Efficacy of etifoxine versus phenazepam in the treatment of patients with adjustment disorders (open

"Russian Psychiatric Journal"; Therapy of the mentally ill; No. 1; 2010; 74-78.

Yu.A. Aleksandrovsky 1 , V.N. Krasnov 2 , N.G. Neznanov 3 , L.V. Romasenko 1

1 FSI "State Scientific Center for Social and Forensic Psychiatry. V.P. Serbsky, Moscow , 2 Moscow Research Institute of Psychiatry, Moscow , 3 St. Petersburg Research Psychoneurological Institute

In the article, based on the study of 90 patients with symptoms of adjustment disorders, the results indicate a pronounced anxiolytic effect of etifoxine in the absence of a benzodiazepine-type muscle relaxant and inhibitory effect characteristic of phenazepam and other tranquilizers of the benzodiazepine group. This allows attributing etifoxine to the number of daytime tranquilizers.

The adjustment disorder (AD) is defined as "the state of subjective distress and emotional anxiety, usually affecting the performance of social functions and performance, during the period of adaptation to a major change in life or a stressful event in the life of the patient" (ICD-10 code F43.2) . AD is a frequent cause of primary treatment of patients for help to doctors of different specialties [2, 14]. According to a number of researchers, in general medical practice, 10% of patients show AD, usually evaluated in the group of patients with anxiety disorders. In the treatment of AD, in addition to psychotherapy, anxiolytics are widely used, among which benzodiazepines are used most often [11]. The original domestic anxiolytic phenazepam, a benzodiazepine derivative, is most often prescribed in Russia for the treatment of patients with AD and anxiety disorders. At the same time, as in the treatment with other benzodiazepine anxiolytics, many patients experience cognitive impairment, and in a number of cases, withdrawal and addiction syndrome [3, 13], which adversely affect the quality of life of patients. The high demand for tranquilizers in the treatment of mental disorders and the likelihood of the formation of adverse events in the long-term administration of benzodiazepine tranquilizers served as a basis for the search for tranquilizers that did not have these drawbacks. These drugs include the anxiolytic non-benzodiazepine structure of etifoxine, produced by Biocodex (France) under the trade name Stresam. Between 1995 and 2007, etifoxine was used in 40 countries to treat more than 11.3

million patients. In Russia, the drug was registered in 2008. An analysis of the results of special studies of the drug Stresam conducted in various clinics in France (in psychiatric institutions, as well as in the psychoneurological and cardiological departments of multi-profile hospitals) attests to its proven high anxiolytic effectiveness and safety [8, 9, 15 ]. The investigators associate the high efficacy and safety of Stresam with its specific dual mechanism of action directed toward GABA receptors and stimulation of neurosteroids [7, 12].

The aim of the study was to compare the effectiveness and safety of the use of etifoxine and phenazepam in patients with an adaptation disorder.

Material and methods

To conduct an open, randomized controlled trial, 90 patients were selected in 3 psychiatric centers in Moscow and St. Petersburg. The study included patients aged 18 to 65 years male and female with symptoms of adaptation disorder, as defined by ICD-10 (code F43.2), lasting at least 4 weeks. The level of anxiety on the Hamilton scale was to exceed 20 points, and on the scale MADRS - be no more than 20 points. The criteria for excluding patients from the study were: concomitant psychiatric illness, chronic disease or a threat to life, alcohol abuse, drug addiction or the period of stopping the use of drugs, as well as pregnancy.

The study did not include patients treated with benzodiazepines during the previous 4 weeks, who took medications that were able to influence the metabolism of the test compounds (carbamazepine, phenytoin, primidone, rifampicin, griseofulvin, phenobarbital, probenecid) during the last month before or during the study, , as well as beta-blockers and other drugs, the effect of which on the central nervous system could affect the results of the study. Patients were randomized into two groups who received oral phenazepam 0.5 mg twice daily (morning and evening) or etifoxine at a dose of 150 mg per day (50 mg in the morning and 100 mg in the evening). The treatment was conducted for 6 weeks. Efficiency and safety were assessed on the 7th and 42nd days of course therapy. The withdrawal syndrome was assessed 1 week after the end of the study (day 49).

The level of anxiety was recorded in accordance with the Hamilton anxiety scale (HAM-A) at baseline, on the 7th and 42nd days. The overall development of the disease was assessed using the CGI (Global Clinical Improvement Scale) scale: global clinical improvement on days 7 and 42, disease severity at baseline, on days 7 and 42, and therapeutic index for The 7th and 42nd days.

Side effects diagnosed independently or during observation were recorded throughout the study. The withdrawal syndrome after the end of therapy was assessed on the 49th day on the HAM-A and CGI scales and was defined as the difference between the results of the indicators of the 49th and 42nd day.

The Hamilton anxiety scale (HAM-A) [6] was used in clinical trials of medications, it assessed both psychiatric and somatic manifestations of anxiety. The Global Clinical Improvement Scale (CGI) was used to conduct a reliable overall assessment of the patient's condition at each examination (scores on "severity of the disease" and "global clinical improvement"), and to assess the risk-benefit ratio of therapy [10].

The randomization list for each center was created before the study began to determine its design. Each center assigned patients numbers sequentially, in accordance with the chronological order of inclusion in the study.

Statistical methods

For the analysis, the following patient populations were considered: a safety list including all patients randomized in the study and authentically receiving at least one dose of the study drug; a complete analysis list (SPA), including all patients randomized in the study, provided that any information is known of the outcome of follow-up; the protocol list (NGN), which includes all patients from the SPA group, for which no serious violation of the protocol was registered.

The statistical analysis was carried out using SAS software version 9.2 for Windows OS and consisted of descriptive statistics and hypothesis testing.

The lack of superiority of phenazepam compared with etifoxine was assessed by calculating 95% CI (confidence interval) on the average difference in anxiety level detected by the Hamilton scale between the two treatments. The 95% confidence interval was based on the ANOVA model. It was found that etifoxine is no less effective than phenazepam if the upper limit of 95% did not exceed 2.5 points. The ANOVA model was also used to compare the efficacy index in two therapeutic groups for each time point studied. Comparison of the results on the CGI scale was carried out using Cochran-Mantel-Haenszel tests. For comparison, we used the Fisher test for binary variables and the Cochran-Mantel-Haenszel test for ordinal variables. These tests were carried out with a bilateral restriction with a significance level of 5%.

The effectiveness analysis took into account the incidence of side effects and withdrawal syndrome. For this purpose, individual data on side effects were analyzed. A comparison of the two therapeutic groups was performed using the Cochran-