Etifoxine Versus Alprazolam for the Treatment of Adjustment Disorder with Anxiety: a Randomized Controlled Trial

Adv Ther DOI 10.1007/s12325-015-0176-6 ORIGINAL RESEARCH Etifoxine Versus Alprazolam for the Treatment of Adjustment Disorder with Anxiety: a Randomized Controlled Trial Dan J. Stein To view enhanced content go to www.advancesintherapy.com Received: September 6, 2014 Ó The Author(s) 2015. This article is published with open access at Springerlink.com ABSTRACT was treated with 150 mg/day for etifoxine, and the other with 1.5 mg/day for alprazolam for Background: Adjustment disorder with anxiety 28 days. Patients were followed for 4 weeks of (ADWA) is a highly prevalent condition, treatment, and for an additional week after particularly in primary care practice. There are treatment discontinuation. The primary relatively few systematic treatment trials in the outcome measure was the Hamilton Anxiety area of ADWA, and there are few data on Rating Scale (HAM-A), while secondary predictors of treatment response. Etifoxine is a outcome measures included the Sheehan promising agent insofar as it is not associated Disability Scale (SDS), the Clinical Global with dependence, but in primary care settings Impressions-Change Scale (CGI-C), and the benzodiazepines continue to be frequently Self-Report for the Assessment of Adjustment prescribed for psychiatric symptoms. A Disorders. Non-inferiority analysis was used to randomized controlled trial of etifoxine versus assess the primary outcome measure, and a alprazolam for ADWA was undertaken, focusing multivariate logistic regression was employed to on efficacy and safety measures, and including investigate predictors of response. an investigation of predictors of clinical Results: Two hundred and two adult response. outpatients with ADWA were enrolled at 17 Methods: This was a comparative, multicenter, primary care sites. One hundred and seventy double-blind, randomized trial in two parallel seven patients completed the study (n = 87 in groups of outpatients with ADWA. One group the etifoxine group; n = 90 in the alprazolam group). Etifoxine and alprazolam were Electronic supplementary material The online version of this article (doi:10.1007/s12325-015-0176-6) accompanied by decreases in the HAM-A at contains supplementary material, which is available to day 28, with a difference between treatment authorized users. groups in HAM-A score of 1.78 [90% CI; 0.23, D. J. Stein (&) 3.33] in favor of alprazolam. However, after Department of Psychiatry, Groote Schuur Hospital medication discontinuation, HAM-A scores J2, University of Cape Town, Anzio Rd, Observatory, Cape Town 7925, South Africa continued to improve in the etifoxine group, e-mail: [email protected] Adv Ther but increased in the alprazolam group; the such as posttraumatic stress disorder [2]. difference between groups in mean change Adjustment disorders are prevalent in the between day 28 and day 35 was significant community, with point prevalence estimates (p = 0.019). Secondary outcome measures ranging from 0.9% to 2.3% [3], and even higher showed similar results for etifoxine and in clinical samples, where point prevalence alprazolam at day 35. More treatment-related estimates range from 5% to 24%, with adverse events were reported in patients treated adjustment disorder with anxiety (ADWA) with alprazolam, particularly central nervous being the most frequent [4]. Adjustment system-related AEs, and especially after disorders are associated with substantial medication discontinuation. No significant morbidity and impaired quality of life [3, 5, 6]. predictors of treatment response were found. Both psychotherapy and pharmacotherapy Conclusion: This randomized controlled trial of adjustment disorders have been investigated. provides support for the efficacy and safety of A Cochrane review of interventions to facilitate etifoxine in the management of adjustment return to work in adults with adjustment disorder with anxiety, particularly when disorders included nine studies of treatment discontinuation data are also psychological interventions, and concluded assessed. Etifoxine has the important clinical that cognitive behavioral therapy (CBT) did advantage of having anxiolytic effects, which not significantly reduce time until return to are not being associated with dependence. work, compared with no treatment [7]. There is Pharmacotherapy was equally efficacious in also a small literature on the investigation of patients with more severe anxiety symptoms antidepressants and benzodiazepines for at baseline. Additional work using longer-term adjustment disorder; to date, however, no follow-up and collecting data on cost-efficiency agent has been registered for this indication of management options would further advance [3]. In clinical practice, benzodiazepines are the field of ADWA. very often prescribed [8], even though concerns Funding: Sponsorship and article processing have been raised about the adverse event profile charges for this study were provided by of these agents, including cognitive dysfunction Biocodex, Gentilly, France. and the potential risk for dependence [9]. Etifoxine is a benzoxazin drug that does not Keywords: Adjustment disorder with anxiety; belong to the benzodiazepine family, but that Alprazolam; Etifoxine nevertheless has anxiolytic properties [10]. Etifoxine directly interacts with the chloride INTRODUCTION channel of the GABAA receptor complex and therefore potentiates GABAergic synaptic Adjustment disorders are characterized by the transmission [11–13]. Further, etifoxine may development of clinically significant emotional have indirect effects, acting at peripheral or behavioral symptoms in response to an benzodiazepine receptors (PBR) to increase identifiable stressor or stressors [1]. In the fifth brain neurosteroids (pregnenolone, edition of the Diagnostic and Statistical Manual allopregnanolone) with anti-anxiety effects of Mental Disorders (DSM-5), adjustment [14, 15]. Previous trials have found that disorders are categorized as trauma- and etifoxine has similar efficacy compared to stressor-related disorders, alongside conditions buspirone [16] and to lorazepam [17]in Adv Ther ADWA. Furthermore, etifoxine has few adverse Before starting the trial, all investigators cognitive or psychomotor effects and is not (n = 35) were trained by the study coordinator associated with dependence [18]. to diagnose ADWA. The full day of training The objective of the present study was to included viewing videos of clinical cases, compare the efficacy and safety of etifoxine training in ADWA diagnosis, and training in with the high potency benzodiazepine, study symptom scales. After the inclusion visit, alprazolam, in the treatment of ADWA, and to participants attended three visits: after 1 week evaluate the persistence of clinical effects as of treatment (day 7), at the end of the treatment well as any rebound effects after treatment period (day 28) and 1 week after treatment discontinuation. The tertiary outcome was to discontinuation (day 35). Efficacy and safety determine the predictors of pharmacotherapy measures were undertaken at each of these response in ADWA. visits. ADWA patients included in the study were randomly assigned to receive etifoxine or MATERIALS AND METHODS alprazolam per os. A randomization list was established and study treatments were Study Design assigned by each investigator in ascending order of numbering based on the This prospective study was conducted in South chronological enrollment order. Study drug Africa as a comparative, multicenter, double- was to be taken daily for 28 days (one capsule blind, randomized trial in two parallel groups of in the morning, at noon and in the evening), outpatients with ADWA. Seventeen centres in at usual dosages (150 mg/day for etifoxine, two locations (Cape Town, Johannesburg) and 1.5 mg/day for alprazolam), in conformity participated. A non-inferiority design with the summary of product characteristics comparing etifoxine with a commonly (SmPC) of the two drugs. Study treatments prescribed anxiolytic agent rather than with a were presented as capsules identical in their placebo was chosen, and attention was paid to appearance. the visit after treatment discontinuation. Exploratory analyses of socio-demographic and Patients clinical predictors of scores on the Hamilton Anxiety Rating Scale (HAM-A), the primary To be eligible for inclusion, male or female outcome measure, were also undertaken to outpatients aged 18–65 years had to meet the determine the predictors of pharmacotherapy criteria for ADWA as defined by the DSM-IV response in ADWA. [19]. In addition, baseline score on the All procedures followed were in accordance Hamilton Anxiety Rating Scale (HAM-A) [20] with the ethical standards of the responsible was C20, with a baseline score in at least one committee on human experimentation of three subscales (work, family and social life) (institutional and national) and with the of the Sheehan Disability Scale (SDS) [21] C5, Helsinki Declaration of 1975, as revised in 2000 and a baseline score on the Montgomery– and 2008. Informed consent was obtained from A˚ sberg Depression Rating Scale (MADRS) all patients for being included in the study. [22] \20. Adv Ther Participants had no comorbid psychiatric or Statistical Analyses substance use disorder (as assessed by the Mini- International Neuropsychiatric Interview [23]), Sample size was determined to achieve 80% no suicidal thoughts, present or past history of power to detect a difference inferior to 2.5 epilepsy, no medical disorder physiologically points in HAM-A total score on day 28 between responsible

Load more