Genetic polymorphisms in the treatment of depression: speculations from an augmentation study using atomoxetine

Treatment-resistant depression may be related to polymorphisms in the promoter region of the serotonin transporter gene (5-HTTLPR) or dysregulation of noradrenergic systems. To examine 5-HTTLPR genotypes and responses to treatment, adult patients (N=261) with current major depression and a symptom severity rating > or =8 on the 17-item Hamilton Depression Rating Scale (HAMD(17)) were treated for 8 weeks with open-label sertraline (100-200 mg/d). Patients remaining symptomatic (total score >4, or >1 on any item of the HAMD(17) Maier-Philipp subscale) were randomly assigned to double-blind therapy with sertraline plus either atomoxetine (40-120 mg/d) or placebo for 8 additional weeks. 5-HTTLPR genotype did not predict responses to sertraline monotherapy or discontinuation rates. Among the 138 patients remaining symptomatic after sertraline monotherapy (L/L = 21%, S/L = 50%, S/S = 29%), significantly more S/S-genotype patients achieved remission under combined sertraline/atomoxetine treatment relative to the other genotypes (S/S = 81.8%; non-S/S = 32.7%), but not under sertraline/placebo treatment (S/S = 35.7%; non-S/S = 37.7%). Minor genotypic differences were noted in adverse event profiles. In patients with poor responses to sertraline monotherapy for depression, addition of atomoxetine may improve responses to treatment of depression in S/S-genotyped patients. Although this study is speculative, it represents a pharmacologically and genotypically well-defined patient population.