Version May 2024
INTRODUCTION — Tardive dyskinesia (TD) is a medication-induced hyperkinetic movement disorder associated with the use of dopamine receptor-blocking agents, including first- and second-generation antipsychotic drugs, metoclopramide, and prochlorperazine.
The most common manifestations of TD involve spontaneous movements of the mouth and tongue, but the arms, legs, trunk, and respiratory muscles can also be affected. Less commonly, the prominent feature is dystonia involving a focal area of the body such as the neck. TD can be irreversible and lifelong, with major negative impacts on psychologic health and quality of life.
TD is important to recognize, since early discontinuation of the offending drug offers the best chance of recovery. However, in patients who require ongoing antipsychotic drug therapy for management of psychiatric disorders, symptomatic therapies for TD can help lessen movements, if only partially.
This topic will review the prevention and management of TD. Other aspects of TD are discussed separately. (See "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis".)
PREVENTION — Prevention and early detection of TD are of paramount importance. The only certain method to prevent TD is to remain vigilant when treating with dopamine receptor-blocking agents.
Safe prescribing practices — When a dopamine receptor-blocking agent is deemed necessary, prevention of TD begins at the time of prescription. Guidelines for prescribing drugs to help decrease the risk of TD include the following [1-3]:
●Use dopamine receptor-blocking agents only when there is a clear indication for their clinical use and safer effective alternatives are lacking.
•For antipsychotic drugs, continuous treatment beyond three to six months should only be considered when the need for continuous treatment and potential harms of nontreatment are deemed to be greater than the risks of TD and other potential toxicities (mainly chronic psychotic illness).
•For metoclopramide, continuous use for longer than 12 weeks should be avoided. The association between metoclopramide and TD is discussed in detail separately. (See "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis", section on 'Metoclopramide'.)
●Prescribe the lowest effective dose of these agents for the shortest duration necessary.
●Consider choosing second-generation antipsychotics over first-generation antipsychotics to lessen the risk of TD, especially in older patients, while acknowledging that second-generation antipsychotics still carry risk. (See "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis", section on 'Antipsychotic drugs'.)
●Monitor for acute drug-induced parkinsonism and akathisia, which serve as risk factors and potential warning signs for TD. Drug-induced parkinsonism may also mask signs of TD. Use the lowest effective dose when treating with dopamine receptor blockers.
●Use particular care in older adults (50 years and older), patients with affective disorder, patients with treatment-resistant schizophrenia, and females, as these groups are at an increased risk for TD (table 1).
●Avoid chronic use of prophylactic anticholinergic drugs whenever possible, since they do not prevent TD and may mask or even aggravate extrapyramidal symptoms when they arise.
Informed consent and education — As an iatrogenic disorder, TD has medicolegal implications [4]. Thus, it is important to inform patients of the risk of developing TD before treating with antipsychotic drugs, certain antiemetics, and metoclopramide, to discuss treatment goals and alternatives, and to document discussion in the medical record.
Although there is no consensus, some experts also advocate obtaining written informed consent from patients with decision-making capacity or from family members of patients who are unable to consent.
Informed consent provides an opportunity to educate the patient and family members or caregivers, so that they recognize abnormal movements should they occur.
Monitoring during treatment — All patients receiving long-term antipsychotic drugs or metoclopramide should be regularly screened for signs of TD.
Screening for TD consists of physical examination, evaluating for abnormal involuntary movements of the face, mouth, jaw, or extremities. The tongue should be observed with the mouth held open. While standing or walking, the patient is observed for abnormal movements of the trunk or limbs.
Clinicians may choose to use the Abnormal Involuntary Movement Scale (AIMS) for documenting the examination (form 1). The AIMS is a 14-item scale that includes examination of the head, dentition, neck, limb, and truncal movements and rating of severity between 0 (normal-absent) and 4 (severe).
INITIAL MANAGEMENT — Current therapies for TD relieve symptoms but do not treat the underlying dopaminergic blockade. Thus, early detection of the offending agent is crucial.
Discontinue offending agent, if possible — The offending drug should be discontinued when TD first emerges, if possible (algorithm 1). TD is not always permanent, and the earlier the drug is discontinued, the better chance for improvement or resolution of TD. (See 'Prognosis' below.)
Antipsychotic drug cessation (or dose reduction) must be carefully considered in the context of the underlying psychiatric illness and the potential for relapse or worsening of psychotic symptoms. In those with severe psychiatric illness, including schizophrenia, antipsychotic drug cessation is often not possible. (See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Antipsychotic therapy'.)
When tapering a dopamine receptor-blocking agent, clinicians and patients should be aware of the following [5,6]:
●The drug should be withdrawn slowly, over weeks to months depending on the underlying condition and the duration of TD. Abrupt withdrawal may worsen or precipitate TD.
●TD may take several weeks to improve. In some cases, TD may take months or years to remit or may never completely resolve.
●New-onset or worsened dyskinesia may occur during drug withdrawal (withdrawal-emergent dyskinesia). Such dyskinesias often clear spontaneously over several weeks and do not require specific treatment. In severe cases, the drug may need to be reintroduced and tapered more slowly [7]. Alternatively, concurrent symptomatic therapy for TD may be initiated in an attempt to facilitate the taper. (See 'Persistent, moderate to severe TD' below.)
●TD may recur if a dopamine receptor-blocking agent is reintroduced. When possible, a second-generation antipsychotic drug with a low risk of TD should be used in preference to high-potency, first-generation drugs in patients with a history of TD who require reintroduction of antipsychotic therapy.
Despite the presumption and practice of discontinuing or reducing the dopamine receptor blocker, the effectiveness of this practice has not been well studied prospectively [8-10]. Studies primarily involve patients with chronic psychiatric illness and longstanding TD. A 2018 systematic review identified two trials that evaluated antipsychotic dose reduction versus dose maintenance in a total of 17 patients with TD [9]. Pooled data showed that dose reduction was associated with a trend toward a clinically important reduction in TD severity (relative risk 0.42, 95% CI 0.17-1.04).
Patients who require ongoing antipsychotic therapy
Patients on a first-generation antipsychotic drug — Often when patients with severe psychiatric disease develop TD on a first-generation antipsychotic drug, antipsychotic therapy cannot be safely discontinued. For such patients, we suggest switching to a second-generation antipsychotic drug with lower TD risk, whenever possible [11]. Such a switch may not exacerbate TD and may result in a reduction in TD severity over time, particularly for early and mild symptoms.
For longstanding TD, clinicians and patients should be aware that improvement in symptoms may take months or years, and in some cases there may be no observable benefit. Therefore, the potential benefits of a switch may not outweigh the risk of worsening psychosis for longstanding TD.
There are no randomized trials comparing the effects of different second-generation antipsychotic drugs in patients with TD caused by a first-generation antipsychotic drug. Risk of TD varies among second-generation drugs, largely in relation to their potency as dopaminergic D2 receptor blockers. Clozapine, quetiapine, and iloperidone have relatively weak affinity for dopamine receptors and thus carry a potentially lower risk of causing or exacerbating TD. (See "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis", section on 'Antipsychotic drugs'.)
The low affinity for dopamine receptors makes clozapine a preferable second-generation antipsychotic in the setting of TD. The evidence in support of clozapine consists largely of observational studies and secondary analyses of randomized trials [12-18]. However, the rare but potentially serious risk of bone marrow toxicity and the need for monitoring of blood counts make it an impractical choice for most practitioners. Because quetiapine does not carry this same risk, it is a more practical option and may have similar ameliorating effects on TD [19-21]. Administration of clozapine is reviewed separately. (See "Schizophrenia in adults: Guidelines for prescribing clozapine".)
Choosing a second-generation antipsychotic drug such as risperidone and olanzapine is also an option that may be preferable over continuing the first-generation antipsychotic therapy [11,22-27]. Sixty patients with TD on a first-generation antipsychotic were randomly assigned to either risperidone or olanzapine after a three- to seven-day washout period of the original antipsychotic [25]. At 24 weeks, Abnormal Involuntary Movement Scale (AIMS) scores by blinded raters improved over baseline in both groups (risperidone: -7.4 points, olanzapine: -6.2 points).
The mechanism of benefit of clozapine or other second-generation drugs is likely primarily an antipsychotic drug "sparing" effect, in which gradual improvement of TD occurs with weaker dopamine-blocking effects. A direct antidyskinetic effect is less likely. With high doses of antipsychotic drugs, TD may be masked by parkinsonism, but this practice is not recommended [11].
Patients on a second-generation antipsychotic drug — When patients develop TD on a second-generation antipsychotic drug with no prior exposure to dopamine receptor-blocking agents, the indication and dose of the drug should be reviewed. In some cases, a lower effective dose or an alternative class of drugs may be used.
If the patient requires ongoing therapy for psychiatric disease and the severity of TD is bothersome, clinicians may consider a switch to clozapine, based on the data reviewed above. (See 'Patients on a first-generation antipsychotic drug' above.)
Other patients may elect to stay on the same second-generation drug and try a symptomatic therapy such as vesicular monoamine transporter type 2 (VMAT2) inhibitor if movements are bothersome enough to require treatment. (See 'Persistent, moderate to severe TD' below.)
Assess need for symptomatic therapy — Symptoms of TD can be disfiguring and stigmatizing. However, some patients are less troubled or aware of their symptoms and may not require as aggressive an approach. For patients with ongoing symptoms despite an optimized medical regimen, drug treatment for TD should be considered after weighing an individual's level of disability and quality of life with potential side effects and burden of additional treatments.
PERSISTENT, MODERATE TO SEVERE TD
Overview of approach
●For patients with persistent and bothersome TD, vesicular monoamine transporter type 2 (VMAT2) inhibitors are the primary symptomatic therapy (algorithm 1). Benzodiazepine therapy is sometimes helpful for mild symptoms but is unlikely to help more severe TD. (See 'Vesicular monoamine transporter type 2 inhibitors' below and 'Other drug treatments' below.)
●For the subset of patients with tardive dystonia (eg, cervical and truncal dystonia, blepharospasm), botulinum toxin injections are a localized option that may spare the need for systemic drug therapy (algorithm 1). (See 'Tardive dystonia' below.)
●Patients with refractory TD despite symptomatic therapies should be referred to a movement disorder specialist for consideration of deep brain stimulation (DBS). (See 'Deep brain stimulation (DBS)' below.)
Vesicular monoamine transporter type 2 inhibitors — VMAT2 inhibitors are the main symptomatic drug therapy available for TD. In patients with moderate to severe or disabling TD associated with antipsychotic therapy, VMAT2 inhibitors can be associated with meaningful reductions in motor signs and symptoms [28-30].
They can be used with or without concurrent antipsychotic drug therapy. The drugs act centrally to suppress TD by depleting dopamine storage in presynaptic vesicles.
Selecting an agent — There are three available VMAT2 inhibitors for hyperkinetic disorders such as TD. Tetrabenazine has been available for decades and was approved by the US Food and Drug Administration (FDA) in 2008 for chorea in patients with Huntington disease. Two newer VMAT2 inhibitors, valbenazine and deutetrabenazine, were FDA approved in 2017 for the treatment of TD.
The three drugs have not been compared directly, and regional availability and cost influence agent selection in some cases. Valbenazine and deutetrabenazine are not approved in Canada, for example. Assuming availability of all three, we generally prefer the newer agents, based primarily on longer half-life and convenience.
The quality of the evidence for each of the three drugs is not uniform, but the overall finding of benefit over placebo is consistent. For valbenazine and deutetrabenazine, the available evidence consists of randomized trials with low risk of bias and good sample sizes [28]. The duration of the randomized phase of the trials was relatively short, and as little as four to six weeks in some studies. Long-term follow-up data are based primarily on open-label extension phases of the randomized trials. Data on tetrabenazine have a higher risk of bias, smaller sample sizes, and inadequate blinding, yielding lower confidence; on the other hand, tetrabenazine is associated with greater cumulative clinical experience than the newer drugs.
Dosing and efficacy
Valbenazine
●Dosing – The recommended starting dose of valbenazine is 40 mg daily. The dose can be increased as needed after one or more weeks to a maximum dose of 80 mg daily. The maximum recommended dose is 40 mg/day in patients taking strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine, bupropion) (table 2) or strong CYP3A4 inhibitors (table 3). Specific interactions may be determined using the drug interactions program included within UpToDate.
●Efficacy – Valbenazine was approved for treatment of TD based on the six-week KINECT-2 and KINECT-3 trials [31-34]. The larger KINECT-3 trial enrolled 225 patients with schizophrenia, schizoaffective disorder, or a mood disorder and moderate or severe TD [31]. Patients were randomly assigned to treatment with valbenazine 80 mg once daily, valbenazine 40 mg once daily, or placebo. By intention-to-treat analysis, valbenazine reduced the mean Abnormal Involuntary Movement Scale (AIMS) dyskinesia score, items 1 to 7 of the AIMS (form 1), from baseline to week 6 for the 80 mg/day (-3.2) and 40 mg/day groups (-1.9) compared with placebo (-0.1). Valbenazine treatment at both doses was generally well tolerated. Responses were sustained in a 48-week open-label follow-up study, where there were no differences in efficacy or tolerability for older (>50 years) versus younger patients [35,36].
Deutetrabenazine
●Dosing – The starting dose of deutetrabenazine is 6 mg twice daily. The dose can be increased weekly in 6 mg/day increments depending on response and tolerability. In a two-year open-label extension study, the mean daily maintenance dose was 38 mg [37]. The maximum recommended dose is 36 mg/day in patients taking strong CYP2D6 inhibitors (table 2) and 48 mg/day in all others. Specific interactions may be determined using the Lexicomp drug interactions tool (Lexi-Interact online) included in UpToDate.
●Efficacy – In the ARM-TD trial, 117 patients with moderate to severe TD were randomly assigned to deutetrabenazine or placebo (titrated to a mean total daily dose of approximately 39 mg/day). Over 12 weeks, deutetrabenazine significantly reduced the AIMS score compared with placebo (-3.0 versus -1.6) [38]. However, a clinical global impression of change was not significantly different, despite a trend favoring deutetrabenazine. In the larger 12-week AIM-TD trial, AIMS scores were improved with 36 mg daily of deutetrabenazine (-3.3 versus -1.4) and 24 mg daily (-3.2 versus -1.4) but not with the 12 mg dose [39].
The effect of deutetrabenazine appears to be maintained over time, although follow-up data beyond two years are not available. In an open-label extension study that enrolled 343 patients who had completed the AIM-TD or ARM-TD trial, AIMS scores remained stable over a mean treatment duration of approximately one year, and no new safety concerns arose [37]. Limitations of the study included a relatively high rate of attrition, with only 69 percent of patients available for efficacy analysis by week 28.
Tetrabenazine
●Dosing – Tetrabenazine is initiated with 12.5 mg daily for one week and increased by 12.5 mg increments every five to seven days, to a usual effective dose of 75 to 150 mg daily. Because of its relatively short half-life, tetrabenazine is typically dosed three times daily. The maximum recommended single and daily doses are lower (25 and 50 mg, respectively) for patients taking strong CYP2D6 inhibitors (table 2). Specific interactions may be determined using the Lexicomp drug interactions tool (Lexi-Interact online) included in UpToDate.
●Efficacy – Efficacy data for tetrabenazine consist of several small, mostly open-label trials in patients with TD [8]. In a double-blind, crossover trial with 24 patients, marked reduction or resolution of dyskinesia occurred in 70 percent of patients treated with tetrabenazine (up to 150 mg daily) [40]. An open-label study in a small group of patients with chronic psychosis found that tetrabenazine was less effective for TD than haloperidol [41]. Several open-label studies have demonstrated improvement in TD with tetrabenazine in doses of up to 200 mg daily [42,43].
Adverse effects and precautions — All three VMAT2 inhibitors share common toxicities, most of which relate to their action of depleting synaptic dopamine.
The most common side effects are somnolence and fatigue. Somnolence usually improves with time and/or slower titration. Less common side effects, reported mainly in studies of tetrabenazine, include akathisia, parkinsonism, depression, tremor, insomnia, confusion, nausea, vomiting, hypotension, and dizziness. With long-term use, the most commonly reported side effects are anxiety, somnolence, and depression [37].
In addition, all VMAT2 inhibitors carry a boxed warning regarding the risk of depression and suicidality in patients with Huntington disease. Additional warnings include the potential for QT prolongation and neuroleptic malignant syndrome.
Benzodiazepines — Prior to the availability of VMAT2 inhibitors, benzodiazepines were commonly used for TD. Although evidence of efficacy is limited, our experience is that a benzodiazepine such as clonazepam can be helpful to reduce both dyskinesia and associated anxiety in patients with mild TD, at least in the short term. Patients with more severe TD are less likely to benefit. Tolerance and loss of efficacy limit usefulness as a long-term therapy [8].
●Dosing – Clonazepam is typically started at 0.5 mg daily and titrated by 0.5 mg increments every five days according to response and as tolerated, up to a maximum of 3 to 4 mg/day.
●Adverse effects – Side effects of benzodiazepines include sedation, confusion, ataxia, and risk of falls, particularly in older adults. Central nervous system depressant effects may be potentiated by barbiturates, hypnotics, anxiolytic, antipsychotic, and antidepressant drugs.
●Efficacy – Evidence of benefit in patients with TD is limited and inconclusive [44,45]. A systematic review identified four trials in a total of 75 patients with schizophrenia or other chronic psychiatric illness that compared benzodiazepines with placebo, inactive control, or no intervention [45]. In two trials with 32 patients, there was no difference between benzodiazepine treatment and placebo for clinically important improvement, defined as a ≥50 percent improvement in any validated scale for TD (relative risk 1.12, 95% CI 0.60-2.09). A single trial in 21 patients found that more patients taking clonazepam had clinically important improvement compared with phenobarbital (60 versus 9 percent).
Other drug treatments — Beyond VMAT2 inhibitors and benzodiazepines, there is insufficient evidence to support routine use of any other drugs for TD, although many have been studied.
●Amantadine – Amantadine may be useful as an adjunct therapy if antipsychotics need to be continued [8]. An 18-week crossover trial that randomly assigned 16 patients to amantadine (300 mg/day) or placebo showed that amantadine could be used without exacerbating psychotic symptoms [46].
●Ginkgo biloba extract – A Chinese randomized controlled trial evaluated the effects of a standardized extract of Ginkgo biloba leaves known as EGb-761 in 157 patients with schizophrenia and TD [47]. After 12 weeks, treatment with EGb-761 significantly decreased the AIMS score, with 51 percent of the treatment group achieving ≥30 percent reduction in the AIMS score versus 5.1 percent of the placebo group.
●Others – A number of other agents have been evaluated for TD with mixed or negative results, including vitamin E, beta blockers, calcium channel blockers, serotonin antagonists, gamma-aminobutyric acid (GABA) agonists, valproate, levetiracetam, buspirone, vitamin B6, and lithium [8,48-55].
Deep brain stimulation (DBS) — Patients with persistent, disabling TD that is unresponsive to pharmacologic treatment may benefit from referral to a multidisciplinary movement disorders clinic for consideration of DBS.
DBS of the globus pallidus interna (GPi) is well established as a treatment for medically refractory idiopathic primary dystonia and Parkinson disease, with a particular benefit in reduction of levodopa-induced dyskinesia. It follows that pallidal DBS was adopted for other hyperkinetic disorders such as TD. (See "Device-assisted and lesioning procedures for Parkinson disease" and "Treatment of dystonia in children and adults", section on 'Surgical therapy'.)
Limited data in patients with refractory TD suggest that it is reasonable to pursue in select patients [8,11,29].
●Refractory TD – One of the larger prospective studies of DBS for TD included 19 patients with resolved or stabilized psychiatric disease who had severe TD refractory to medical treatment [56]. All were treated with bilateral DBS of the GPi. Six months after surgical lead implantation, blinded evaluations revealed significantly lower Extrapyramidal Symptoms Rating Scale (ESRS) scores with stimulation on compared with stimulation off (mean decrease 49 percent, range 9 to 84 percent). Among 14 patients with long-term (6 to 11 years) follow-up, the improvement in ESRS scores with stimulation "on" was maintained (mean decrease 60 percent, range 22 to 90 percent). Similar short-term and long-term improvement was observed when outcome was assessed with the AIMS.
●Refractory tardive dystonia – In case reports and small series, patients with severe forms of TD manifesting primarily as dystonia were successfully treated with DBS of the GPi or subthalamic nucleus [57-62]. These patients displayed various combinations of orofacial, cervical, and truncal dyskinesia and dystonia that improved dramatically within a relatively short period of time after surgery. One unblinded and uncontrolled study of nine patients with refractory tardive dystonia found that benefit of DBS persisted for longer than one year [62].
TARDIVE DYSTONIA — Although less common than the classic orofacial dyskinesias of TDs, tardive dystonia is important to recognize because patients may benefit from botulinum toxin injections, which can spare the systemic side effects of oral therapies.
Botulinum toxin injections — We suggest botulinum toxin injections for patients with local forms of debilitating tardive dystonia, such as cervical dystonia, retrocollis, oromandibular dystonia, and blepharospasm (algorithm 1) [5].
●Administration – The dose of botulinum toxin used depends on site of injection, the serotype, and the formulation. The most common forms of TD treated with botulinum toxin are cervical dystonia, oromandibular dystonia, and blepharospasm (involuntary forced eye closure). Injections are repeated approximately every three months. Adverse effects include excessive weakness of injected or neighboring muscles. Botulinum toxin should be avoided in patients with myasthenia gravis or related neuromuscular conditions.
Dosing is individualized according to the form of dystonia, target muscles, and brand and serotype of toxin used. For cervical dystonia, 150 units of onabotulinumtoxinA (Botox) is a general starting dose that can be increased as needed and tolerated to 300 to 400 units. Blepharospasm can be treated with a lower dose of onabotulinumtoxinA, with typical doses varying between 25 to 75 units in orbicularis oculi and associated facial muscles.
IncobotulinumtoxinA (Xeomin) and abobotulinumtoxinA (Dysport) are alternative formulations of botulinum toxin type A, approved for cervical and other forms of dystonia. It is important to note that dosing of incobotulinumtoxinA is similar to onabotulinumtoxinA (but not equivalent), while abobotulinumtoxinA requires a larger-unit dose (approximately three to five times higher).
For patients who do not respond or become refractory to a type A toxin, rimabotulinumtoxinB (Myobloc) can be used. Although it is customary to use rimabotulinumtoxinB as an alternative to type A toxins, it is also possible to use this as the first toxin in a treatment-naive patient. RimabotulinumtoxinB is typically administered in unit doses approximately 40 to 50 times higher than onabotulinumtoxinA or incobotulinumtoxinA.
●Efficacy – Evidence for the effectiveness of botulinum toxin for TD consists of retrospective case series and case reports [8]. In one multicenter study, botulinum toxin produced marked or moderate improvement in 29 of 34 patients with relatively localized TD manifesting as cervical dystonia or blepharospasm in most cases [63]. In another retrospective study, botulinum toxin treatment was associated with similar improvement in tardive cervical dystonia (n = 7) and idiopathic cervical dystonia (n = 156) [64].
Nonfocal or refractory dystonia — For patients with more widespread tardive dystonia, botulinum toxin injections may not be safe or practical. Vesicular monoamine transporter type 2 (VMAT2) inhibitors are the primary drug therapy for TD. DBS may also be an option in select patients, as reviewed above. (See 'Vesicular monoamine transporter type 2 inhibitors' above and 'Deep brain stimulation (DBS)' above.)
Anticholinergic drugs (eg, trihexyphenidyl, benztropine) are one additional option for refractory tardive dystonia. Although they are usually ineffective in patients with TD or may even exacerbate choreiform dyskinesias, they are sometimes helpful in ameliorating tardive dystonia. This is consistent with the observation that anticholinergics often exacerbate other hyperkinetic disorders but may be useful in primary dystonia. (See "Treatment of dystonia in children and adults".)
Retrospective studies have shown improvement in tardive dystonia following trihexyphenidyl (10 to 32 mg daily) in three of eight patients [42] and with trihexyphenidyl (6 to 12 mg daily) in 8 of 21 patients [65].
When used for tardive dystonia, trihexyphenidyl can be initiated at 1 mg twice daily and titrated to a total dose of 4 to 6 mg daily as tolerated.
Narrow-angle glaucoma, confusion, and dementia are contraindications to the use of trihexyphenidyl. The possibility of exacerbating underlying psychosis is a particular concern in patients with TD. Trihexyphenidyl should be used with caution in people over 60, and in patients with benign prostatic hypertrophy or obstructive gastrointestinal disorders. Other anticholinergic side effects include dry mouth, blurred vision, constipation, urinary hesitancy or retention, tachycardia, pupillary dilatation, and increased intraocular pressure. Patients may develop tolerance to these effects with continued low-dose treatment. Additional side effects of trihexyphenidyl include dizziness, confusion, memory impairment, nausea, vomiting, and anxiety.
PROGNOSIS — Although once considered a persistent or permanent condition, TD is often reversible. In historical studies, remission rates of persistent TD were only 5 to 40 percent, but early identification of TD in younger outpatient populations has been associated with remission in 50 to 90 percent of patients [66]. Remission of TD usually occurs within several months after withdrawal of the offending agent, but may occur as late as one to three years after withdrawal [67].
Prognosis of TD in patients who require continued antipsychotic drug treatment is not well established, but fortunately, continued antipsychotic drug exposure does not appear to worsen the severity of TD once it becomes established or chronic [68,69]. In most cases, TD either remains unchanged or is suppressed by the hypokinetic effects of an antipsychotic drug.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Tardive dyskinesia (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition – Tardive dyskinesia (TD) is a medication-induced hyperkinetic movement disorder that can be disabling and irreversible. All dopamine receptor-blocking agents have the potential to cause TD. The most commonly implicated drugs are antipsychotics and metoclopramide. (See 'Introduction' above.)
●Prevention – The only certain way to prevent TD is to avoid chronic administration of dopamine receptor-blocking agents. The use of antipsychotic drugs should be limited to situations where there is no alternative effective therapy. Metoclopramide should not be used continuously for longer than 12 weeks. Particular caution is required in high-risk groups (table 1). (See 'Prevention' above.)
•Patients receiving long-term antipsychotic drugs or metoclopramide should be regularly screened for the development of TD (form 1). (See 'Monitoring during treatment' above.)
•If dyskinesia develops during treatment with a dopamine receptor-blocking agent, the offending drug should be discontinued, whenever possible (algorithm 1). Dyskinesias may worsen transiently during withdrawal and may take weeks to months to improve. (See 'Discontinue offending agent, if possible' above.)
•For most patients who develop TD on a first-generation antipsychotic but still require antipsychotic therapy, we suggest switching to a second-generation antipsychotic drug (Grade 2C). Such a switch seldom worsens TD and may result in a reduction in TD severity, particularly for early and mild symptoms. (See 'Patients on a first-generation antipsychotic drug' above.)
•For patients who develop TD on a second-generation antipsychotic drug that cannot be discontinued, options include lowering the dose, when possible, switching to clozapine, and using symptomatic therapy to suppress TD. (See 'Patients on a second-generation antipsychotic drug' above.)
●Symptomatic therapy – Mild TD may not be sufficiently bothersome to require treatment and its associated side effects. For patients with moderate to severe TD, vesicular monoamine transporter type 2 (VMAT2) inhibitors and botulinum toxin injections are the main symptomatic therapies (algorithm 1). (See 'Overview of approach' above.)
•For patients with ongoing moderate to severe TD, we suggest treatment with a VMAT2 inhibitor (valbenazine, deutetrabenazine, or tetrabenazine) (Grade 2B). Benzodiazepines are sometimes helpful for mild symptoms but are unlikely to help more severe TD. (See 'Vesicular monoamine transporter type 2 inhibitors' above.)
The three VMAT2 inhibitors have not been compared directly, and regional availability and cost may vary. When available, we generally prefer the newer agents (valbenazine and deutetrabenazine), based primarily on longer half-life and convenience.
•For the subset of patients with focal tardive dystonia (eg, cervical dystonia), we suggest botulinum toxin injections (Grade 2C). VMAT2 inhibitors and anticholinergic drugs are an alternative if botulinum toxin is not effective or practical. (See 'Botulinum toxin injections' above.)
●Refractory dyskinesia – Patients with permanent, disabling TD may be candidates for surgical therapy with deep brain stimulation (DBS) and should be referred to a multidisciplinary movement disorder center for consideration. (See 'Deep brain stimulation (DBS)' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Daniel Tarsy, MD, who contributed to earlier versions of this topic review.
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