Bipolar Bozukluğun Farmakogenomiği…

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pharmacogenomics[1]

 

Abstract and Introduction

Abstract

Bipolar disorder (BD) is a lifelong severe psychiatric condition with high morbidity, disability and excess mortality. The longitudinal clinical trajectory of BD is significantly modified by pharmacological treatment(s), both in acute and in long-term stages. However, a large proportion of BD patients have inadequate response to pharmacological treatments. Pharmacogenomic research may lead to the identification of molecular predictors of treatment response. When integrated with clinical information, pharmacogenomic findings may be used in the future to determine the probability of response/nonresponse to treatment on an individual basis. Here we present a selective review of pharmacogenomic findings in BD. In light of the evidence suggesting a genetic effect of lithium reponse in BD, we focused particularly on the pharmacogenomic literature relevant to this trait. The article contributes a detailed overview of the current status of pharmacogenomics in BD and offers a perspective on the challenges that can hinder its transition to personalized healthcare.

Introduction

Bipolar disorder (BD) is a debilitating psychiatric condition characterized by the recurrence of depressive and hypomanic or manic episodes alternating with intervals of partial or full recovery.[1] With a prevalence of 1–4%[2–4] and its high morbidity,[5] disability[6] and excess mortality,[5,7] BD has a profound socioeconomic impact. Indeed, healthcare costs for subjects with onset of BD in 1998 have been estimated at US$24 billion in the USA,[8] significantly exceeding the expenditures for several other common chronic diseases.[9]

The clinical decision-making algorithms for the treatment of BD propose pharmacological intervention as a first-line approach, both in acute mania and depression, as well as for maintenance and prophylaxis.[10–12] Lithium remains the mainstay of BD treatment as it is effective in the acute phases of illness (manic and depressive) and in the prevention of manic, and at least in part, depressive recurrences.[13,14] Similarly, anticonvulsants such as valproate (VPA), carbamazepine (CBZ) and lamotrigine (LTG) are effective in the treatment of acute mania (VPA, and as second-line agent CBZ) and depression (LTG, and as a second-line agent, VPA), although they are not as effective as lithium in the prevention of recurrences of both polarities.[13,15,16] Monotherapy with atypical antipsychotics (namely risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole or asenapine) is particularly effective in the treatment of acute manic symptoms of BD.[13,16,17] Conversely, given the potential risk of manic switch or induction of rapid cycling,[18] antidepressants (both tricyclics and selective serotonin reuptake inhibitors [SSRIs]) are generally used in BD in combination with mood stabilizers (lithium or anticonvulsants) or atypical antipsychotics.[10,13]

Naturalistic and randomized controlled studies of mood stabilizers have provided data on the clinical and familial characteristics of treatment-responsive BD patients.[19–21] For instance, lithium-responsive BD appears to represent a specific subgroup of patients with distinct clinical features, such as an episodic course of illness and absence of rapid cycling, corresponding to the BD ‘core phenotype’.[22,23] In addition, lithium response is a heritable subtype of BD: it has been shown to be familial[24,25] and it is associated with family history of BD.[26,27] Similarly, responders to LTG seem to have family history of schizoaffective disorders, major depression and panic attacks.[28] Taken together, these findings suggest that treatment response in BD, particularly lithium response, might be a heritable trait. In addition, they also offer the rationale for genetic studies of treatment response in BD.

Here we provide an overview of the current state of pharmacogenomic research in BD. To this end, we selectively reviewed existing evidence on molecular predictors (genes and proteins) of treatment response to antidepressants, atypical antipsychotics, anticonvulsants and lithium. Higher priority was given to pharmacogenomic studies that showed significant genetic associations with treatment outcomes (negative findings are only reported inTables 1&Table 2), or presented findings of altered gene or protein expression with respect to treatment response outcome or provided evidence of the effect of these drugs on molecular regulatory mechanisms in the CNS. The latter point concerns particularly the gene- and protein-expression studies for antidepressants and antipsychotics performed using brain tissues from the Stanley Collection.[29] Although the information on the use of medications at the time of death is available for the subjects of the Stanley Collection, there are no data on clinical response to treatment.

In this manuscript, we focus on data concerning genetic, transcriptomic and proteomic variation with respect to treatment outcomes in BD patients. Therefore, we have not included pharmacogenomic evidence gathered from animal studies.

In the final section of the review, we focus on the limitations of the pharmacogenomic evidence collected so far in BD. These include the heterogeneity in the measurement of treatment response (phenotypic assessment), the issue of insufficient statistical power of case–control studies, the stratification of BD patient populations included in the analyses, and the use of post-mortem brain tissues and lymphoblastoid cell lines (LCLs) for experimental pharmacogenomics. We then comment on the status of pharmacogenomic research in BD in light of the most recent genome-wide association study (GWAS) findings on lithium response. Finally, hypotheses (and challenges) regarding future research directions for the pharmacogenomics of BD are presented.

http://www.medscape.com/viewarticle/782472?src=nl_topic&uac=149316FV

 

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