Novel investigational therapeutics for generalized anxiety disorder (GAD)

Expert Opin Investig Drugs. 2019 Nov;28(11):1003-1012. doi: 10.1080/13543784.2019.1680638. Epub 2019 Oct 28.


Introduction: Generalized anxiety disorder (GAD) is a common and disabling psychiatric condition that affects 3% of the population and exacts significant costs to society if untreated. There are numerous treatment options available, but all have side effects, and none are reliably effective; hence, there is a significant need for new medications.Areas covered: The authors reviewed clinical Phase II and III studies listed on the and websites, 2007-present. Additional information was gathered from the study sponsor websites and Pubmed. The categories of mechanisms investigated include: modulators of GABAergic or glutamatergic activity; modulators of monoaminergic systems including serotonin, norepinephrine, and dopamine; and modulators of neuropeptide corticotropin release factor.Expert opinion: There are few investigational drugs in the later stages of clinical development. Challenges include high placebo response rates, enrollment of symptomatic volunteers with minimal depressive and anxiety comorbidity, and the lack of a unifying pathophysiological model. Drug developers should consider implementing trial designs such as sequential parallel comparison design to enhance signal detection. Inclusion of depressive comorbidity may also enhance signal detection by reducing placebo-responsivity. More studies examining glutamate-mediated neuroplasticity in GAD are needed.

Keywords: Generalized anxiety disorder; clinical trials; non-benzodiazepine anxiolytics; novel therapies.

Publication types

  • Review

MeSH terms

  • Animals
  • Anti-Anxiety Agents / administration & dosage*
  • Anti-Anxiety Agents / pharmacology
  • Anxiety Disorders / drug therapy*
  • Anxiety Disorders / physiopathology
  • Drug Development
  • Drugs, Investigational / administration & dosage*
  • Drugs, Investigational / pharmacology
  • Humans
  • Research Design


  • Anti-Anxiety Agents
  • Drugs, Investigational