GABAergic Effects of Etifoxine and Alprazolam Assessed by Double Pulse TMS

Abstract

Introduction There is a need for novel anxiolytics with improved side effect profiles compared to benzodiazepines. A promising candidate with alternative pharmacodynamics is the translocator protein ligand, etifoxine.

Methods To get further insight into its mechanisms of action and side effects compared to the benzodiazepine alprazolam, we performed a double-blind, placebo-controlled, repeated-measures study in 36 healthy male subjects. Participants were examined for trait anxiety and side effects and underwent repeated transcranial magnetic stimulation (TMS) assessments, including motor evoked potentials (MEP), short intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP).

Results We observed attenuation of MEPs by alprazolam but not by etifoxine. SICI was not significantly affected by alprazolam or etifoxine. However, the response pattern indicated a lowered SICI threshold after the administration of etifoxine and alprazolam compared to the placebo. ICF and CSP were influenced by neither medication. Alprazolam led to higher sedation and subjective impairment of concentration compared to etifoxine. Individual anxiety trait scores did not affect TMS parameters.

Discussion This study indicated a favorable side effect profile of etifoxine in healthy volunteers. Moreover, it revealed differential GABA-related effects on neuromuscular function by means of TMS. The side effects and TMS profile of etifoxine are compatible with the involvement of neurosteroidogenesis and a predominant α3 subunit modulation compared to alprazolam.

Key words

TMS - TSPO - benzodiazepines - etifoxine - GABA

• References

• 1 Poisbeau P, Gazzo G, Calvel L.. Anxiolytics targeting GABAA receptors: Insights on etifoxine. World J Biol Psychiatry 2018; 19: S36-S45
• 2 Nguyen N, Fakra E, Pradel V. et al. Efficacy of etifoxine compared to lorazepam monotherapy in the treatment of patients with adjustment disorders with anxiety: A double-blind controlled study in general practice. Hum Psychopharmacol Clin Exp 2006; 21: 139-149
• 3 Stein DJ.. Etifoxine versus alprazolam for the treatment of adjustment disorder with anxiety: A randomized controlled trial. Adv Ther 2015; 32: 57-68
• 4 Rupprecht R, Rammes G, Eser D. et al. Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science 2009; 325: 490-493
• 5 Rupprecht R, Wetzel CH, Dorostkar M. et al. Translocator protein (18kDa) TSPO: A new diagnostic or therapeutic target for stress-related disorders. Mol Psychiatry 2022; 27: 2918-2926
• 6 Belelli D, Hogenkamp D, Gee KW. et al. Realising the therapeutic potential of neuroactive steroid modulators of the GABAA receptor. Neurobiol Stress 2020; 12: 100207-100207
• 7 Zorumski CF, Paul SM, Izumi Y. et al. Neurosteroids, stress and depression: Potential therapeutic opportunities. Neurosci Biobehav Rev 2013; 37: 109-122
• 8 Mattei C, Taly A, Soualah Z. et al. Involvement of the GABAA receptor α subunit in the mode of action of etifoxine. Pharmacol Res 2019; 145
• 9 Kujirai T, Caramia MD, Rothwell JC. et al. Corticocortical inhibition in human motor cortex. J Physiol 1993; 471: 501-519
• 10 Rossini PM, Burke D, Chen R. et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol 2015; 126: 1071-1107
• 11 Ziemann U, Lönnecker S, Steinhoff BJ. et al. The effect of lorazepam on the motor cortical excitability in man. Exp Brain Res 1996; 109: 127-135
• 12 Ziemann U, Rothwell JC, Ridding MC.. Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol 1996; 496: 873-881
• 13 Kimiskidis VK, Papagiannopoulos S, Kazis DA. et al. Lorazepam-induced effects on silent period and corticomotor excitability. Exp Brain Res 2006; 173: 603-611
• 14 Ackenheil M, Stotz-Ingenlath G, Dietz-Bauer R. et al. MINI mini international neuropsychiatric interview, German version 5.0. 0 DSM IV. Munich Psychiatr Univ Clin Published online. 1999
• 15 Laux L.. Das State-Trait-Angstinventar (STAI): Theoretische Grundlagen und Handanweisung. Weinheim: Beltz Testgesellschaft; 1981
• 16 Gerlach AL, Andor T, Patzelt J.. Die Bedeutung von Unsicherheitsintoleranz für die Generalisierte Angststörung Modellüberlegungen und Entwicklung einer deutschen Version der Unsicherheitsintoleranz-Skala. Z Für Klin Psychol Psychother 2008; 37: 190-199
• 17 Kemper CJ, Ziegler M, Taylor S.. ASI-3-Angstsensitivitätsindex-3. Published online. 2011
• 18 Awiszus F.. Chapter 2 TMS and threshold hunting. In: Supplements to Clinical Neurophysiology. Vol 56. Elsevier; 2003: 13-23
• 19 Chen R, Tam A, Bütefisch C. et al. Intracortical inhibition and facilitation in different representations of the human motor cortex. J Neurophysiol 1998; 80: 2870-2881
• 20 Ilić TV, Meintzschel F, Cleff U. et al. Short-interval paired-pulse inhibition and facilitation of human motor cortex: The dimension of stimulus intensity. J Physiol 2002; 545: 153-167
• 21 Garry MI, Thomson RHS.. The effect of test TMS intensity on short-interval intracortical inhibition in different excitability states. Exp Brain Res 2009; 193: 267-274
• 22 Jackson N, Greenhouse I.. VETA: A Matlab toolbox for the collection and analysis of electromyography combined with transcranial magnetic stimulation. bioRxiv Published online April 2019; 610386-610386
• 23 Harris CR, Millman KJ, van der Walt SJ. et al. Array programming with NumPy. Nature 2020; 585: 357-362
• 24 Seabold S, Perktold J.. statsmodels: Econometric and statistical modeling with python.[In: 9th Python in Science Conference. ; 2010.].
• 25 Waskom M, Botvinnik O, O’Kane D. et al. mwaskom/seaborn: v0.8.1 (September 2017). Published online September 2017;
• 26 Smith MJ, Keel JC, Greenberg BD. et al. Menstrual cycle effects on cortical excitability. Neurology 1999; 53: 2069-2069
• 27 Rupprecht R, Holsboer F.. Neuroactive steroids in neuropsychopharmacology. Int Rev Neurobiol 2001; 46: 461-477
• 28 Sartory G, Rust J.. The effects of a single administration of etifoxine on several psychological tests. Psychopharmacologia 1973; 29: 365-384
• 29 Corsico R, Moizeszowicz J, Bursuck L. et al. Evaluation of the psychotropic effect of Etifoxine through pursuit rotor performance and GSR. Psychopharmacologia 1976; 45: 301-303
• 30 Cheng T, Wallace DM, Ponteri B. et al. Valium without dependence? Individual GABA_A receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects. Neuropsychiatr Dis Treat 2018; 14: 1351-1361
• 31 Wolf L, Bauer A, Melchner D. et al. Enhancing neurosteroid synthesis – relationship to the pharmacology of translocator protein (18 kDa) (TSPO) ligands and benzodiazepines. Pharmacopsychiatry 2015; 48: 72-77
• 32 do Rego JL, Vaudry D, Vaudry H.. The non-benzodiazepine anxiolytic drug etifoxine causes a rapid, receptor-independent stimulation of neurosteroid biosynthesis. PLOS ONE 2015; 10: e0120473-e0120473
• 33 Owen DR, Phillips A, O’Connor D. et al. Human pharmacokinetics of XBD173 and etifoxine distinguish their potential for pharmacodynamic effects mediated by translocator protein. Br J Clin Pharmacol 2022; 88: 4230-4236
• 34 Verleye M, Schlichter R, Gillardin JM.. Interactions of etifoxine with the chloride channel coupled to the GABA(A) receptor complex. NeuroReport 1999; 10: 3207-3210
• 35 Verleye M, Akwa Y, Liere P. et al. The anxiolytic etifoxine activates the peripheral benzodiazepine receptor and increases the neurosteroid levels in rat brain. Pharmacol Biochem Behav 2005; 82: 712-720
• 36 Harrison NL, Vicini S, Barker JL.. A steroid anesthetic prolongs inhibitory postsynaptic currents in cultured rat hippocampal neurons. J Neurosci 1987; 7: 604-609
• 37 Hanajima R, Ugawa Y, Terao Y. et al. Paired-pulse magnetic stimulation of the human motor cortex: Differences among I waves. J Physiol 1998; 509: 607-618