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Tardive dyskinesia syndromes: current concepts
Parkinsonism and Related Disorders 20S1 (2014) S113–S117
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Tardive dyskinesia syndromes: current concepts Camila Catherine H. Aquino, Anthony E. Lang * Morton and Gloria Shulman Movement Disorders Center and the Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, Toronto, Canada
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Keywords: Tardive syndrome Tardive dyskinesia Antipsychotics
Tardive syndromes (TS) encompass a broad spectrum of abnormal movements due to chronic exposure to dopamine receptor blocking agents. This review provides a compiled update on TS, including phenomenology, epidemiology, pathophysiology, genetic correlations and therapeutics, highlighting the emerging experience with atypical antipsychotics. The advent of atypical antipsychotics, which have lower affinity for dopamine receptors and act on 5-HT2A and 5-HT2C serotonin receptors, was expected to dramatically reduce the prevalence and incidence of this iatrogenic problem. Recent studies have shown that the reduction has been more modest than expected and TS remains an important challenge. Recent insights on pathophysiology, risk factors and genetic correlations have raised the hope for further individualized treatment for schizophrenic patients, and more strict use of antipsychotics. Up to now, there is no definite treatment for TS, but options range from relatively innocuous low doses of propranolol to more invasive procedures such as deep brain stimulation. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction Tardive dyskinesia (TD) is a term historically used to refer to delayed and persistent abnormal movements caused by exposure to dopamine receptor blocking agents (DRBA). There are several distinct phenomenologies under the definition of TD justifying the term tardive syndrome (TS) to encompass the broad spectrum of symptoms that can develop after chronic use of DRBA [1]. According to the diagnostic and statistical manual of mental disorders, fourth edition (DSM IV), the spectrum of TD includes involuntary movements of the tongue, jaw, trunk, or extremities, and may be choreiform, athetoid, or stereotypic in nature. Abnormal movements should appear during exposure, or within 4 weeks of withdrawal from oral DRBA or 8 weeks from depot formulations. The minimal exposure to DRBA should be 3 months, except for patients older than 60, who can develop TD after using DRBA for 1 month. Finally, the movements should be present for at least 1 month to fulfill the criteria for TD [2]. TS have been strongly associated with antipsychotic drugs, however, several other classes of drugs, such as the antiemetic metoclopramide and the calcium channel blockers cinnarizine and flunarizine, occupy dopamine receptors and have been associated with movement disorders and TS [1,3]. The advent and widespread use of atypical antipsychotics in clinical practice had been expected to dramatically reduce the incidence and prevalence of TS, however the reduction, if any, was modest [4]. * Corresponding author. Dr. Anthony E. Lang, Toronto Western Hospital, 399 Bathurst Street, 7th Floor, McLaughlin pavilion, Toronto, Ontario, Canada M5T 2S8. E-mail address: [email protected] (A.E. Lang). 1353-8020/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
In view of this, TS is a challenging condition for neurologists and psychiatrists, due to lack of definite risk factors to predict patients who will develop this condition; complex and usually mixed presentation; suboptimal results with treatment and the common persistent, chronic course. In this review we provide a compiled update on TS, including phenomenology, epidemiology, pathophysiology, genetic correlations and therapeutics, highlighting the emerging experience with atypical antipsychotics. 2. Phenomenology of tardive syndromes Distinct hyperkinetic movement disorders have been described as part of the TS [3]. More recently there is a tendency to reserve the term “classical tardive dyskinesia” for the oro–buccal– lingual (OBL) dyskinesia, and to apply a more specific terminology based on the phenomenology to each subtype of tardive syndrome, namely: tardive dyskinesia, tardive stereotypy, tardive dystonia, tardive tremor, tardive akathisia, tardive myoclonus and tardive tourettism [1,3]. The clinical aspects of these entities are summarized in Table 1. TS phenomenologies may frequently occur simultaneously in the same patient, for instance, OBL dyskinesia, in association with dystonia and akathisia, increasing the likelihood of TS as the final diagnosis. Drug-induced parkinsonism is not uncommon in patients developing TS while they remain on DRBA. Whether “tardive parkinsonism” exists or not is controversial. Interestingly, approximately 50% of patients who develop parkinsonism during exposure to DRBA are found to have underlying dopaminergic striatal denervation on neuroimaging suggestive of Parkinson’s disease (PD) [5]. In addition,
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Table 1 Phenomenology of tardive syndromes Syndrome
Phenomenology
Tardive dyskinesia
Refers to the classical oro–buccal–lingual (OBL) dyskinesia and to choreic movements in other body parts. The typical pattern is a stereotyped combination of tongue twisting and protrusion, lip smacking and puckering, and chewing movements. Many patients may not be aware of their movements. Speech is usually minimally affected because voluntary action can suppress OBL dyskinesia. When affecting limbs, manifest with piano-playing movements, grasping, flexion and extension of limbs, and foot tapping. Involvement of diaphragm and respiratory muscles may result in loud breathing, hyperventilation, grunting, groaning or distorted speech. TD is more common in elderly patients and women.
Tardive stereotypy
The concept of stereotypy has been changing over the years and has been applied to distinct conditions. We accept “a non-goal-directed movement pattern that is repeated continuously for a period of time in the same form and on multiple occasions, and which is typically distractible” as the most appropriate definition. Tardive stereotypy has been used to describe the classical OBL dyskinesia, due to its stereotyped fashion, however, it fails to fulfill the definition of stereotypy due to lack of distractibility and unpredictable order of movements.
Tardive akathisia
Characterized by a feeling of inner restlessness and jitteriness resulting in inability to sit or stand still. Objectively, patients are seen rocking from foot to foot, walking in place, crossing/uncrossing legs, or body rocking. Akathisia can also occur in the early phase of treatment with DRBA, known as acute akathisia. Pseudoakathisia refers to the appearance of extreme restlessness in the absence of clear subjective feeling of restless.
Tardive dystonia
Tardive dystonia can be focal, segmental or generalized. It frequently coexists with other TS, and can be reduced by voluntary movements, instead of being action induced as primary dystonia. The typical distribution involves the face and neck followed by the arms, trunk, and, less frequently, legs. The classical patterns of movement are: Face: blepharospasm, oculogyric movements, tongue protrusions, jaw closing or opening, and lip retraction; Neck: retrocollis and/or laterocollis; Trunk: hyperextension, resulting in an opisthotonic posturing; Limbs: internal rotation of the arms, extension of the elbows, and flexion of the wrists. Tardive dystonia is more common in young men.
Tardive myoclonus
Myoclonus is a common adverse effect from a variety of drugs, for instance: antidepressants, antiepileptic drugs, neuroleptics, antibiotics, and others. Tardive myoclonus appears after at least 3 months of exposure to DRBA, frequently in association with other TS. It is typically postural and affects the upper extremity.
Tardive tremor
Manifests with kinetic, postural and resting tremor, usually with high amplitude, frequency of 3–5 Hz, in the absence of parkinsonian signs.
Tardive tourettism or tardive tics
May be phenomenologically identical to Tourette syndrome, except for the age of onset and history of chronic exposure to DRBA.
Tardive pain
This is a rare form of tardive syndrome that manifests with chronic pain or other unpleasant sensations in oral or genital areas.
Withdrawal-emergent dyskinesia
Seen in children following sudden discontinuation of chronic antipsychotic drug treatment. The movements are typically choreic and resolve when the offending medication is reinstituted and/or followed by a slow drug-tapering schedule. Many patients do not develop classical OBL dyskinesia until long-term DRBA are withdrawn. If these symptoms completely resolve within a few weeks the term withdrawal emergent dyskinesia can be applied retrospectively.
a recent study in an elderly cohort showed that previous exposure to antipsychotics increased the risk of probable PD by 3.2-fold [6]; the mechanism responsible for this association remains unclear. 3. Epidemiology before and after atypical antipsychotics The real prevalence and incidence of TS is difficult to estimate due to a variety of reasons: most patients, especially those with classical OBL dyskinesia, are not aware of their symptoms, movements may fluctuate over time and the offending drug can mask symptoms [7]. Despite this, overall, the prevalence of TD is estimated to be 30% in outpatients treated with antipsychotics, ranging from 20% to 50% [2]. The incidence has been estimated between 4% and 8%, with a cumulative 5-year incidence of 25%, with approximately 2% spontaneous remissions annually [7]. Differences may be found for distinct subtypes of TS, age, gender, and classes of drugs used. The risk factors currently accepted for TD are older age, female gender, history of brain damage or dementia, presence of a major affective disorder and longer exposure to DRBA. In regard to the dose of DRBA used, data suggest that there is a plateau effect with moderate doses, above which the risk of TS is not further increased [7]. Patients who develop acute extrapyramidal symptoms apparently have higher risk to develop TS, as do nonCaucasians [8]. Atypical antipsychotics are expected to have less extrapyramidal side effects owing to their lower affinity to dopamine D2 receptors
in the dorsal striatum, and associated antagonism of 5-HT2A/2C receptors [9]. Indeed, some studies have suggested an incidence of TD of 2% per year, or a risk reduction of 3.5-fold [10]. Nevertheless, a review of 12 studies involving 30,129 patients suggested a more modest difference in the incidence of TS with typical and atypical antipsychotics, 5.5% versus 3.9%, respectively [4]. Up to this time, the majority of studies searching for reduction in incidence of TS with atypical antipsychotics have been limited by short follow-up, lack of a clear definition of TS, and inclusion of patients with previous exposure to typical antipsychotics [10]. 4. Changing concepts of the pathophysiology of TS TS has been commonly attributed to hypersensitivity or upregulation of dopamine receptors, particularly D2, following chronic blockade; however, this is unlikely to be the sole explanation [11]. It is known that normal movements require a balance between the direct and indirect pathways of the basal ganglia. Activation of the direct pathway results in facilitation of movements, whereas activation of the indirect pathway results in reduction of velocity and amplitude of movements. D2 receptors, expressed on striatal medium-spiny-neurons, are inhibitory for the indirect pathway, thus D2 hypersensitivity would cause hyperkinesia. This mechanism is supported by animal models of “vacuous chewing movements” induced by prolonged exposure to haloperidol [12], and by a study in humans showing increased D2-receptor binding in PET of patients with long-term exposure to DRBA [13].
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Table 2 Practical management of tardive syndromes Therapeutic option
Daily dose range
Clinical syndrome
Comments
From 100 to 300 mg/day
Classical tardive dyskinesia, tardive dystonia, tardive akathisia, tardive tremor
Risk of hallucinations and cognitive dysfunction in higher doses, especially in elderly.
From 1 to 40 mg/day or higher according to tolerability
Tardive dystonia
May worsen cognition and psychosis. May worsen OBL dyskinesia.
From 10 to 80 mg/day
Tardive dystonia
Usually tried after failure with anticholinergics or tetrabenazine. May be used in conjunction with anticholinergics.
From 0.25 to 6 mg/day
Tardive dyskinesia, tardive dystonia, tardive myoclonus
Drowsiness may be dose limiting.
Ginkgo biloba
80 to 240 mg/day
Tardive dyskinesia, tardive dystonia
Clinical trials for TD used 240 mg/day. Caution in patients with antiplatelet agent anticoagulants.
Propranolol
From 20 to 160 mg/day
Classical tardive dyskinesia, tardive akathisia
Blood pressure and heart rate monitoring required.
Tetrabenazine
12.5 to 200 mg/day
Tardive dyskinesia, tardive dystonia, tardive tourettism, tardive tremor
Drowsiness, parkinsonism, depression and akathisia may be dose limiting.
Botulinum toxin injections
Varies with product injected and selected muscle.
Tardive dystonia: blepharospasm, cervical dystonia, oromandibular dystonia
Oral agents Amantadine Anticholinergics, e.g. Trihexyphenidyl
Baclofen Benzodiazepines Clonazepam
Surgical procedures Deep brain stimulation
Severe and refractory tardive dyskinesia, tardive dystonia and tardive tourettism
A more recent hypothesis to explain TS relates to synaptic plasticity. Synapses have the ability to increase or decrease their transmission based on previous learning through distinct mechanisms mediated by increase in intracellular calcium. Chronic blockade of D2 receptors and its consequent hypersensitisation provoke a maladaptive plasticity in cortico-striatal transmission, resulting in imbalance between direct and indirect pathways. It has been proposed that this maladaptive plasticity could be responsible for perpetuating abnormal movements even after discontinuation of DBRA due to the inability to unlearn the miscoded motor program [14]. Oxidative stress has also been invoked in the pathogenesis of TS. This theory proposes that chronic blockade of dopamine receptors increases dopamine turnover and consequently generates hydrogen peroxide and free radicals, causing neurotoxicity [15]. In favor of this hypothesis, variances in the gene that encodes manganese superoxide-dismutase (MnSOD), an enzyme that eliminates free radicals, have been found to correlate with TS [16]. In addition to dopamine, other neurotransmitters are probably involved in the pathogenesis of TS; for instance, it is known that the activity of 5-HT2A and 5-HT2C receptors inhibits dopamine release. Certain atypical antipsychotics such as clozapine and quetiapine have 5-HT2A/2C antagonism properties increasing dopamine release and this might account for a reduction in the risk of TS and other extrapyramidal effects [9,11]. 5. From pharmacogenetics to pharmacogenomics Familial clusters of patients with schizophrenia and antipsychoticinduced comorbidities have prompted a large number of studies on pharmacogenetics of antipsychotic adverse effects, including TS, weight-gain, metabolic syndrome, agranulocytosis, QT prolongation, and auto-immune disorders [17]. In regard to TD, polymorphisms in the genes coding for D2 and D3 dopamine receptors (DRD2, DRD3), catechol-O-methyl-transferase
Globus pallidus has been the preferred target.
(COMT), 5-HT2A receptors (HTR2A), MnSOD and cytochrome P450 gene (CYP2D6) have been shown to influence the risk for TD. Variances in other genes have also been linked to TD, including genes related to GABAergic pathways (SLCA11, GABRB2, GABRC3), genes related to N-methyl-D-aspartate (NMDA) receptor (GRIN2A), and oxidative stress related genes (GSTM1, GSTP1, NQO1, NOS3) [17]. Interestingly, pharmacogenetics have correlated not only with the risk of developing TS, but also with its persistence and response to treatment. For example, a recent study found that the polymorphism Val66Met in the gene of brain-derived-neurotrophic factor (BDNF) predicts a good response to Ginkgo biloba [18]. The growing number of correlations found in pharmacogenetics motivated the more recent approaches using genome-wide association studies to search for genes and pathways mediating TS. These later studies have generated a growing number or results, however validation and replication are still needed [17]. 6. Treatment of tardive syndromes Treatment of TS is quite challenging, emphasizing the critical need to avoid the causative drugs whenever possible. Patients should be advised about the inherent risk of TD, and maintenance of treatment should be reviewed periodically. Once TD is detected, reduction or discontinuation of the etiologic agent should be considered. The therapeutic options currently used in the management of TS are summarized in Table 2. There is no reliable evidence that typical and atypical antipsychotics differ in regards to efficacy in treating non-resistant schizophrenia [9]. Two important non-industry sponsored trials designed to compare effectiveness between typical and atypical antipsychotics, the CATIE [19] and CUtLASS [20] studies, alleged non-superiority of the atypical antipsychotics; however, both have been disregarded by clinicians due to important methodological flaws [9]. In view of the lower incidence of TS with atypical
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antipsychotics, these should be preferred when possible [10]. Some clinicians advocate the use of anticholinergics as prophylaxis for extrapyramidal reactions and TS; this practice can worsen cognition in schizophrenic patients [21] and should not be encouraged. There is no convincing evidence that these drugs reduce the incidence of TS and they can worsen the symptoms in established OBL dyskinesia. Tetrabenazine (TBZ) is a monoamine-depleting agent that inhibits the vesicular monoamine transporter 2 (VMAT2) on dopaminergic terminals. It has been used since 1971 in the treatment of chorea, hemiballism and other hyperkinesias. It is probably the most effective drug in the treatment of TD [22]. Eleven studies investigated the effectiveness of TBZ in TD, altogether including a total of 403 patients. In nine of those studies, the authors concluded that TBZ was safe and effective, however, limitations included small sample size, open-label treatment and retrospective design. A recent evidence-based guideline from the American Academy of Neurology (AAN) concluded that TBZ possibly reduces TS and may be considered an option with level C of evidence [23]. TBZ may be effective for different subtypes of TS in addition to classical TD, including tardive dystonia, tardive akathisia and tardive tremor. As regards the safety of TBZ, it is generally well tolerated. Due to its short half-life and reversibility, adverse effects remit soon after reduction or discontinuation [22]. Drowsiness, parkinsonism, depression, and akathisia are the most commonly reported adverse effects [22] and these are not infrequently dose limiting or result in drug discontinuation, especially in elderly patients experiencing problematic drug-induced parkinsonism. Recently TD associated with TBZ has been described in a patient treated for cervical dystonia. The cranial and generalized choreic movements followed a 10-month course of low-dose (12.5 mg bid) treatment and were self-limited, remitting ~3 months after drug withdrawal. TBZ’s weak D2 antagonist effects were proposed as a possible underlying pathogenic mechanism [24]. Amantadine, a non-competitive blocker of NMDA receptors, has been used to treat drug-induced dyskinesia, such as levodopainduced dyskinesia and TS. Beyond its anti-glutamatergic action, other distinct mechanisms have been claimed, for instance, direct effect on dopamine receptors, and anticholinergic effects. A recent double-blind placebo-controlled trial showed an improvement of 21% in dyskinesia score in patients treated with amantadine, compared to no improvement in patients treated with placebo [25]. In spite of this and other open-label studies, the AAN guideline verified that amantadine, when given in association with antipsychotics, has evidence level C in treating TS [23]. In the early 1980s, propranolol was examined for treatment of TD in open-label or crossover studies and found to be effective in low doses. However, some years later, that benefit was attributed to the increment in plasma levels of antipsychotics induced by propranolol. Recently, low doses of propranolol (lower than 80 mg/day) have again been found to be effective in the treatment of OBL and respiratory dyskinesia, secondary to metoclopramide and risperidone, suggesting a direct anti-dyskinesia effect, since both patients were no longer using the offending agents [26]. Although further studies are clearly needed to confirm the efficacy of propranolol in TD, a trial of this drug is readily justified in patients with bothersome typical TD, given its safety, low cost, and prior successful experiences. Based on the theoretical role of oxidative stress in the pathophysiology of TS [15], several antioxidants have been studied, including vitamin E, vitamin B6 and Ginkgo biloba [23,27,28]. Efficacy of vitamin E has been evaluated in several studies, with conflicting results. In those with positive results, improvement ranged from 18.5% to 43%, whereas other studies were negative [23]. A randomized, double-blind, placebo-controlled, crossover trial
with 1200 mg per day of vitamin B6 have found a reduction in the Extrapyramidal Symptom Rating Scale of 2.4 units in the vitamin B6 group, compared to 0.2 in the placebo group, suggesting a possible benefit of vitamin B6 in TS [27]. Despite some positive studies with vitamins E and B6, overall the data are insufficient to support or refute their use in TS, according to the AAN guideline [23]. Ginkgo biloba (EGb-761), an herbal product, has been used worldwide over-the-counter to treat or prevent several conditions, such as cerebrovascular and peripheral vascular insufficiency, tinnitus, vertigo, and mild cognitive decline. A free-radical scavenging action has been proposed to underlie its utility, and has been the reason it has been studied in TS. A randomized, double-blind, placebo-controlled study with 240 mg of EGb-761 per day showed not only a symptomatic improvement of dyskinesia in 53% of 157 patients, but also a carry-over effect lasting for at least 6 months after discontinuation of the drug [28]. The response of TS to Ginkgo biloba apparently can be predicted by a polymorphism in the BDNF gene [18]. In spite of being considered a safe drug owing to its herbal origin, in vivo and in vitro studies have suggested that EGb-761 also has an antiplatelet effect, and cases of hemorrhagic complications and cerebral bleeding have been published [29], and so, caution should be exercised in patients using antiplatelet drugs or anticoagulants. The AAN guideline considered that Ginkgo biloba is probably useful in the treatment of TS, with evidence level B [23]. A wide variety of other therapeutic agents have been tried for TS, e.g. biperiden, levetiracetam, melatonin, nifedipine, acetazolamide, baclofen, buspirone, galantamine, botulinum toxin, and others. All of these lack sufficient evidence-based support, with the exception of clonazepam, which has been considered useful (evidence level B) [23]. Benzodiazepines may be particularly useful for tardive myoclonus. Even though there are not enough studies providing evidence for the use of botulinum toxin in TS, clinical experience and small series have shown that it may benefit patients with tardive dystonia, especially those with blepharospasm, oromandibular and cervical dystonia. When TS is disabling and refractory to treatment, deep brain stimulation (DBS) becomes an option. A recent systematic review estimated an improvement of 77.5% on scales used to evaluate TD and tardive dystonia across 17 studies. Moreover, of the 50 patients included, exacerbation of psychiatric illness after surgery occurred in only two, suggesting that DBS treatment is safe if patients are carefully screened [30], and indeed some patients have experienced an improvement in their mood after surgery. The globus pallidus has been the preferred target for DBS in TS, with onset of improvement varying from immediately after surgery to several months later. Most patients have had a sustained effect for more than 6 months. 7. Conclusions Despite the widespread use of atypical antipsychotics in clinical practice, and the recent advances in knowledge regarding pathophysiology, risk factors and genetic correlations, TS remains a challenging problem. It is hoped that in the future, treating physicians will be able to identify patients at risk by delineating a pharmacogenomic profile, and will then be able to select individualized treatment for each patient. Further studies are necessary to permit stronger evidence-based treatment recommendations for TS. Currently, a variety of treatment options exist ranging from relatively innocuous low doses of propranolol to more invasive procedures such as DBS. TS can have considerable negative impact on quality of life and may have a persistent course, two important reasons why prevention remains the best treatment. Conflict of interests The authors have no conflicts of interest to declare.
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Tardive dyskinesia syndromes: current concepts Camila Catherine H. Aquino, Anthony E. Lang * Morton and Gloria Shulman Movement Disorders Center and the Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, Toronto, Canada
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Keywords: Tardive syndrome Tardive dyskinesia Antipsychotics
Tardive syndromes (TS) encompass a broad spectrum of abnormal movements due to chronic exposure to dopamine receptor blocking agents. This review provides a compiled update on TS, including phenomenology, epidemiology, pathophysiology, genetic correlations and therapeutics, highlighting the emerging experience with atypical antipsychotics. The advent of atypical antipsychotics, which have lower affinity for dopamine receptors and act on 5-HT2A and 5-HT2C serotonin receptors, was expected to dramatically reduce the prevalence and incidence of this iatrogenic problem. Recent studies have shown that the reduction has been more modest than expected and TS remains an important challenge. Recent insights on pathophysiology, risk factors and genetic correlations have raised the hope for further individualized treatment for schizophrenic patients, and more strict use of antipsychotics. Up to now, there is no definite treatment for TS, but options range from relatively innocuous low doses of propranolol to more invasive procedures such as deep brain stimulation. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction Tardive dyskinesia (TD) is a term historically used to refer to delayed and persistent abnormal movements caused by exposure to dopamine receptor blocking agents (DRBA). There are several distinct phenomenologies under the definition of TD justifying the term tardive syndrome (TS) to encompass the broad spectrum of symptoms that can develop after chronic use of DRBA [1]. According to the diagnostic and statistical manual of mental disorders, fourth edition (DSM IV), the spectrum of TD includes involuntary movements of the tongue, jaw, trunk, or extremities, and may be choreiform, athetoid, or stereotypic in nature. Abnormal movements should appear during exposure, or within 4 weeks of withdrawal from oral DRBA or 8 weeks from depot formulations. The minimal exposure to DRBA should be 3 months, except for patients older than 60, who can develop TD after using DRBA for 1 month. Finally, the movements should be present for at least 1 month to fulfill the criteria for TD [2]. TS have been strongly associated with antipsychotic drugs, however, several other classes of drugs, such as the antiemetic metoclopramide and the calcium channel blockers cinnarizine and flunarizine, occupy dopamine receptors and have been associated with movement disorders and TS [1,3]. The advent and widespread use of atypical antipsychotics in clinical practice had been expected to dramatically reduce the incidence and prevalence of TS, however the reduction, if any, was modest [4]. * Corresponding author. Dr. Anthony E. Lang, Toronto Western Hospital, 399 Bathurst Street, 7th Floor, McLaughlin pavilion, Toronto, Ontario, Canada M5T 2S8. E-mail address: [email protected] (A.E. Lang). 1353-8020/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
In view of this, TS is a challenging condition for neurologists and psychiatrists, due to lack of definite risk factors to predict patients who will develop this condition; complex and usually mixed presentation; suboptimal results with treatment and the common persistent, chronic course. In this review we provide a compiled update on TS, including phenomenology, epidemiology, pathophysiology, genetic correlations and therapeutics, highlighting the emerging experience with atypical antipsychotics. 2. Phenomenology of tardive syndromes Distinct hyperkinetic movement disorders have been described as part of the TS [3]. More recently there is a tendency to reserve the term “classical tardive dyskinesia” for the oro–buccal– lingual (OBL) dyskinesia, and to apply a more specific terminology based on the phenomenology to each subtype of tardive syndrome, namely: tardive dyskinesia, tardive stereotypy, tardive dystonia, tardive tremor, tardive akathisia, tardive myoclonus and tardive tourettism [1,3]. The clinical aspects of these entities are summarized in Table 1. TS phenomenologies may frequently occur simultaneously in the same patient, for instance, OBL dyskinesia, in association with dystonia and akathisia, increasing the likelihood of TS as the final diagnosis. Drug-induced parkinsonism is not uncommon in patients developing TS while they remain on DRBA. Whether “tardive parkinsonism” exists or not is controversial. Interestingly, approximately 50% of patients who develop parkinsonism during exposure to DRBA are found to have underlying dopaminergic striatal denervation on neuroimaging suggestive of Parkinson’s disease (PD) [5]. In addition,
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Table 1 Phenomenology of tardive syndromes Syndrome
Phenomenology
Tardive dyskinesia
Refers to the classical oro–buccal–lingual (OBL) dyskinesia and to choreic movements in other body parts. The typical pattern is a stereotyped combination of tongue twisting and protrusion, lip smacking and puckering, and chewing movements. Many patients may not be aware of their movements. Speech is usually minimally affected because voluntary action can suppress OBL dyskinesia. When affecting limbs, manifest with piano-playing movements, grasping, flexion and extension of limbs, and foot tapping. Involvement of diaphragm and respiratory muscles may result in loud breathing, hyperventilation, grunting, groaning or distorted speech. TD is more common in elderly patients and women.
Tardive stereotypy
The concept of stereotypy has been changing over the years and has been applied to distinct conditions. We accept “a non-goal-directed movement pattern that is repeated continuously for a period of time in the same form and on multiple occasions, and which is typically distractible” as the most appropriate definition. Tardive stereotypy has been used to describe the classical OBL dyskinesia, due to its stereotyped fashion, however, it fails to fulfill the definition of stereotypy due to lack of distractibility and unpredictable order of movements.
Tardive akathisia
Characterized by a feeling of inner restlessness and jitteriness resulting in inability to sit or stand still. Objectively, patients are seen rocking from foot to foot, walking in place, crossing/uncrossing legs, or body rocking. Akathisia can also occur in the early phase of treatment with DRBA, known as acute akathisia. Pseudoakathisia refers to the appearance of extreme restlessness in the absence of clear subjective feeling of restless.
Tardive dystonia
Tardive dystonia can be focal, segmental or generalized. It frequently coexists with other TS, and can be reduced by voluntary movements, instead of being action induced as primary dystonia. The typical distribution involves the face and neck followed by the arms, trunk, and, less frequently, legs. The classical patterns of movement are: Face: blepharospasm, oculogyric movements, tongue protrusions, jaw closing or opening, and lip retraction; Neck: retrocollis and/or laterocollis; Trunk: hyperextension, resulting in an opisthotonic posturing; Limbs: internal rotation of the arms, extension of the elbows, and flexion of the wrists. Tardive dystonia is more common in young men.
Tardive myoclonus
Myoclonus is a common adverse effect from a variety of drugs, for instance: antidepressants, antiepileptic drugs, neuroleptics, antibiotics, and others. Tardive myoclonus appears after at least 3 months of exposure to DRBA, frequently in association with other TS. It is typically postural and affects the upper extremity.
Tardive tremor
Manifests with kinetic, postural and resting tremor, usually with high amplitude, frequency of 3–5 Hz, in the absence of parkinsonian signs.
Tardive tourettism or tardive tics
May be phenomenologically identical to Tourette syndrome, except for the age of onset and history of chronic exposure to DRBA.
Tardive pain
This is a rare form of tardive syndrome that manifests with chronic pain or other unpleasant sensations in oral or genital areas.
Withdrawal-emergent dyskinesia
Seen in children following sudden discontinuation of chronic antipsychotic drug treatment. The movements are typically choreic and resolve when the offending medication is reinstituted and/or followed by a slow drug-tapering schedule. Many patients do not develop classical OBL dyskinesia until long-term DRBA are withdrawn. If these symptoms completely resolve within a few weeks the term withdrawal emergent dyskinesia can be applied retrospectively.
a recent study in an elderly cohort showed that previous exposure to antipsychotics increased the risk of probable PD by 3.2-fold [6]; the mechanism responsible for this association remains unclear. 3. Epidemiology before and after atypical antipsychotics The real prevalence and incidence of TS is difficult to estimate due to a variety of reasons: most patients, especially those with classical OBL dyskinesia, are not aware of their symptoms, movements may fluctuate over time and the offending drug can mask symptoms [7]. Despite this, overall, the prevalence of TD is estimated to be 30% in outpatients treated with antipsychotics, ranging from 20% to 50% [2]. The incidence has been estimated between 4% and 8%, with a cumulative 5-year incidence of 25%, with approximately 2% spontaneous remissions annually [7]. Differences may be found for distinct subtypes of TS, age, gender, and classes of drugs used. The risk factors currently accepted for TD are older age, female gender, history of brain damage or dementia, presence of a major affective disorder and longer exposure to DRBA. In regard to the dose of DRBA used, data suggest that there is a plateau effect with moderate doses, above which the risk of TS is not further increased [7]. Patients who develop acute extrapyramidal symptoms apparently have higher risk to develop TS, as do nonCaucasians [8]. Atypical antipsychotics are expected to have less extrapyramidal side effects owing to their lower affinity to dopamine D2 receptors
in the dorsal striatum, and associated antagonism of 5-HT2A/2C receptors [9]. Indeed, some studies have suggested an incidence of TD of 2% per year, or a risk reduction of 3.5-fold [10]. Nevertheless, a review of 12 studies involving 30,129 patients suggested a more modest difference in the incidence of TS with typical and atypical antipsychotics, 5.5% versus 3.9%, respectively [4]. Up to this time, the majority of studies searching for reduction in incidence of TS with atypical antipsychotics have been limited by short follow-up, lack of a clear definition of TS, and inclusion of patients with previous exposure to typical antipsychotics [10]. 4. Changing concepts of the pathophysiology of TS TS has been commonly attributed to hypersensitivity or upregulation of dopamine receptors, particularly D2, following chronic blockade; however, this is unlikely to be the sole explanation [11]. It is known that normal movements require a balance between the direct and indirect pathways of the basal ganglia. Activation of the direct pathway results in facilitation of movements, whereas activation of the indirect pathway results in reduction of velocity and amplitude of movements. D2 receptors, expressed on striatal medium-spiny-neurons, are inhibitory for the indirect pathway, thus D2 hypersensitivity would cause hyperkinesia. This mechanism is supported by animal models of “vacuous chewing movements” induced by prolonged exposure to haloperidol [12], and by a study in humans showing increased D2-receptor binding in PET of patients with long-term exposure to DRBA [13].
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Table 2 Practical management of tardive syndromes Therapeutic option
Daily dose range
Clinical syndrome
Comments
From 100 to 300 mg/day
Classical tardive dyskinesia, tardive dystonia, tardive akathisia, tardive tremor
Risk of hallucinations and cognitive dysfunction in higher doses, especially in elderly.
From 1 to 40 mg/day or higher according to tolerability
Tardive dystonia
May worsen cognition and psychosis. May worsen OBL dyskinesia.
From 10 to 80 mg/day
Tardive dystonia
Usually tried after failure with anticholinergics or tetrabenazine. May be used in conjunction with anticholinergics.
From 0.25 to 6 mg/day
Tardive dyskinesia, tardive dystonia, tardive myoclonus
Drowsiness may be dose limiting.
Ginkgo biloba
80 to 240 mg/day
Tardive dyskinesia, tardive dystonia
Clinical trials for TD used 240 mg/day. Caution in patients with antiplatelet agent anticoagulants.
Propranolol
From 20 to 160 mg/day
Classical tardive dyskinesia, tardive akathisia
Blood pressure and heart rate monitoring required.
Tetrabenazine
12.5 to 200 mg/day
Tardive dyskinesia, tardive dystonia, tardive tourettism, tardive tremor
Drowsiness, parkinsonism, depression and akathisia may be dose limiting.
Botulinum toxin injections
Varies with product injected and selected muscle.
Tardive dystonia: blepharospasm, cervical dystonia, oromandibular dystonia
Oral agents Amantadine Anticholinergics, e.g. Trihexyphenidyl
Baclofen Benzodiazepines Clonazepam
Surgical procedures Deep brain stimulation
Severe and refractory tardive dyskinesia, tardive dystonia and tardive tourettism
A more recent hypothesis to explain TS relates to synaptic plasticity. Synapses have the ability to increase or decrease their transmission based on previous learning through distinct mechanisms mediated by increase in intracellular calcium. Chronic blockade of D2 receptors and its consequent hypersensitisation provoke a maladaptive plasticity in cortico-striatal transmission, resulting in imbalance between direct and indirect pathways. It has been proposed that this maladaptive plasticity could be responsible for perpetuating abnormal movements even after discontinuation of DBRA due to the inability to unlearn the miscoded motor program [14]. Oxidative stress has also been invoked in the pathogenesis of TS. This theory proposes that chronic blockade of dopamine receptors increases dopamine turnover and consequently generates hydrogen peroxide and free radicals, causing neurotoxicity [15]. In favor of this hypothesis, variances in the gene that encodes manganese superoxide-dismutase (MnSOD), an enzyme that eliminates free radicals, have been found to correlate with TS [16]. In addition to dopamine, other neurotransmitters are probably involved in the pathogenesis of TS; for instance, it is known that the activity of 5-HT2A and 5-HT2C receptors inhibits dopamine release. Certain atypical antipsychotics such as clozapine and quetiapine have 5-HT2A/2C antagonism properties increasing dopamine release and this might account for a reduction in the risk of TS and other extrapyramidal effects [9,11]. 5. From pharmacogenetics to pharmacogenomics Familial clusters of patients with schizophrenia and antipsychoticinduced comorbidities have prompted a large number of studies on pharmacogenetics of antipsychotic adverse effects, including TS, weight-gain, metabolic syndrome, agranulocytosis, QT prolongation, and auto-immune disorders [17]. In regard to TD, polymorphisms in the genes coding for D2 and D3 dopamine receptors (DRD2, DRD3), catechol-O-methyl-transferase
Globus pallidus has been the preferred target.
(COMT), 5-HT2A receptors (HTR2A), MnSOD and cytochrome P450 gene (CYP2D6) have been shown to influence the risk for TD. Variances in other genes have also been linked to TD, including genes related to GABAergic pathways (SLCA11, GABRB2, GABRC3), genes related to N-methyl-D-aspartate (NMDA) receptor (GRIN2A), and oxidative stress related genes (GSTM1, GSTP1, NQO1, NOS3) [17]. Interestingly, pharmacogenetics have correlated not only with the risk of developing TS, but also with its persistence and response to treatment. For example, a recent study found that the polymorphism Val66Met in the gene of brain-derived-neurotrophic factor (BDNF) predicts a good response to Ginkgo biloba [18]. The growing number of correlations found in pharmacogenetics motivated the more recent approaches using genome-wide association studies to search for genes and pathways mediating TS. These later studies have generated a growing number or results, however validation and replication are still needed [17]. 6. Treatment of tardive syndromes Treatment of TS is quite challenging, emphasizing the critical need to avoid the causative drugs whenever possible. Patients should be advised about the inherent risk of TD, and maintenance of treatment should be reviewed periodically. Once TD is detected, reduction or discontinuation of the etiologic agent should be considered. The therapeutic options currently used in the management of TS are summarized in Table 2. There is no reliable evidence that typical and atypical antipsychotics differ in regards to efficacy in treating non-resistant schizophrenia [9]. Two important non-industry sponsored trials designed to compare effectiveness between typical and atypical antipsychotics, the CATIE [19] and CUtLASS [20] studies, alleged non-superiority of the atypical antipsychotics; however, both have been disregarded by clinicians due to important methodological flaws [9]. In view of the lower incidence of TS with atypical
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antipsychotics, these should be preferred when possible [10]. Some clinicians advocate the use of anticholinergics as prophylaxis for extrapyramidal reactions and TS; this practice can worsen cognition in schizophrenic patients [21] and should not be encouraged. There is no convincing evidence that these drugs reduce the incidence of TS and they can worsen the symptoms in established OBL dyskinesia. Tetrabenazine (TBZ) is a monoamine-depleting agent that inhibits the vesicular monoamine transporter 2 (VMAT2) on dopaminergic terminals. It has been used since 1971 in the treatment of chorea, hemiballism and other hyperkinesias. It is probably the most effective drug in the treatment of TD [22]. Eleven studies investigated the effectiveness of TBZ in TD, altogether including a total of 403 patients. In nine of those studies, the authors concluded that TBZ was safe and effective, however, limitations included small sample size, open-label treatment and retrospective design. A recent evidence-based guideline from the American Academy of Neurology (AAN) concluded that TBZ possibly reduces TS and may be considered an option with level C of evidence [23]. TBZ may be effective for different subtypes of TS in addition to classical TD, including tardive dystonia, tardive akathisia and tardive tremor. As regards the safety of TBZ, it is generally well tolerated. Due to its short half-life and reversibility, adverse effects remit soon after reduction or discontinuation [22]. Drowsiness, parkinsonism, depression, and akathisia are the most commonly reported adverse effects [22] and these are not infrequently dose limiting or result in drug discontinuation, especially in elderly patients experiencing problematic drug-induced parkinsonism. Recently TD associated with TBZ has been described in a patient treated for cervical dystonia. The cranial and generalized choreic movements followed a 10-month course of low-dose (12.5 mg bid) treatment and were self-limited, remitting ~3 months after drug withdrawal. TBZ’s weak D2 antagonist effects were proposed as a possible underlying pathogenic mechanism [24]. Amantadine, a non-competitive blocker of NMDA receptors, has been used to treat drug-induced dyskinesia, such as levodopainduced dyskinesia and TS. Beyond its anti-glutamatergic action, other distinct mechanisms have been claimed, for instance, direct effect on dopamine receptors, and anticholinergic effects. A recent double-blind placebo-controlled trial showed an improvement of 21% in dyskinesia score in patients treated with amantadine, compared to no improvement in patients treated with placebo [25]. In spite of this and other open-label studies, the AAN guideline verified that amantadine, when given in association with antipsychotics, has evidence level C in treating TS [23]. In the early 1980s, propranolol was examined for treatment of TD in open-label or crossover studies and found to be effective in low doses. However, some years later, that benefit was attributed to the increment in plasma levels of antipsychotics induced by propranolol. Recently, low doses of propranolol (lower than 80 mg/day) have again been found to be effective in the treatment of OBL and respiratory dyskinesia, secondary to metoclopramide and risperidone, suggesting a direct anti-dyskinesia effect, since both patients were no longer using the offending agents [26]. Although further studies are clearly needed to confirm the efficacy of propranolol in TD, a trial of this drug is readily justified in patients with bothersome typical TD, given its safety, low cost, and prior successful experiences. Based on the theoretical role of oxidative stress in the pathophysiology of TS [15], several antioxidants have been studied, including vitamin E, vitamin B6 and Ginkgo biloba [23,27,28]. Efficacy of vitamin E has been evaluated in several studies, with conflicting results. In those with positive results, improvement ranged from 18.5% to 43%, whereas other studies were negative [23]. A randomized, double-blind, placebo-controlled, crossover trial
with 1200 mg per day of vitamin B6 have found a reduction in the Extrapyramidal Symptom Rating Scale of 2.4 units in the vitamin B6 group, compared to 0.2 in the placebo group, suggesting a possible benefit of vitamin B6 in TS [27]. Despite some positive studies with vitamins E and B6, overall the data are insufficient to support or refute their use in TS, according to the AAN guideline [23]. Ginkgo biloba (EGb-761), an herbal product, has been used worldwide over-the-counter to treat or prevent several conditions, such as cerebrovascular and peripheral vascular insufficiency, tinnitus, vertigo, and mild cognitive decline. A free-radical scavenging action has been proposed to underlie its utility, and has been the reason it has been studied in TS. A randomized, double-blind, placebo-controlled study with 240 mg of EGb-761 per day showed not only a symptomatic improvement of dyskinesia in 53% of 157 patients, but also a carry-over effect lasting for at least 6 months after discontinuation of the drug [28]. The response of TS to Ginkgo biloba apparently can be predicted by a polymorphism in the BDNF gene [18]. In spite of being considered a safe drug owing to its herbal origin, in vivo and in vitro studies have suggested that EGb-761 also has an antiplatelet effect, and cases of hemorrhagic complications and cerebral bleeding have been published [29], and so, caution should be exercised in patients using antiplatelet drugs or anticoagulants. The AAN guideline considered that Ginkgo biloba is probably useful in the treatment of TS, with evidence level B [23]. A wide variety of other therapeutic agents have been tried for TS, e.g. biperiden, levetiracetam, melatonin, nifedipine, acetazolamide, baclofen, buspirone, galantamine, botulinum toxin, and others. All of these lack sufficient evidence-based support, with the exception of clonazepam, which has been considered useful (evidence level B) [23]. Benzodiazepines may be particularly useful for tardive myoclonus. Even though there are not enough studies providing evidence for the use of botulinum toxin in TS, clinical experience and small series have shown that it may benefit patients with tardive dystonia, especially those with blepharospasm, oromandibular and cervical dystonia. When TS is disabling and refractory to treatment, deep brain stimulation (DBS) becomes an option. A recent systematic review estimated an improvement of 77.5% on scales used to evaluate TD and tardive dystonia across 17 studies. Moreover, of the 50 patients included, exacerbation of psychiatric illness after surgery occurred in only two, suggesting that DBS treatment is safe if patients are carefully screened [30], and indeed some patients have experienced an improvement in their mood after surgery. The globus pallidus has been the preferred target for DBS in TS, with onset of improvement varying from immediately after surgery to several months later. Most patients have had a sustained effect for more than 6 months. 7. Conclusions Despite the widespread use of atypical antipsychotics in clinical practice, and the recent advances in knowledge regarding pathophysiology, risk factors and genetic correlations, TS remains a challenging problem. It is hoped that in the future, treating physicians will be able to identify patients at risk by delineating a pharmacogenomic profile, and will then be able to select individualized treatment for each patient. Further studies are necessary to permit stronger evidence-based treatment recommendations for TS. Currently, a variety of treatment options exist ranging from relatively innocuous low doses of propranolol to more invasive procedures such as DBS. TS can have considerable negative impact on quality of life and may have a persistent course, two important reasons why prevention remains the best treatment. Conflict of interests The authors have no conflicts of interest to declare.
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