US Pharm. 2014;39(1):HS13-HS16.

ABSTRACT: Tardive dyskinesia (TD), a drug-induced movement disorder, is a serious side effect resulting primarily from the prolonged use of dopamine-blocking agents. TD is distressing because this adverse effect is likely to be permanent. Age is a consistent risk factor for TD, and the disorder occurs more frequently in women. Most treatments for TD have not proven to be successful, and therefore the best treatment option is prevention of the disorder. If a drug known to cause TD is prescribed, the clinician should monitor the patient for symptoms. Early detection may improve the likelihood of remission.

Tardive dyskinesia (TD) is a drug-induced movement disorder (DIMD) characterized by the presence of abnormal involuntary movements.1-3 TD was named and classified in the early 1960s, a number of years after chlorpromazine was marketed in the United States as an antipsychotic agent.4 Chlorpromazine revolutionized the treatment of schizophrenia.4 Neurologic side effects such as involuntary movements and tics began to be reported.2,3 Initially, these neuromuscular disorders (i.e., movement disorders) were attributed to the psychiatric disease, rather than to incitement by a drug. However, based on the prevalence of TD in psychiatric patients, it was eventually established that these movement disorders were linked to the use of antipsychotics that block dopamine receptors.3

Causes

These early agents used in the treatment of psychosis were termed first-generation antipsychotics (FGAs), or typical antipsychotics. TD has been reported with all FGAs. When the second-generation antipsychotics (SGAs), or atypical antipsychotics, were developed, researchers expected lower rates of TD based on the weaker affinity of these drugs for blocking dopamine receptors.5

While the risk of TD may be lower with SGAs, it still does occur. TD is listed in all of these agents’ package inserts, although clozapine has had only rare or unconvincing reports of TD.6-10 Quetiapine also appears to have a lower tendency to cause TD; however, for both quetiapine and clozapine, data have been conflicting.2,7-9

Antipsychotics are the primary drugs associated with TD, but there are nonpsychiatric drugs that also block dopamine receptors and are associated with TD (TABLE 1).2,8,9,11 One of these agents, metoclopramide, has been on the U.S. market since 1979, and its use has increased over the past decade. In 2009, the FDA issued a warning about the risk of TD associated with metoclopramide use. At that time, more than 2 million patients were taking metoclopramide. Failure to recognize the importance of the warning became a concern because of the possibility that nonpsychiatric clinicians prescribing metoclopramide were less familiar with the side effect than were psychiatric clinicians, who were aware of the connection between antipsychotics and TD.12


Incidence

TD develops in approximately 20% of patients on long-term antipsychotic drugs, although there is some debate over a lower incidence with SGAs.4,13,14 Prevalence rates are widely variable, depending upon the study design, participants, duration of use of previous inciting agents, and diagnostic criteria.4 The incidence of TD with metoclopramide (a gastrointestinal prokinetic agent used to treat symptomatic gastroesophageal reflux disease, diabetic gastroparesis, and nausea and vomiting) has been reported to range from 1% to 10%.15 A more recent review of TD associated with metoclopramide stated that the risk may be closer to less than 1%.3,12

DIMD Classification and Symptoms

The various movement disorders—which can be confusing to patients and clinicians alike—are classified based on timing and specific symptomatology. There are two major categories of DIMD: acute (transient) and chronic (persistent). Acute symptoms occur during the early phase of drug therapy and are frequently short-lived. Chronic symptoms commonly arise with prolonged use of the inciting drug. Some thought leaders believe that permanent movement disorders may arise after a single dose of a dopamine receptor antagonist, but the general consensus supports the chronic-use concept.13

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), developed and published by the American Psychiatric Association, includes classifications of all currently recognized mental health disorders. In DSM-5, DIMDs are termed medication-induced movement disorders (MIMDs). The MIMDs listed in DSM-5 include neuroleptic-induced parkinsonism and other medication-induced parkinsonism; neuroleptic malignant syndrome (NMS); medication-induced acute dystonia; medication-induced acute akathisia; TD; tardive dystonia and tardive akathisia; medication-induced postural tremor; and other medication-induced movement disorders (TABLE 2).16


Medication-induced parkinsonism can be misdiagnosed as Parkinson disease (PD) because of the similarity of symptoms, including tremor, bradykinesia, and abnormal gait. Sudden transient freezing, one of the most distressing symptoms of PD, is not seen in medication-induced parkinsonism.2 NMS, which can be life-threatening, occurs in 0.01% to 0.02% of patients treated with antipsychotics.16 Symptoms of NMS include altered mental status, hyperthermia, altered blood pressure, tachycardia, tachypnea, and muscle stiffness.16 Withdrawal of the inciting drug, fluid and electrolyte replacement, lowering of the body temperature, and management of cardiac and renal complications are essential.3

Acute dystonia and akathisia can occur very quickly after the drug is taken. Acute dystonia involves abnormal and prolonged contraction of the muscles of the eye, head, neck, limbs, or trunk.2,16 In tardive dystonia, a variant of TD, the abnormal movements are distinct from those of classic TD. TD more often develops in older women; tardive dystonia more often manifests in younger patients and has no affinity for gender.2 TD can occur after brief exposure to a dopamine-blocking agent, but it usually manifests after months or years of therapy.3 Acute akathisia is characterized by a sensation of restlessness, a constant urge to move, and anxiety.16 Tardive akathisia, a subtype of TD, occurs after prolonged use of dopamine-blocking therapy and is clinically similar to acute akathisia.2

Medication-induced postural tremor is expressed as a fine tremor that occurs when the patient attempts to maintain a posture. The tremor is similar to that seen with anxiety and the use of caffeine and other stimulants.16

TD is a DIMD of particular concern for the clinician, patient, and family because of the severe and potentially irreversible motor effects. TD is characterized by persistent, involuntary, rapid, and repetitive stereotypical movements that involve the oral, buccal, and lingual areas (tongue, cheeks, lips, and jaw). The patient may experience twisting and protrusion of the tongue, smacking of the lips, and chewing or puckering of the mouth. Some involuntary movements, such as the tongue pushing food out of the mouth, can be particularly problematic.4,13,17,18 Frequently, the continual movement of the tongue causes sores to develop inside the cheeks. This can lead to considerable difficulty for patients with dentures.13

TD can cause other facial movements, such as grimacing, eyebrow raising or furrowing, and eye closing. If the limbs are involved, quick movements of the fingers or toes occur, and nonrhythmic movements of the arms and legs also take place. The patient may extend the toes and tap the foot while sitting.4 The larynx and diaphragm may be involved, although they rarely cause vocal or breathing problems.18 The patient may be unaware of the movements or underrate their magnitude.13 Symptoms are more pronounced when the patient is awake and/or excited, and they tend to resolve during sleep. At times, it may be possible for the patient to contain the movements with a strong, concentrated effort.4,19 The major risk factors associated with TD are advanced age, female sex, mood disorders, organic brain dysfunction, greater total drug exposure, and early extrapyramidal symptoms (EPS).2,4

Etiology

The exact pathophysiology of DIMDs is unknown, but several mechanisms of action have been proposed. The chronic blockade of dopamine receptors by these drugs, leading to an escalation in receptor sensitivity, is one of the most frequently postulated causes.3,20

Diagnosis

To determine whether a patient’s movement disorder is TD, the clinician first must exclude other movement disorders, and the diagnosis is usually validated by a physical examination, along with a neuropsychiatric and medication history.4,7 Several scales are available to help the clinician accurately assess TD. The Abnormal Involuntary Movement Scale (AIMS) is widely used to detect TD and track its severity over a period of time.21 The AIMS includes 12 items that assess orofacial movements, extremity and truncal dyskinesia, and global severity from the examiner’s evaluation, along with the patient’s awareness of the movements. The last section of the AIMS contains questions on problems with teeth and dentures.

Treatment

The optimal treatment path for TD is to prevent the disorder from occurring.11 Many studies have evaluated treatments for TD, with a few showing slight or modest improvements for patients. In July 2013, the American Academy of Neurology (AAN) published evidence-based guidelines for the treatment of tardive syndromes (TDS), including TD. The panel defined TDS as including lingual-facial-buccal dyskinesia, as well as the variant forms. TDS encompasses all types of persistent dyskinesia caused by dopamine-blocking agents.22

TDS are disorders that meet the following criteria: a history of at least 3 months of neuroleptic exposure; the presence of at least moderate abnormal involuntary movements in one or more body areas, or at least mild movements in two or more body areas; and the absence of other conditions.

The AAN panel recommended that five questions be addressed to determine the management of TDS, including TD. The questions are as follows: 1) Is withdrawal of the dopamine receptor blocker an effective treatment for TDS? 2) Does switching from typical to atypical dopamine-blocking agents reduce TDS symptoms? 3) What is the efficacy of pharmacologic agents in treating TDS? 4) Do patients with TDS benefit from chemodenervation with botulinum toxin? and 5) Do patients with TDS benefit from surgical therapy?22

The guidelines state that data are insufficient to support or refute withdrawal of the agent as treatment; however, from a clinical context, if TDS is present, it is recommended that the clinician withdraw the antipsychotic. This applies only to patients who can tolerate this, however. Although evidence is limited, the guidelines note that short-term withdrawal may worsen TDS, whereas adding an antipsychotic with stronger EPS can reduce it. Data were insufficient to support or refute switching from a typical dopamine receptor blocking antagonist to an atypical agent to reduce TDS symptoms.22

The AAN panel reviewed studies involving several pharmacologic agents for the treatment of TDS. In a randomized, controlled study, amantadine (300 mg/day) used conjointly with neuroleptics reduced TDS during the first 7 weeks. The panel suggested consideration of treatment with amantadine plus neuroleptics for short-term use, based on weak evidence.22

Tetrabenazine, a dopamine-depleting agent, is licensed in other countries for treatment of TD. In the U.S., tetrabenazine (Xenazine) is approved to treat chorea associated with Huntington disease (HD), but not to treat TD. The initial dosing for HD-associated chorea is 12.5 mg/day.20 The AAN panel found weak evidence to support the use of tetrabenazine for TDS. In a trial involving haloperidol, tetrabenazine was dosed at 100 mg/day for 14 weeks. A second nonrandomized study had participants discontinue the neuroleptic and other TDS treatments at least 30 days before baseline. Reductions in symptoms were seen posttreatment with tetrabenazine at a mean dose of 57.9 mg/day.22

Benzodiazepine trials have yielded limited results. In a Cochrane Review, one small study provided preliminary evidence that benzodiazepines may have an effect in the treatment of TD.23 Clonazepam was the benzodiazepine used in this study, and the AAN stated that this drug may be helpful for short-term (3 months) use in decreasing TD symptoms, with moderate evidence supporting its use.22

Trials utilizing melatonin, ginkgo biloba, vitamin E, and vitamin B6 have had mixed results.22,24 Melatonin dosed at 2 mg/day was “possibly ineffective,” but a dosage of 10 mg/day for a longer period of time was purported to be feasibly effective in treating TDS, although the AAN panel deemed that the evidence was insufficient. There was moderate evidence supporting the use of ginkgo biloba in inpatients with schizophrenia who had TD. Vitamin E, which was used to neutralize free radicals, generated some improvement in newly diagnosed TD present for less than 5 years. Another study, which used vitamin E dosages of 1,200-1,600 IU/day for 4 to 12 weeks, reported reduced TD severity.22,25 However, the AAN panel determined that the data were conflicting and insufficient to determine efficacy.

Data also were insufficient to support or refute the efficacy of TDS treatment with acetazolamide, bromocriptine, thiamine, baclofen, vitamins B12 and B22, selegiline, clozapine, olanzapine, nifedipine, fluperlapine, sulpiride, flupenthixol, thiopropazate, haloperidol, levetiracetam, quetiapine, ziprasidone, sertindole, aripiprazole, buspirone, yi-gan san, botulinum, alpha-methyldopa, reserpine, electroconvulsive therapy, or biperiden discontinuation. Diltiazem, galantamine, and eicosapentaenoic acid should not be considered treatment options, according to the AAN panel.22

Surgical interventions have been explored as treatment for TD. Deep brain stimulation (DBS), currently used in many PD patients, may be a potential treatment option for TD.26 A systematic review of studies (many of which were case studies) in which DBS was used to treat medication-induced TD and/or dystonia found improvement in these treatment-resistant patients. Results were not reported for TD and dystonia separately, although the authors stated that this was not an issue since most patients experience both conditions. The mean improvement 3 to 76 months after DBS was 77.5% according to the Burke-Fahn-Marsden Dystonia Rating Scale.27 However, the AAN deemed that the evidence was insufficient to determine benefit.22

Conclusion

TD can significantly alter the patient’s quality of life. The pharmacist can actively educate patients about the risk of DIMDs when the prescribed medications are associated with these side effects. The pharmacist can also provide patients with information about the initial signs and symptoms of TD. Remission rates are inversely correlated with the severity and length of time of TD.17 Early detection may improve the chances of minimizing the disorder or achieving remission.2,21,25,28

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