Pharmacological Treatment of Generalised Anxiety Disorder: Current Practice and Future Directions

ABSTRACT

Introduction

Generalized Anxiety Disorder (GAD) is a common psychiatric condition, characterized by the presence of general apprehensiveness and excessive worry. Current management consists of a range of pharmacological and psychological treatments. However, many patients do not respond to first-line pharmacological treatments and novel anxiolytic drugs are being developed.

Areas covered

In this review, the authors first discuss the diagnostic criteria and epidemiology of GAD. The effective pharmacological treatments for GAD and their tolerability are addressed. Current consensus guidelines for treatment of GAD are discussed, and maintenance treatment, the management of treatment resistance, and specific management of older adults and children/adolescents are considered. Finally, novel anxiolytics under development are discussed, with a focus on those which have entered clinical trials.

Expert opinion

A range of effective treatments for GAD are available, particularly duloxetine, escitalopram, pregabalin, quetiapine, and venlafaxine. There is a limited evidence base to support the further pharmacological management of patients with GAD who have not responded to initial treatment. Although many novel anxiolytics have progressed to clinical trials, translation from animal models has been mostly unsuccessful. However, the potential of several compounds including certain psychedelics, ketamine, oxytocin, and agents modulating the orexin, endocannabinoid, and immune systems merits further study.

KEYWORDS:

• Generalized Anxiety Disorder
• GAD
• novel anxiolytics
• pharmacological treatment
• pharmacotherapy

Article highlights

• Generalized Anxiety Disorder (GAD) is a psychiatric condition, characterized by the presence of general apprehensiveness and excessive worry.

• A range of pharmacological treatments are available for GAD, with the greatest evidence for the efficacy of quetiapine, duloxetine, pregabalin, venlafaxine, and escitalopram.

• Although effective, benzodiazepines, paroxetine, and quetiapine are associated with poorer tolerability in the treatment of GAD.

• Current consensus treatment guidelines recommend prescription of a selective serotonin reuptake inhibitor (SSRI) as a first-line pharmacological approach, with serotonin-noradrenaline reuptake inhibitors (SNRIs) or pregabalin suggested if SSRIs are not tolerated or unsuitable.

• A range of novel anxiolytics are currently under development, including modulators of the serotonergic, GABAergic, and glutamatergic neurotransmitters systems, several neuropeptide systems, and the immune system.

• Several failures of novel anxiolytics have occurred in recent clinical trials, including two α2/α3-GABAA receptor positive allosteric modulators (AZD7325 and PF-06372865), a NK1R antagonist, a CRF1 receptor antagonist, and simvastatin.

Declaration of interest

The authors are planning to initiate a study investigating the anxiolytic effect of an orexin receptor antagonist in healthy volunteers. In February 2023, an application for complete funding of this study and provision of an orexin receptor antagonist (daridorexant) was requested from Idorsia Pharmaceuticals Ltd, through their Investigator Sponsored Study (ISS) program. At the time of submission, no decision had been made. DS Baldwin has acted as an advisor to Idorsia Pharmaceuticals Ltd (no honorarium sought or paid) and is a Medical Patron of Anxiety UK. He is also the current president of the British Association for Psychopharmacology. HA Fagan is also supported to carry out this work through an Academic Clinical Fellowship, funded by the National Institute of Health and Care Research (NIHR), the United Kingdom (Award reference: ACF-2022-26-003).

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.