Screening genetic variability at the CNR1 gene in both major depression etiology and clinical response to citalopram treatment.

RATIONALE: The endocannabinoid system has been implicated in the pathogenesis of major depression (MD) as well as in the mediation of antidepressant drug effects. OBJECTIVES: To analyze CNR1 gene variants in MD and clinical response to citalopram (selective serotonin re-uptake inhibitors [SSRI]). METHODS: The role of CNR1 gene (rs806368, rs1049353, rs806371, rs806377 and rs1535255) was investigated in 319 outpatients with MD and 150 healthy individuals. A subsample of 155 depressive patients were treated with citalopram and evaluated for response (fourth week) and remission (12th week) by the 21-item Hamilton Depression Rating Scale (HDRS). RESULTS: We observed a higher frequency of rs806371 G carriers in MD patients with both presence of melancholia (p = 0.018) and psychotic symptoms (p = 0.007) than in controls. Haplotype frequency distributions between MD sample and controls showed a significant difference for Block 1 (rs806368-rs1049353-rs806371) (p = 0.008). This haplotype finding was consistent when we compared controls with MD subsample stratified by melancholia (p = 0.0009) and psychotic symptoms (p = 0.014). The TT homozygous of the rs806368 and rs806371 presented more risk of no Remission than the C carriers (p = 0.008 and 0.012, respectively). Haplotype frequency distributions according to Remission status showed a significant difference for Block 1 (p = 0.032). Also, we observed significant effect of time-sex-genotype interaction for the rs806368, showing that the C carrier men presented a better response to antidepressant treatment throughout the follow-up than TT homozygous men and women group (p = 0.026). CONCLUSIONS: These results suggest an effect of CNR1 gene in the etiology of MD and clinical response to citalopram.