# Genetic Variations Associated with Long-Term Treatment Response in Bipolar Depression
## 4 Discussion  
In recent years, substantial progress has been made in the field of pharmacogenetics in psychiatry. Particularly, several studies have demonstrated that pharmacogenetic-guided treatment significantly improves the efficacy and tolerability of medication in patients with a main diagnosis of major depressive disorder [37; 38; 39]. However, the clinical utility of pharmacogenetic testing for the treatment of BD has been less studied [40]. This observational retrospective study objectively evaluated the impact of the gene-drug pairs analyzed by a commercial pharmacogenetic-based tool in the response to pharmacological treatment in a well-characterized cohort of patients with BD [41]. As expected, the pharmacogenetic variable \"response to SNRIs\", determined from the analysis of the genetic variation in the transporter gene \(ABCB1\)[42], was associated with lower scores in the CGI-BP-M overall and depression subscales (as well as the HDRS-17 scale), suggesting a role for this gene in predicting a good response to SNRI antidepressants in the context of BD treatment. These results are in accordance with previous studies linking genetic variation in \(ABCB1\) to the efficacy of antidepressant medications that are substrates of this protein [43; 44; 45; 46]. Interestingly, in line with other studies, our results also suggested the association of \(ABCB1\) polymorphisms with an increased number of adverse effects [47; 48]. The \(ABCB1\) gene--formerly known as the multi-drug resistance gene \(MDR1\)--codes for the drug efflux transporter permeability-glycoprotein (P-gp). P-gp actively drives the efflux of its substrates across cellular membranes in the intestine, liver, kidney, and the blood-brain barrier [49]. The presence of polymorphisms lowering the activity of this protein is thought to be linked with higher concentrations of its substrates in the brain, which may explain the increased likelihood of response, but also the poorer tolerability observed in our study. The pharmacogenetic variable \"reduced metabolism of quetiapine\", based on the analysis of the \(CYP3A4\)*22 allele, was associated with lower scores in the CGI-BP-M overall and depression subscales, thus positively impacting the likelihood of response. The CYP3A subfamily of enzymes is responsible for the metabolism of more than 50% of medications that undergo first-pass hepatic metabolism. The activity of CYP3A4 is highly variable due to changes in its expression levels that mainly occur in response to physiological states and environmental factors. Genetic variation has also been described to impact CYP3A4 activity. Particularly, the \(CYP3A4\)*22 polymorphism has been associated with reduced CYP3A4 expression levels and decreased enzyme activity in human livers [50; 51]. Individuals carrying this variant have plasma levels of quetiapine 2.5 times higher than non-carriers at comparable doses [52]. Higher than expected serum concentrations of quetiapine in carriers of the \(CYP3A4\)*22 allele could explain a good response to this antipsychotic in our population. It is remarkable that the presence of this polymorphism did not correlate with an increased number of adverse effects in the studied cohort. The genetic variable \"lower side effects of risperidone or paliperidone\" was correlated with a lower number of adverse effects when this outcome variable included switch and autolytical ideation. This genetic variable is based on the research carried out by [PERSON] and collaborators [53], who developed a model for the prediction of antipsychotic-induced extrapyramidal symptoms through the analysis of the epistatic interactions of four genes of the DRD1-activated mTOR pathway (_AKT1, FCHSDQ, RPTOR,_ and \(DDIT4\)). Surprisingly, this pharmacogenetic marker was associated with a much broader definition of adverse effects in our population, which warrants further studies.