Tedatioxetine

Polymorphism of the CYP2D6 gene leads to substantial interindividual variability in CYP2D6 enzyme activity. Despite improvements in prediction of CYP2D6 activity based on genotype information, large interindividual variability within CYP2D6 genotypes remains and ethnicity could be a contributing factor. The aim of this study was to investigate interethnic differences in CYP2D6 activity using clinical datasets of three CYP2D6 substrates: (i) brexpiprazole (N = 476), (ii) tedatioxetine (N = 500), and (iii) vortioxetine (N = 1073). The CYP2D6 activity of all individuals in the dataset was estimated through population pharmacokinetic analyses as previously reported. Individuals were assigned a CYP2D6 phenotype and CYP2D6 genotype group based on their CYP2D6 genotype and interethnic differences were investigated within each group. Among individuals categorized as CYP2D6 normal metabolizers, African Americans had a lower CYP2D6 activity compared to Asians (p < 0.01) and in the tedatioxetine and vortioxetine analyses also compared to Whites (p < 0.01). Among CYP2D6 intermediate metabolizers, interethnic differences were also observed, but the findings were not consistent across the substrates. Asian carriers of CYP2D6 decreased function alleles tended to exhibit higher CYP2D6 activity compared to Whites and African Americans. The observed interethnic differences within the CYP2D6 phenotype and genotype groups appeared to be driven by differences in CYP2D6 allele frequencies across ethnicities rather than interethnic differences in enzyme activity for individuals carrying identical CYP2D6 genotypes.

Pharmacological treatment of acute anxiety still relies on benzodiazepines, while chronic anxiety disorders and depression are treated with different antidepressants, according to specific indications. The monoaminergic axis is represented by two families which are being developed: (i) serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRI), also called triple reuptake inhibitors (TRI), for the treatment of depression (amitifadine), (ii) multimodal antidepressants for depression and anxiety disorders (generalized anxiety disorder mainly) (tedatioxetine, vortioxetine and vilazodone). Third-generation antipsychotics (aripiprazole, lurasidone, brexpiprazole, cariprazine) appear relevant in the treatment of resistant depression and some anxiety disorders. Among the modulators of the glutamatergic axis, promising compounds include: (i) ionotropic regulators of NMDA receptors: esketamine, AVP-923 and AVP-786, CERC-301, rapastinel (Glyx-13), NRX-1074 developed for depression, rapastinel and bitopertine developed for obsessive compulsive disorder, (ii) metabotropic glutamate receptors modulators: decoglurant and basimglurant developed for depression and mavoglurant developed for obsessive compulsive disorder.