Advances in Tardive Dyskinesia:

PUBLISHED AS A SUPPLEMENT TO

  

A Review of Recent Literature

Brian J. Miller, MD, PhD, MPH

Dr Miller is Associate Professor, Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA, and the Schizophrenia & Psychosis Section Editor for Psychiatric Times. The author reports that he receives research funding from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

In the past three years, the US Food and Drug Administration (FDA) has approved two medications for tardive dyskinesia (TD): val- benazine and deutetrabenazine. These approvals have contributed to a resurgent interest in the recognition, management, and treatment

of this important phenomenon. Although the precise causes of TD are still unclear, Schonecker1 rst reported cases of antipsychotic-associated involuntary and persistent abnormal (perioral) movements in 1957. Faur- bye and colleagues2 introduced the term “tardive dyskinesia” in 1964.

This supplement provides a brief review of primarily recent literature on TD, including signs and symptoms, risk factors and epidemiology, potential mechanisms, and screening and treatment. Each section pro- vides an overview followed by key recent or seminal articles, including concise summaries of selected studies.

Signs and symptoms

Although DSM-5 de nes TD as following at least a few months of anti- psychotic exposure, symptoms of TD may emerge more rapidly in some patients, especially the elderly. Speci cally, DSM-5 de nes TD as

For research purposes, the Schooler-Kane criteria de ne TD as:3
• At least 3 months of cumulative antipsychotic treatment;
• Mild dyskinesias in two or more body areas or moderate

dyskinesias in one body area;

• Persistence of movements for at least 3 months; and

• The absence of other conditions causing involuntary dyskinesias.
The functional disability associated with TD can range from mild to moderate to severe. Potential functional domains associated with TD

include physical (eg, medical complications such as aphasia, aspiration, respiratory distress, falls), psychiatric (eg, worsening of psychopatholo- gy such as increased depression or anxiety due to abnormal movements), social (eg, social isolation due to embarrassment of going out in public by the patient, family, and/or caregivers), and occupational (eg, move- ments interfering with job functioning).

Risk factors and epidemiology

Spontaneous dyskinesias are abnormal involuntary movements in an- tipsychotic-naïve patients that are indistinguishable from TD. Thus, spontaneous dyskinesias are an important consideration in the dif- ferential diagnosis of TD. A review of studies of antipsychotic-naïve patients with schizophrenia from the pre-antipsychotic era or developing countries found that the prevalence of spontaneous dyskinesias ranges from 4% to 40% and increases with age.4

TD remains highly prevalent in patients with schizophrenia treated with antipsychotics. A review of 56 studies from 1959 through 1979 found a mean 20% prevalence of TD.5 Similarly, in their meta-analysis of 41 studies (N = 11,493 patients), Carbon and colleagues6 found a mean 25% prevalence of TD. Rates of TD were lower with second-generation anti- psychotics than with rst-generation antipsychotics (21% versus 30%).

Evidence from both prevalence and incidence studies shows that TD risk may be lower (but not negligible) in patients treated with second-generation antipsychotics versus rst-generation antipsychot- ics.6–8 For example, a recent study in a large community-dwelling sam- ple of patients with schizophrenia from France (N = 674), of whom over 90% were taking second-generation antipsychotics, found an overall 8.3% prevalence of TD. The cumulative duration of an- tipsychotic exposure, however, is an important consideration in these estimates.9

Meta-analyses have identi ed several risk genes for TD with modest effect sizes, including COMT (catechol-O-methyltransferase), DRD2

Involuntary athetoid or choreiform movements (lasting at least a few weeks) generally of the tongue, lower face and jaw, and extremities (but sometimes involving the pharyngeal, diaphrag-matic, or trunk muscles), developing in association with the use of a neuroleptic (antipsychotic) medication for at least a few months.

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(dopamine receptor D2), CYP1A2 and CYP2D6 (cytochrome P450 1A2 and 2D6), and MnSOD (manganese superoxide dismutase).10,11 Other potential candidate genes associated with TD include DRD3 (dopamine receptor D3), HTR2A and HTR2C (serotonin 2A and 2C re- ceptors), and SLC18A2 (vesicular monoamine transporter 2 [VMAT2]).12 A recent meta-analysis found that the G allele of the Perlecan (HSPG2 [heparan sulfate proteoglycan 2]) rs2445142 polymorphism was associ- ated with risk of TD.13

Nongenetic risk factors for incident TD have also been identi ed in qualitative reviews and meta-analysis. These factors may be classi- ed as nonmodi able or modi able, as well as being patient, illness, or treatment related. Nonmodi able risk factors for TD include older age, female sex, race (white and African descent), illness duration, in- tellectual disability, and negative symptoms.14,15 Modi able risk factors include diabetes, smoking, substance use, cumulative lifetime exposure to antipsychotics, treatment with rst-generation antipsychotics, and early extrapyramidal symptoms.

Interactions between genetic and nongenetic risk factors for TD are not well characterized and warrant further investigation. Evidence also shows that patients with TD have greater health care resource utiliza- tion and costs, medical comorbidity (evidenced by a higher Charlson Comorbidity Index score and medical hospitalizations), and increased mortality.16-18 An interesting recent case report also described a patient with new-onset abnormal movements associated with aspartame con- sumption following discontinuation (and later reinstitution) of treatment with a second-generation antipsychotic.19 Risk factors for TD are sum- marized in Table 1.

chronic exposure to increased D2 receptor blockade results in an actual increase in the postsynaptic number of D2 receptors. The “dopamine D2 receptor hypersensitivity” theory hypothesizes that the D2 receptors themselves become hypersensitive to their response to dopamine and not related to upregulation. It is likely that both phenomena are involved to differing degrees (D2 receptor hypersensitivity and upregulation). Find- ings broadly consistent with these hypotheses include data from rodent VCM models, associations between genes involved in the dopaminergic system (eg, COMT, DRD2, VMAT2) and TD, and the ef cacy of VMAT2 inhibitors in patients with TD.

By contrast, the “oxidative stress” hypothesis posits that antipsychotic treatment is associated with increased production of reactive oxygen species and/or free radicals that overwhelm the endogenous antioxidant defense system in the metabolically active, dopamine-rich striatum, which contributes to neurotoxicity and subsequent cell death. Findings consistent with this theory include an association between the MnSOD gene (antioxidant enzyme) and TD, and evidence (albeit modest) for ef cacy of agents with antioxidant properties, including Ginkgo biloba and vitamin B6.

Several recent animal model studies have investigated novel potential prophylactic agents with antioxidant properties against the development of TD. A study of uphenazine-induced VCMs in rats found that cotreat- ment with resveratrol, a phytoalexin found in grapes with antioxidant and neuroprotective properties, reduced orofacial dyskinesias and that monoamine oxidase B (MAO-B) activity in the striatum was negatively correlated with the number of VCMs.22

Two studies by the same research group found that treatment with L-theanine, a potent antioxidant found in green tea, protected against haloperidol- and reserpine-induced orofacial dyskinesias in rats, with evidence implicating the nitric oxide pathway in the induction of these movements.23,24 Another study found that haloperidol-induced VCMs were not reduced with low-dose lipoic acid and the movements were increased with high-dose lipoic acid.25

Screening and treatment

As previously described, spontaneous dyskinesias are an important consideration in the evaluation of TD. Withdrawal-emergent dyskine- sias are another important consideration in the differential diagnosis of TD. Antipsychotic withdrawal-emergent dyskinesias are TD-like movements that may also appear after changes in dose or discontin- uation of antipsychotics. Because this phenomenon is usually time limited (< 4–8 weeks), dyskinesia persisting for a longer duration sug-

“For patients at increased risk for TD, assessments should be done every 3 months ( rst-generation antipsychotics) or every 6 months (second- generation antipsychotics).”

gests probable TD.26 Although both TD and spontaneous dyskinesias are more common in patients with schizophrenia, they are also found in the general population without psychosis. TD may occur in the gen- eral population for patients exposed to dopamine-2-receptor blocking agents for medical or nonpsychotic conditions (eg, metoclopramide for gastroesophageal re ux disease, diabetic gastroparesis, nausea and vom- iting, augmentation of nonpsychotic major depressive disorder, and other off-label psychiatric uses).27

Two of the most commonly used instruments for the assessment of TD in both clinical practice and research are the Abnormal Involuntary Move-

Table 1: Risk factors for tardive dyskinesia

• Genetics

• Diabetes

• Increasing age

• Smoking

• Females

• Substance use

• Race (African descent >
Caucasian > Asian)

• Cumulative antipsychotic exposure

• Illness duration

• Treatment with rst- generation antipsychotics

• Intellectual disability

• Early extrapyramidal symptoms

• Negative symptoms

Mechanisms of action

The causes of TD remain unknown, but they are likely to be complex and multifactorial. As detailed previously, evidence exists for a poly- genic contribution to TD risk, which may interact with other nongenetic factors to moderate risk. Several animal models have been developed to increase our understanding of potential mechanisms contributing to TD. One such model is the use of long-term antipsychotic treat- ment in nonhuman primates. Another key model is antipsychotic- induced vacuous chewing movements (VCM) in rodents.

Leading hypotheses for the etiopathophysiology of TD involve dopamine receptors and oxidative stress; however, there is con ict- ing evidence regarding each theory.20,21 Other neurotransmitter sys- tems that may be implicated in the pathophysiology of TD include gamma-aminobutyric acid (GABA), glutamate, and opioids.

Prevailing theories of TD pathogenesis involve dopamine-2-receptors. The “dopamine-2-receptor upregulation” hypothesis theorizes that the

 

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Table 2: Adjunctive treatment options for tardive dyskinesia

Agent

MOA

Dose

Comments

Valbenazine

VMAT2 inhibitor

40–80 mg/d

FDA approved for TD

Deutetrabenazine

VMAT2 inhibitor

6–48 mg/d

FDA approved for TD and chorea associated with Huntington disease

Tetrabenazine

VMAT2 inhibitor

25–100 mg/d

FDA approved for chorea associated with Huntington disease

Clozapine

SGA

25–900 mg/d

Switching, when indicated, may reduce TD

Ginkgo biloba

Antioxidant

240 mg/d

3 RCTs

Melatonin

Antioxidant

2–20 mg/d

4 RCTs

Vitamin E

Antioxidant

400–1600 IU/d

May help with deterioration of TD symptoms

MOA, mechanism of action; SGA, second-generation antipsychotic; RCTs, randomized controlled trials; TD, tardive dyskinesia; VMAT2, vesicular monoamine transporter 2.

ment Scale (AIMS) and the Extrapyramidal Symptom Rating Scale (ESRS).28,29 The AIMS is an observer-rated, 12-item scale that takes ap- proximately 5 to 10 minutes to administer. The ESRS was developed to assess TD and other drug-induced movement disorders.

The American Psychiatric Association practice guidelines for the treat- ment of schizophrenia recommend the clinical assessment of abnormal involuntary movements at baseline and every 6 months in patients taking rst-generation antipsychotics and every 12 months in patients taking second-generation antipsychotics.30 For patients at increased risk for TD, assessments should be done every 3 months ( rst-generation antipsychotics) or every 6 months (second-generation antipsychotics).

Early screening for and recognition of TD based on risk factors and reg- ular AIMS exams is paramount, because this leads to earlier intervention and potentially better outcomes. A reasonable rst step in the treatment of new-onset TD, whenever possible (based on a discussion of risks and bene ts with the patient), is to discontinue (or lower the dose of) the pre- sumed causative antipsychotic. A slow taper of the offending agent may also prevent antipsychotic withdrawal-emergent dyskinesias. Given that most patients with schizophrenia require chronic antipsychotic treatment, switching to a different agent with lower risk of TD is recommended.

“Early screening for and recognition of TD based on risk factors and regular AIMS exams is para- mount, because this leads to earlier intervention and potentially better outcomes.”

For patients with chronic, established TD, treatment with a myriad of different adjunctive agents has been investigated (Table 2). To date, only two agents—valbenazine and deutetrabenazine, both (reversible) VMAT2 inhibitors that decrease presynaptic dopamine release are FDA approved for adults with TD. Recent trials of valbenazine and deutetrabenazine sup- port their ef cacy and safety.31-39 Treating TD with either agent allows patients to remain on their antipsychotic regimens.

Several recent meta-analyses and Cochrane Schizophrenia Group system- atic reviews have investigated a variety of other potential pharmacologic treatment strategies for TD. All found inconclusive and/or unconvincing evidence for GABA agonists, calcium channel blockers, buspirone, ergot alkaloids, pemoline, promethazine, insulin, branched-chain amino acids, and isocarboxazid, as well as benzodiazepines and vitamin B6.40–44 Al- though not associated with improvement in the symptoms of TD, some evidence indicates that adjunctive vitamin E may be associated with sig- ni cantly less deterioration of TD symptoms compared with placebo.45 There is also a positive meta-analysis of three randomized controlled trials (RCTs) for Ginkgo biloba for reduction in TD symptoms.46 A recent meta-analysis found that switching to clozapine was associated with a signi cant reduction in TD severity, and therefore, when clinically indi- cated, may be a bene cial treatment approach.47 Another meta-analysis found a nonsigni cant trend for improvement in TD with melatonin.48

  

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In addition to pharmacologic approaches, one recent study investigated the potential ef cacy of neurostimulation for TD. Khedr and colleagues49 reported a signi cant reduction in AIMS scores with real (versus sham) repetitive transcranial magnetic stimulation. This nding piques interest for further investigation of neurostimulation approaches for the treatment of TD.

Conclusion

TD is a serious and potentially disabling movement disorder that affects approximately one-quarter of patients with schizophrenia. In patients treated with antipsychotics, it is critical to regularly screen for TD via clinical assessment (ie, using AIMS). Several genetic variants are asso- ciated with increased risk for TD. Other replicated risk factors for TD include older age and early extrapyramidal symptoms.

The etiopathophysiology of TD remains unknown, although leading the- ories involve abnormalities in dopaminergic and antioxidant defense sys- tems that are being investigated in nonhuman primate and rodent models.

When symptoms of TD manifest, it is recommended to discontinue the offending medication (or lowering the dose) via slow taper or switch to a different, lower-risk antipsychotic (if clinically an option). If the patient requires continued antipsychotic treatment for symptom control, adding a VMAT2 inhibitor may reduce the severity of the abnormal movements to a degree acceptable to the patient.

In 2017, the FDA approved the rst two medications for TD: the VMAT2 inhibitors valbenazine and deutetrabenazine. In 2018, the American Academy of Neurology guidelines recommended VMAT2 inhibitors as rst-line therapy for the treatment of TD. Many other treatment approaches are being vigorously investigated. Future research in this area is clearly warranted to elucidate mechanisms and other novel treatment strategies.

Summaries of key articles

Lower prevalence of TD with second-generation antipsychotics
Results of a meta-analysis of 41 studies (N = 11,493) on the prevalence of TD with second-generation antipsychotic use found a 25% prevalence of TD, with signi cant variation in individual studies.6 Findings from this study indicate that rates of TD were lower with second-generation antipsychotics compared with rst-generation antipsychotics (21% ver- sus 30%, respectively).

“The researchers concluded that TD remains highly prevalent, with a higher incidence with rst-generation antipsychotics.”

This association was moderated by older age, geography (lower rates in Asia), longer illness duration, and higher frequency of parkinsonism. The researchers concluded that TD remains highly prevalent, with a higher incidence with rst-generation antipsychotics. Information was insuf cient, however, on the severity of TD to allow interpretation of its clinical impact.

Prevalence of TD in schizophrenia cohort

Misdrahi and colleagues9 report an overall 8.3% prevalence of TD in a community-dwelling large sample of patients with schizophrenia in France (N = 674). More than 90% of patients were being treated with

second-generation antipsychotics. Using the Schooler-Kane criteria, pa- tients were assessed for TD with AIMS.

Mean illness duration was 11 ± 8 years, but details on the duration of second-generation antipsychotic and rst-generation antipsychotic ex- posure were not provided. TD was associated with higher Positive and Negative Syndrome Scale (PANSS) disorganized factor scores (odds ratio [OR], 1.1) after controlling for potential confounding effects of age, sex, negative symptoms, rst-generation antipsychotic use, and ben- zodiazepine and anticholinergic drug use. Furthermore, extrapyramidal symptoms were associated with higher PANSS negative subscale scores (OR, 1.1) in the cohort.

“These ndings strengthen the evidence for a polygenetic component for the pharmacogenetic interactions underlying TD.”

COMT, DRD2, and MnSOD genes linked to antipsychotic- induced TD
Bakker and colleagues10 undertook a meta-analysis to understand the association between polymorphisms in COMT, DRD2, CYP1A2, and MnSOD genes and TD. For the COMT Val158Met polymorphism, the researchers found a signi cant protective effect in Val-Met heterozy- gotes and Met carriers (OR, 0.63–0.66). For the Taq1A polymorphism in DRD2, a risk-increasing effect for the A2 variant (OR, 1.3) and the A2- A2 homozygotes (OR, 1.8) was seen. For the MnSOD Ala-9Val polymor- phism, a signi cant protective effect was seen in Ala-Val heterozygotes and Val carriers (OR, 0.4–0.5). These ndings strengthen the evidence for a polygenetic component for the pharmacogenetic interactions un- derlying TD.

Perlecan (HSPG2) gene associated with TD risk

The Perlecan (HSPG2) rs2445142 G allele has been associated with TD in several recent genome-wide association studies. Perlecan has been found in the neuromuscular junction and is required for synaptic ace- tylcholinesterase clustering, as well as the basement membrane extra- cellular matrix of part of the blood–brain barrier. Zai and colleagues13 performed a meta-analysis that included 324 patients with TD and 515 controls without TD. The results showed that the HSPG2 rs2445142 G polymorphism was associated with a signi cant 1.2-fold increased odds of TD. The largest effect of this gene was seen in a Japanese sample (OR, 2.2). These ndings support further molecular genetic studies of HSPG2.

Clinical risk factors for TD

Solmi and colleagues14 reviewed clinical risk factors for TD, which they classi ed as being nonmodi able or modi able, as well as patient, ill- ness, or treatment related. Nonmodi able patient-related risk factors for TD include older age, female sex, race, and genetics (dopamine, cyto- chrome P450). Illness-related nonmodi able risk factors include longer duration of severe illness, intellectual disability and brain damage, and negative symptoms.

Modi able comorbidity-related risk factors include diabetes, smoking, and alcohol and other substance use disorders. Modi able treatment-re- lated risk factors include treatment with rst-generation antipsychotics, extrapyramidal symptoms, high antipsychotic dose and plasma levels, intermittent antipsychotic treatment, and co-treatment with anticholin- ergic medications.

Resveratrol protects against VCMs in rats

Resveratrol found in grapes, cranberries, and peanuts is a phytoalexin with antioxidant and neuroprotective properties. Resveratrol may modulate dopaminergic proteins, including MAO. Busanello and colleagues22

  

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exposed rats (n = 9) to the rst-generation antipsychotic uphenazine by intramuscular injection for 18 weeks and uphenazine plus resveratrol (n = 8) 20 mg/kg daily in drinking water. Fluphenazine increased the prev- alence and severity of VCMs, resulting in 8 of 9 rats with VCMs. VCMs were reduced by co-treatment with resveratrol (2 of 8 rats with VCMs).

The total number of VCMs was reduced by approximately one-third in the resveratrol group. They also found a signi cant negative correlation between number of VCMs and striatal MAO-B activity. Findings warrant further investigation of resveratrol in the prevention of TD.

L-theanine protects against VCMs in rats

L-theanine, a potent antioxidant found in green tea, also has neuropro- tective effects. Tsai and colleagues23 looked at the effects of L-theanine on rst-generation antipsychotic-induced VCMs. Rats were exposed to treatment with 1 mg/kg haloperidol (n = 8) intraperitoneally for 21 days. Pretreatment with 100 mg/kg L-theanine (n = 8) orally for 35 days was started 14 days prior to haloperidol exposure. L-theanine prevented most of the haloperidol-induced orofacial dyskinesias.

Co-pretreatment with L-arginine (nitric oxide [NO] precursor) eliminat- ed the protective effect of L-theanine, whereas L-NAME (NO synthase inhibitor) potentiated its protective effect. Findings raise the possibility of L-theanine in the prevention and/or treatment of TD and implicate the NO pathways in the pathophysiology of orofacial dyskinesias.

Valbenazine improves TD in adults

Hauser and colleagues32 undertook a 6-week randomized, double-blind, placebo-controlled, xed-dose study of once-daily valbenazine (40 mg or 80 mg) to further evaluate its ef cacy, safety, and tolerability in adults with TD. The study included 234 participants who were randomized to active drug (40 mg or 80 mg) or placebo. A total of 205 (88%) partici- pants completed the study.

At endpoint, valbenazine 40 mg and 80 mg were associated with sig- ni cant reductions in TD symptoms compared with placebo on AIMS dyskinesia score (-1.9 and -3.1 points, respectively, versus -0.1 for pla- cebo). Moreover, 24% of participants in the 40-mg valbenazine group and 40% of those in the 80-mg valbenazine group were AIMS responders (> 50% reduction from baseline) compared with 9% in the placebo group. Treatment-emergent adverse effects were reported in fewer than 5% of participants. The adverse effects were primarily somnolence and dry mouth. Valbenazine may be an effective treatment option for TD.

Long-term safety and tolerability of valbenazine

Factor and colleagues35 undertook a 42-week valbenazine extension period and a subsequent 4-week washout period with participants of the KINECT 3 trial.32 Those who received placebo in the earlier trial were re-randomized 1:1 to valbenazine 40 mg or 80 mg, and the other subjects were continued at their current dose. Initially, 198 patients were entered in the study; 124 (63%) participants completed 48 weeks of treatment and 121 (61%) completed the follow-up visit after washout. Due to treatment-related adverse events, 16% of participants discontinued valbenazine. Participants generally remained psychiatrically stable during the study. The AIMS as- sessment indicated sustained improvement in TD, with scores returning toward baseline after 4 weeks of valbenazine washout.

Long-term safety and tolerability of valbenazine

Marder and colleagues36 undertook an extension KINECT 4 trial. The 48- week, open-label treatment study of valbenazine and a 4-week washout period included 163 patients. Dosing was initiated at valbenazine 40 mg daily and increased to 80 mg daily at week 4 based on tolerability and ef cacy. After week 4, 12% of patients had a treatment-emergent adverse effect leading to discontinuation, most commonly a urinary tract infec- tion and/or headache. The mean decrease from baseline to week 48 in AIMS total score was 10 points in the 40-mg group and 11 points in the

80-mg group. Approximately 90% of subjects in both groups had at least a 50% improvement that was classi ed as much or very much improved. Some evidence of loss of effect after valbenazine washout was found.

Deutetrabenazine signi cantly improved TD

Deutetrabenazine is a novel, selective VMAT2 inhibitor that contains deuterium, which attenuates metabolism and decreases plasma uctu- ations of tetrabenazine levels. Fernandez and colleagues37 undertook a 12-week RCT to evaluate the ef cacy, safety, and tolerability of deu- tetrabenazine treatment of TD (N = 117). The mean deutetrabenazine dosage was 39 mg daily.

Results showed a signi cant reduction (-3 points) in AIMS scores com- pared with placebo. Moreover, the number of psychiatric adverse ef- fects was low. Thus, deutetrabenazine signi cantly reduced TD and was well tolerated.

Deutetrabenazine improved TD with favorable safety and tolerability
Anderson and colleagues38 undertook a 12-week, multisite RCT of deu- tetrabenazine (12, 24, or 36 mg per day) or placebo in 298 patients with TD aged 18 to 80 years. The mean improvement in AIMS total score was 3.3 points in the 36-mg daily group, 3.2 in the 24-mg daily group, and 2.1 in the 12-mg daily group compared with a 1.4-point improvement with placebo. These differences were statistically signi cant for the 24-mg and 36-mg groups. Rates of serious adverse events were low.

Long-term deutetrabenazine treatment safe, ef ca- cious, and well tolerated
Patients with TD who completed the 12-week phase 3 trial of deutetra- benazine were eligible to enter an extension study undertaken by Fer- nandez and colleagues.39 The open-label, single-arm, 2-year extension study included 343 patients. Patients were started at deutetrabenazine 12 mg daily, which was titrated based on tolerability and ef cacy, with a maximum dose of 48 mg daily. Exposure-adjusted incident rates of adverse events were comparable to or lower than those observed in the past three trials. The mean decrease in AIMS total score was -4.9 at week 54, -6.3 at week 80, and -5.1 at week 106.

“They found that switching to clozapine was associated with a signi cant decrease in TD with a small-to-medium effect size (0.40), with greater effects in studies with TD severity as the primary outcome.”

Switching to clozapine may decrease symptoms of TD

Mentzel and colleagues47 performed a meta-analysis of 16 studies on the effect of switching to clozapine on symptoms of TD. Inclusion criteria were a diagnosis of schizophrenia or related disorder, a switch to clozap- ine monotherapy, and TD rating scale scores before and after the switch. They found that switching to clozapine was associated with a signi cant decrease in TD with a small-to-medium effect size (0.40), with greater effects in studies with TD severity as the primary outcome. Effects were also greater in patients with moderate-to-severe TD.

Adjunctive melatonin may decrease symptoms of TD

Sun and colleagues48 undertook a meta-analysis of the effect of adjunc- tive melatonin on symptoms of TD. They identi ed four RCTs (N = 130) for inclusion. There was a nonsigni cant trend for improvements in TD with adjunctive melatonin (weighted mean difference of 1.5 points on AIMS total score). Larger RCTs of this agent may be warranted.

 

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References

1. Schonecker M. Paroxysmal dyskinesia as the effect of megaphen [German]. Nervenarzt. 1957;28:550-553.
2. Faurbye A, Rasch PJ, Petersen PB, et al. Neurological symptoms in pharma- cotherapy of psychoses. Acta Psychiatr Scand. 1964;40:10-27.

3. Schooler NR, Kane JM. Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry. 1982;39:486-487.
4. Fenton WS. Prevalence of spontaneous dyskinesia in schizophrenia. J Clin Psychiatry. 2000;61(Suppl 4):10-14.

5. Kane JM, Smith JM. Tardive dyskinesia: prevalence and risk factors, 1959 to 1979. Arch Gen Psychiatry. 1982;39:473-481.
6. Carbon M, Hsieh CH, Kane JM, Correll CU. Tardive dyskinesia prevalence in the period of second-generation antipsychotic use: a meta-analysis. J Clin Psychiatry. 2017;78:e264-e278.

7. Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry. 2004;161:414-425.
8. O’Brien A. Comparing the risk of tardive dyskinesia in older adults with rst-generation and second-generation antipsychotics: a systematic review and meta-analysis. Int J Geriatr Psychiatry. 2016;31:683-693.

9. Misdrahi D, Tessier A, Daubigney A, et al. Prevalence of and risk factors for extrapyramidal side effects of antipsychotics: results from the National FACE-SZ Cohort. J Clin Psychiatry. 2019;80:18m12246.
10. Bakker PR, van Harten PN, van Os J. Antipsychotic-induced tardive dyskine- sia and polymorphic variations in COMT, DRD2, CYP1A2, and MnSOD genes: a meta-analysis of pharmacogenetic interactions. Mol Psychiatry. 2008;13:544-556. 11. Patsopoulos NA, Ntzani EE, Zintzaras E, Ioannidis JPA. CYP2D6 polymor- phisms and the risk of tardive dyskinesia in schizophrenia: a meta-analysis. Phar- macogenet Genomics. 2005;15:151-158.

12. Zai CC, Maes MS, Tiwari AK, et al. Genetics of tardive dyskinesia: promising leads and ways forward. J Neurol Sci. 2018;389:28-34.
13. Zai CC, Lee FH, Tiwari AK, et al. Investigation of the HSPG2 gene in tardive dyskinesia: new data and meta-analysis. Front Pharmacol. 2018;9:974.

14. Solmi M, Pigato G, Kane JM, Correll CU. Clinical risk factors for the devel- opment of tardive dyskinesia. J Neurol Sci. 2018;389:21-27.
15. Tenback DE, van Harten PN, van Os J. Non-therapeutic risk factors for onset of tardive dyskinesia in schizophrenia: a meta-analysis. Mov Disord. 2009;24:2309-2315.

16. Caroff SN, Leong SH, Roberts C, et al. Cumulative burden of illness in veterans with tardive dyskinesia and serious mental disorders. J Clin Psycho- pharmacol. 2020;40:38-45.
17. Carroll B, Irwin DE. Health care resource utilization and costs for patients with tardive dyskinesia. J Manag Care Spec Pharm. 2019;25:810-816.

18. Ballesteros J, Gonzalez-Pinto A, Bulbena A. Tardive dyskinesia associated with higher mortality in psychiatric patients: results of a meta-analysis of seven independent studies. J Clin Psychopharmacol. 2000;20:188-194.
19. Schultz J, Furnish K, El-Mallakh RS. Consumption of aspartame asso- ciated with tardive dyskinesia: new observation. J Clin Psychopharmacol. 2019;39:690-691.

20. Casey DE. Tardive dyskinesia: pathophysiology and animal models. J Clin Psychiatry. 2000;61(Suppl)4:5-9.
21. Lister J, Nobrega JN, Fletcher PJ, Remington G. Oxidative stress and the antipsychotic-induced vacuous chewing movement model of tardive dyskine- sia: evidence for antioxidant-based prevention strategies. Psychopharmacology (Berl). 2014;231:2237-2249.

22. Busanello A, Leal CQ, Peroza LR, et al. Resveratrol protects against vacuous chewing movements induced by chronic treatment with uphenazine. Neurochem Res. 2017;42:3033-3040.
23. Tsai CC, Wang MH, Chang KC, et al. Possible nitric oxide mechanism in- volved in the protective effect of L-theanine on haloperidol-induced orofacial dyskinesia. Chin J Physiol. 2019;62:17-26.

24. Soung HS, Wang MH, Chang KC, et al. L-theanine decreases orofacial dys- kinesia induced by reserpine in rats. Neurotox Res. 2018;34:375-387.
25. Lister J, Andreazza AC, Navaid B, et al. Lipoic acid and haloperidol-induced vacuous chewing movements: implications for prophylactic antioxidant use in tardive dyskinesia. Prog Neuropsychopharmacol Biol Psychiatry. 2017;72:23-29. 26. Rakesh G, Muzyk A, Szabo ST, et al. Tardive dyskinesia: 21st century may

bring new treatments to a forgotten disorder. Ann Clin Psychiatry. 2017;29: 108-119.
27. Merrill RM, Lyon JL, Matiaco PM. Tardive and spontaneous dyskinesia in- cidence in the general population. BMC Psychiatry. 2013;13:152

28. Guy W. ECDEU Assessment Manual for Psychopharmacology. Revised. Rockville, MD: National Institute of Mental Health; 1976:534–537. US Dept of Health, Education, and Welfare publication ADM 76-338.
29. Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand. 1970;212(suppl):11-19.

30. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2020; draft Epub ahead of print. 31. O’Brien CF, Jimenez R, Hauser RA, et al. NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: a randomized, dou- ble-blind, placebo-controlled study. Mov Disord. 2015;30:1681-1687.

32. Hauser RA, Factor SA, Marder SR, et al. KINECT 3: a phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry. 2017;174:476-484.
33. Josiassen RC, Kane JM, Liang GS, et al. Long-term safety and tolerability of valbenazine (NBI-98854) in subjects with tardive dyskinesia and a diagnosis of schizophrenia or mood disorder. Psychopharmacol Bull. 2017;47:61-68.

34. Kane JM, Correll CU, Liang GS, et al. Ef cacy of valbenazine (NBI-98854) in treating subjects with tardive dyskinesia and schizophrenia or schizoaffective disorder. Psychopharmacol Bull. 2017;47:69–76.
35. Factor SA, Remington G, Comella CL, et al. The effects of valbenazine in participants with tardive dyskinesia: results of the 1-year KINECT 3 extension study. J Clin Psychiatry. 2017;78:1344–1350.

36. Marder SR, Singer C, Lindenmayer JP, et al. A phase 3, 1-year, open-label trial of valbenazine in adults with tardive dyskinesia. J Clin Psychopharmacol. 2019;39:620-627.
37. Fernandez HH, Factor SA, Hauser RA, et al. Randomized controlled tri- al of deutetrabenazine for tardive dyskinesia: the ARM-TD study. Neurology. 2017;88:2003-2010.

38. Anderson KE, Stamler D, Davis MD, et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry. 2017;4:595-604.

39. Fernandez HH, Stamler D, Davis MD. Long-term safety and ef cacy of deutetrabenazine for the treatment of tardive dyskinesia. J Neurol Neurosurg Psychiatry. 2019;90:1317-1323.
40. Alabed S, Latifeh Y, Mohammad HA, Bergman H. Gamma-aminobutyric acid agonists for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev. 2018;4:CD000203.

41. Essali A, Soares-Weiser K, Bergman H, Adams CE. Calcium channel block- ers for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev. 2018;3:CD000206.
42. Soares-Weiser K, Rathbone J, Ogawa Y, et al. Miscellaneous treatments for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev. 2018;3:CD000208.

43. Bergman H, Soares-Weiser K. Anticholinergic medication for antipsychot- ic-induced tardive dyskinesia. Cochrane Database Syst Rev. 2018;1:CD000204. 44. Adelufosi AO, Abayomi O, Ojo TM. Pyridoxal 5 phosphate for neurolep- tic-induced tardive dyskinesia. Cochrane Database Syst Rev. 2015;4:CD010501. 45. Soares-Weiser K, Maayan N, Bergman H. Vitamin E for antipsychotic-in- duced tardive dyskinesia. Cochrane Database Syst Rev. 2018;1:CD000209.

46. Zheng W, Xiang YQ, Ng CH, et al. Extract of Ginkgo biloba for tardive dyskinesia: meta-analysis of randomized controlled trials. Pharmacopsychiatry. 2016;49:107-111.
47. Mentzel TQ, van der Snoek R, Lieverse R, et al. Clozapine monotherapy as a treatment for antipsychotic-induced tardive dyskinesia: a meta-analysis. J Clin Psychiatry. 2018;79.

48. Sun CH, Zheng W, Yang XH, et al. Adjunctive melatonin for tardive dyski- nesia in patients with schizophrenia: a meta-analysis. Shanghai Arch Psychiatry. 2017;29:129-136.
49. Khedr EM, Al Fawal B, Abdelwarith A, et al. Repetitive transcranial magnetic stimulation for treatment of tardive syndromes: double randomized clinical trial. J Neural Transm (Vienna). 2019;126:183-191. ❒

APRIL 2020

PUBLISHED AS A SUPPLEMENT TO PSYCHIATRIC TIMES 6

                                                                                 

IN ADULT PATIENTS WITH TARDIVE DYSKINESIA (TD) Choose INGREZZA for results you can see1

INGREZZA® (valbenazine) capsules reduced TD severity at 6 weeks, with results you can start to see as early as 2 weeks1-3

  

Not an actual patient

See how INGREZZA reduced TD severity in patients at INGREZZAHCP.com/results Important Information

INDICATION & USAGE

INGREZZA® (valbenazine) capsules is indicated for the treatment of adults with tardive dyskinesia.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

INGREZZA is contraindicated in patients with a history of hypersensitivity to valbenazine or any components of INGREZZA. Rash, urticaria, and reactions consistent with angioedema
(e.g., swelling of the face, lips, and mouth) have been reported.

WARNINGS & PRECAUTIONS

Somnolence

INGREZZA can cause somnolence. Patients should not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by INGREZZA.

QT Prolongation

INGREZZA may prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing. INGREZZA 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, assess the QT interval before increasing the dosage.

WARNINGS & PRECAUTIONS (continued)

Parkinsonism

INGREZZA may cause parkinsonism in patients with tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. Reduce the dose or discontinue INGREZZA treatment in patients who develop clinically significant parkinson-like signs or symptoms.

ADVERSE REACTIONS

The most common adverse reaction (≥5% and twice the rate
of placebo) is somnolence. Other adverse reactions (≥2% and >Placebo) include: anticholinergic effects, balance disorders/falls, headache, akathisia, vomiting, nausea, and arthralgia.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch at http://www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see the adjacent page for Brief Summary of Prescribing Information and visit http://www.INGREZZAHCP.com/PI for full Prescribing Information.

REFERENCES: 1. INGREZZA [package insert]. San Diego, CA: Neurocrine Biosciences, Inc; 2019. 2. Hauser RA, Factor SA, Marder SR, et al. KINECT 3: a phase 3 randomized, double- blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry. 2017;174(5):476-484. 3. Data on file. Neurocrine Biosciences, Inc.

         

   

 

©2020 Neurocrine Biosciences, Inc. All Rights Reserved. CP-VBZ-US-1040 02/2020

                             

for oral use

Brief Summary: for full Prescribing Information and Patient Information,

refer to package insert.

INDICATION AND USAGE

INGREZZA® (valbenazine) capsules is indicated for the treatment of adults with tardive dyskinesia.

CONTRAINDICATIONS

INGREZZA is contraindicated in patients with a history of hypersensitivity to valbenazine or any components of INGREZZA. Rash, urticaria, and reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth) have been reported.

WARNINGS AND PRECAUTIONS
Somnolence
INGREZZA can cause somnolence. Patients should not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by INGREZZA.
QT Prolongation
INGREZZA may prolong the QT interval, although the degree of QT prolongation is not clinically signi cant at concentrations expected with recommended dosing. In patients taking a strong CYP2D6 or CYP3A4 inhibitor, or who are CYP2D6 poor metabolizers, INGREZZA concentrations may be higher and QT prolongation clinically signi cant. For patients who are CYP2D6 poor metabolizers or are taking a strong CYP2D6 inhibitor, dose reduction may be necessary. For patients taking a strong CYP3A4 inhibitor, reduce the dose of INGREZZA to 40 mg once daily. INGREZZA 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, assess the QT interval before increasing the dosage.
Parkinsonism
INGREZZA may cause parkinsonism in patients with tardive dyskinesia. Parkinsonism has also
been observed with other VMAT2 inhibitors. In the 3 placebo-controlled clinical studies in patients with tardive dyskinesia, the incidence of parkinson-like adverse events was 3% of patients
treated with INGREZZA and <1% of placebo-treated patients. Postmarketing safety reports have described parkinson-like symptoms, some of which were severe and required hospitalization. In
most cases, severe parkinsonism occurred within the rst 2 weeks after starting or increasing the dose of INGREZZA. Associated symptoms have included falls, gait disturbances, tremor, drooling,
and hypokinesia. In cases in which follow-up clinical information was available, parkinson-like symptoms were reported to resolve following discontinuation of INGREZZA therapy. Reduce the dose or discontinue INGREZZA treatment in patients who develop clinically signi cant parkinson-like signs or symptoms.

ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling: • Hypersensitivity
• Somnolence
• QT Prolongation

• Parkinsonism

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not re ect the rates observed in practice.

Variable and Fixed Dose Placebo-Controlled Trial Experience

The safety of INGREZZA was evaluated in 3 placebo-controlled studies, each 6 weeks in duration ( xed dose, dose escalation, dose reduction), including 445 patients. Patients were 26 to 84 years of age with moderate to severe tardive dyskinesia and had concurrent diagnoses of mood disorder (27%) or schizophrenia/schizoaffective disorder (72%). The mean age was 56 years. Patients were 57% Caucasian, 39% African-American, and 4% other. With respect to ethnicity, 28% were Hispanic or Latino. All subjects continued previous stable regimens of antipsychotics; 85% and 27% of subjects, respectively, were taking atypical and typical antipsychotic medications at study entry. Adverse Reactions Leading to Discontinuation of Treatment

A total of 3% of INGREZZA treated patients and 2% of placebo-treated patients discontinued because of adverse reactions.
Common Adverse Reactions

Adverse reactions that occurred in the 3 placebo-controlled studies at an incidence of ≥2% and greater than placebo are presented in Table 1.

Other Adverse Reactions Observed During the Premarketing Evaluation of INGREZZA

Other adverse reactions of ≥1% incidence and greater than placebo are shown below. The following list does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative,
4) which were not considered to have clinically signi cant implications, or 5) which occurred at a rate equal to or less than placebo.

Endocrine Disorders: blood glucose increased
General Disorders: weight increased
Infectious Disorders: respiratory infections
Neurologic Disorders: drooling, dyskinesia, extrapyramidal symptoms (non-akathisia) Psychiatric Disorders: anxiety, insomnia

During controlled trials, there was a dose-related increase in prolactin. Additionally, there was a dose- related increase in alkaline phosphatase and bilirubin, suggesting a potential risk for cholestasis.

Postmarketing Experience

The following adverse reactions have been identi ed during post-approval use of INGREZZA that are not included in other sections of labeling. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: hypersensitivity reactions (including allergic dermatitis, angioedema, pruritis, and urticaria)
Skin and Subcutaneous Tissue Disorders: rash

DRUG INTERACTIONS
Drugs Having Clinically Important Interactions with INGREZZA

Table 2:

Clinically Significant Drug Interactions with INGREZZA

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Implication:

Concomitant use of INGREZZA with MAOIs may increase the concentration of monoamine neurotransmitters in synapses, potentially leading to increased risk of adverse reactions such as serotonin syndrome, or attenuated treatment effect of INGREZZA.

Prevention or Management:

Avoid concomitant use of INGREZZA with MAOIs.

Examples:

isocarboxazid, phenelzine, selegiline

Strong CYP3A4 Inhibitors

Clinical Implication:

Concomitant use of INGREZZA with strong CYP3A4 inhibitors increased the exposure (Cmax and AUC) to valbenazine and its active metabolite compared with the use of INGREZZA alone. Increased exposure of valbenazine and its active metabolite may increase the risk of exposure-related adverse reactions.

Prevention or Management:

Reduce INGREZZA dose when INGREZZA is coadministered with a strong CYP3A4 inhibitor.

Examples:

itraconazole, ketoconazole, clarithromycin

Strong CYP2D6 Inhibitors

Clinical Implication:

Concomitant use of INGREZZA with strong CYP2D6 inhibitors may increase the exposure (Cmax and AUC) to valbenazine’s active metabolite compared with the use of INGREZZA alone. Increased exposure of active metabolite may increase the risk of exposure- related adverse reactions.

Prevention or Management:

Consider reducing INGREZZA dose based on tolerability when INGREZZA is coadministered with a strong CYP2D6 inhibitor.

Examples:

paroxetine, uoxetine, quinidine

Strong CYP3A4 Inducers

Clinical Implication:

Concomitant use of INGREZZA with a strong CYP3A4 inducer decreased the exposure of valbenazine and its active metabolite compared to the use of INGREZZA alone. Reduced exposure of valbenazine and its active metabolite may reduce ef cacy.

Prevention or Management:

Concomitant use of strong CYP3A4 inducers with INGREZZA is not recommended.

Examples:

rifampin, carbamazepine, phenytoin, St. John’s wort1

Digoxin

Clinical Implication:

Concomitant use of INGREZZA with digoxin increased digoxin levels because of inhibition of intestinal P-glycoprotein (P-gp).

Prevention or Management:

Digoxin concentrations should be monitored when
coadministering INGREZZA with digoxin. Increased digoxin exposure may increase the risk of exposure-related adverse reactions. Dosage adjustment of digoxin may be necessary.

Table 1:

Adverse Reactions in 3 Placebo-Controlled Studies of 6-week Treatment Duration Reported at ≥2% and >Placebo

Adverse Reaction1

INGREZZA (n=262) (%)

Placebo (n=183) (%)

General Disorders

Somnolence (somnolence, fatigue, sedation)

10.9%

4.2%

Nervous System Disorders

Anticholinergic effects (dry mouth, constipation, disturbance in attention, vision blurred, urinary retention)

5.4%

4.9%

Balance disorders/fall (fall, gait disturbance, dizziness, balance disorder)

4.1%

2.2%

Headache

3.4%

2.7%

Akathisia (akathisia, restlessness)

2.7%

0.5%

Gastrointestinal Disorders

Vomiting

2.6%

0.6%

Nausea

2.3%

2.1%

Musculoskeletal Disorders

Arthralgia

2.3%

0.5%

1 Within each adverse reaction category, the observed adverse reactions are listed in order of decreasing frequency.

Distributed by:
Neurocrine Biosciences, Inc. SanDiego,CA92130

INGREZZA is a registered trademark of Neurocrine Biosciences, Inc. CP-VBZ-US-0203v4 07/19

1 The induction potency of St. John’s wort may vary widely based on preparation.

Drugs Having No Clinically Important Interactions with INGREZZA

Dosage adjustment for INGREZZA is not necessary when used in combination with substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 based on in vitro study results.

OVERDOSAGE
Human Experience
The pre-marketing clinical trials involving INGREZZA in approximately 850 subjects do not provide information regarding symptoms with overdose.
Management of Overdosage
No speci c antidotes for INGREZZA are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a Certi ed Poison Control Center (1-800-222-1222 or http://www.poison.org).
For further information on INGREZZA, call 84-INGREZZA (844-647-3992).

         

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