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Introduction
Tardive syndromes (TS) are characterized by abnormal, involuntary movements, and are typically caused by exposure to dopamine receptor blocking agents (DRBAs). The original description of TS was that of Schonecker in 1957, following the introduction of neuroleptics to treat psychiatric conditions (1). The term “tardive” was first used by Faurbye et al. in 1964, and refers to the delayed onset of the movements in relation to the DRBA exposure (2,3). TS consist of several subgroups, including tardive dyskinesia, dystonia, akathisia, myoclonus, stereotypy, tremor, and tourettism (4,5).
One form of TS, tardive dyskinesia (TD), is characterized by repetitive, stereotypic, involuntary, choreiform movements of the face, tongue, and jaw (oro-buccal-lingual dyskinesia), torso, and extremities. Symptoms of TD may include lip smacking, tongue twisting and thrusting, lip pursing, cheek puffing, grimacing, chewing, pelvic thrusting, piano-playing movements of the hands, foot tapping, and bridling (retraction of corners of the mouth) (6,7). TD may severely impact quality of life, leading to speaking and chewing difficulty, and may cause embarrassment (8). It is estimated to affect approximately 20% to 50% of patients who have been exposed to DRBAs, with a yearly incidence ranging from 5% in younger patients to 12% in older patients (9). Risk factors are thought to include older age, female gender, drug or alcohol addiction, preexisting brain damage, diabetes mellitus, and negative schizophrenic symptoms (5,10). The exact etiology of TD is unknown, but hypotheses include dopaminergic receptor hypersensitivity, upregulation of dopamine (D) 2 receptors, overactivity of striatal dopamine transmission, cerebral imbalance of dopaminergic and cholinergic activity, gamma-aminobutyric acid depletion, and oxidative stress (11–14).
The following criteria are necessary to meet the diagnosis of TS: 3 months total cumulative neuroleptic exposure during which it can be continuous or discontinuous, the presence of at least moderate abnormal involuntary movements in one or more body area or at least mild movements in 2 or more body areas, and the absence of other conditions that might produce abnormal involuntary movements (15). Criteria of TD diagnosis according to the American Psychiatric Association includes at least 3 months of DRBA exposure, or 1 month exposure in persons over age 60 years (4), dyskinesia that occurs during exposure to a DRBA or within 6 months of discontinuation of the DRBA, and movements that must persist for at least one month following DRBA withdrawal (16).
Treatment of TD may be challenging. It may be prevented by avoiding DRBAs, but these medications are often necessary to manage psychiatric conditions. Second-generation antipsychotics have generally replaced the use of first-generation antipsychotics for treatment of psychosis, due to their more favorable side effect profile for extrapyramidal symptoms compared to first-generation antipsychotics. However, second-generation agents may also cause TD, in rates similar to those of first-generation agents (17–19). Little evidence exists that discontinuation of neuroleptics actually results in resolution of TD (20). Although the most common cause of TD is exposure to neuroleptics, an initial reduction in neuroleptic dose often worsens TD symptoms (21) by “unmasking” the underlying disorder.
The risk of TD versus the benefit of using neuroleptics must be considered individually. Before prescribing DRBAs, patients should be advised of the possible risk of TD, and the American Psychiatric Association recommends evaluation for the presence of TD at least every 3 to 6 months using the Abnormal Involuntary Movement Scale (AIMS) (16), which is mandated by some states’ laws. Health care providers may consider a slow reduction or discontinuation of DRBAs if TD occurs, but frequent mental health monitoring must occur. In cases of gastrointestinal dysfunction, ondansetron (Zofran) may be used rather than conventional DRBA antinausea agents, including metoclopramide, prochlorperazine, and promethazine (22).
Treatment with pharmaceutical agents
Anticholinergics
Anticholinergic medications have been considered as treatment of TD based on the hypothesis that DRBA exposure contributes to a reduction in the number of acetylcholine-containing cells in the striatal and accumbal subregions (23). However, there are currently no convincing controlled trials that suggest that anticholinergic medications effectively treat TD. One systematic review of anticholinergic treatment of TD concluded that, “no confident statement can be made about the effectiveness of anticholinergics to treat people with neuroleptic-induced tardive dyskinesia” (24). Pretreatment with anticholinergic agents prior to use of DRBAs is not recommended, as these medications may actually worsen cognition, particularly in the elderly (21). Trihexyphenidyl and ethopropazine have shown some efficacy in the treatment of tardive dystonia (4). We think that anticholinergics are contraindicated in dyskinetic forms of TD, especially the most common, oral-buccal-lingual.
Antiepileptics
Several antiepileptics have been evaluated as possible treatments for TD, including levetiracetam, piracetam, and zonisamide. Levetiracetam (LEV) is a stereoisomer of piracetam, and is approved by the United States Food and Drug Administration (FDA) to treat partial and generalized seizures in adults and absence seizures in children (25). LEV has shown promise in ameliorating symptoms of TD, although research is limited (26,27). One double blind, placebo controlled trial randomized 50 TD patients to receive LEV 500–3000mg/day or placebo for 12 weeks, followed by an additional 12-week open-label extension phase, using the AIMS as the primary endpoint (28). Patients receiving LEV experienced a mean 43.5% improvement in total AIMS scores compared to 18.3% improvement in the placebo arm (p = 0.022).
Piracetam is an antiepileptic medication chemically related to LEV that has been used to treat myoclonus and other movement disorders (27). Libov et al. performed a 9-week double blind, placebo controlled, crossover study in 40 TD patients with schizophrenia or schizoaffective disorder (29). Patients were randomized to receive either piracetam (4800 mg/day) or placebo for two 4-week periods, separated by a 1-week washout phase. A mean reduction of three points was reported in the Extrapyramidal Symptom Rating Scale (ESRS) in patients treated with piracetam. The ESRS includes all the extrapyramidal syndromes so an improvement by three points is not clinically interpretable.
Zonisamide is an antiepileptic drug that was tested in a four-week, open-label study using the AIMS as a primary endpoint (30). The study reported a significant decrease in the AIMS score from 24.1 to 19.5 in 11 patients treated with zonisamide. Approximately 36% of study participants experienced a decrease of 20% or more in the AIMS scale, with a mean dose of zonisamide of 81.2 mg/day +/– 25.2 mg/day.
Antihypertensives
There are suggestions that propranolol, a beta blocker, may improve oral-buccal dyskinesia and respiratory dyskinesia in low doses (31–33). Propranolol was first proposed as a possible treatment for TD in the 1980s (32), and was recently revisited by Factor in the presentation of two cases (34). The first patient was a 67-year-old female with metoclopramide-induced TD who was treated with 20 mg propranolol three times a day. The patient experienced a reduction in orofacial dyskinesia and complete remission of respiratory dyskinesia after 8 months of therapy. The second patient was a 77-year-old male with neuroleptic-induced TD who showed improvement of buccal and respiratory dyskinesia with propranolol 80mg/day. As with any antihypertensive agent, caution is recommended with use in depressed patients, and blood pressure should be monitored periodically.
Additional antihypertensive agents have also been identified as potential treatments of TD. Acetazolamide is a carbonic anhydrase inhibitor that was evaluated in a controlled trial in 8 elderly and 25 younger patients (35). Patients older than 73 years received acetazolamide 1.5 g/day in 3 divided doses, while younger patients received 2 g/day along with thiamine administration for 3 weeks. Thiamine was added to the treatment to decrease the risk of kidney stones that may occur with acetazolamide use. AIMS scores decreased at endpoint relative to baseline by 46% in the elderly patients and 41% in younger patients. Diltiazem, a calcium channel blocker, failed to show significant improvement in TD in a controlled trial, and received a Level B recommendation from the AAN guideline (“probably does not treat”) (36). In another trial, nifedipine was reported to have improved TD symptoms in doses up to 90 mg/day (37). Double blind, randomized, placebo controlled trials should be undertaken to further evaluate the efficacy of propranolol in the treatment of TD.
Antioxidants
Antioxidants have been considered as possible treatments for TD, including ginkgo biloba, vitamin E, vitamin B6, melatonin, branched chain amino acids, resveratrol, essential fatty acids, omega 3, and eicosapentaenoic acid (11,23,38).
EGb-761, an extract from Ginkgo biloba, was evaluated in a double blind, placebo controlled clinical trial in 157 TD patients with schizophrenia (39). Patients were randomized to 240 mg/day of Egb-761 or placebo for 12 weeks. The primary outcome measures were the AIMS score, and the proportion of patients who experienced greater than 30% improvement in TD symptoms. There were significant improvements in the AIMS score in patients taking Egb-761 compared to placebo, and 51% of patients treated with Egb-761 showed improvement of 30% or more in the AIMS score. Egb-761 received a Level B recommendation (“probably improves TD”) according to the AAN guideline, but it should be noted that the data on Egb-761 exists for schizophrenic patients only (36).
Vitamin E is a potent antioxidant that has been evaluated as treatment for TD in several studies. One metaanalysis of 221 patients found significant improvements in the AIMS scores in patients treated with vitamin E 400–1600IU compared to those who received placebo (28.4% in patients treated with vitamin E versus 4.6% in those given placebo, p = 0.004) (38). Other clinical trials have failed to replicate these findings (40–43). A double blind, placebo controlled trial randomized 158 patients to receive either vitamin E 1,600 IU/day or placebo for at least one year and up to two years, but there were no significant effects of vitamin E on AIMS scores or additional outcome measures (40). Due to the variability in study outcomes, vitamin E received a Level U recommendation from the AAN guideline (Data insufficient to support or refute benefit) (36).
Melatonin, a naturally occurring antioxidant, is a neurohormone secreted by the pineal gland and is six- to tenfold more potent than vitamin E (44). Melatonin in doses of 2 mg/day was evaluated in a short duration study, but no differences were noted in outcome measures with its use (45). Another study that utilized higher doses of melatonin (10 mg/day) for a longer duration of 16 weeks found >30% of improvement in TD symptoms (46). Seventy-seven percent of patients (n = 17) reported higher AIMS score reductions that those taking placebo.
Branch Chain Amino Acids (BCAAs, leucine, isoleucine, valine) have also been studied as possible treatments for TD. In one study, 6 children with TD who had been previously or currently taking neuroleptics, were treated with 222 mg/kg BCAA in 148 ml water three times/day for two weeks (47). The clinical diagnosis of TD was made through the use of the Simpson Abbreviated Dyskinesia Scale (SADS). TD symptoms reportedly improved about 50%–60% in five out of six children, although one child showed increased symptoms. In another study, 36 male patients with TD were randomized to receive BCAAs in a dose of 222 mg/kg (high; N = 18), 167mg/kg (medium), or 56mg/kg (low) three times daily or placebo (N = 18) for 3 weeks (48). A 36.5% (p = 0.0009) mean improvement was noted in patients treated with BCAAs compared to 3.4% mean improvement in the placebo group.
Vitamin B6. In one double blind, placebo controlled, crossover clinical trial, 15 TD patients with schizophrenia or schizoaffective disorder were randomized to receive vitamin B6 or placebo for 4 weeks with crossover phase following a 1 week washout period (49). Patients treated with 400 mg daily experienced greater improvements in the TD subscale of the Extrapyramidal Symptom Rating Scale than those patients who received placebo (68.6% versus 32.8%, respectively). Another double blind, placebo controlled trial randomized 50 patients to receive vitamin B6 1200 mg/day or placebo for a 12-week crossover study (50). There was a significant reduction in the ESRS clinical global impression scores of 2.4 units in patients treated with vitamin B6 compared to 0.2 units in the placebo group (p < 0.001).
Essential fatty acids (EFAs, omega-3): A double blind, placebo controlled trial compared EPA 2g/day and placebo in TD patients, but failed to find any significant improvements in outcome measures (23).
First generation antipsychotics
First-generation antipsychotics (FGAs) may improve TD symptoms for short periods, but they are not recommended to treat TD, as they may mask symptoms while worsening the underlying condition. Side effects of FGAs may include parkinsonism and rigidity (51–54).
Second-generation antipsychotics
Risperidone: Several controlled trials have studied the effect of risperidone on TD. In one study, 135 schizophrenic patients were randomized to receive risperidone (6–16 mg/day) or placebo for 8 weeks (55). Patients treated with risperidone had lower Extrapyramidal Symptom Rating Scale (ESRS) scores (p < 0.05) than those receiving placebo. A randomized, double blind, placebo controlled trial in 49 TD patients with schizophrenia assigned patients to receive risperidone 6mg/day or placebo for 12 weeks (56). There was a mean AIMS reduction of 5.5+/−3.8 in the risperidone group versus a score of 1.1+/−4.8 in the placebo group (p < 0.05). More significant improvements in lingual-facial-buccal movements were observed in the risperidone group starting in the 8th week of the study. Another controlled trial compared the effects of risperidone and olanzapine in patients with schizophrenia with TD (57). AIMS scores decreased significantly in both groups (risperidone: –7.4+/−6.9, P < 0.0001; olanzapine: −6.2+/–8.0, P = 0.0002), but more so in patients taking risperidone (P = 0.0001). Risperidone is probably effective in reducing TD short term, but is also a cause for TD, and is not generally recommended as treatment, particularly long term.
Clozapine is a weak blocker of D2 receptors, and its administration carries a lower risk of TD than other FGAs (4,58). There have been reports that clozapine may even improve TD symptoms. In one study, 12 TD patients who were treated with clozapine (dose range of 20–900mg) for 18 weeks experienced improvement in the mean Tardive Dyskinesia Rating Scale (TDRS) score (decrease from 26 to 12)(59). Five patients dropped out of the study—two due to non–study-associated issues and three due to clozapine side effects (new onset grand mal seizures [1 patient] and leukopenia [2 patients]). In another 6-month study, patients with severe TD were treated with clozapine for at least 6 months and also had marked improvement in symptoms (60). Bassitt et al. conducted a 6-month, open-label study evaluating the effects of clozapine in 7 patients with schizophrenia and severe TD. There was a 52% improvement in Extrapyramidal Symptom Rating Scale (ESRS) and a 41% mean improvement in the AIMS score was noted with mean clozapine dose of 393 mg/day (61). Alternatively, Gerlach et al. compared clozapine and haloperidol in a single-blind, crossover trial of eight schizophrenic patients, and found no effect (62).
Clozapine may be an attractive option for patients with psychiatric illness, as it offers antipsychotic benefit with limited risk of extrapyramidal symptoms. However, a potentially serious side effect of clozapine is agranulocytosis, and patients who take Clozaril must undergo periodic blood count monitoring (76).
Olanzapine: One controlled trial compared the effects of risperidone and olanzapine in patients with schizophrenia and TD, and found that AIMS scores improved significantly in both groups (risperidone: –7.4+/–6.9, P < 0.0001; olanzapine: –6.2+/–8.0, P = 0.0002). Patients taking olanzapine showed approximately 30% improvement in the AIMS score relative to baseline scores (57). In another 8-month open-label study of 95 patients with schizophrenia, olanzapine significantly reduced the mean AIMS score from baseline of 11.8 to 7.3 (p < 0.001) at a mean dose of 12mg/day (63). Olanzapine received a Level U rating by the AAN (possibly effective in reducing TD) (36).
The pharmacology of quetiapine is similar to clozapine without the risk of agranulocytosis, and its associated risk of TD is lower than that of FGAs (4). Further research is warranted regarding its effect on TD.
Aripiprazole is an atypical antipsychotic that acts as a partial D2 receptor agonist, 5-HT2A receptor antagonist, and 5-HT1A receptor partial agonist. Multiple case reports have demonstrated a modest reduction to full remission of TD with the institution of aripiprazole in doses ranging from 5–30mg per day (64). However, at present, no randomized, double blind, placebo controlled trials testing the efficacy of aripiprazole have been completed.
Cholinergics
According to the cholinergic deficiency theory, TD may be associated with an imbalance between cerebral acetylcholine and dopamine (23). A systematic review including studies that investigated the anticholinergics such as lecithin containing phosphatide choline, cetanol, and meclofenoxate concluded that the use of cholinergics in the treatment of TD was unclear since sample sizes were small (5–20) (65).
One open-label, pilot study of donepezil in the treatment of tardive dyskinesia was conducted on ten patients with schizophrenia or schizoaffective disorder. The patients were administered donepezil, 5–10mg/day for six weeks after a two-week baseline. The AIMS scale was conducted at two-week intervals. The study reported statistically significant improvement (p = 0.0009) in overall AIM scores, with the most substantial reductions in orofacial movement and upper arm movement (66).
Dopamine-depleting agents
Dopamine-depleting agents are used in the treatment of TD in response partially to the proposed hypothesis of dopamine receptor hypersensitivity, and partially to the observation that drugs that cause parkinsonism reduce choreic movements. Hyperactive dopamine receptors produce the movement of tardive dyskinesia, and the continued blockade of these receptors may be useful to treat TD.
Tetrabenazine (TBZ) is a dopamine-depleting agent that inhibits vesicular monoamine transporter 2 (VMAT2). It is approved by the FDA as an orphan drug for the treatment of chorea in Huntington’s disease. Open-label and controlled trials indicate that TBZ has efficacy in treating TD. One double blind, placebo controlled trial evaluated the effect of TBZ in 24 hospitalized patients by testing the frequency of movements in a 3-minute time period (67). Antipsychotics were withdrawn in a run-in phase, and TBZ (up to 150 mg/day) was administered for 14 weeks, followed by a placebo period for 2 weeks. Patients treated with TBZ experienced a 60% reduction in TD. Ondo et al. performed a 20-week open-label study of TBZ in TD patients using blinded video for AIMS rating (68). There was a 54% decrease in AIMS scores from 17.9 to 8.2 (p < 0.001) in patients treated with TBZ at a mean dose of 58 mg/day. Guay et al. retrospectively reviewed ten trials that cumulatively enrolled a total of 1,142 patients who received TBZ for TD, and found that approximately 70% of patients showed marked, excellent, or complete improvement in TD symptoms (69). Side effects of TBZ include parkinsonism, depression, akathisia, nausea, vomiting, nervousness, anxiety, insomnia, and rarely, hyperthermia and neuroleptic malignant syndrome (11,69,70).
Reserpine is an irreversible, dopamine-depleting agent that inhibits vesicular monoamine transporter (VMAT1) (5). Due to untoward side effects such as depression and hypotension, its use as treatment for TD has been limited (4,70). In a double blind, controlled study of reserpine, 30 patients received reserpine 0.75–1.5mg daily, alpha-methyldopa 750–1,500mg daily, or placebo for two weeks. Reserpine improved TD about 50%, on a scale that rated TD from 0 (absent) to 3(severe) (71).
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