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.
Reimherr
Frederick
F
Department of Psychiatry, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA. fred.reimherr@hsc.utah.edu
Amsterdam
Jay
J
Dunner
David
D
Adler
Lenard
L
Zhang
Shuyu
S
Williams
David
D
Marchant
Barrie
B
Michelson
David
D
Nierenberg
Andrew
A
Schatzberg
Alan
A
Feldman
Peter
P
D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use; D000069445:Atomoxetine Hydrochloride; D003863:Depression / Q000188:drug therapy* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011437:Propylamines / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D020280:Sertraline / Q000627:therapeutic use; D018709:Statistics, Nonparametric
D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D011437:Propylamines; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D000069445:Atomoxetine Hydrochloride; D020280:Sertraline