Emerging drugs for the treatment of anxiety.

INTRODUCTION: Anxiety disorders are among the most prevalent and disabling psychiatric disorders in the United States and worldwide. Basic research has provided critical insights into the mechanism regulating fear behavior in animals and a host of animal models have been developed in order to screen compounds for anxiolytic properties. Despite this progress, no mechanistically novel agents for the treatment of anxiety have come to market in more than two decades. AREAS COVERED: The current review will provide a critical summary of current pharmacological approaches to the treatment of anxiety and will examine the pharmacotherapeutic pipeline for treatments in development. Anxiety and related disorders considered herein include panic disorder, social anxiety disorder, generalized anxiety disorder and post-traumatic stress disorder. The glutamate, neuropeptide and endocannabinoid systems show particular promise as future targets for novel drug development. EXPERT OPINION: In the face of an ever-growing understanding of fear-related behavior, the field awaits the translation of this research into mechanistically novel treatments. Obstacles will be overcome through close collaboration between basic and clinical researchers with the goal of aligning valid endophenotypes of human anxiety disorders with improved animal models. Novel approaches are needed to move basic discoveries into new, more effective treatments for our patients.

Epigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder.

INTRODUCTION: HTR2A gene has been the subject of numerous studies in psychiatric genetics because LSD, which resembles serotonin causes psychosis and atypical antipsychotic drugs target the HTR2A receptor. However, evidence for the role of HTR2A polymorphism(s) in schizophrenia (SCZ) and bipolar disorder (BD) has been elusive. We hypothesized that epigenetic dysregulation of HTR2A may be involved in psycho-pathogenesis and analyzed promoter DNA methylome and expression of HTR2A in SCZ, BD and control subjects. METHOD: DNA derived from post-mortem brains of patients with SCZ and BD and matched control subjects (each 35) were obtained from the Stanley Medical Research Institute. While bisulfite DNA sequencing was used to screen and quantify cytosine methylation in the HTR2A promoter, corresponding gene expression was analyzed by qRT-PCR. RESULTS: We found strong evidence for epigenetic fine-tuning of HTR2A expression. In general, the expression of HTR2A in individuals carrying the C allele of T102C (or G allele of -1438A/G polymorphism) was higher than TT genotype. Interestingly, promoter DNA of HTR2A was hypermethylated at and around the -1438A/G polymorphic site, but was hypomethylated at and around T102C polymorphic site in SCZ and BD compared to the controls. Furthermore, epigenetic down-regulation of HTR2A was associated with early age of disease onset in SCZ and BD. CONCLUSION: Epigenetic dysregulation of HTR2A may contribute to SCZ, BD and earlier age of disease onset. Further research is required to delineate the dysregulation of other components of serotoninergic pathway to design new therapeutics based on the downstream effects of serotonin.