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Glutamate Systems in DSM-5 Anxiety Disorders: Their Role and a Review of Glutamate and GABA Psychopharmacology.

ABSTRACT: Serotonin reuptake inhibitors and benzodiazepines are evidence-based pharmacological treatments for Anxiety Disorders targeting serotonin and GABAergic systems, respectively. Although clearly effective, these medications fail to improve anxiety symptoms in a significant proportion of patients. New insights into the glutamate system have directed attention toward drugs that modulate glutamate as potential alternative treatments for anxiety disorders. Here we summarize the current understanding of the potential role of glutamate neurotransmission in anxiety disorders and highlight specific glutamate receptors that are potential targets for novel anxiety disorder treatments. We also review clinical trials of medications targeting the glutamate system in DSM-5 anxiety disorders. Understanding the role of the glutamate system in the pathophysiology of anxiety disorder may aid in developing novel pharmacological agents that are effective in treating anxiety disorders.

SUBMITTER: Nasir M

PROVIDER: S-EPMC7710541 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Glutamate Systems in DSM-5 Anxiety Disorders: Their Role and a Review of Glutamate and GABA Psychopharmacology.

Nasir Madeeha M Trujillo Daniel D Levine Jessica J Dwyer Jennifer B JB Rupp Zachary W ZW Bloch Michael H MH

Frontiers in psychiatry 20201119

Serotonin reuptake inhibitors and benzodiazepines are evidence-based pharmacological treatments for Anxiety Disorders targeting serotonin and GABAergic systems, respectively. Although clearly effective, these medications fail to improve anxiety symptoms in a significant proportion of patients. New insights into the glutamate system have directed attention toward drugs that modulate glutamate as potential alternative treatments for anxiety disorders. Here we summarize the current understanding of ...[more]

PMID: 33329087

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Project description:There is ample evidence that genetic factors play an important role in anxiety disorders. In support, human genome-wide association studies have implicated several novel candidate genes. However, illumination of such genetic factors involved in anxiety disorders has not resulted in novel drugs over the past decades. A complicating factor is the heterogeneous classification of anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and diverging operationalization of anxiety used in preclinical and clinical studies. Currently, there is an increasing focus on the gene × environment (G × E) interaction in anxiety as genes do not operate in isolation and environmental factors have been found to significantly contribute to the development of anxiety disorders in at-risk individuals. Nevertheless, extensive research on G × E mechanisms in anxiety has not resulted in major breakthroughs in drug discovery. Modification of individual genes in rodent models has enabled the specific study of anxiety in preclinical studies. In this context, two extensively studied neurotransmitters involved in anxiety are the gamma-aminobutyric acid (GABA) and 5-HT (5-hydroxytryptamine) system. In this review, we illustrate the complex interplay between genes and environment in anxiety processes by reviewing preclinical and clinical studies on the serotonin transporter (5-HTT), 5-HT1A receptor, 5-HT2 receptor, and GABAA receptor. Even though targets from the serotonin and GABA system have yielded drugs with known anxiolytic efficacy, the relation between the genetic background of these targets and anxiety symptoms and development of anxiety disorders is largely unknown. The aim of this review is to show the vast complexity of genetic and environmental factors in anxiety disorders. In light of the difficulty with which common genetic variants are identified in anxiety disorders, animal models with translational validity may aid in elucidating the neurobiological background of these genes and their possible role in anxiety. We argue that, in addition to human genetic studies, translational models are essential to map anxiety-related genes and to enhance our understanding of anxiety disorders in order to develop potentially novel treatment strategies.

Project description:IntroductionIn both the ICD-11 Classification of Personality Disorders and the DSM-5 Alternative Model of Personality Disorders (AMPD) personality disorders (PD) are characterized by impairments in self- and interpersonal functioning which distinguish the various levels of dysfunction. Moreover, pathological traits are used by these classification systems to define the stylistic expression of personality dysfunction. Negative affectivity, detachment, antagonism/dissociality, and disinhibition feature as trait domains in each of these models. However, there are also differences between the two models, namely, in the psychoticism domain, which does not feature as a personality trait domain in the ICD-11, and in the anankastia domain, corresponding to compulsivity in the DSM-5, which was removed from the final AMPD model. Furthermore, facets are acknowledged by the DSM-5 within each trait domain, while this does not occur in the ICD-11. In view of the similarity between these classification systems, their harmonization would be beneficial for the clinical profession. With this goal in mind, the PID5BF + M, an algorithm that assesses the DSM-5 and ICD-11 six trait domains and 18 facets, was developed and has proven to adequately characterize the ICD-11 trait domains by means of DSM-5 trait facets.MethodsThe current study compares a community sample (N = 280, M age = 48.01, 53.2% females) with a PD sample (N = 131, M age = 42.66, 45.0% females) along with the PID5BF + M, the LPFS-SR and the PID-5. Given that the PID5BF + M total can be seen as a measure of the level of personality dysfunction, strong relations between the PID5BF + M total and the LPFS-SR total are expected. Strong relations between the trait specifiers measured by the PID5BF + M and the PID-5 are also expected. Finally, the community and clinical samples are expected to differentiate by means of the dimensions assessed through the three afore-mentioned measures. The Spearman rank-order correlation coefficient was used to measure the strength and direction of associations between the PID5BF + M total and the LPFS-SR total and between the PID5BF + M and the PID-5 traits. Group differences were explored using the Mann-Whitney U test for independent samples.ResultsAs expected, there were strong, significant, and positive relations between the measures. Furthermore, higher scores were observed in all the variables for the PD group against the community group.DiscussionAlthough this study has limitations, its findings sustain that the PID5BF + M has potential to assess the severity of personality disfunction and to characterize the stylistic features of PD as they are conceived by both the ICD-11 and the DSM-5. Although more research is needed regarding the convergent validity of the PID5BF + M, this new test contributes to the harmonization of both systems and to parsimony in the assessment of PD, which is the main objective of clinical practice.

Dataset Information

Glutamate Systems in DSM-5 Anxiety Disorders: Their Role and a Review of Glutamate and GABA Psychopharmacology.

Publications

Glutamate Systems in DSM-5 Anxiety Disorders: Their Role and a Review of Glutamate and GABA Psychopharmacology.

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