Novel investigational therapeutics for generalized anxiety disorder (GAD)

ABSTRACT

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.

KEYWORDS:

• Generalized anxiety disorder
• novel therapies
• clinical trials
• non-benzodiazepine anxiolytics

Article highlights

• GAD is a common disorder that causes immeasurable disability. To provide reliable relief, alternative options and new novel mechanisms must be developed.

• Current Phase II and III clinical trials are focused on several targets; GABA and glutamate modulators are established targets, but treatments acting on the GABA/glutamate system are associated with sedation, memory issues and potential for misuse.

• Studies from the European Group for the Study of Resistant Depression (GSRD) have documented the pernicious impact of concurrent anxiety in major depressive disorder (MDD) and its consistent relationship to treatment resistance.

• Challenges in clinical research include the high placebo response rates and enrollment of symptomatic volunteers with minimal depressive and anxiety comorbidity.

• The greatest challenge for the development of new drugs for GAD is the lack of a unifying pathophysiological model of illness.

• Future drug development efforts should consider implementing sequential parallel comparison designs and subjects with higher depressive comorbidities.

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Declaration of interest

S Mathew has served as a consultant to the following companies: Allergan, Alkermes, Clexio Biosciences, Intra-Cellular Therapies, Janssen, and Sage Therapeutics. He has received research support from Biohaven Pharmaceuticals and VistaGen Therapeutics and is supported by the use of facilities and resources at the Michael E. DeBakey VA Medical Center, Houston, Texas. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.