The objective of the Genome-based Therapeutic Drugs for Depression study is to investigate the function of variations in genes encoding key proteins in serotonin, norepinephrine, neurotrophic and glucocorticoid signaling in determining the response to serotonin-reuptake-inhibiting and norepinephrine-reuptake-inhibiting antidepressants. A total of 116 single nucleotide polymorphisms in 10 candidate genes were genotyped in 760 adult patients with moderate-to-severe depression, treated with escitalopram (a serotonin reuptake inhibitor) or nortriptyline (a norepinephrine reuptake inhibitor) for 12 weeks in an open-label part-randomized multicenter study. The effect of genetic variants on change in depressive symptoms was evaluated using mixed linear models. Several variants in a serotonin receptor gene (HTR2A) predicted response to escitalopram with one marker (rs9316233) explaining 1.1% of variance (P = 0.0016). Variants in the norepinephrine transporter gene (SLC6A2) predicted response to nortriptyline, and variants in the glucocorticoid receptor gene (NR3C1) predicted response to both antidepressants. Two HTR2A markers remained significant after hypothesis-wide correction for multiple testing. A false discovery rate of 0.106 for the three strongest associations indicated that the multiple findings are unlikely to be false positives. The pattern of associations indicated a degree of specificity with variants in genes encoding proteins in serotonin signaling influencing response to the serotonin-reuptake-inhibiting escitalopram, genes encoding proteins in norepinephrine signaling influencing response to the norepinephrine-reuptake-inhibiting nortriptyline and a common pathway gene influencing response to both antidepressants. The single marker associations explained only a small proportion of variance in response to antidepressants, indicating a need for a multivariate approach to prediction.