Treatment Strategies for Tardive Dyskinesia

Abstract

Tardive dyskinesia (TD), a condition of potentially irreversible abnormal involuntary movements that is associated with dopamine receptor blocking agents (DRBAs), produces significant impairment of functioning and quality of life for patients. Contrary to expectations, TD has not vanished despite the introduction of SGAs. Instead, changing prescription practices and increased off-label prescription of DRBAs have placed more patients than ever at risk of this potentially dangerous and disabling condition. This activity provides an overview of treatment strategies for TD as part of an individualized management plan, including DRBA medication adjustment and antidyskinetic treatment.

Overview

What steps do you take when patients exhibit tardive dyskinesia? Are you familiar with treatment guidelines and data on approved and non-approved strategies? Explore recommendations from Dr Daniel Kremens.

From the Series: Early Recognition and Treatment of Tardive Dyskinesia in Patients with Mood Disorders and Schizophrenia
To cite: Kremens DE. Treatment strategies for tardive dyskinesia. J Clin Psychiatry. 2020;81(1):NU18041BR4C.
To share: https://doi.org/10.4088/JCP.NU18041BR4C
© Copyright 2019 Physicians Postgraduate Press, Inc.

Target Audience

Psychiatrists, Neurologists, nurse practitioners, and physician assistants

Support Statement

Supported by an educational grant from Neurocrine Biosciences, Inc.

Learning Objective

After completing this educational activity, you should be able to:

• Use evidence ratings, consensus recommendations, and FDA guidance when devising treatment strategies for patients with TD

Release, Review, and Expiration Dates

This brief report activity was published in November 2019 and is eligible for AMA PRA Category 1 Credit™ through November 30, 2021. The latest review of this material was October 2019.

Statement of Need and Purpose

Because some clinicians underestimate the risk of TD, especially with newer antipsychotics, they do not advise patients and caregivers of the risk of TD or educate them about early signs to watch for and report. A substantial proportion of patients with TD do not have a timely diagnosis. Clinicians may not recognize early TD symptoms, as mild cases may be more easily missed. Due to TD movements, patients may stop taking their treatments for mood disorders or schizophrenia. Clinicians may inaccurately rate how bothersome side effects are to patients. New medications for TD are available, and evidence-based treatment recommendations have been published. Recent research has explored longer-term safety and efficacy with newer medications. Physicians need up-to-date guidance on the prevalence of TD, risk factors for the development of TD, how to recognize early signs and symptoms of TD, and assessment tools that will help them diagnose and monitor TD. They also need education about discussing TD risk and signs with patients and caregivers. Physicians need awareness of the burden of TD and need up-to-date, evidence-based, expert guidance on using new medications in the treatment of TD in patients with mood disorders and schizophrenia, including longer-term use. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on TD.

Disclosure of Off-Label Usage

Dr Kremens has determined that, to the best of his knowledge, tetrabenazine, levetiracetam, zonisamide, piracetam, propranolol, vitamin B6, botulinum toxin, clonazepam, gingko biloba, pallidal DBS, and ECT are not approved by the US Food and Drug Administration for the treatment of tardive dyskinesia.

Review Process

The faculty member(s) agreed to provide a balanced and evidence-based presentation and discussed the topic(s) and CME objective(s) during the planning sessions. The faculty’s submitted content was validated by CME Institute staff, and the activity was evaluated for accuracy, use of evidence, and fair balance by the Chair and a peer reviewer who is without conflict of interest.

Acknowledgment

This Brief Report is derived from the teleconference series “Early Recognition and Treatment of Tardive Dyskinesia in Patients with Mood Disorders and Schizophrenia,” which was held in April, May, and June 2019 and supported by an educational grant from Neurocrine Biosciences, Inc. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.

Faculty Affiliation

Daniel E., Kremens, MD, JD
Department of Neurology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships.

Dr Kremens is a consultant for Teva, UCB, Sunovion, Impax, Lundbeck, Acadia, USWorldMeds, Adamas, AbbVie, Merz, Allergan, Acorda, Kyowa, Neurocrine, GE Healthcare, and St Jude Medical; is a member of the speakers/advisory boards for Teva, UCB, Impax, Lundbeck, Acadia, USWorldMeds, and Adamas; and has received grant/research support from Acorda, and Enterin. The Chair for this activity, Joseph McEvoy, MD, has received grant/research support from Takeda, Alkermes, Boehringer Ingelheim, Teva, Neurocrine, and Otsuka; has received honoraria from Neurocrine; and is a member of the speakers/advisory boards for Merck, Neurocrine, and Alkermes.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note: The American Nurses Credentialing Center (ANCC) and the American Academy of Physician Assistants (AAPA) accept certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by the ACCME.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

MOC Approval Statement Through the American Board of Medical Specialties (“ABMS”) ongoing commitment to increase access to practice relevant Continuing Certification Activities through the ABMS Continuing Certification Directory, Treatment Strategies for Tardive Dyskinesia has met the requirements as a MOC Part II CME Activity (apply toward general CME requirement) for the following ABMS Member Boards:

MOC Part II CME Activity Psychiatry and Neurology
Available Credit

• 0.50 AMA PRA Category 1 Credit™
• 0.50 Participation

This CME activity is expired. For more CME activities, visit cme.psychiatrist.com.
Find more articles on this and other psychiatry and CNS topics:
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Tardive dyskinesia (TD), a condition of potentially irreversible abnormal involuntary movements that is associated with dopamine receptor blocking agents (DRBAs) such as antipsychotics, can produce substantial impairment of functioning and diminished quality of life for patients.¹ Contrary to expectations, TD has not vanished as SGAs have become more widely used than FGAs. In fact, expanded drug indications and increased off-label prescription of SGAs have placed more patients than ever at risk for this potentially dangerous and disabling condition.

Specific medication for TD should be considered part of a comprehensive management plan that is individualized for each patient (AV 1).³ This activity provides an overview of managing patients’ medications and selecting appropriate antidyskinetic treatments based on current evidence.

AV 1. Steps for the Treatment of Tardive Dyskinesia (TD)

Based on Caroff et al.³

Manage Medications Associated With TD

Antipsychotic agents. Ideally, TD can be prevented by avoiding long-term use of antipsychotics for conditions in which evidence of their benefit is lacking or other treatment options are available.^4,5 Antipsychotics were initially used in patients with schizophrenia and schizoaffective disorder, but they are now also used for mood disorders including bipolar disorder and major depression. Off-label uses of antipsychotics include treatment of OCD, personality disorders, PTSD, insomnia, and agitation in dementia.⁵For many patients with severe psychiatric conditions, antipsychotic agents may be the best available option. These patients and their families should be informed of the risk of TD, and the smallest effective dose of the drug should be used.⁴ Throughout antipsychotic treatment, clinicians must monitor for symptoms of TD.⁶

After TD is identified, clinicians should try to withdraw DRBAs if possible. Some patients can be safely tapered off treatment if alternative therapies are available. DRBAs should be withdrawn slowly, as sudden withdrawal may worsen or precipitate TD and worsen the underlying psychiatric disorder.^3,7

A recent meta-analysis¹ found an annualized TD incidence of 6.5% for FGAs vs 2.6% for SGAs. TD risk and annualized rates were significantly lower with SGAs vs FGAs (both P < .0001), and meta‐regression showed no FGA dose effect on FGA–SGA comparisons (P = .30). In SGA comparisons, results showed an advantage for olanzapine vs other (non‐clozapine) SGAs (P = .006, NNT = 100).¹

The 2013 AAN guidelines cautioned against the use of SGAs in the treatment of TD as they may themselves cause TD and even mask TD symptoms.⁸ The updated AAN guidelines concluded that there is insufficient evidence to support or refute the withdrawal of DRBAs or a switch from an FGA to an SGA,⁹ but some patients may benefit from a switch to olanzapine or risperidone.³

Anticholinergic medications. If the patient is taking an anticholinergic drug, the clinician must decide whether continuation is necessary or gradual tapering should be considered. Anticholinergic drugs probably worsen TD, as up to 60% of patients withdrawn from these medications show improved TD severity ratings.¹⁰ However, reducing or tapering anticholinergics if acute drug-induced movements or tardive dystonia are present could cause these conditions to re-emerge or worsen after withdrawal.

A reasonable alternative to anticholinergics may be amantadine.¹⁰  In a small study¹¹ (N = 22), patients with TD who were taking amantadine had a reduction in AIMS scores after 2 weeks of treatment, while those taking placebo experienced no change.

Benztropine is an anticholinergic medication used as an adjunct in the treatment of parkinsonism and is useful in the control of extrapyramidal disorders (except TD) due to neuroleptic drugs. The labeling precautions note that antiparkinsonism agents do not reduce the symptoms of TD and may even aggravate them.¹² Thus, this agent is not recommended for use in patients with TD.

Consider Antidyskinetic Treatments

If TD remains a problem after the antipsychotic and anticholinergic treatment regimens are reviewed and adjusted, specific antidyskinetic drugs should be considered.¹⁰ Over the years, an extensive number of clinical trials of agents to treat TD were conducted, and the evidence of their effectiveness was largely inconclusive.⁸ However, 2 tetrabenazine analogs, valbenazine and deutetrabenazine,¹⁰ have garnered level A evidence, are recommended as treatment for TD in the updated AAN guidelines, and are FDA-approved for this indication.⁸ Both have low NNTs (AV 2).^13–16 For more details on these agents and others used in the treatment of TD, see the activity “FDA-Approved Medications to Treat Tardive Dyskinesia” by Joseph P. McEvoy, MD.

AV 2. Response Rates for Valbenazine and Deutetrabenazine Phase 3 Studies

Data from Hauser et al,15 Citrome,13 Anderson et al,16 and Citrome.¹⁴
Response = ≥ 50% reduction from baseline in AIMS score

Dopamine receptor hypersensitivity is thought to be a cause of TD.¹⁷ Although the exact mechanism of VMAT2 inhibition is not known, VMAT2 inhibitors are believed to selectively bind to and inhibit VMAT2, thus preventing it from storing dopamine in synaptic vesicles. The reduced level of dopamine in the synaptic cleft means that the receptors, while still reacting hyperactively to dopamine, receive less dopamine and thus have a response similar to that of average receptors.¹⁷ The active metabolites of the VMAT2 inhibitors have high affinity for VMAT2 and minimal off-target binding, which gives them favorable pharmacokinetic and tolerability advantages over tetrabenazine.⁷

Valbenazine. Valbenazine received FDA approval for the treatment of TD in 2017 based largely on the positive results of KINECT 3, a phase 3 double-blind RCT. In this study,¹⁵ participants (N = 225) with schizophrenia, schizoaffective disorder, or a mood disorder who had moderate or severe TD were randomly assigned in a 1:1:1 ratio to once-daily placebo, valbenazine 40 mg/d, or valbenazine 80 mg/d. About 86% of participants were taking antipsychotics. Least-squares mean change in AIMS dyskinesia scores was –3.2 for the 80-mg/d group, –1.9 for the 40-mg/d group, and –0.1 for the placebo group  (P < .001 for 80 mg/d vs placebo). The 1-year KINECT 3 extension study¹⁸ demonstrated long-term efficacy, safety, and tolerability of valbenazine for the treatment of TD.

The only adverse effect with ≥ 5% incidence for valbenazine and occurring ≥ 2 times than with placebo was somnolence/fatigue/sedation, with rates of 10.9% for valbenazine (both doses) and 4.2% for placebo, resulting in an NNH of 15 (95% CI 9–52).¹³ The product label has a precaution against driving until the drug’s sleep effects on the patient are known.¹⁹

Besides somnolence, the other labeled precaution is for QT prolongation.¹⁹ For patients at increased risk for prolonged QT interval, clinicians must assess the QT interval before increasing the dosage, but valbenazine prescribing information does not require an electrocardiogram to start treatment. A pooled analysis²⁰ of cardiovascular outcomes showed no significant differences between placebo and valbenazine groups. Long-term data (up to 48 weeks) Other adverse effects may include anticholinergic effects, balance problems, headache, gastrointestinal issues, and arthralgia.¹⁹

Valbenazine is slowly metabolized, allowing for once-daily dosing, with or without food, starting at 40 mg and increasing to 80 mg after 1 week.¹⁹

Deutetrabenazine. Deutetrabenazine is a highly selective VMAT2 inhibitor that contains deuterium, which is a naturally occurring, nontoxic form of hydrogen that attenuates drug metabolism and improves tolerability by reducing adverse events related to peak plasma concentrations.¹⁴ Deutetrabenazine received FDA approval for the treatment of TD in 2017 on the basis of results from 2 double-blind RCTs: the phase 2/3 trial ARM-TD and the phase 3 trial AIM-TD.¹⁴ In both studies, patients could continue the use of DRBAs or antidepressants as long as there had been no recent change in these medications.

The ARM-TD study²¹ examined a flexible dose of deutetrabenazine starting at 12 mg/d (6 mg BID) and titrated weekly by 6 mg/d, if required, versus placebo in 117 patients with moderate to severe TD. The mean total daily dose was 38.8 mg/d at the end of the 12-week study period. AIMS scores decreased significantly in the deutetrabenazine group versus the placebo group (–3.0 vs –1.6; P = .019), and the drug was well tolerated.

The AIM-TD fixed-dose study¹⁶ randomized 298 patients 1:1:1:1 to receive placebo or deutetrabenazine 12, 24, or 36 mg/d (divided in 2 doses) for 8 weeks after a 4-week titration period. Least-squares mean AIMS scores improved by –3.2 (P = .003) and –3.3 (P = .001) in the groups receiving deutetrabenazine 24 and 36 mg/d, respectively, compared with –1.4 for placebo.

Deutetrabenazine was well tolerated, with low rates of side effects in both ARM-TD and AIM-TD.^16,21 The adverse effects that occurred in ≥ 4% of participants taking deutetrabenazine and at a greater rate than with placebo were nasopharyngitis and insomnia,²² with NNH values of 50 (not significant) and 34 (95% CI 18–725), respectively.¹⁴ Depression/dysthymia and akathisia/restlessness also occurred more often than with placebo.²² Prescribing information²² states that the use of deutetrabenazine in combination with other drugs known to prolong QTc may result in clinically significant QT prolongations. For patients requiring deutetrabenazine doses greater than 24 mg/d and who are taking other drugs known to prolong QTc, assess the QTc interval before and after increasing the dose of deutetrabenazine or the other drugs.

Deutetrabenazine is dosed twice daily, is titrated typically over several weeks, and should be taken with food.²²

 PATIENT PERSPECTIVES

 Family PERSPECTIVES

Additional treatments. Other treatments with lower levels of evidence than the novel VMAT2 inhibitors include tetrabenazine and BCAAs. Tetrabenazine is a reversible and specific VMAT2 inhibitor that was FDA-approved in 2008 for the treatment of choreiform movements associated with Huntington’s disease.²³ Despite showing improvement for TD in observational studies, tetrabenazine’s use is limited by side effect burden, short half-life (with multiple daily doses), and drug interactions.³ It is not FDA-approved for TD treatment.²³BCAAs have been studied in the treatment of TD because of the observed association between dyskinetic movements and impaired clearance of phenylalanine. It is thought that ingesting BCAAs decreases the availability of phenylalanine to the brain and improves TD by decreasing amine neurotransmitter synthesis.²⁴ In a 3-week study²⁵ of high-dose BCAAs compared with placebo in men with TD (N = 36), dyskinetic movements decreased by a mean of 36.5% in the BCAA group but increased by a mean of 3.4% in the placebo group.The FDA approved a combination of 3 BCAAs as a medical food for the dietary management of TD in male patients. Although the branded product is no longer available, compounding pharmacies can make it using the BCAAs valine, isoleucine, and leucine in a 3:3:4 ratio.²⁴ The product was a flavored powder mixed with water and taken 3 times a day. The presence of sugar adds calories, 52 in each 15-g packet, totaling 156 extra calories per day for the average patient. Thus, the main risk of this treatment is weight gain, which is already problematic in patients with psychiatric disorders taking long-term antipsychotics.²⁴

 PATIENT PERSPECTIVES

Weight gain is often a concern for patients taking antipsychotics, as the following individuals with schizophrenia noted:

“I was afraid of the weight gain, and I wanted to lose a significant amount I gained on previous antipsychotics, so I started off aggressively fighting weight gain.”²⁶

“I sleep well on the [olanzapine], but it has made me really pack on the pounds.”²⁶

Other treatments with possible efficacy but insufficient evidence in the treatment of TD include levetiracetam, zonisamide, piracetam, propranolol, and vitamin B6.³ Botulinum toxin may have benefit for focal dystonia,³ and clonazepam and gingko biloba extract have level B evidence of benefit for TD.⁸Pallidal DBS received a level C recommendation from AAN for possibly improving TD and for use in refractory cases.⁹ The growing literature on DBS targeting the globus pallidus interna for TD contains predominantly case reports and case series, which in many instances have demonstrated 50% long-term improvement of symptoms on standardized rating scales.^27,28 Given the lack of controlled studies, as well as the invasive nature of the treatment, DBS cannot be recommended for routine use in the treatment of TD.A few case reports and retrospective series report improvement of TD with ECT,²⁹ although no firm conclusions can be made.⁸ One retrospective study²⁹ reported a 39% response rate (> 50% improvement in AIMS score) in 18 patients with TD or tardive dystonia who received a standard course of ECT.ConclusionEven with SGAs, TD continues to be a risk for patients taking DRBAs. Communication with patients and their families regarding the risk of TD is important, and education about early signs will aid in the recognition and management of symptoms. Attempting prevention through judicious use of DRBAs is mandatory. Whenever possible, DRBAs should be slowly withdrawn or switched to an alternative with less risk of TD, although evidence is currently insufficient to support or refute these strategies. When TD does occur, the VMAT2 inhibitors deutetrabenazine and valbenazine are now the mainstay of treatment.

 CLINICAL POINTS

• Withdraw or switch dopamine receptor blocking agents (DRBAs) that cause TD if possible.
• Choose deutetrabenazine or valbenazine to treat TD in patients who must remain on DRBAs.
• Consider DBS and ECT for severe, refractory cases of TD, but watch for more evidence.

© Copyright 2021 Physicians Postgraduate Press, Inc.

Abbreviations: AAN = American Academy of Neurology, AIMS = Abnormal Involuntary Movement Scale, AIM-TD = Addressing Involuntary Movements in TD, ARM-TD = Aim to Reduce Movements in TD, BCAAs = branched-chain amino acids, CGI-C = Clinical Global Impression of Change, DBS = deep brain stimulation, DRBAs = dopamine receptor blocking agents, ECT = electroconvulsive therapy, FGA = first-generation antipsychotic, NNH = number needed to harm, NNT = number needed to treat, OCD = obsessive-compulsive disorder, PTSD = posttraumatic stress disorder, RCT = randomized controlled trial, SGA = second-generation antipsychotic, TD = tardive dyskinesia, VMAT2 = vesicular monoamine transporter 2

References

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29. Yasui-Furukori N, Kikuchi A, Katagai H, et al. The effects of electroconvulsive therapy on tardive dystonia or dyskinesia induced by psychotropic medication: a retrospective study. Neuropsychiatr Dis Treat. 2014;10:1209–1212. PubMed CrossRef