Despite regulation of AKT1 and GSK3B by DRD2, we found no evidence that these two kinases play a major role in the pathogenesis of antipsychotic-induced TD.
Although met with conflicting data, the following genes may be involved with TD development: the cytochrome P450 gene CYP2D6, involved with metabolism of most antipsychotics, Dopamine D2 and D3 receptor genes, serotonin 2A and 2C receptor genes, vesicular monoamine transporter 2 (VMAT 2) gene, involved with intracellular neurotransmitter packaging, and the manganese superoxide dismutase (MnSOD) gene, an antioxidant enzyme.
Although met with conflicting data, the following genes may be involved with TD development: the cytochrome P450 gene CYP2D6, involved with metabolism of most antipsychotics, Dopamine D2 and D3 receptor genes, serotonin 2A and 2C receptor genes, vesicular monoamine transporter 2 (VMAT 2) gene, involved with intracellular neurotransmitter packaging, and the manganese superoxide dismutase (MnSOD) gene, an antioxidant enzyme.
Although met with conflicting data, the following genes may be involved with TD development: the cytochrome P450 gene CYP2D6, involved with metabolism of most antipsychotics, Dopamine D2 and D3 receptor genes, serotonin 2A and 2C receptor genes, vesicular monoamine transporter 2 (VMAT 2) gene, involved with intracellular neurotransmitter packaging, and the manganese superoxide dismutase (MnSOD) gene, an antioxidant enzyme.
The evidence of vesicular monoamine transporter 2 inhibitors as a first-line therapy for tardive dyskinesia is well supported by several controlled clinical trials.
Most recently, the VMAT2 inhibitors valbenazine and deutetrabenazine were rigorously studied in TD in large, phase III clinical trials, and were shown to be beneficial in this population.
Our results suggest that upregulation of putamen dopamine D3 receptor and alterations along the noncanonical GRK6/β-arrestin2/Akt/GSK-3β molecular cascade are associated with the development of tardive dyskinesia in nonhuman primates.
Two vesicular monoamine transporter type 2 (VMAT2) inhibitors for the treatment of TD were approved by the US Food and Drug Administration in 2017: valbenazine and deutetrabenazine.
Tardive dyskinesia (TD) research is at a crossroads because of renewed interest in this syndrome following the successful development and regulatory approval of two novel vesicular monoamine transport 2 (VMAT2) inhibitors.
In particular, a functional genetic polymorphism in SLC18A2, which is a target of recently approved tardive dyskinesia medication valbenazine, was associated with tardive dyskinesia.
Valbenazine is a selective VMAT2 inhibitor that the FDA approved in April 2017 for the specific treatment of tardive dyskinesia (TD), a movement disorder commonly caused by dopamine blocking agents.
Characterization of the VMAT2 inhibitor tetrabenazine, which was identified as a therapeutic agent for TD in older clinical trials, has yielded two distinct pharmacologic strategies to optimize response.
While two novel vesicular monoamine transporter inhibitors, deutetrabenazine and valbenazine, have shown acute efficacy for TD, the majority of patients do not remit, and TD appears to recur once treatment is withdrawn.
Once TD has emerged and is associated with dysfunction or distress, treatment with a VMAT2 inhibitor such as deutetrabenazine or valbenazine is well supported by several controlled clinical trials.
By contrast, recent evidence from Phase III trials of novel vesicular monoamine transporter-2 inhibitors demonstrates they could have a significant effect on TD symptom severity and suggests these agents may have the potential to transform treatment of TD in coming years.
Deutetrabenazine, a reversible inhibitor of vesicular monoamine transporter type 2 (VMAT2), received approval for the treatment of TD in adults based on a clinical trial development programme that included two 12-week parallel group, randomised and placebo-controlled studies.
Valbenazine, a reversible inhibitor of Vesicular Monoamine Transporter Type 2 (VMAT2), received approval for the treatment of TD in adults based on a clinical trial development programme that included three 6-week parallel group, randomised, placebo-controlled studies, including one Phase III trial described in product labeling.
Once TD has emerged and is associated with dysfunction or distress, treatment with a VMAT2 inhibitor such as deutetrabenazine or valbenazine is well supported by several controlled clinical trials.
Analysis of covariance (ANCOVA) with age, sex, duration of disease, chlorpromazine equivalent (CPZEQ) incorporated as covariates showed that limb-truncal, but not orofacial TD, is associated with CYP1A2 (-163C>, rs762551) polymorphism (F = 3.27, P = 0.039).