title: Pharmacotherapy in Generalized Anxiety Disorder: Novel Experimental Medicine Models and Emerging Drug Targets.
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 CO2challenge 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.
authors.affiliation: Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK. dsb1@soton.ac.uk.|University Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa. dsb1@soton.ac.uk.|University Department of Psychiatry, Academic Centre, College Keep, 4-12 Terminus Terrace, Southampton, SO14 3DT, UK. dsb1@soton.ac.uk.
authors.forename: David S
authors.initials: DS
authors.lastname: Baldwin
authors.affiliation: Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Hou
authors.affiliation: Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Gordon
authors.affiliation: Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Nathan T M
authors.initials: NT
authors.lastname: Huneke
authors.affiliation: Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.|Academic Unit of Psychology, Faculty of Social, Human and Mathematical Sciences, University of Southampton, Southampton, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Garner
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000503:physiopathology; D002245:Carbon Dioxide / Q000008:administration & dosage; D015195:Drug Design; D006801:Humans; D058990:Molecular Targeted Therapy; D016896:Treatment Outcome
chemical_list: D014151:Anti-Anxiety Agents; D002245:Carbon Dioxide