GAD: experimental medicine models, emerging targets: Pharmacotherapy in generalized anxiety disorder: novel experimental medicine models and emerging drug targets

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 which 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 to develop novel approaches, which could have greater overall effectiveness or acceptability than currently available interventions, or which have particular effectiveness in specific clinical sub-groups. �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 channelsKey Points� Generalized anxiety disorder (GAD) is a common and impairing condition for which currently available pharmacological and psychological treatments are not ideal, having sub-optimal efficacy and acceptability problems in both short-term and long-term treatment.� �Experimental medicine� studies in healthy volunteers provide useful �proof-of-concept� approaches in the development of novel pharmacological and psyschological interventions: two promising avenues include the development of novel agents targeted at central chemosensors, or at modulating immunological responses.� 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