Epidemiology
Similar to DIP, published TD prevalence and incidence rates may be falsely low [
43]. In contrast to DIP, this is likely not due to confusion with an idiopathic disorder as much as to a decreased ability of providers to recognize the insidious development of TD [
44]. However, it does appear that TD prevalence and incidence estimates vary with past antipsychotic exposure, antipsychotic class, and age. For example, a large meta-analysis conducted by Carbon et al. found that, in middle-aged patients, most of whom had a schizophrenia-spectrum disorder, the mean prevalence of TD among atypical antipsychotic users was approximately 21%, compared to 30% among current typical antipsychotic users [
45]. However, more long-term studies that exclude patients with past typical antipsychotic use will be necessary to develop a clearer picture of the impact of atypical antipsychotics on TD risk [
43]. On a cautionary note, in a real-world prospective study, the adjusted TD incidence rate-ratio for subjects treated with atypical antipsychotics alone versus typical antipsychotics alone was 0.68 [
46]. This suggests a small advantage for the newer agents, but the 95% confidence interval of 0.29–1.64 implies that there may be no difference [
46]. Alarmingly, the severity of the TD was only slightly lower among incident cases of TD appearing after recent atypical antipsychotic exposure versus recent typical antipsychotic exposure.
The rates of TD increase with duration of therapy, as in younger adults taking typical antipsychotics, reported rates of TD were approximately 4–5% annually, but this effect is magnified by age [
47]. For example, a longitudinal study of TD in elderly patients noted that 31% (95% CI 20–42) of patients developed TD after 43 weeks [
48]. Prevalence rates become more complex when looking at symptom persistence in individuals diagnosed with TD. In patients taking typical antipsychotics, although about 50% appear to have TD symptoms that stagnate, 10–30% will experience remission or improvement of symptoms, and another 10–30% may have a worsening of symptoms [
49].
Management
The APA recommends monitoring patients with schizophrenia for the development of TD every 3–12 months, depending on the patient’s risk factors and the type of antipsychotic prescribed [
18]. Standards include every 6 months for patients on a typical antipsychotic to every 12 months for patients on an atypical antipsychotic, and to monitor twice as frequently for elderly patients and those with early, involuntary, movement patterns after starting an antipsychotic [
18]. These guidelines are likely reasonable for most patients being treated with antipsychotics, regardless of diagnosis.
Once TD is diagnosed and treatment is initiated, a baseline assessment should be obtained, and the AIMS examination is recommended for this purpose [
54]. Advantages of using the AIMS include its ubiquity both in the clinic and in drug development, and that it can facilitate communication among providers. Follow-up assessments to assess the effectiveness of the intervention(s) should be carried out on a regular basis.
One of the first steps in the management of TD should be to gradually discontinue any anticholinergic medications, as they may worsen current symptoms [
7]. In fact, symptoms have been noted to improve in up to 60% of people with TD after discontinuing an anticholinergic [
49,
59]. Unlike DIP, discontinuing an antipsychotic or switching from a typical to an atypical antipsychotic does not produce clear evidence of benefit in patients requiring antipsychotic use [
60]. However, switching antipsychotics, including a switch to clozapine, is generally supported by older treatment algorithms [
61]. A recent review updating the American Academy of Neurology (AAN) TD treatment guidelines ranks treatment options based on available evidence from A to C, where A corresponds to established efficacy, B corresponds to probable efficacy, and C corresponds to potential efficacy [
60]. Level A evidence for efficacy exists for the two VMAT2 inhibitors, valbenazine and deutetrabenazine, both recently approved for the treatment of TD by the United States Food and Drug Administration (FDA), with a hypothesized mechanism of action related to dopamine D
2 receptor hypersensitivity in the presence of chronic dopamine D
2 receptor blockade (Fig.
2).
Valbenazine was the first medication to be approved for TD in the United States, and improves upon tetrabenazine by having a more tolerable side effect profile, potentially through less off-site binding to dopaminergic, serotonergic, adrenergic, histaminergic, and muscarinic receptors, in addition to a more convenient once-daily dosing regimen [
62]. In a Phase III, double-blind, randomized, 6-week, placebo-controlled study of 234 participants randomized 1:1:1 to placebo or valbenazine 40 or 80 mg/day, daily doses of 80 mg were shown to reduce AIMS total dyskinesia scores by − 3.2 points (
P < 0.001 when compared to the placebo change score of − 0.1 points) and by − 1.9 points in the 40 mg daily group (
P = 0.002 when compared to placebo) after 6 weeks of therapy [
63]. The most common side effects in the valbenazine group were somnolence (5%), akathisia (3%), and dry mouth (3%), and discontinuation rates due to adverse events were 4% in the valbenazine group versus 3% in the placebo group [
63]. A 1-year extension of this study, which included 198 participants, demonstrated continued efficacy and tolerability, with the most common side effects being headache (7%) and urinary retention (7%), with 16% discontinuing treatment due to an adverse drug event [
64].
Although the target dose for valbenazine is 80 mg/day (achieved after 1 week at 40 mg/day), 40 mg daily should not be exceeded in those with moderate to severe hepatic impairment, or with concomitant use of strong CYP3A4 inhibitors [
62]. This is because valbenazine is primarily metabolized by CYP3A4 to inactive metabolites, although CYP2D6 also plays a role in its metabolism [
62]. In the case of strong CYP2D6 inhibitors, or known CYP2D6 poor metabolizers, it is recommended to consider reducing the dose based on tolerability [
62]. Valbenazine does not appear to impact the common CYP isoenzymes itself, but does inhibit P-glycoprotein, so digoxin should be monitored carefully in patients requiring both medications [
62].
Valbenazine may prolong the electrocardiographic QT interval, but the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing; nonetheless, valbenazine should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. For patients at increased risk of a prolonged QT interval, it is suggested that the QT interval be assessed before increasing the dosage (i.e., from 40 to 80 mg/day) [
62].
Deutetrabenazine was the second VMAT2 inhibitor approved by the FDA for the treatment of TD. Deutetrabenazine is a deuterated formulation of tetrabenazine; deuterium atoms are substituted for hydrogen atoms at key locations in the molecule, altering its pharmacokinetics because deuterium–carbon chemical bonds are many-fold stronger than hydrogen–carbon bonds. Deuterium is naturally occurring “heavy hydrogen” and is not radioactive. Compared to tetrabenazine, metabolism is slowed, reducing the number of doses required per day, decreasing plasma level variability, and improving tolerability [
30]. Recommended dosing for deutetrabenazine is twice daily with food, starting at 6 mg twice daily and increasing by 6 mg weekly up to a maximum dose of 24 mg twice daily, based on tolerability and reduction of TD [
30]. In a Phase II, 12-week, clinical trial (
n = 117) which allowed titration to optimal efficacy and tolerability, the mean dose achieved was 38.8 mg/day [
65]. A Phase III, double-blind, 12-week, placebo-controlled, randomized trial was conducted to compare deutetrabenazine at doses of 12, 24, and 36 mg/day to placebo in 298 patients [
66]. The randomization scheme was 1:1:1:1 and the deutetrabenazine dose was increased over 4 weeks. The primary end-point measure was change in AIMS scores from baseline to week 12. At week 12, the treatment difference from baseline (SE) was − 1.4 in the placebo group and − 2.1 (
P = 0.217 when compared with placebo), − 3.2 (
P = 0.003) and − 3.3 (
P = 0.001) for the 12-, 24-, and 36-mg/day treatment groups, respectively [
66]. The most common side effects in the deutetrabenazine groups were headache (5%), anxiety (4%), and diarrhea (4%), and discontinuation due to side effects occurred in 4% of the treatment group and 3% of the placebo group [
66]. Deutetrabenazine metabolism involves CYP2D6; in the presence of CYP2D6 inhibitors or in patients who are known poor CYP2D6 metabolizers, the total daily dosage of deutetrabenazine should not exceed 36 mg [
30]. Deutetrabenazine may prolong the QT interval and use should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. For patients at increased risk of a prolonged QT interval, it is suggested that the QT interval be assessed before and after increasing the total dose above 12 mg BID [
30].
Unlike valbenazine, deutetrabenazine is also approved for the treatment of Huntington’s disease, and contains language in its product label that is specific to tolerability concerns for that population and differs from that for TD (for example, there is a boxed warning for depression and suicidality that has been observed in patients with Huntington’s disease). Other differences between valbenazine and deutetrabenazine are summarized in Table
2.
Table 2
A comparison of the key characteristics and recommended dosing considerations for valbenazine and deutetrabenazine use in the management of TD.
Brand name | Ingrezza | Austedo |
Available dose formulation | Capsules: 40 and 80 mg | Tablets: 6, 9, and 12 mg |
Other indications | None | Chorea associated with Huntington’s disease |
Active metabolites | [+]-α-HTBZ | Deuterated α-HTBZ and β-HTBZ |
Half-life | Valbenazine and [+]-α-HTBZ: 15–22 h | Total (α + β)-HTBZ from deutetrabenazine: 9–10 h |
Contraindications relevant to TD | None | Hepatic impairment, use of reserpine, MAOIs, tetrabenazine or valbenazine |
Warnings and precaution contained in Highlights of Prescribing Information | Somnolence; QT interval prolongation | QT interval prolongation; neuroleptic malignant syndrome; akathisia, agitation, restlessness, and parkinsonism (latter not applicable to TD); sedation/somnolence |
Dosing frequency | Once daily | Twice daily |
Recommended dosing | Take with or without food; start at 40 mg daily, increase to 80 mg daily after 1 week | Take with food; start at 12 mg/day, increase by 6 mg/day at weekly intervals up to 48 mg/day, based on tolerability and response |
CYP2D6 poor metabolizers | Base dose on tolerability | Maximum recommended dose is 36 mg/day |
Hepatic impairment | Moderate-to-severe hepatic impairment: maximum recommended dose is 40 mg/day | Contraindicated |
Renal impairment | Avoid in severe renal impairment; no dosing changes are recommended for mild-to-moderate impairment | Package insert does not provide any recommendations (cites a lack of studies in this population), but the metabolites are excreted renally |
Drug-drug interactions | Valbenazine increases digoxin levels; consider valbenazine dose reduction with strong CYP2D6 inhibitors; with strong CYP3A4 inhibitors the maximum recommended dose is 40 mg daily; use is not recommended with MAOIs or CYP3A4 inducers | Additive sedation may occur with alcohol and other CNS depressants; with strong CYP2D6 inhibitors, the recommended maximum dose is 36 mg/day |
QT prolongation recommendation | If the patient is at increased risk for QT prolongation, assess QT interval before increasing the dose | If the patient is at increased risk for QT prolongation, assess QT interval before and after increasing the dose above 24 mg/day |
Additional medication interventions for TD are not FDA-approved and carry lower levels of evidence compared to valbenazine and deutetrabenazine in the AAN guidelines. Level B AAN recommendations for the treatment of TD include
Ginkgo biloba and clonazepam. Level C options that might be considered include amantadine, tetrabenazine, and pallidal deep brain stimulation [
60]. Amantadine is unique among medications used to treat DIP and TD, in the respect that it has evidence supporting its use for both indications. However, the therapeutic effect for TD is modest. When compared to placebo, amantadine has been shown to decrease AIMS scores by approximately 15–22% in small, relatively short-term, placebo-controlled, crossover studies [
67,
68]. Drowsiness, fatigue, insomnia, constipation, and dizziness occurred more frequently with amantadine than placebo in these studies [
67,
68]. Tetrabenazine is used off-label for the treatment of TD in the United States; however, in other jurisdictions, such as the UK, Canada, New Zealand, Australia, Germany, Italy, Israel, France, and Portugal, it is approved for this purpose [
69]. Two small, clinical trials were cited in the AAN recommendation supporting the use of tetrabenazine for the treatment of TD symptoms, as supported by significant reductions in AIMS scores [
70,
71]. Although tolerability was not a major issue in these studies, clinical experience with side effects of tetrabenazine that occur in more than 5% of patients in persons with Huntington’s disease (such as sedation, insomnia, depression, akathisia, parkinsonism, instability, irritability) [
72], and the requirement to dose the medication up to 3 times per day, and assessing for CYP 2D6 poor/extensive metabolizers if doses greater than 50 mg/day need to be used, led to the development of the two tetrabenazine alternatives, valbenazine and deutetrabenazine, discussed previously.