Towards precision medicine in generalized anxiety disorder: Review of genetics and pharmaco(epi)genetics.

Generalized anxiety disorder (GAD) is a prevalent and chronic mental disorder that elicits widespread functional impairment. Given the high degree of non-response/partial response among patients with GAD to available pharmacological treatments, there is a strong need for novel approaches that can optimize outcomes, and lead to medications that are safer and more effective. Although investigations have identified interesting targets predicting treatment response through pharmacogenetics (PGx), pharmaco-epigenetics, and neuroimaging methods, these studies are often solitary, not replicated, and carry several limitations. This review provides an overview of the current status of GAD genetics and PGx and presents potential strategies to improve treatment response by combining better phenotyping with PGx and improved analytical methods. These strategies carry the dual benefit of delivering data on biomarkers of treatment response as well as pointing to disease mechanisms through the biology of the markers associated with response. Overall, these efforts can serve to identify clinical, genetic, and epigenetic factors that can be incorporated into a pharmaco(epi)genetic test that may ultimately improve treatment response and reduce the socioeconomic burden of GAD.

The role of brain-derived neurotrophic factor (BDNF) gene variants in antipsychotic response and antipsychotic-induced weight gain.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has extensive effects on the nervous system including cell survival, differentiation, neuronal growth and maintenance, as well as cell death. Moreover, it promotes synaptic plasticity and interacts with dopaminergic and serotonergic neurons, suggesting an important role on the alteration of brain function with antipsychotic medications and induced weight gain in schizophrenia patients. The differential effects of BDNF gene variants could lead to changes in brain circuitry that would in turn cause variable response to antipsychotic medication. Therefore, we hypothesized that genetic variation in this candidate gene helps in explaining the inter-individual variation observed in antipsychotic drug treatment with respect to response and induced weight gain. METHOD: We examined four single-nucleotide polymorphisms across the BDNF gene, including Val66Met (rs6265). Prospective BPRS change scores and weight change after six weeks were obtained from a total of 257 schizophrenia patients of European ancestry. RESULTS: The markers rs11030104 and Val66Met were associated with antipsychotic response (P=0.04; 0.007, respectively). On the other hand, marker rs1519480 was associated with weight gain (P=0.04). Moreover, a two-marker haplotype across rs6265 and rs1519480 was associated with weight change (P=0.001). Results with Val66Met in response, and results with rs6265-rs1519480 haplotypes remained significant at the modified Bonferroni corrected alpha of 0.017. CONCLUSION: BDNF genetic variants might play an important role in predicting antipsychotic response and antipsychotic-induced weight gain. However, replication in larger and independent samples is required.