Despite the availability of a range of treatments, a majority of patients with Generalized Anxiety Disorder (GAD) report lack of functional recovery, and newer agents are needed for this unmet therapeutic need. This is a systematic review of newer agents in development for GAD, grouped by primary pharmacological activity, including clinical and late preclinical agents. The analysis also includes dose-response analysis for established drugs with substantial additional recently published data. Newer agents can be clustered in three groups: (i) ligands for novel pharmacological targets (e.g. specific glutamate receptor agonists; mitochondrial transporter protein ligands; beta-3-adrenoceptor agonists); (ii) refinements of ligands for established targets (e.g. subtype-selective benzodiazepine positive allosteric modulators); and (iii) new molecules that target established pharmacology (e.g. 5HT1A partial agonists; 5HT2A/2C antagonists; new formulations of or single enantiomers of approved drugs). Most agents in clusters (i) and (ii) have not yet been tested in patients with GAD, and despite their promising nature, still have a high risk of development failure. Agents in cluster (iii) have reported that positive clinical results do not appear to differentiate from earlier agents with the same mechanisms of action. Analysis of pregabalin and quetiapine dose-response data suggests these are flatter than previously reported. At this time, the prospects for availability of novel drugs for GAD with improved efficacy or safety profiles over current treatments are at best modest.
Keywords: Generalized anxiety disorder, glutamate receptor agonists, mitochondrial transporter protein ligands, beta-3-adrenoceptor agonists, subtype-selective benzodiazepine positive allosteric modulators, serotonin 1A partial agonists, serotonin 2A/2C antagonists