Preclinical and Clinical Pharmacology of Cyamemazine: Anxiolytic Effects and Prevention of Alcohol and Benzodiazepine Withdrawal Syndrome

Abstract

Several studies have suggested that the antipsychotic compound, cyamemazine, possesses anxiolytic properties in humans. The original pharmacological profile of cyamemazine (D 2 , 5-HT 2A , 5-HT 2C , and 5-HT 3 receptor antagonist), which was established by binding, microdialysis and behavioral studies, is consistent with these observations. In the light/dark exploration test, cyamemazine demonstrated anxiolytic-like activity by acute, but not chronic administration. By chronic administration, however, cyamemazine increased the time spent in the open arms of the elevated plus maze (EPM) test demonstrating anxiolytic-like activity. The discrepancy between the results obtained in these tests by acute and chronic administration, could be due to a combination of dopamine D 2 receptor antagonism with antagonism of the 5-HT 2C and 5-HT 3 receptors. The action of cyamemazine on both the dopaminergic system and 5-HT 3 receptors could also explain the activity of cyamemazine in the management of alcohol withdrawal demonstrated in preclinical studies. This potential indication for cyamemazine and its activity in benzodiazepine withdrawal syndrome have recently been investigated in clinical trials and the results of these studies are presented in this review.

Active cyamemazine metabolites in patients treated with cyamemazine (Tercian®): influence on cerebral dopamine D2 and serotonin 5-HT2A receptor occupancy as measured by positron emission tomography (PET)

“…Since maximal plasma concentrations (C max ) of cyamemazine was expected to be reached between 2 and 3 h postadministration according to previous pharmacokinetic data ( Bourin et al 2004), post-dose plasma levels could be considered as assessed around the plasma peak for all subjects.…”

“…1), which are both excreted into the urines for 72 h (Bourin et al 2004). Recently, N-desmethyl cyamemazine was found to have similar affinity for h5-HT 2A receptors as cyamemazine, whereas its affinity for hD 2 receptors is eight times lower (Benyamina et al 2008).…”

“…Moreover, it has demonstrated reductions in the anxiety associated with benzodiazepine withdrawal (Lemoine et al 2006). Finally, clinical experience has shown that cyamemazine induces few extrapyramidal adverse effects (Bourin et al 2004).…”

“…Cyamemazine was primarily developed as an antipsychotic agent blocking central dopamine D 2 receptors. It is currently used as a symptomatic anxiolytic, particularly in schizophrenia and in depression with suicidal tendencies (Bourin et al 2004). Moreover, it has demonstrated reductions in the anxiety associated with benzodiazepine withdrawal (Lemoine et al 2006).…”

Current animal models of anxiety, anxiety disorders, and anxiolytic drugs

“…Geller-Seifter test Punished responses for food [8] Vogel test Punished drinking [9] Four plate test Punished crossings [10] Defensive burying Shock prod burying [11] Hyponeophagia Feeding in an unfamiliar arena [12] Distress vocalization Ultrasonic vocalizations in isolated pups [13] Conditioned responses Active/passive avoidance Avoidance of aversive stimuli [14] Fear potentiated startle Startle in aversive environments [15] Conditioned fear Freezing in aversive environments [16] anxiety to test the efficacy of classical and novel anxiolytics [68][69][70]. The assumption that defense against natural threats models stress-induced anxiety better than, for example, electric shocks led to the development of predator-induced anxiety models in rats [63] and mice [71].…”