Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed.

[2][14] It also showed preliminary effectiveness in institutionalized individuals with chronic psychosis and high anxiety levels.

[4] The anxiolytic effectiveness of alpidem, for example measured by reductions on the Hamilton Anxiety Rating Scale (HAM-A), was superior to placebo and comparable or equivalent to that of benzodiazepines including diazepam (10–15 mg/day), lorazepam (1–6 mg/day), and clorazepate (30 mg/day) in directly comparative randomized controlled trials.

[21][22] The central side effects of alpidem were found to be no worse in elderly people than in young adults.

[2] No rebound anxiety or withdrawal symptoms have been observed with alpidem after abrupt discontinuation following 4 weeks to 6–12 months of treatment.

[3][2][4] Conversely, substantial withdrawal symptoms, including rebound anxiety, were observed with lorazepam.

[3] In directly comparative trials, alpidem produced similar anxiolytic effects with less fatigue, asthenia, depressive mood, and psychomotor impairment than benzodiazepines, while rates of somnolence and drowsiness were comparable to benzodiazepines but described as milder in severity.

[2] In addition, alpidem significantly antagonized the amnestic effects of lorazepam and showed similar trends for other cognitive measures in a clinical study in which the two drugs were combined and assessed for interaction.

[27][28][29][19] It may be related to interactions of alpidem with the translocator protein (TSPO), which is present in high amounts in the liver and which may mediate toxic effects in this tissue.

[3] In addition to its affinity for the benzodiazepine site of the GABAA receptor (Ki = 1–28 nM), alpidem has similarly high affinity for the translocator protein (TSPO) (formerly the peripheral benzodiazepine receptor (PBR)) (Ki = 0.5–7 nM).

[3][5][39][30] High doses of alpidem antagonize the sedative and muscle relaxant effects of diazepam in animals.

[5] Besides acting directly via the GABAA receptor, interactions with the TSPO might also contribute to the anxiolytic effects of alpidem.

[3] The pharmacodynamic mechanisms underlying the anxioselective (anxiolytic-selective) profile of alpidem as a GABAA receptor positive allosteric modulator are unclear.

[3][45][5][49][39][50][51] Although anxioselective profiles have been observed for many GABAA receptor positive allosteric modulators in preclinical research, alpidem is the only GABAA receptor positive allosteric modulator for which anxioselective effects have been unambiguously demonstrated in human clinical trials.

[3] Ocinaplon has also shown preliminary signs of an anxioselective profile in clinical studies, but development of this agent was discontinued in late-stage trials due to findings of elevated liver enzymes in a small subset of patients.

[31][52][48][38] Despite many developmental failures, alpidem serves as a potential proof of concept that anxioselective GABAA receptor positive allosteric modulators may be possible.

[1] Alpidem is a highly lipophilic compound and in animals is extensively distributed into lipid-rich tissues.

[1] Similarly, alpidem has been shown to cross the blood–brain barrier in animals, and showed a brain/plasma ratio of about 2.0 to 2.5 following systemic administration.

[1] The plasma protein binding of alpidem is 99.4%, with similar isolated fractions bound to albumin (97.0%) and α1-acid glycoprotein (97.3%).

[1] The free fraction of alpidem is slightly higher in people with cirrhosis (0.86 ± 0.06%) and renal failure (0.72 ± 0.03%) relative to normal individuals (0.61 ± 0.05%).

[1] Conversely, in children age 8 to 12 years, the half-life of alpidem was considerably reduced (11.4 ± 1.9 hours).

[1] Conversely, the half-lives of alpidem and its metabolites were unchanged in people with different stages of renal impairment, though plasma concentrations were significantly increased.

[8][54][9] Alpidem is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, and DCFTooltip Dénomination Commune Française.