Genetic variability at HPA axis in major depression and clinical response to antidepressant treatment

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been observed in major depression. Normalization of HPA axis has been suggested to play a role in the mechanisms of action of antidepressants. Our aim was to investigate the influence of genetic variants in CRHR1, CRHR2, CRH-BP and FKBP5 genes on both the vulnerability for depression and the response to antidepressant treatment.

The sample consisted of 159 depressive outpatients and 96 healthy controls of Spanish origin. Patients were assessed for clinical features including, among others, age of onset, seasonality or suicidal behavior. The episode was treated with citalopram and followed along 12 weeks. Severity of symptoms was evaluated at the inclusion and then monthly along the follow-up using a 21-item Hamilton Depression Rating Score (HDRS). SNPs were assayed using Applied Biosystems SNaP-Shot and TaqMan technology.

rs110402, in CRHR1 gene, was associated with an increased risk to present a seasonal pattern and an early age of onset of the first depressive episode. Allele G carriers of rs2270007 of CRHR2 gene, showed a worse overall response to citalopram along time of follow-up (Genotype effect F=7.45, P=0.007). G allele carriers showed 2.93 increased risk (95% CI [1.24-6.90]) for non-responding at 4th week to citalopram treatment (chi(2)=7.59, df=1, P=0.006).

On the light of the moderate sample size, associations based on the mentioned polymorphisms need to be considered with caution and require further replication studies in other samples.

Variability at genes encoding proteins with a pivotal role in HPA axis regulation seems to influence i) the expression of severity variables of the depressive spectrum including early age of onset or a seasonal pattern and ii) the interindividual variation in clinical response to SSRI antidepressants.