Etifoxine (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

; also known as etafenoxine; trade name Stresam) is an

anxiolytic An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiet ...

and anticonvulsant drug developed by Hoechst in the 1960s. It is sold in approximately 40 countries for anxiety disorders, without the sedation and ataxia associated with benzodiazepine drugs. It has similar anxiolytic effects to benzodiazepine drugs, but is structurally distinct, although it has structural elements in common with them. Studies suggest is as effective as

lorazepam Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety disorders, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and c ...

as an anxiolytic, but has fewer side effects. Etifoxine is not approved by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

. The European Medicines Agency (EMA) started a review procedure regarding the effectiveness and safety of etifoxine following a French study that compares etifoxine's effectiveness to placebo and lorazepam. In January 2022, the EMA "finalized its review of Stresam and concluded that the medicine can continue to be used for the treatment of anxiety disorders, but it must not be used in patients who previously had severe skin reactions or severe liver problems after taking etifoxine."

Medical use

It is used for treating

adjustment disorder Adjustment disorder is a maladaptive response to a psychosocial stressor. It is classified as a mental disorder. The maladaptive response usually involves otherwise normal emotional and behavioral reactions that manifest more intensely than usual ...

Side effects

Severe adverse events are in general rare. Skin and subcutaneous disorders are the most frequently reported, but these generally resolve after drug cessation. Etifoxine shows less adverse effects of anterograde amnesia, sedation, impaired psychomotor performance, and withdrawal syndromes than those of benzodiazepines. A 2012 review of etifoxine by the French National Pharmacovigilance Committee determined that etifoxine was safe and continued to provide a favorable alternative to benzodiazepine anxiolytics. The committee found (for a ten-year pharmacovigilance period) that safety concerns were rare or very rare and that the incidence of idiosyncratic hepatic (liver) problems were very rare.

Mechanism of action

Unlike benzodiazepines, etifoxine may produce its anxiolytic effects through a dual mechanism, by directly binding to GABA_A receptors and (purportedly, exact binding site undetermined) to the mitochondrial

translocator protein Translocator protein (TSPO) is an 18 kDa protein mainly found on the outer mitochondrial membrane. It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for diazepam, but subsequent research has found the re ...

(TSPO), resulting in increases in endogenous neurosteroids. At GABA_A receptors etifoxine binds at the α+β−

interface Interface or interfacing may refer to: Academic journals * ''Interface'' (journal), by the Electrochemical Society * '' Interface, Journal of Applied Linguistics'', now merged with ''ITL International Journal of Applied Linguistics'' * '' Int ...

and preferentially potentiates α2β3γ2 and α3β3γ2 receptor types. This direct allosteric potentiation can only be observed at relatively high concentrations (starting at > 1 micromolar) and is perhaps not physiologically relevant at normal human doses. This is different from benzodiazepines and etifoxine can be used alongside benzodiazepines to potentiate their effects without competing for binding sites; however, it also means that the direct effects of etifoxine are not reversed by the benzodiazepine antagonist

flumazenil Flumazenil (also known as flumazepil, code name Ro 15-1788) is a selective GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines ( ...

. Etifoxine stimulates the biosynthesis of endogenous neurosteroids, for example: allopregnanolone (3-alpha,5-alpha THP), a nanomolar potentiator of GABA activity.

References

{{GABAAR PAMs Anxiolytics Chloroarenes Benzoxazines GABAA receptor positive allosteric modulators TSPO ligands