# Genetic Variations Associated with Long-Term Treatment Response in Bipolar Depression
## 1 Introduction
Likewise, the presence of the _HLA-A*31:01_ allele has been associated with carbamazepine-induced hypersensitivity reactions in individuals of European, Korean, and Japanese ancestry [24]. Therefore, recommendations for _HLA-B*15:02_ and/or _HLA-A*31:01_ are included in the summary of products characteristics (SmPC) of carbamazepine, as well as in guidelines by the Clinical Pharmacogenetics Implementation Consortium (CPIC) or the Canadian Pharmacogenomics Network for Drug Safety (CPNDS) [25; 26]. Another interesting example is the cytochrome (CYP) P450 superfamily, which includes the major drug-metabolizing enzymes involved in phase I reactions. Even though specific studies in BD are generally lacking, most drugs used to treat BD are metabolized by CYP450 enzymes. Therefore, genotyping the _CYP450_ genes to characterize the metabolizer profile of a patient becomes a potentially useful tool for medication selection and dose adjustment [27]. Neuropharmagen(r) (AB-Biotics S.A., Barcelona, Spain) is a commercial PGx-based tool that generates psychopharmacological recommendations based on pharmacogenetic guidelines issued by the CPIC and other reference organizations, PGx information included in the SmPC approved by regulatory agencies, and additional relevant information from selected clinical studies. The psychopharmacological recommendations are displayed using a safety-first approach that grades genetic polymorphisms associated with risk of adverse effects above the genetically determined metabolizer status and genetic variants of efficacy. The clinical utility of Neuropharmagen(r) in major depression was initially evaluated in a twelve-week randomized controlled trial (RCT) in Spain, including 316 participants with major depressive disorder (MDD). In this trial, the PGx-guided arm showed a higher responder rate when compared to treatment as usual (TAU), with the PGx-guided treatment effects being more consistent in patients with 1-3 failed drug trials, as well as higher odds of achieving better tolerability [28]. A reanalysis of this study showed that PGx-guided treatment was mostly beneficial in non-elderly subjects, and in those with moderate-to-severe depression, but not in patients with mild depression [28]. These results were further replicated in an eight-week, industry-independent RCT in South Korea, including 100 adult patients with MDD, in which the PGx-guided arm showed higher response rates, less depressive symptoms, and better tolerability of treatments compared to TAU [29]. The output of multigene PGx-based tools is based on the integrated analysis of several genes which could differ in their individual clinical utility in a disorder-related manner. Two small pilot trials have suggested a potential clinical utility of Neuropharmagen(r) in patients with BD. A three-month prospective, observational trial including 30 patients with BD suggested that at baseline less than 5% of patients had an optimal treatment according to the PGx-guided information provided by Neuropharmagen(r). The evolution of severity (as assessed by the Clinical Global Impression of Severity, CGI-S) displayed a statistically significant treatment x time interaction, favoring those patients whose therapy had been changed following the test recommendations. Additionally, after the three-month follow-up period, the percentage of adverse effects was reduced when prescribing treatments concordant with the test [30]. The second pilot study with Neuropharmagen(r) in a BD cohort consisted of a 2-year mirror analysis of the expenditure of 30 patients with BD. Comparison of the expenditure before and after the change of therapy in agreement with the Neuropharmagen(r) recommendations resulted in cost savings in terms of the number of consultations to the emergency room, and the number and mean duration of hospitalizations [31].