depressed patients from the MARS project, 10% of whom had bipolar disorder. The most predictive SNPs from these two genes and rs1360780 in FKBP5 were then genotyped in a total of 387 German depressed in-patients to analyze potential additive and interactive effects of these variants. We could not replicate previous findings of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study in our sample. Although not statistically significant, the effect for the best GRIK4 SNP of STAR*D (rs1954787, p ¼ 0.076, p corrected ¼ 0.98) seemed to be in the same direction. On the other hand, the nominally significant association with the top HTR2A SNPs of STAR*D (rs7997012, allelic, p ¼ 0.043, p corrected ¼ 0.62) was with the opposite risk allele. The GRIK4 SNP (rs12800734, genotypic, p ¼ 0.0019, p corrected ¼ 0.12) and the HTR2A SNP (rs17288723, genotypic, p ¼ 0.0011, p corrected ¼ 0.02), which showed the strongest association with remission in our sample, had not been reported previously. Associations across all genetic markers within the GRIK4 (genotypic, p ¼ 0.022) or HTR2A (genotypic, p ¼ 0.012) locus using the Fisher's product method (FPM) were also significant. In all 374 patients, the best predictive model included a main effect for GRIK4 rs12800734 and two significant interactions between GRIK4 rs12800734 and FKBP5 rs1360780, and GRIK4 rs12800734 and HTR2A rs17288723. This three SNP model explained 13.1% of the variance for remission after 5 weeks (p ¼ 0.00051 for the model). Analyzing a sub-sample of 194 patients, plasma ACTH (p ¼ 0.002) and cortisol (p ¼ 0.021) responses of rs12800734 GG (GRIK4) carriers, who also showed favorable treatment response, were significantly lower in the second combined dexamethasone (dex)/corticotrophin-releasing hormone (CRH) test before discharge compared with the other two genotype groups. Despite large differences in ethnicity and design compared with the STAR*D study, our results from the MARS study further support both independent and interactive involvement of GRIK4, HTR2A and FKBP5 in antidepressant treatment response.

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Section: Discussionmentioning

confidence: 99%

Polymorphisms in GRIK4, HTR2A, and FKBP5 Show Interactive Effects in Predicting Remission to Antidepressant Treatment

Horstmann

Lucae

Menke

et al. 2009

Neuropsychopharmacol

171

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“…Other genes of interest that were previously reported to be significant included FKBP5 (38), PDE11A (39,40), and BDNF (41). Finally, genes with pharmacokinetic function were also assessed in this group and included CYP2D6, CYP2C19, CYP3A4, CYP3A5, and ABCB1 (42). …”

Section: Results Of Pharmacogenetics Studies In Star*dmentioning

confidence: 99%

“…Finally, a tolerance outcome was based on study exit data. All participants who continued with citalopram were considered tolerant, and patients who refused to continue level 1 treatment or who left the study because of side effects were considered intolerant (42). …”

Section: Results Of Pharmacogenetics Studies In Star*dmentioning

confidence: 99%

“…The ABCB1, another pharmacokinetic gene, also known as MDR1 (multidrug resistance) encodes the p-glycoprotein and is expressed in tissues that have elimination or protective roles, such as the intestines, liver, kidney, and blood-brain barrier. Peters and colleagues (42) published a study using a split-sample design to assess 15 polymorphisms from five pharmacokinetic genes, including CYP2D6, CYP2C19, CYP3A4, CYP3A5, and ABCB1. Using the UCSF phenotype definitions, they found no association with citalopram outcome in any of these genes (Table 1).…”

Section: Results Of Pharmacogenetics Studies In Star*dmentioning

confidence: 99%

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Pharmacogenetics Studies in STAR*D: Strengths, Limitations, and Results

Laje

Perlis²,

Rush³

et al. 2009

Psychiatric Services

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Several lines of evidence support an important genetic contribution to the wide individual variation in therapeutic response to antidepressant medications. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study provided the largest cohort assembled to date of DNA from patients with nonpsychotic major depressive disorder, uniformly treated with citalopram and followed prospectively for up to 12 weeks. This pivotal study changed the face of pharmacogenetics research by increasing the sample size by an order of magnitude as well as by providing detailed prospective information about antidepressant response and tolerability. Several groups have identified markers in genes and tested the replication of previous findings of genes associated with outcome and side effects of antidepressant treatment. Variants in HTR2A, GRIK4, and KCNK2 were associated with citalopram treatment outcome. Replication was achieved in markers in the FKBP5 gene. Other findings in PDE11A and BDNF were not successfully replicated, and reports of potential confounders in previous associations with serotonin transporter variation (SLC6A4) were identified. Polymorphisms in pharmacokinetic genes involved in metabolism and transmembrane transport were also not associated with antidepressant response. Adverse events were also tested. Treatment-emergent suicidal ideation was associated with GRIK2, GRIA3, PAPLN, IL28RA, and CREB1. Sexual dysfunction was linked with variation in GRIN3A, GRIA1 GRIA3, and GRIK2. Reported and future findings of pharmacogenetics studies in STAR*D could help elucidate pathways involved in major depression and those pertinent to antidepressant outcome and side effects. Replication of these findings in independent samples could lead to the development of new treatments and to optimization of available treatments.

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“…Pharmacogenetic studies of antidepressants in the STAR*D trial have identified genes associated with treatment response (Hu et al, 2007;Lekman et al, 2008a;McMahon et al, 2006;Paddock, 2008), treatment resistance (Perlis et al, 2008), and treatment-emergent suicidal ideation (Laje et al, 2009;Laje et al, 2007;Perlis et al, 2007). In addition, polymorphisms in genes that encode drug-metabolizing enzymes and transporters have been tested for correlation with treatment response (Peters et al, 2008). Genes that were significantly associated with response to citalopram include FKBP5 (Lekman et al, 2008a), glutamate receptor, ionotropic kainite 1 (GRIK1), N-methyl d-aspartate 2A (GRIN2A), 5-hydrxytryptamine receptor 2A (HTR2A), potassium channel, subfamily K, member 2 (KCNK2), phosphodiesterase (PDE), and solute carrier family 6 member 4 (SLC6A4) (E. Lin & Chen, 2008).…”

Section: Genetic Predictors Of Depression and Antidepressant Responsementioning

confidence: 99%

Biological Alterations in Depression

Benton¹,

Wiltshire²

2011

Psychiatric Disorders - Trends and Developments

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Pharmacokinetic Genes Do Not Influence Response or Tolerance to Citalopram in the STAR*D Sample

Cited by 148 publications

References 41 publications

Polymorphisms in GRIK4, HTR2A, and FKBP5 Show Interactive Effects in Predicting Remission to Antidepressant Treatment

Polymorphisms in GRIK4, HTR2A, and FKBP5 Show Interactive Effects in Predicting Remission to Antidepressant Treatment

Pharmacogenetics Studies in STAR*D: Strengths, Limitations, and Results

Biological Alterations in Depression

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