Pharmacogenetic Analysis of Genes Implicated in Rodent Models of Antidepressant Response: Association of TREK1 and Treatment Resistance in the STAR*D Study

Abstract

Recent rodent models of antidepressant response implicate a novel set of genes in mechanisms of antidepressant action. The authors examined variants in four such genes (KCNK2 (TREK1), SLC18A2 (VMAT2), S100A10, and HDAC5) for association with remission in a large effectiveness trial of antidepressant treatments. Subjects were drawn from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a multicenter, prospective, effectiveness trial in major depressive disorder (MDD). Outpatients with nonpsychotic MDD were initially treated with citalopram for up to 14 weeks; those who did not remit with citalopram were sequentially randomized to a series of next-step treatments, each for up to 12 weeks. Single-nucleotide polymorphisms in four genes were examined for association with remission, defined as a clinician-rated Quick Inventory of Depressive Symptomatology (QIDS-C 16 ) score p5. Of 1554 participants for whom DNA was available, 565 (36%) reached remission with citalopram treatment. No association with any of the four genes was identified. However, among the 751 who entered next-step treatment, variants in KCNK2 were associated with treatment response (Bonferroni-corrected, gene-based empirical po0.001). In follow-up analyses, KCNK2 was also associated with effects of similar magnitude for third-step treatment among those with unsatisfactory benefit to both citalopram and one next-step pharmacotherapy (n ¼ 225). These findings indicate that genetic variation in KCNK2 may identify individuals at risk for treatment resistance. More broadly, they indicate the utility of animal models in identifying genes for pharmacogenetic studies of antidepressant response.

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

“…Novel associations with citalopram response were reported within HTR2A (the gene that encodes the serotonin 2A receptor) (32) and GRIK4 (encodes the KA1 subunit of the glutamate-kainate receptor) (35). The KCNK2 gene (encodes a potassium channel of the K subfamily) was associated with treatment resistance (31). …”

“…On the basis of rodent models of anti-depressant response, Perlis and colleagues (31) examined variants in four genes—KCNK2 (TREK1), SLC18A2 (VMAT2), S100A10, and HDAC5—for association with treatment resistance in STAR * D, which they defined as not achieving remission despite two adequately tolerated treatment trials (that is, levels 1 and 2). The remission phenotype was defined as a QIDS-C score <6.…”

“…One approach applied in clinical investigations is to examine “patterns” of response that are characteristic of “true-drug” response and patterns characteristic of placebo response (27–29), although more recent data cast some doubt on the utility of these parameters (30). Alternatively, one might focus on response to next-step treatments (that is, level 2 and subsequent levels), presuming that placebo response should be greatly diminished after an initial treatment failure (31). …”

Biological Alterations in Depression

“…Alternatively, an increased risk were found for the methylenetetrahydrofolate reductase MTHFR C677T polymorphism (pooled OR, 1.36), the guanine nucleotide binding protein 3 GNB3 C825T variant (pooled OR, 1.38; CI, 1.13-1.69), and the dopamine transporter SLC6A3 40 bp VNTR (pooled OR, 2.06; CI, 1.25-3.40) (Lopez-Leon et al, 2008). 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).…”

Spadin, a Sortilin-derived peptide: a new concept in the antidepressant drug design

“…Deletion of the TREK-1 gene (also called kcnk2) results in a depression-resistant phenotype that mimics treatment with antidepressants (Heurteaux et al, 2006). Interestingly, the Star*D study has identified an association between the existence of four genetic variants (SNPs) in the TREK-1 locus, and a resistance to multiple antidepressant classes (Perlis et al, 2008;Dillon et al, 2010). All these findings indicate that 1) genetic variations in TREK-1 may identify individuals at risk for depression treatment resistance and 2) a search of selective blockers of TREK-1, hitherto not available, might potentially lead to a new generation of antidepressants.…”