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Pharmacotherapy in Generalized Anxiety Disorder: Novel Experimental Medicine Models and Emerging Drug Targets

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Abstract

Many pharmacological and psychological approaches have been found efficacious in patients with generalized anxiety disorder (GAD), but many treatment-seeking patients will not respond and others will relapse despite continuing with interventions that initially had beneficial effects. Other patients will respond but then stop treatment early because of untoward effects such as sexual dysfunction, drowsiness, and weight gain. There is much scope for the development of novel approaches that could have greater overall effectiveness or acceptability than currently available interventions or that have particular effectiveness in specific clinical subgroups. ‘Experimental medicine’ studies in healthy volunteers model disease states and represent a proof-of-concept approach for the development of novel therapeutic interventions: they determine whether to proceed to pivotal efficacy studies and so can reduce delays in translating innovations into clinical practice. Investigations in healthy volunteers challenged with the inhalation of air ‘enriched’ with 7.5% carbon dioxide (CO2) indicate this technique provides a validated and robust experimental medicine model, mirroring the subjective, autonomic, and cognitive features of GAD. The anxiety response during CO2 challenge probably involves both central noradrenergic neurotransmission and effects on acid-base sensitive receptors and so may stimulate development of novel agents targeted at central chemosensors. Increasing awareness of the potential role of altered cytokine balance in anxiety and the interplay of cytokines with monoaminergic mechanisms may also encourage the investigation of novel agents with modulating effects on immunological profiles. Although seemingly disparate, these two approaches to treatment development may pivot on a shared mechanism in exerting anxiolytic-like effects through pharmacological effects on acid-sensing ion channels.

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Correspondence to David S. Baldwin.

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Conflict of interest

Over his academic career, DSB has held research grants from the following pharmaceutical and biotechnology companies: Bristol-Myers Squibb, Cephalon, Eli Lilly Ltd, GlaxoSmithKline, H. Lundbeck A/S, Pierre Fabre, Pfizer Ltd, Roche, and Vernalis Ltd. He has served on advisory boards hosted by Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly Ltd, GlaxoSmithKline, Grunenthal, H. Lundbeck A/S, Pierre Fabre, and Pfizer Ltd. He is a past President of Depression Alliance and a current Medical Patron of Anxiety UK. RG, NH, RH, and MG have no potential conflicts of interest.

Funding

RG and NH are National Institute for Health Research (NIHR) Academic Clinical Fellows with supportive grants from the Research Management Committee of the Faculty of Medicine at the University of Southampton. No specific funding was sought or received for the preparation of this review.

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Baldwin, D.S., Hou, R., Gordon, R. et al. Pharmacotherapy in Generalized Anxiety Disorder: Novel Experimental Medicine Models and Emerging Drug Targets. CNS Drugs 31, 307–317 (2017). https://doi.org/10.1007/s40263-017-0423-2

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