Genetic variation within the hypothalamic-pituitary-adrenal (HPA) axis has been linked to risk for depression and antidepressant response. However, these associations have yet to produce clinical gains that inform treatment decisions. The authors investigated whether variation within HPA axis genes predicts antidepressant outcomes within two large clinical trials.

The test sample comprised 636 patients from the International Study to Predict Optimized Treatment in Depression (iSPOT-D) who completed baseline and 8-week follow-up visits and for whom complete genotyping data were available. The authors tested the relationship between genotype at 16 candidate HPA axis single-nucleotide polymorphisms (SNPs) and treatment outcomes for three commonly used antidepressants (escitalopram, sertraline, and extended-release venlafaxine), using multivariable linear and logistic regression with Bonferroni correction. Response and remission were defined using the Hamilton Depression Rating Scale. Findings were then validated using the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study of outcome predictors in treatment-naive patients with major depression.

The authors found that the rs28365143 variant within the corticotropin-releasing hormone binding protein (CRHBP) gene predicted antidepressant outcomes for remission, response, and symptom change. Patients homozygous for the G allele of rs28365143 had greater remission rates, response rates, and symptom reductions. These effects were specific to drug class. Patients homozygous for the G allele responded significantly better to the selective serotonin reuptake inhibitors escitalopram and sertraline than did A allele carriers. In contrast, rs28365143 genotype was not associated with treatment outcomes for the serotonin norepinephrine reuptake inhibitor venlafaxine. When patients were stratified by race, the overall effect of genotype on treatment response remained. In the validation sample, the GG genotype was again associated with favorable antidepressant outcomes, with comparable effect sizes.

These findings suggest that a specific CRHBP SNP, rs28365143, may have a role in predicting which patients will improve with antidepressants and which type of antidepressant may be most effective. The results add to the foundational knowledge needed to advance a precision approach to personalized antidepressant choices.

下丘脑-垂体-肾上腺（HPA）轴内的遗传变异与抑郁和抗抑郁反应的风险有关。但是，这些关联尚未产生可指导治疗决策的临床获益。作者调查了两项大型临床试验中HPA轴基因内的变异是否可预测抗抑郁药的预后。

测试样本包括来自国际研究预测抑郁症最佳治疗（iSPOT-D）的636位患者，这些患者完成了基线和8周的随访，并获得了完整的基因分型数据。作者使用Bonferroni校正的多变量线性和逻辑回归，测试了16种候选HPA轴单核苷酸多态性（SNP）的基因型与三种常用抗抑郁药（依他普仑，舍曲林和文拉法辛缓释药）的治疗结果之间的关系。使用汉密尔顿抑郁量表对缓解和缓解进行定义。然后，使用未接受过治疗的重度抑郁患者的预后预测因子（PReDICT）对个体和联合治疗后抑郁缓解的预测因子（PReDICT）的研究结果进行了验证。

作者发现，促肾上腺皮质激素释放激素结合蛋白（CRHBP）基因中的rs28365143变体可预测缓解，缓解和症状改变的抗抑郁效果。rs28365143的G等位基因纯合的患者有更高的缓解率，反应率和症状减轻。这些效果是特定于药物类别的。与G等位基因纯合的患者对选择性5-羟色胺再摄取抑制剂依他普仑和舍曲林的反应明显优于A等位基因携带者。相反，rs28365143基因型与5-羟色胺去甲肾上腺素再摄取抑制剂文拉法辛的治疗结果无关。当按种族对患者进行分层时，基因型对治疗反应的总体影响仍然存在。在验证样本中，

这些发现表明，特定的CRHBP SNP rs28365143在预测哪些患者将使用抗抑郁药改善以及哪种类型的抗抑郁药可能最有效方面可能具有一定作用。结果增加了基础知识，需要先进的精确方法来进行个性化抗抑郁药选择。