An update on the anxiolytic and neuroprotective properties of etifoxine: from brain GABA modulation to a whole-body mode of action

Figures & data

Figure 1 Comparison of the mechanism of action of etifoxine and benzodiazepines on the GABA_A receptor. (A) Benzodiazepines bind principally within the between the α and γ₂ subunits of the GABA_A receptor. The nature of the α subunit influences the pharmacological properties of agents binding to it (sedation, myorelaxation, amnesia, etc). Flumazenil specifically inhibits binding of benzodiazepines to the GABA_A receptor. (B) Etifoxine acts on the GABA_A receptor, both by binding directly to the β₂/β₃ subunits and by indirectly stimulating neurosteroid production (allopregnanolone). Flumazenil does not affect the binding of etifoxine to the GABA_A receptor. Reproduced with kind permission from Biocodex.

Abbreviation: TSPO, translocator protein of 18 kDa.

Figure 2 Mechanism of action of etifoxine. Etifoxine stimulates GABAergic transmission through two complementary mechanisms. Firstly, etifoxine binds directly to the β₂/β₃ subunits of the GABA_A receptor. Secondly, etifoxine reinforces GABAergic transmission via an indirect mechanism by binding to the TSPO receptor on mitochondria, thus facilitating the synthesis of neurosteroids, which are powerful positive allosteric modulators of the GABA_A receptor. Reproduced with kind permission from Biocodex.

Table 1 Etifoxine efficacy and tolerability in patients

Study (year)	Design and sample size	Scale used	Sample	Results	Notes
Servant et al,^Citation52 (1998)	DSM-IV criteria for adjustment disorders with anxiety 4-week double-blind RCT Multicenter Outpatients (GPs) N=170 ETX vs BUS Superiority test	Primary endpoint: improvement in HAM-A mean score at Week 4 Secondary endpoints: improvement in CGI mean score at Week 4 Efficacy/tolerability index: TI	Inclusion HAM-A score ≥18 Mean age: 44 yrs, female: 73% ETX (flexible 150–200 mg/day) n=83. Mean (± SD) HAM-A inclusion score: 25.27±4.73 BUS (flexible 15–20 mg/day) n=87. Mean (± SD) HAM-A inclusion score: 27.17±5.29	HAM-A mean (± SD) total score at D28: ETX: 9.48±0.61 and BUS: 11.18±0.60 Greater improvement in HAM-A with ETX vs BUS at W4 (p<0.05) Greater improvement in CGI with ETX at D7 (p<0.001), D14 and D28 (p=0.02)	Greater and faster efficacy of ETX vs BUS with better tolerability TI improvement better with ETX at D14 (p=0.01) and D28 (p=0.05)
Nguyen et al,^Citation54 (2006)	DSM-IV criteria for adjustment disorders with anxiety 4-week double-blind RCT Multicenter Outpatients (GPs) N=191 ETX vs LOR Noninferiority test	Primary endpoint: improvement in HAM-A mean score at Week 4 SAS-SR Secondary endpoints: improvement in CGI-Improvement, SDS, and SAS–SR mean scores at Week 4 Efficacy/tolerability index: TI	Inclusion HAM-A score ≥20 Mean age: 43 yrs, female: 66% ETX: 50 mg t.i.d (n=91) LOR: 2 mg/day (t.i.d) (n=96)	Baseline HAM-A (mean ± SD):25.3±3.5 in ETX group vs 25.7±4.4 in LOR group At W4, decrease in HAM-A score: 54.6% for ETX vs 52.3%, for LOR, noninferiority (p=0.0002)	Percentage of responders at W4 (≥50% decrease in HAM-A score) higher with ETX than with LOR (72% vs 56%, p=0.03) More ETX patients with marked improvement (CGI score <3) than LOR patients (p=0.022) TI higher in ETX group (78.9% vs 62.6%) than in LOR group (p=0.0383) At W1 after stopping treatment, rebound anxiety greater with LOR (p=0.034)
Aleksandrovsky et al,^Citation58 (2010)	ICD-10 criteria for adjustment disorders 6-week open-label RCT Multicenter Outpatients (GPs) N=90 ETX or PHE Noninferiority test	HAM-A Primary endpoint: improvement in HAM-A mean score at Week 6 Secondary endpoint: improvement in CGI-Severity mean score at Week 6 Efficacy/tolerability index: TI	Mean age: 45 yrs, female: 66.6% two groups ETX (150 mg/day) PHE (1 mg/day) Baseline HAM-A: 29.73±7.62 for ETX group and 27.83±5.95 for PHE group	HAM-A mean score at Week 6 was 12.98±4.16 for ETX group and 15.21±6.02 for PHE group Noninferiority of ETX was proven with first least-square mean (95% CI ETX vs −3.2 PHE [−5.3; −1.1]) Greater decrease in CGI-Severity score at W6 for ETX than for PHE (p=0.004)	56.44% vs 45.35% decrease in HAM-A score for ETX vs PHE at Week 6 (p=0.003) Fewer adverse events leading to discontinuation for ETX group (p=0.002) at Week 6 Fewer withdrawal symptoms after treatment cessation for ETX (p<0.001) at Week 6
Stein et al,^Citation55 (2015)	DSM-IV criteria for adjustment disorders with anxiety 4-week double-blind RCT Multicenter Outpatients (GPs) N=201 ETX vs ALP Noninferiority test	HAM-A Primary endpoint: improvement in HAM-A mean score at Week 4 Secondary endpoint: improvement in CGI-Improvement, SDS and SAS-SR mean scores at Week 4	Inclusion criteria: - HAM-A score ≥20 - Score ≥5 on at least one SDS subscale - MADRS score <20 Mean age: 39.4 yrs, female: 73.1% ETX (150 mg/day) ALP (1.5 mg/day)	Decrease in mean HAM-A total score: 72.5% for ETX vs 79.7% for ALP. Noninferiority of ETX was not demonstrated At W5 (ie, 1 week after medication discontinuation), HAM-A continued to decrease for ETX (−0.6±4.5), but increased (+2.2±7.0) for ALP (p=0.019)	All other outcome measures underwent similar improvements in the two treatment groups Faster improvement in somatic symptoms with ALP Adverse effects more often deemed to be treatment-related by investigators in the ALP group

Table 2 Etifoxine tolerability in healthy volunteers

Study (year)	Design and sample size	Scale used	Sample	Results	Notes
Micallef et al,^Citation62 (2001)	Comparison of psychomotor and amnesic effects of single oral doses of ETX and LOR RCT N=48	VAS Barrage test CRT Digit span: immediate and delayed free recall of heard numbers Immediate and delayed free recall of pictures	Inclusion criteria: HAM-A < 2 with no history of substance abuse 24 women, 24 men Age: 18–35 years (M =24.9±3.5) 12 participants received a single dose of ETX (50 mg) 12 participants received a single dose of ETX (100 mg) 12 participants received a single dose of LOR (2 mg) 12 participants received a single dose of a placebo	LOR participants displayed longer mean CRTs (p<0.001) than the other groups At 2 hrs, LOR participants scored lower on the Barrage test (p=0.002) compared with ETX 50 mg and placebo The VAS showed a significant Group ⨰ Time interaction, with LOR participants being more tired, clumsy, drowsy, and less energetic at 2and 4 hrs LOR participants had significantly lower scores on immediate and delayed recall than the other groups	In contrast to LOR, ETX did not induce either psychomotor, attention, or memory effects Adverse events were more frequent (n=5) with LOR than with either ETX (n=1) or placebo (n=1)
Deplanque et al,^Citation63 (2018)	Comparison of alertness and cognitive effects of ETX (2⨰ 50 mg), LOR (2 ⨰1 mg), and placebo in older participants (65–75 years) Double-blind, crossover RCT N=30	Cambridge Neuropsychological Test Automated Battery Testing 2 hrs after treatment administration Primary endpoint: reaction time	N=30 (20 female) 3 testing days separated by a washout period of 14–30 days ETX (50 mg b.i.d.) LOR (1 mg b.i.d.) Placebo (b.i.d.)	ETX has no deleterious effects on alertness or cognition, compared with placebo (reaction time: 744 ± 146 ms vs 770 ± 153 ms; p = 1.00) LOR impaired alertness (reaction time: 957 ± 251 ms) compared with placebo (p < 0.0001), and the most frequent adverse event involved cognitive functions LOR impaired alertness, attention, and both working and verbal memory	ETX and placebo had identical adverse events LOR adverse events were three times higher, with drowsiness being the most frequent one

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