Novel investigational therapeutics for generalized anxiety disorder (GAD).

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 clinicaltrials.gov and clinicaltrialsregister.eu 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.