VMAT2 Inhibitors for Tardive Dyskinesia—Practice Implications

Pathophysiology

The most widely recognized underlying mechanism of TD is D₂ receptor hypersensitivity. ^1,5 In the nigrostriatal dopamine pathway, which is part of the extrapyramidal nervous system, short-term blockade of postsynaptic D₂ receptors may lead to transient EPS movement disorders such as parkinsonism. ^5,6 However, upon chronic blockade, postsynaptic D₂ receptor hypersensitivity occurs due to upregulation of D₂ receptors. ^5,6 This theory best explains acute resolution of TD symptoms upon increasing the dose of DRAs, while abrupt withdrawal may exacerbate or trigger onset of TD. ¹ Theoretically, downregulation of D₂ receptors should occur upon withdrawal of chronic DRA. ¹ However, the hypersensitivity theory is limited in that it does not account for the longevity of TD, which has the potential to persist for months to years upon discontinuation of DRAs. ¹

Of note, 2 other proposed mechanisms include (1) neurotoxicity due to oxidative stress and (2) genetic predisposition. ⁷ For neurotoxicity, DRAs may disrupt electron transfer and indirectly increase turnover of dopamine through receptor blockade, which in turn creates a neurotoxic environment of hydrogen peroxide and free radicals, both of which perpetuate oxidative stress. ⁷ The damage resulting from oxidative stress may be a factor in the chronicity of TD and potential irreversibility. ⁷ For genetic predisposition, genes and enzymes from the dopaminergic pathway (ie, dopamine receptor D4 and catechol-O-methyltransferase) and the CYP450 family (ie, CYP1A2*1C and CYP2D6*4) have been previously described as contributors to TD susceptibility and severity ⁸ ; however, lack of robust data precludes recommendations for genetic testing at this time.

Targeting Vesicular Monoamine Transporter 2

Vesicular monoamine transporter 2 (VMAT2) are expressed on monoaminergic and sympathetic postganglionic neurons in the central nervous system. ⁹ Under normal conditions, VMAT2s function to package monoamines, such as dopamine, into presynaptic vesicles in preparation for release into the synaptic cleft. ¹⁰ Upon VMAT2 inhibition, vesicular uptake of monoamines is blocked which yields a decreased amount available for postsynaptic binding. ¹⁰ In the case of TD owing to the dopamine receptor hypersensitivity theory, there is less dopamine available to bind to the hypersensitive postsynaptic D₂ receptors, theoretically offsetting movement-related side effects of DRAs. ¹⁰

Tetrabenazine (TBZ), proprietary name Xenazine®, is a VMAT2 inhibitor with off-label recommendations as an agent that “might” be effective for TD, ¹¹ though its feasibility is largely limited as discussed herein. The Food and Drug Administration (FDA) recently approved 2 VMAT2 inhibitors, deutetrabenazine (DTBZ), proprietary name Austedo®, ¹² and valbenazine (VBZ), proprietary name Ingrezza®, ¹³ for chorea related to Huntington’s disease (HD) ¹² and TD, ¹³ respectively. Although DTBZ does not carry an FDA-approved indication for TD, ¹² it offers unique pharmacologic modifications, as does VBZ, that may increase the practicality of their use in the course of TD treatment. The objective of this article is to compare available VMAT2 inhibitor structural modifications, pharmacologic profiles, and clinical trials as it pertains to practice implications for the management of TD.

Tetrabenazine

TBZ is a reversible, high-affinity VMAT2 inhibitor with very low oral bioavailability that is then rapidly converted into 2 active metabolites, alpha-dihydrotetrabenazine (DHTBZ) and beta-DHTBZ. ¹⁴ The alpha-DHTBZ metabolite has higher bioavailability and higher plasma concentrations in comparison with TBZ but has a half-life of 4 to 8 hours versus 10 hours seen with TBZ. ^14,15 In turn, TBZ is usually dosed 3 to 4 times daily, starting at 12.5 mg/d with weekly titrations of 12.5 mg/d to a maximum daily dose of 100 mg/d (25 mg is the maximum amount per dose). ¹⁵ The maximum amount per dose is increased to 37.5 mg in extensive or intermediate CYP2D6 metabolizers, and the maximum daily dose is decreased to 50 mg in poor CYP2D6 metabolizers. ¹⁵ Given this, should a patient require a dose exceeding 50 mg/d, genetic testing for CYP2D6 polymorphisms is recommended. ¹⁵ In addition, TBZ is contraindicated in patients with any degree of impaired hepatic function based on a study involving patients with Child-Pugh scores of 5 to 9 where peak plasma concentrations rose up to 190-fold greater than those without hepatic impairment. ¹⁵

Alpha-DHTBZ is a strong inhibitor of VMAT2, but beta-DHTBZ has demonstrated off-target affinity for D₂ receptors in addition to VMAT2 which can be a possible source of increased side effects such as worsening TD or other dystonic reactions. ^{16 –18} In addition, TBZ carries a black box warning for increased suicidality and depression. ¹⁵ This stems from 1 small study, where 10 (19%) of 54 of participants taking TBZ for HD endorsed depression, one participant committed suicide and one participant endorsed suicidal ideation as compared to zero reports in the placebo group. ¹⁹ However, it should be noted that the suicide rate among patients with HD is higher than the general population. ²⁰ Other adverse effects (AEs) that could be exacerbated by concomitant DRAs are the potential development of neuroleptic malignant syndrome and/or QTc prolongation of approximately 8 milliseconds. ¹⁵ Lastly, the most commonly observed side effects are sedation/somnolence (31%), fatigue (22%), insomnia (22%), akathisia (19%), and nausea (13%). ¹⁵

The first 18-week efficacy trial was conducted in 13 participants with bucco-linguo-masticatory oral dyskinesia who were randomly assigned to either haloperidol (n = 7) or TBZ (n = 6). ²¹ TBZ was initiated and maintained at 50 mg twice daily for 14 weeks and then increased to 100 mg twice daily for weeks 15 to 18. ²¹ Blinded psychiatrists counted mouth movements per minute weekly for the first 4 weeks and then biweekly through week 18. ²¹ For the TBZ arm, 2 participants experienced complete resolution at the end of the second week, whereas dyskinetic symptoms for 4 participants remained unchanged. ²¹ The average frequency of mouth movements per minute decreased from 25.7 to 12.8 at the end of the second week and then remained steady at approximately 16.8 movements per minute from weeks 6 to 15. On week 15, after the TBZ dose increase, participants displayed initial transient improvement in symptoms, though symptoms increased again at week 18 evaluation. ²¹ The authors reported TBZ was associated with a statistically significant reduction in oral dyskinesia from baseline to week 18. ²¹ Of note, AEs were not reported, and zero participants dropped out of the TBZ arm. ²¹

Another double-blind trial assessed TBZ treatment in participants with HD (n = 9), TD (n = 12), and various other dystonic disorders (n = 11). ²² All completers underwent 3 phases of the study, (1) pretreatment, (2) active drug, and (3) placebo with 1 clinic visit per phase. ²² During their 3 clinic visits, participants were videotaped and asked to perform the following tasks: sit quietly, walk, drink, perform repetitive tasks (ie, fastening buttons), and read aloud. ²² The investigators reviewed the tapes of the study phases in a random, rearranged order to note severity of movement disorder, though a specific rating scale was not described. ²² Participants were started on TBZ 25 mg twice daily and titrated by 25 mg every 3 days until therapeutic response, AE, or maximum dose of 200 mg/d. ²² Of those in the TD arm, 10 completed the study with total daily doses ranging from 100 to 200 mg/d. ²² Six participants were noted to have moderate to marked improvement, whereas 4 remained unchanged. ²² Of the 32 participants in the study overall, 18 did not have any AEs, and the 2 most common of those who did have AEs were drowsiness (n = 10) and drooling (n = 4). ²²

A case series involving 23 patients prescribed TBZ to treat TD received doses ranging from 37.5 to 150 mg/d, as dose was determined by clinical response. ²³ All patients were rated before and after TBZ treatment, though no specific follow-up time was described. ²³ The Involuntary Movement Scale was utilized which assigns scores of zero = no movement, 1 = minimal, 2 = mild, 3 = moderate, and 4 = severe to areas of face/mouth/tongue, trunk, limbs, and overall appearance. ²³ The scores of all 23 patients improved across all 4 assessment domains, except 2 patients who did not display improvement in the degree of movement of their limbs, as each patient received a score of 1 at both pretreatment and posttreatment evaluations. ²³ Side effects were minimal overall, though drooling (n = 2), and signs of parkinsonism and tremor (n = 1) were reported. ²³

Two long-term, follow-up studies of 18 months ²⁴ and 15 years ²⁵ were conducted assessing TBZ in TD. In the first follow-up study, 217 patients were enrolled in the study with various movement disorders, 44 of which were treated for TD. ²⁴ Participants were hospitalized and were initiated on TBZ at 25 mg/d and were increased by 25 mg/d until a maximum dose of 100 mg/d or emergence of AE occurred. ²⁴ Once a stable dose was achieved, patients were discharged, reevaluated at week 6 postdischarge and then every 3 months thereafter. ²⁴ The primary author was the only evaluator, and he used a scale of 1 to 5 to rate patients where 1 = marked reduction in abnormal movements, 2 = moderate, 3 = fair, 4 = poor or no response, and 5 = worsening of movement disorder. ²⁴ For evaluation, participants performed activities of daily living such as dressing, eating, writing, and maintaining hygiene. ²⁴ In the TD arm, 14% displayed marked reduction (n = 6), 57% moderate reduction (n = 25), 25% fair reduction (n = 11), 2% poor or no response (n = 1), and 2% worsening of movement disorder (n = 1). ²⁴ The mean effect of TBZ treatment in participants with TD was reported to be 2.3, and the 3 most commonly reported AEs in all study participants were parkinsonism (n = 53), drowsiness/fatigue (n = 28), and depression (n = 23). ²⁴

The second follow-up study conducted by the same primary author utilizing the same evaluation method and rating scale previously described ²⁴ included 400 patients with various hyperkinetic movements disorders who were treated with TBZ. Of the total study enrollment, 94 patients were being treated for TD. ²⁵ Compared to the other hyperkinetic disorders, patients with TD displayed the best response to TBZ with 89.2% (n = 83) and 84.9% (n = 79) of patients displaying marked improvement at the initial and final follow-up visits, respectively. ²⁵ The TD group was maintained on an average dose (standard deviation [SD]) of 96.91 (62.01) mg/d. ²⁵ Of the total study population, the most commonly reported AEs were drowsiness/fatigue (n = 146), parkinsonism (n = 114), and depression (n = 60). ²⁵

Another single-blind, randomized study administered TBZ 12.5 mg twice daily, titrated to a maximum of 50 mg 3 times daily to 21 participants with TD. ²⁶ Participants were assessed via the Abnormal Involuntary Movement Scale (AIMS) at baseline and at 3-month follow-up. ²⁶ The AIMS assessments were video recorded and reviewed by a blinded investigator for rating. ²⁶ At the end of approximately 20 weeks, mean (SD) dose of TBZ was 57.9 (22.8) mg/d, and the AIMS score improved from 17.9 (4.4) to 8.2 (5.3), P < .001, and participants subjectively reported statistically significant improvement as well. ²⁶ Sedation was the only subjective complaint (n = 5), and mild parkinsonism was observed in another 5 participants. ²⁶

Most recently, 3 retrospective observational studies were conducted including TBZ-treated patients with TD. ^{27 –29} The first study observed 118 participants prescribed TBZ for various hyperkinetic movement disorders, of which 14.4% (n = 17) were prescribed TBZ for TD. ²⁷ The mean follow-up time was 22 months, and the mean (SD) TBZ dose was 76.2 (38.4) mg/d for the total study population. ²⁷ Patients were evaluated using the Clinical Global Impression of Change, where −3 was marked worsening, −2 moderate worsening, −1 mild worsening, zero no change, +1 was mild improvement, +2 moderate improvement, and +3 marked improvement. ²⁷ In the TD group, scores of −3 and −2 did not occur in any patients, though 1 patient experienced score of −1. ²⁷ A score of zero was given to 4 patients, and scores of +1, +2, and +3 were given to 3, 6, and 1 patient(s) respectively. ²⁷ Of note, there was no data available for 2 patients. ²⁷ Although zero patients in the TD group discontinued TBZ due to lack of benefit or emergence of AEs, 2 discontinued TBZ due to worsening TD. ²⁷ Of the total study population, 16.1% (n = 19) reported AEs of somnolence, weakness, or apathy (n = 7), parkinsonism (n = 6), depression (n = 2), acute akathisia (n = 2), dyspnea (n = 1), and gait disorder (n = 1). ²⁷

As a follow-up to previous studies, ^24,25 another retrospective observational study (n = 448) ²⁸ evaluated TBZ in various hyperkinetic movement disorders utilizing the 1- to 5-point response scale. ^24,25 In the TD group (n = 149), 83.5% and 85.7% received a score of 1 or 2 at initial and last visit signifying marked or moderate reduction in symptoms. ²⁸ Of the total study population, the mean (SD) dose was 60.4 (35.7) mg/d, and the most commonly reported AEs were drowsiness (25%, n = 112), parkinsonism (15.4%, n = 69), and depression and akathisia (7.6%, n = 34 each.) ²⁸

Lastly, a retrospective observational study (n = 111) found that although 87% of participants were found to have clinical improvement while on TBZ at a maximum dose of 37.5 mg/d, 90.4% of these participants remained symptomatic. ²⁹ Of the 13% of participants that did not improve, the TBZ dose was either not increased or was discontinued due to AEs in 78.6% of this group (oromandibular dyskinesia [n = 7], tics [n = 2], vascular chore [n = 1], dystonia [n = 1], and other [n = 1]), while the remaining participants did not experience effective benefit up to a maximum dose of 62.5 mg/d. ²⁹

Despite potential efficacy of TBZ, the associated pharmacokinetic properties may serve as a barrier to successfully treating some patients attributable to (1) frequent dosing due to short half-life, (2) dosing adjustments and potential genetic testing, and (3) side effect profile due to receptor nonselectivity. With this, future VMAT2 inhibitors required pharmacokinetic optimization to address these shortcomings.

Deutetrabenazine

DTBZ is a reversible, VMAT2 inhibitor derivative of TBZ. ³⁰ It was structurally modified to contain deuterium, an atom that extends the half-life of metabolites (ie, alpha-DHTBZ and beta-DHTBZ) to approximately 9 hours and allows for more stable drug concentrations. ³⁰ This enables DTBZ to be administered less frequently (ie, twice daily) and in smaller doses (starting at 6 mg/d and titrated weekly by 6 mg/d until a maximum dose of 48 mg/d) while still providing the same systemic exposure. ^{30 –32} Additionally, its structure minimizes effects of altered metabolism via CYP2D6, allowing for management via dose adjustment without need for genotyping. ³¹ For those who are either CYP2D6 poor metabolizers or receiving concurrent CYP2D6 inhibitors, the maximum daily dose is 36 mg/d with single doses not to exceed 18 mg/d. ³⁰ DTBZ is contraindicated in patients with any degree of hepatic impairment due to increased plasma concentrations observed with TBZ, ^15,30 though it is important to note that the effect of hepatic impairment on the pharmacokinetics of DTBZ and its metabolites has not been studied. ³⁰ Lastly, even with these pharmacokinetic improvements, DTBZ still produces active metabolites alpha-DHTBZ and beta-DHTBZ, meaning receptor nonselectivity still remains at the D₂ receptor leaving the potential for side effects such as acute dystonic reactions. ^16,17

DTBZ was studied in 2 main trials, the Aim to Reduce Movements in Tardive Dyskinesia (ARM-TD) trial and the Addressing Involuntary Movements in Tardive Dyskinesia (AIM-TD) trial. ^33,34 The ARM-TD trial was a 12-week, randomized, double-blind, parallel-group, multicenter phase II/III study across 46 sites in the United States and Europe. ³³ Participants (n = 117) were randomized to either DTBZ (n = 58) or placebo (n = 59) and were started on 12 mg/d with weekly titrations of 6 mg/d until 1 of the following occurred: (1) adequate control of dyskinesia, (2) AE, or (3) maximum dose of 48 mg/d (36 mg/d for those with concurrent strong CYP2D6 inhibitors). ³³ For the remaining 6 weeks, participants were maintained on their respective dose, and AIMS was administered at weeks 2, 4, 6, 9, and 12 and then again on week 13 after 1-week washout period. ³³ All AIMS assessments were video recorded. ³³

Likewise, the AIM-TD trial was a similar 12-week randomized, double-blind, placebo-controlled, multicenter phase III study across 75 sites in the United States and Europe. ³⁴ Participants (n = 298) were randomized to 1 of 4 groups: (1) DTBZ 12 mg/d (n = 67), (2) DTBZ 24 mg/d (n = 65), (3) DTBZ 36 mg/d (n = 65), or (4) placebo (n = 67). ³⁴ During the first 4 weeks, all DTBZ-treated groups were initiated on 12 mg/d and titrated weekly by 6 mg/d until assigned DTBZ dose was achieved. ³⁴ For the remaining 8 weeks of the study, participants were maintained on their respective dose, and clinical assessment was done at weeks 2, 4, 8, and 12 and then again on week 13 after 1-week washout period. ³⁴ All AIMS assessments were video recorded. ³⁴

In both studies, 2 expert movement disorder personnel scored each participant via review of videotapes and 1 AIMS consensus score per participant per visit was reached. ^33,34 For efficacy, the primary end point in both trials was change in AIMS from baseline to week 12. ^33,34

In the ARM-TD trial, reduction from baseline AIMS was significant in the DTBZ group versus placebo group (least-squares [LS] mean [standard error, SE] = −3.0 [0.45] vs −1.6 [0.46], P =.019). ³³ In terms of safety, similar rates of AEs were reported between the 2 groups, though the most commonly reported in the DTBZ-treated group were somnolence, fatigue, and insomnia. ³³ DTBZ was well tolerated with 89.7% of participants completing the study along with 88.1% in the placebo group. ³³ Three serious adverse events (SAEs) occurred in the DTBZ-treated group including community-acquired pneumonia, substance-induced manic episode, and exacerbation of schizophrenia (n = 1 for each AE). ³³ In the placebo group, 5 SAEs occurred of accidental heroin overdose, jaw fracture secondary to falling, jaw infection, pneumonia, and laryngeal hypertrophy (n = 1 for each AE). ³³ The SAEs in both groups were not considered treatment-related. ³³ Also, there were similar reports of psychiatric AEs between DTBZ and placebo groups in terms of anxiety (3.4% vs 6.8%) and depressed mood/depression (1.7% vs 1.7%). ³³ Lastly, zero participants reported suicidal ideation in the DTBZ group while 3 reported suicidal ideation and 1 reported suicidal behavior in the placebo group. ³³

In the AIM-TD trial, reduction from baseline AIMS scores to week 12 were significant for DTBZ 24 mg/d group (LS [SE] = −3.2 [0.45], treatment difference = −1.8 [0.60], 95% confidence interval [CI] = −3.00 to −0.63; P = .003), and DBTZ 36 mg/d group (LS [SE] =-3.3 [0.42], treatment difference = −1.9 [0.58], 95% CI = −3.09 to −0.79; P = .001) versus placebo group (LS [SE] = −1.4 [0.41]). ³⁴ In terms of safety, AEs were similar between groups (19% in DTBZ-treated vs 26% in placebo group), including rates of depression, depressed mood, and suicidal ideation. ³⁴ SAEs occurred in 16 participants total, 4 (5%) from DTBZ 36 mg/d group, 6 (8%) from DTBZ 24 mg/d group, 2 (3%) from DTBZ 12 mg/d group, and 4 (6%) from placebo group, though the specific SAEs were not described. ³⁴ Three participants had incidence of suicidal ideation, 2 from the DTBZ 24 mg/d group and 1 from the DTBZ 36 mg/d group. ³⁴ Two of these participants, 1 in each of the treatment groups, were deemed unrelated to treatment, though the remaining participant in the 24 mg/d group was deemed possibly related. ³⁴ There were 2 deaths, 1 in the DTBZ 24 mg/d group and the DTBZ 36 mg/d group each of sudden cardiac death and cardiorespiratory arrest, respectively. ³⁴ Both of these deaths were deemed unrelated to treatment. ³⁴ Lastly, nervous system disorders (ie, parkinsonism, somnolence) were the most common AEs resulting in dose reduction although they only occurred in 2 participants, both from the DTBZ 36 mg/d group. ³⁴ Overall, dose reduction, suspension, and discontinuation rates were low and similar across all groups. ³⁴

In summary, DTBZ offers clinical advantages over TBZ with less frequent daily dosing and eliminated need for genetic testing, though shortcomings remain related to the need for dosing adjustments and the potential for treatment-emergent adverse effects (TEAEs) such as acute dystonic reactions.

Valbenazine

VBZ is a reversible, selective VMAT2 inhibitor. ³⁵ Like TBZ and DTBZ, it is broken down to active metabolite alpha-DHTBZ ³⁵ ; however, unlike TBZ and DTBZ, it is also broken down into a mono-oxy metabolite called NBI-136110. ¹⁰ NBI-136110 displays affinity for VMAT2 rather than off-target affinity for D₂ receptor, ¹⁰ which theoretically may prohibit emergence of dystonic reactions. In addition, VBZ is administered once daily starting at 40 mg/d titrated to 80 mg/d after 1 week. ³⁶ Dose reductions are required with strong CYP2D6 inhibitors, though they must be individualized based on tolerability. ³⁶ In the presence of strong CYP3A4 inhibitors, the maximum dose of VBZ becomes 40 mg/d, and use is not recommended in the presence of CYP3A4 inducers due to reduced drug exposure. ³⁶ In addition, the recommended dose for patients with moderate to severe hepatic impairment (Child-Pugh score greater than 7) is 40 mg/d. ³⁶ Overall, in comparison with other VMAT2 inhibitors, VBZ offers an even simpler, once-daily dosing regimen in addition to more selectivity for VMAT2 receptor. ³⁶ However, additional drug–drug interactions (ie, CYP3A4 inhibitors) are to be considered, ³⁶ and dose adjustments may still be required.

VBZ was studied in a series of clinical trials, KINECT 1 through KINECT 4, in the treatment of TD. ^{37 –41} KINECT 1, a phase IIb randomized, double-blind, placebo-controlled trial enrolled 109 participants with moderate to severe TD to receive either VBZ 100 mg/d for 2 weeks, followed by VBZ 50 mg/d for 4 weeks (n = 26), VBZ 50 mg/d for 6 weeks (n = 27), or placebo for 6 weeks (n = 54). ³⁷ The primary end point was change in AIMS dyskinesia score from baseline to end of week 6 as assessed via videotape by blinded expert raters. ³⁷ Of note, the results of this trial have only been reported via press releases from the manufacturer Neurocrine Biosciences, Inc. The manufacturer has reported that while the primary end point was not met, VBZ 100 mg/d group achieved significant improvement at week 2 compared to placebo with AIMS reduction of −5.5 versus −2.7 (P = .008), respectively. ³⁷ In addition, 48% versus 23% of participants experienced a greater than 50% improvement on AIMS from baseline at week 2 in VBZ 100 mg/d versus placebo, respectively. ³⁷ The company reported VBZ to be well-tolerated overall, though reported TEAEs arose in 37% and 26% of participants in the placebo and VBZ groups, respectively, with the most common TEAE to be transient somnolence. ³⁷ A detailed description of other TEAEs was not reported. ³⁷

KINECT 2, another phase IIb randomized, double-blind, placebo-controlled trial enrolled 205 participants of which 102 were randomized to receive either placebo (n = 49) or VBZ (n = 51) started at 25 mg/d and titrated by 25 mg/d to a maximum of 75 mg/d, based on tolerability, for 6 weeks. ³⁸ The primary end point was change from baseline AIMS at end of week 6 as scored via videotapes by 2 blinded expert raters. ³⁸ At the end of week 6, a statistically significant reduction from baseline AIMS was observed in the VBZ group versus placebo group (LS [SE] = −2.6 [1.2] vs −0.2 [1.1], 95% CI = −3.7 to −1.1; P = .0005.) ³⁸ In addition, 48.9% versus 18.2% of participants experienced a greater than 50% improvement in AIMS from baseline at week 6 in the VBZ and placebo groups, respectively. ³⁸ Of note, there were zero deaths or serious TEAEs in the VBZ group, though 2 subjects experienced 4 serious TEAEs in the placebo group where 1 subject died of SAE myocardial infarction and the other subject was discontinued from the study. ³⁸ TEAEs had an occurrence rate of 49% for VBZ group and 32.7% for placebo group. ³⁸ The 2 most common TEAEs in the VBZ group were fatigue and headache at 9.8% each, whereas the 2 most common in the placebo group were constipation and urinary tract infection at 6.1% each. ³⁸

KINECT 3, the first phase III study, was a randomized, double-blind, placebo-controlled, multinational, trial administering VBZ 40 mg (n = 70), VBZ 80 mg (n = 79), or placebo (n = 76) to participants daily for 6 weeks. ³⁹ The primary end point was change in AIMS from baseline to week 6 for the VBZ 80 mg/d group, as rated by review of AIMS videotapes by 2 blinded expert raters. ³⁹ Both VBZ doses provided statistically significant reduction in AIMS as compared to placebo (−3.2 for 80 mg/d [P < .001] and −1.9 for 40 mg/d [P = .002] vs −0.1 for placebo). ³⁹ Safety assessment via TEAE monitoring returned most common side effects of somnolence (VBZ groups combined = 5.3%, placebo = 3.9%), akathisia (3.3% and 1.3%), dry mouth (3.3% and 1.3%), and suicidal ideation (2.6% and 5.3%). ³⁹ Of note, suicidal ideation was more common in the placebo group. ³⁹ Seven participants were withdrawn from the study due to serious TEAEs. ³⁹ Two of the TEAEs were experienced in the placebo group of altered mental status due to exacerbation of chronic obstructive pulmonary disease (n = 1) and exacerbation of schizoaffective disorder (n = 1). ³⁹ One was experienced in the VBZ 40 mg/d group of hostility/altered mental status, and 4 were experienced in the VBZ 80 mg/d group of worsening of schizoaffective disorder, suicide attempt, suicidal ideation, and reactivation of viral hepatitis (n = 1 for each). ³⁹ These were deemed unrelated or not likely related to study medication, except reactivation of viral hepatitis in VBZ 80 mg/d group was deemed possibly related. ³⁹ There was 1 sudden death in the study from a VBZ 80 mg/d-treated participant, possibly from cardiovascular disease, and was deemed unlikely to be related to study drug. ³⁹

Participants who completed the 6-week KINECT 3 were able to enroll in a 42-week extension study to either continue their KINECT 3 study dose or be randomized to either 40 or 80 mg/d VBZ if they were originally in the placebo group. ⁴⁰ At the end of the 48-week treatment period, 52.4% and 28.3% of participants in VBZ 80 and 40 mg/d, respectively, were considered responders; however, in posttreatment follow-up after a 4-week washout period, average AIMS scores began reverting toward baseline levels. ⁴⁰

KINECT 4, an open-label 48-week study of safety and tolerability of once daily VBZ has been completed and results are forthcoming and expected in late 2017. ⁴¹

Implications for Practice

In 2013, prior to the development of DTBZ and VBZ, the American Academy of Neurology (AAN) released evidence-based practice guidelines for the management of TD. ⁵ Although AAN reviewed and critiqued many agents across various pharmacologic classes, much of these medications either lacked sufficient evidence to support or refute a recommendation or displayed negative data to which AAN advised against its use. ⁵ Per AAN, TBZ was considered an agent that “might” be considered for treatment, ⁵ though its usefulness in practice may be limited by its need for frequent daily dosing and potentially intolerable side effect profile due to receptor nonselectivity and fluctuations in plasma concentrations.

When comparing DTBZ and VBZ to TBZ, the newer VMAT2 inhibitors are likely to be preferred given predicted similar pharmacologic activity with decreased incidence of complex dosing regimens, side effects, and variable concentrations. DTBZ, by addition of deuterium, addressed the complex dosing regimen with an increased half-life and therefore, less frequent dosing. It also allows for more stable plasma levels in an effort to decrease emergence of concentration-dependent side effects. However, it should be noted that TBZ has been available in the United States much longer than DTBZ and VBZ and therefore, more practice-based information regarding side effect profile and long-term effects is available. DTBZ and VBZ are still under postmarket investigation with the potential for new side effects or clinical caveats to arise. However, it is clear that DTBZ and VBZ offer some advantages over TBZ, though the lack of head-to-head trials among these agents largely restricts cross-comparison.

When comparing VBZ to DTBZ, even greater improvements in tolerability and dosing simplification were seen via once daily dosing and lack of affinity for the D₂ receptor. It is predicted that VBZ will be more tolerable than DTBZ, ³⁵ just as DTBZ has been indirectly deemed more tolerable than TBZ. ³² However, advancements in the structural modifications come at a price, as VBZ displays interactions with CYP3A4 inducers and inhibitors, in addition to the CYP2D6 inhibitor interaction also seen with TBZ and DTBZ. On the other hand, DTBZ is contraindicated in patients with any degree of hepatic impairment, though VBZ may still be administered at the usual recommended dose for mild hepatic impairment (Child-Pugh score 5-6) or at a reduced dose for those with moderate to severe hepatic impairment (Child-Pugh score greater than 7). In any case, these restrictions may limit usefulness in some patient populations for both medications.

Clinically, reductions in AIMS from baseline to end of treatment period were similar among DTBZ and VBZ, particularly with higher doses, although it is VBZ only that carries FDA approval for TD. FDA approval is important when considering treatment options, as some insurance companies will not reimburse for medications that lack FDA approval if agents with FDA approval are available and have not been trialed. Furthermore, tolerability and emergence of AEs were comparable among the 2 agents.

In terms of cost, neither DTBZ nor VBZ are generic, though they remain cost competitive with generic TBZ. The average wholesale price (AWP) for one 40 mg capsule of VBZ is US$211.00, translating to a cost of $422.00 for a 1-day supply of maximum dose 80 mg/d. ⁴² For DTBZ, the AWP for one 12 mg tablet costs $98.64, translating to a cost of $394.56 for a 1-day supply of maximum dose 48 mg/d, making VBZ and DTBZ similarly priced. ⁴³ As a reference, the lowest AWP for 1 generic 25 mg tablet of TBZ is $84.43, translating to a cost of $337.72 for a 1-day supply of maximum dose 100 mg/d. ⁴⁴ Of note, cost comparisons such as these do not account for insurance coverage, which may result in reduced costs incurred by patients. ⁴⁵ Lastly, pill burden is reduced with less frequent daily dosing and in turn, adherence may improve with the availability of a once-daily medication. ⁴⁶ Taking into account the advantages and disadvantages of each medication, these authors align with recent recommendations ^47,48 that VBZ ultimately appears to be the more feasible VMAT2 inhibitor for TD as it is FDA-approved, cost-competitive, dosed once daily, and is selective for VMAT2.