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

Adjustment disorder with anxiety (ADWA) is a highly prevalent condition, particularly in primary care practice. There are relatively few systematic treatment trials in the area of ADWA, and there are few data on predictors of treatment response. Etifoxine is a promising agent insofar as it is not associated with dependence, but in primary care settings benzodiazepines continue to be frequently prescribed for psychiatric symptoms. A randomized controlled trial of etifoxine versus alprazolam for ADWA was undertaken, focusing on efficacy and safety measures, and including an investigation of predictors of clinical response. This was a comparative, multicenter, double-blind, randomized trial in two parallel groups of outpatients with ADWA. One group was treated with 150 mg/day for etifoxine, and the other with 1.5 mg/day for alprazolam for 28 days. Patients were followed for 4 weeks of treatment, and for an additional week after treatment discontinuation. The primary outcome measure was the Hamilton Anxiety Rating Scale (HAM-A), while secondary outcome measures included the Sheehan Disability Scale (SDS), the Clinical Global Impressions-Change Scale (CGI-C), and the Self-Report for the Assessment of Adjustment Disorders. Non-inferiority analysis was used to assess the primary outcome measure, and a multivariate logistic regression was employed to investigate predictors of response. Two hundred and two adult outpatients with ADWA were enrolled at 17 primary care sites. One hundred and seventy seven patients completed the study (n = 87 in the etifoxine group; n = 90 in the alprazolam group). Etifoxine and alprazolam were accompanied by decreases in the HAM-A at day 28, with a difference between treatment groups in HAM-A score of 1.78 [90% CI; 0.23, 3.33] in favor of alprazolam. However, after medication discontinuation, HAM-A scores continued to improve in the etifoxine group, but increased in the alprazolam group; the difference between groups in mean change between day 28 and day 35 was significant (p = 0.019). Secondary outcome measures showed similar results for etifoxine and alprazolam at day 35. More treatment-related adverse events were reported in patients treated with alprazolam, particularly central nervous system-related AEs, and especially after medication discontinuation. No significant predictors of treatment response were found. This randomized controlled trial provides support for the efficacy and safety of etifoxine in the management of adjustment disorder with anxiety, particularly when treatment discontinuation data are also assessed. Etifoxine has the important clinical advantage of having anxiolytic effects, which are not being associated with dependence. Pharmacotherapy was equally efficacious in patients with more severe anxiety symptoms at baseline. Additional work using longer-term follow-up and collecting data on cost-efficiency of management options would further advance the field of ADWA. Sponsorship and article processing charges for this study were provided by Biocodex, Gentilly, France.