# Genetic Variations Associated with Long-Term Treatment Response in Bipolar Depression
## 1 Introduction  
Bipolar disorder (BD) is a complex and severe psychiatric condition characterized by biphasic mood episodes of mania or hypomania and depression, which are expressed as recurrent episodes of changes in energy levels and behavior that last from days to weeks, each with subsyndromal symptoms commonly present between major episodes [1]. The total lifetime prevalence of BD is approximately 2.4% [2]. Despite an apparent lower prevalence than unipolar depression [3], BD is associated with higher levels of functional impairment and compromised quality of life, posing a greater socioeconomic burden [4]. With a typical age at onset between late adolescence and early adulthood, BD represents one of the leading causes of disability among young people [5, 6]. Regarding gender distribution, while BD type I is considered to affect men and women equally, BD type II has been more frequently reported among women [7]. Due to the progressive and debilitating course of this disorder, an early and effective therapeutic approach is key for patient prognosis [8, 9]. Pharmacological intervention, combined with psychotherapy and psychoeducation, are the therapeutic tools for managing BD. The choice of treatment options is guided by the phase of illness (mania/hypomania/depression/mixed) and past treatment history. Therefore, treatment guidelines include the use of mood stabilizers (lithium and some anticonvulsants such as carbamazepine and valproate) but also a variety of other psychoactive drugs, including antipsychotics, antidepressants, anxiolytics, and combinations thereof [10; 11; 12; 13; 14; 15]. However, treatment response is often inadequate, and the rate of remission, particularly in patients in a depressive episode, is low. This leads to multiple unsuccessful drug trials for many patients, with the probability of achieving remission decreasing with every additional treatment line. In addition, common side effects and poor tolerability to treatment are usually observed, particularly when multimodal drug therapy is used. Patient's characteristics impacting drug response include endogenous and environmental factors, such as age, sex, body mass index, organ function, disease, concomitant medications, or lifestyle. Variability in treatment efficacy and tolerability has also been shown to be influenced by inherited genetic variation. Common genetic variation has been estimated to explain up to 42% of the variance in antidepressant response [16], and several genes with polymorphisms of pharmacogenetic (PGx) relevance in the treatment of major depression have been identified [17], although genome-wide association studies (GWAS) suggest no single polymorphisms of large effect [18]. The effect of genetic variants in BD has been understudied in comparison with major depression, with lithium being the medication most extensively investigated [19]. The largest GWAS to date in BD suggests that 15 genes robustly linked to BD encode druggable targets such as HTR6--a serotonin receptor targeted by antidepressants and antipsychotics[20]. Another important GWAS on lithium response, conducted by the International Consortium on Lithium Genetics (ConLiGen) in 2563 patients with BD, found a significant association with a single locus of four linked single nucleotide polymorphisms (SNPs) on chromosome 21, which contained two genes coding for long non-coding RNAs of unknown function [21]. Remarkably, an independent prospective study with 73 participants treated with lithium monotherapy showed an association of this region with the rate of relapse in the two-year follow-up [21]. Important PGx progress has also been made in the context of severe life-threatening cutaneous drug reactions observed with antiepileptic mood-stabilizers. Carriers of the human leukocyte antigen _HLA-B*15:02_ allele who are of Asian descent are at an increased risk of developing Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) [22; 23].