title: Pharmacodynamic response profiles of anxiolytic and sedative drugs.
abstract: Centrally-acting acutely anxiolytic drugs, such as benzodiazepines, barbiturates and gabapentinoids, affect various central nervous system (CNS) functions, which reflects not only their anxiolytic effects but also neuropsychological side-effects. To validate the pharmacodynamic biomarkers for GABA-ergic anxiolytics, this study determined the pharmacodynamics of two anxiolytics and a nonanxiolytic control, and linked them to their anxiolytic and sedative effects, during an anxiety-challenge study day.
  
  
  
  Twenty healthy volunteers were randomized in this placebo-controlled, double-blind, four-way cross-over study with single-dose alprazolam (1 mg), diphenhydramine (50 mg), pregabalin (200 mg) or placebo. The Neurocart was used between repeated fear-potentiated startle assessments. Thus, the potential influence of anxiety on CNS pharmacodynamic markers could be examined.
  
  
  
  Compared to placebo, VAScalmnessincreased with alprazolam (2.0 mm) and pregabalin (2.5 mm) but not with diphenhydramine. Saccadic peak velocity (SPV) declined after alprazolam (-57 ° s-1) and pregabalin (-28 ° s-1), more than with diphenhydramine (-14 ° s-1); so did smooth pursuit. The average responses of SPV and smooth pursuit were significantly correlated with the drug-induced increases in VAScalmness. The SPV-relative responses of VASalertness, body-sway and adaptive-tracking also differed among alprazolam, pregabalin and diphenhydramine.
  
  
  
  Compared with the antihistaminergic sedative diphenhydramine, alprazolam and pregabalin caused larger SPV reduction, which was correlated with simultaneous improvement of subjective calmness, during a study day in which anxiety was stimulated repeatedly. The different effect profiles of the three drugs are in line with their pharmacological distinctions. These findings corroborate the profiling of CNS effects to demonstrate pharmacological selectivity, and further support SPV as biomarker for anxiolysis involving GABA-ergic neurons. The study also supports the use of prolonged mild threat to demonstrate anxiolytic effects in healthy volunteers.
authors.affiliation: Phase I Unit, Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, 100032, China.|Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Freerk
authors.initials: F
authors.lastname: Broeyer
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: de Kam
authors.affiliation: Department of Experimental Psychology, Faculty of Social Sciences, Utrecht University, The Netherlands.
authors.forename: Joke
authors.initials: J
authors.lastname: Baas
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Adam
authors.identifier: 0000-0001-7452-6222
authors.initials: A
authors.lastname: Cohen
authors.affiliation: Centre for Human Drug Research, Leiden, The Netherlands.
authors.forename: Joop
authors.initials: J
authors.lastname: van Gerven
mesh_terms: D000293:Adolescent; D000328:Adult; D000525:Alprazolam / Q000494:pharmacology*; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy; D015415:Biomarkers / Q000378:metabolism; D018592:Cross-Over Studies; D004155:Diphenhydramine / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D000069583:Pregabalin / Q000494:pharmacology*; D013216:Reflex, Startle / Q000187:drug effects; D012438:Saccades / Q000187:drug effects; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D015415:Biomarkers; D006993:Hypnotics and Sedatives; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D004155:Diphenhydramine; D000525:Alprazolam
keywords: biomarker; pharmacodynamics; pharmacokinetics; psychopharmacology