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\u2009=\u20090.018) and psychotic symptoms (p\u2009=\u20090.007) than in controls. Haplotype frequency distributions between MD sample and controls showed a significant difference for Block 1 (rs806368-rs1049353-rs806371) (p\u2009=\u20090.008). This haplotype finding was consistent when we compared controls with MD subsample stratified by melancholia (p\u2009=\u20090.0009) and psychotic symptoms (p\u2009=\u20090.014). The TT homozygous of the rs806368 and rs806371 presented more risk of no Remission than the C carriers (p\u2009=\u20090.008 and 0.012, respectively). Haplotype frequency distributions according to Remission status showed a significant difference for Block 1 (p\u2009=\u20090.032). 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\u2009=\u20090.026). CONCLUSIONS: These results suggest an effect of CNR1 gene in the etiology of MD and clinical response to citalopram

TPH1, MAOA, serotonin receptor 2A and 2C genes in citalopram response: possible effect in melancholic and psychotic depression.

BACKGROUND: Serotonergic genes have been widely investigated regarding antidepressant response in major depressive disorder (MDD) but results are still not univocal. METHODS: 159 MDD patients treated with citalopram were genotyped and evaluated by the 21-item Hamilton Depression Rating Scale at the beginning and every 4 weeks during the 12-week follow-up. Four serotonin-related genetic variants were tested for association with treatment outcome: tryptophane hydroxylase 1 (TPH1) rs1800532, monoamine oxidase A \ub5VNTR, serotonin 2A receptor rs6311 and serotonin 2C receptor rs6318. The effect of these polymorphisms was tested both in the whole sample and in depressive subtypes with usually higher clinical severity: psychotic and melancholic MDD. RESULTS: No effect on response, remission and symptom improvement was found for the four polymorphisms. However, rs1800532 was found to affect the outcome depending on the MDD subtype: the A allele predicted worse response both in MDD with psychotic (F\u2086,\u2083\u2087\u2088 = 2.90; p = 0.009) and melancholic (F\u2086,\u2083\u2088\u2081 = 2.86; p = 0.0097) features. CONCLUSIONS: The A allele at TPH1 rs1800532 may be associated with citalopram efficacy only in melancholic and psychotic MDD. These results suggest the usefulness of investigating the effect of genetic variants in conjunction with specific clinical features