Clinical implications
TD remains a substantial public health concern due to the increasing use of antipsychotics for mood and other disorders beyond the initial indications for schizophrenia.1 Although exposure to dopamine D2antagonism results in postsynaptic receptor upregulation and supersensitivity that underlies the development of dyskinesia, this process is often rapidly reversible in animal models.1 The persistence of TD symptoms in up to 80% of patients after dopamine receptor blocking agents (DRBAs) are stopped has led to hypotheses that the underlying pathophysiology of TD is also a problem with neuroplasticity. Aside from DRBA exposure, environmental factors (eg, oxidative stress) and genetic predisposition might contribute to TD risk.1
Before 2017, only 1 medication (branched-chain amino acids) had been FDA-approved for treating TD in the United States, and only a few existing medications (clonazepam, amantadine, and ginkgo biloba extract [EGb-761]) had positive results from controlled trials, most with small effect sizes.8 Moreover, there was only 1 controlled trial each for clonazepam and EGb-761.1 A branched-chain amino acid preparation received FDA approval for managing TD in male patients, but is no longer commercially available, except from compounding pharmacies.9
Tetrabenazine was developed in the mid-1950s to avoid orthostasis and sedation associated with reserpine.10 Both reserpine and tetrabenazine proved effective for TD,11 but tetrabenazine lacked reserpine’s peripheral adverse effects. However, the kinetics of tetrabenazine necessitated multiple daily doses, and CYP2D6 genotyping was required for doses >50 mg/d.2
Receptor blocking. The mechanism that distinguishes the clinical profiles of reserpine and tetrabenazine relates to their differential properties at VMAT.12 VMAT exists in 2 forms (VMAT1 and VMAT2) that vary in distribution, with VMAT1 expressed mainly in the peripheral nervous system and VMAT2 expressed mainly in monoaminergic cells of the CNS.13 Tetrabenazine is a specific and reversible VMAT2 inhibitor, whereas reserpine is an irreversible and nonselective antagonist of VMAT1 and VMAT2. It is reserpine’s VMAT1 inhibition that results in peripheral adverse effects such as orthostasis. Tetrabenazine is rapidly and extensively converted into 2 isomers, alpha-dihydrotetrabenazine (α-DHTBZ) and beta-dihydrotetrabenazine (β-DHTBZ), both of which are metabolized by CYP2D6, with a role for CYP3A4 in α-DHTBZ metabolism.1 These DHTBZ metabolites have a short half-life when generated from oral tetrabenazine, a feature that necessitates multiple daily dosing; moreover, the existence of 2D6 polymorphisms led to FDA-mandated CYP2D6 genotyping for tetrabenazine doses >50 mg/d when it was approved for Huntington’s chorea. The concern is that 2D6 poor metabolizers will have excessive exposure to the VMAT2 effects of DHTBZ, resulting in sedation, akathisia, parkinsonism, and mood symptoms.2
How deuterium impacts medication kinetics. Deuterium is a naturally occurring, stable, nontoxic isotope of hydrogen. Humans have 5 g of deuterium in their body at any time, mostly in the form of heavy water (D2O).14 When deuterium is used to replace selected hydrogen atoms, the resulting molecule will have similar configuration and receptor-binding properties but markedly different kinetics. Because the carbon–deuterium covalent bond requires 8 times more energy to break than a carbon–hydrogen bond, the half-life is prolonged.15 Utilizing this knowledge, a deuterated form of tetrabenazine, deutetrabenazine, was synthesized with such a purpose in mind. While the active metabolites of deutetrabenazine retain the VMAT2 affinity of non-deuterated tetrabenazine, the substitution of deuterium for hydrogen at specific positions slows the breakdown of metabolites, resulting in sustained duration of action, greater active drug exposure, and less impact of 2D6 genotype on drug exposure, thus eliminating the need for genotyping, unless one wants to exceed 36 mg/d.
Deutetrabenazine was first studied in Huntington’s chorea in a 13-week, double-blind, placebo-controlled, parallel-group study (N = 90).4 The maximum daily deutetrabenazine dose was 48 mg, but reduced to 36 mg in those taking strong CYP2D6 inhibitors (bupropion, fluoxetine, or paroxetine). Blinded 2D6 genotyping was performed, but there was no dose modification required based on 2D6 genotype. There was a 36.4% reduction in total maximal chorea score for deutetrabenazine compared with 14.4% for placebo (P < .001).4 Importantly, adverse effects were comparable between both groups, with 1 drop-out in the deutetrabenazine arm vs 2 in the placebo arm. The only adverse event occurring in ≥5% of deutetrabenazine participants and at a rate ≥2 times that of placebo was somnolence: 11.1% for deutetrabenazine vs 4.4% for placebo.4 The mean deutetrabenazine daily dose at the end of the treatment period was 39.7 ± 9.3 mg, and for those with impaired CYP2D6 function (poor metabolizers or those taking strong CYP2D6 inhibiting medications), the mean daily dose was 34.8 mg ± 3.8 mg.4
Use in tardive dyskinesia. The recommended starting dosage for TD treatment is 6 mg, twice daily with food. The dose may be increased at weekly intervals in increments of 6 mg/d to a maximum recommended daily dosage of 48 mg.5 The maximum daily dose is 36 mg (18 mg, twice daily) in patients receiving strong CYP2D6 inhibitors or who are 2D6 poor metabolizers.5
Deutetrabenazine has not been studied in those with moderate or severe hepatic impairment, and its use is contraindicated in these patients.5 No clinical studies have been conducted to assess the effect of renal impairment on the pharmacokinetics of deutetrabenazine.5
Pharmacologic profile, adverse reactions
When the data from the two 12-week, phase 3 placebo-controlled studies were pooled, the most common adverse reactions occurring in >3% of deutetrabenazine patients and greater than placebo were nasopharyngeal symptoms (4% vs 2% placebo) and insomnia (4% vs 1% placebo).5 Importantly, in neither TD study were there clinically significant changes in rating scales for depression, suicidal ideation and behavior, or parkinsonism. There also were no clinically significant changes in measures of schizophrenia symptoms. The mean QT prolongation for a single 24 mg dose of deutetrabenazine in healthy volunteers was 4.5 milliseconds, with the upper bound of the double-sided 90% confidence interval reaching 6.5 milliseconds.5 For tetrabenazine, single 50 mg doses administered to volunteers resulted in mean QT prolongation of 8 milliseconds.5 In patients requiring deutetrabenazine doses >24 mg/d who are taking other medications known to prolong QTc, assess the QTc interval before and after increasing the dose of deutetrabenazine or other medications that are known to prolong QTc.5