Treatment Recommendations for Tardive Dyskinesia

Abstract

Background:

Tardive dyskinesia is a movement disorder characterised by irregular, stereotyped, and choreiform movements associated with the use of antipsychotic medication. We aim to provide recommendations on the treatment of tardive dyskinesia.

Methods:

We performed a systematic review of studies of the treatment of tardive dyskinesia. Studies were rated for methodological quality using the American Academy of Neurology Risk of Bias Classification system. Overall level of evidence classifications and grades of recommendation were made using the Scottish Intercollegiate Guidelines Network framework.

Results:

Preventing tardive dyskinesia is of primary importance, and clinicians should follow best practice for prescribing antipsychotic medication, including limiting the prescription for specific indications, using the minimum effective dose, and minimising the duration of therapy. The first-line management of tardive dyskinesia is the withdrawal of antipsychotic medication if clinically feasible. Yet, for many patients with serious mental illness, the discontinuation of antipsychotics is not possible due to disease relapse. Switching from a first-generation to a second-generation antipsychotic with a lower D2 affinity, such as clozapine or quetiapine, may be effective in reducing tardive dyskinesia symptoms. The strongest evidence for a suitable co-intervention to treat tardive dyskinesia comes from tests with the new VMAT inhibitors, deutetrabenazine and valbenazine. These medications have not been approved for use in Canada.

Conclusion:

Data on tardive dyskinesia treatment are limited, and the best management strategy remains prevention. More long-term safety and efficacy data are needed for deutetrabenazine and valbenazine, and their routine availability to patients outside of the USA remains in question.

Introduction

Tardive dyskinesia (TD) is a movement disorder characterised by irregular movements that most commonly affect movements of the tongue, lips, jaw, and face, and sometimes the peri-orbital areas. In some cases, patients also have irregular movement of the trunk and limbs. These movements are typically choreiform or choreoathetoid in type; although, athetosis of the extremities and axial and limb dystonia are often listed as part of the syndrome, as are gait and trunk posture abnormalities, such as rocking or rotary pelvic movements^1,2.

TD was first described in 1957, 5 y after the introduction of chlorpromazine, when patients who had been exposed to the drug for 2 to 8 weeks showed bucco-oral movements persisting after treatment cessation³. In the late 1960s, the term “tardive dyskinesia” appeared⁴. “Tardive” means late onset, which reflects that the condition is seen more commonly in people who have been receiving antipsychotic (neuroleptic) or dopamine receptor blocking (DRB) medication for a prolonged period. However, the relationship between exposure to antipsychotic treatment and vulnerability to TD appears to vary with age: TD tends to emerge in older persons after a relatively short period of treatment with antipsychotic medications^5–7.

Whereas approximately two-thirds of patients are unaware of the involuntary movements, some report being troubled and embarrassed by them, exhibiting signs of emotional and physical distress⁸. Having reviewed the findings of relevant publications between 1959 and 1979, Kane and Smith⁹ reported a TD prevalence of around 15% among those prescribed first-generation antipsychotic (FGA) medication. A review by Yassa and Jeste¹⁰ 10 y later yielded a higher figure of about 24%. Glazer et al.¹¹ estimated the risk of persistent TD to be around 50% after 10 y of exposure to FGAs. A meta-analysis of 41 studies published since 2000⁷ addressed TD prevalence during contemporaneous treatment with FGAs and/or second-generation (SGA) medications. A significantly lower mean TD prevalence rate (21%) was identified for patients receiving an SGA than an FGA (30%). The reported risk factors for developing TD in association with antipsychotic use include female sex, older age, previous brain injury or dementia, and African and African-American ethnicity^5,6.

There has been a disproportionate increase in antipsychotic use over the past 20 y, likely due to new indications for the use of several antipsychotics as adjunctive treatments for major depression, and off-label uses of these medications in children, older persons, and individuals with sleep disturbances^12,13. SGAs were expected to have fewer extrapyramidal side effects, including the precipitation of TD, as compared with FGAs, particularly haloperidol. Yet, the advantages of SGAs regarding TD risk are still controversial: although equal rates of TD have been reported for SGA and FGA treatments in randomised controlled trials (RCTs)¹⁴, a recent meta-analysis estimates TD risk to be lower for SGAs than FGAs¹⁵. However, SGAs differ in their propensity to cause extrapyramidal side effects, including TD. Indeed, clozapine has a lower risk of extrapyramidal side effects, whereas lurasidone, risperidone, and paliperidone have a much higher risk¹⁶. These differences may reflect individual drug profiles in relation to properties such as selective dopamine D2-like receptor antagonism, potent 5-HT2A antagonism, rapid dissociation from the D2 receptor, and, for aripiprazole as well as brexpiprazole, partial agonism at D2 and 5HT1A receptors. Although there appears to be some reduction in risk of TD with SGAs compared with FGAs, it is clear that 1) all antipsychotics, including SGAs, can be associated with the development of TD, and that 2) there may be other factors involved in the lower apparent risk of TD associated with the increased use of SGAs; this could reflect the general shift toward the use of much lower doses of antipsychotics.

The purpose of this guideline was to comprehensively review the evidence on the treatment of TD, to broaden awareness of the recently available therapeutic options, and to make evidence-based recommendations for TD treatment for practicing clinicians.

Methods

A systematic review of the literature was performed for studies on the treatment of antipsychotic-induced movement disorders. We searched Medline and CENTRAL in November 2016, with a repeat search conducted in June 2017, using the search strategy in Appendix 1. We hand-searched the Cochrane Library for systematic reviews and also searched for published guidelines on this topic and included all references from these papers. Our Medline and CENTRAL search found 5,053 abstracts, which were reviewed independently by 2 researchers. Of these, 250 were chosen for full-text review. From the 10 identified Cochrane reviews on this topic^17–26, and from the American Academy of Neurology (AAN) guideline on tardive syndromes ²⁷ and its recent update²⁸, and the Canadian Alliance on Monitoring of Safety and Effectiveness of Antipsychotic (CAMESA) guideline on management of extrapyramidal symptoms²⁹, we identified an additional 97 articles, bringing the total to 346 articles for full-text review. Of these, 227 papers pertained to the treatment of TD, 192 of which were individual studies, and 35 were review articles. Of the individual studies, 149 were included in 1 of the 10 Cochrane reviews or the AAN guideline on the management of tardive syndromes. Data from the Cochrane reviews, AAN guideline and individual studies were used in the formulation of recommendations on the treatment of TD. We included any type of therapeutic study, including open-label studies and controlled trials. If controlled trials were available for a specific therapeutic intervention, open-label studies were not included in our analysis. Studies were rated for methodological quality using the American Academy of Neurology Risk of Bias Classification system. Each study was given a class rating of I to IV based on the fulfilment of these criteria (see Table 1). Ratings of risk of bias and data extraction were performed by a single researcher and checked by a second researcher for accuracy. Discrepancies were resolved by discussion. The overall level of evidence classification and grade of recommendation were made using the Scottish Intercollegiate Guidelines Network (SIGN) framework (see Table 2). For each therapeutic study included, the risk of bias, population, intervention, comparator, trial length, number of participants, and main outcomes are described in full in Appendix 2 and summarised below within the recommendations. The initial recommendations were drafted by a team of researchers and then put to a vote by the entire panel as to its inclusion in the guideline. The grades of recommendations were made using the SIGN framework. Recommendation statements were formulated based on the evidence obtained from the systematic review, the magnitude of the benefit associated with the intervention, the risk of harm, cost, availability, and variation in patient preference. Each recommendation required agreement by 80% of the panel for inclusion in the guideline. The panel consisted of movement disorder specialists, psychiatrists, and psychopharmacologists with expertise in the therapeutic use of and adverse effects associated with antipsychotics. Due to the length of the manuscript, summaries for medications that were not found to have therapeutic benefit can be found in Appendix 3.

Table 1.

American Academy of Neurology Risk of Bias Classification System.

Class I

Randomised controlled clinical trial (RCT) in a representative population Triple masked studies (i.e., the patient, treating provider, and outcome assessors are unaware of treatment assignment) Relevant baseline characteristics of treatment groups (or treatment order groups for cross-over trials) are presented and substantially equivalent among the treatment groups, or there is appropriate statistical adjustment for differences. Additional Class I criteria:  a. Concealed allocation  b. No more than 2 primary outcomes specified  c. Exclusion and inclusion criteria clearly defined  d. Adequate accounting of dropouts (with at least 80% of participants completing the study) and crossovers  e. For non-inferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required:a    i. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or non-inferiority.    ii. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose, and dosage adjustments are similar to those previously shown to be effective).   iii. The inclusion and exclusion criteria for participant selection and the outcomes of participants on the standard treatment are comparable with those of previous studies establishing efficacy of the standard treatment.   iv. The interpretation of the study results is based on a per-protocol analysis that accounts for dropouts or crossovers.  f. For crossover trials, both period and carryover effects are examined and statistical adjustments performed, if appropriate.

Class II

RCT that lacks 1 or 2 Class I criteria a–e (see above) Cohort studies employing methods that successfully match treatment groups on relevant baseline characteristics (e.g., propensity score matching) meeting Class I criteria b–e (see above) Randomised crossover trial missing one of the following 2 criteria:  a. Period and carryover effects described  b. Baseline characteristics of treatment order groups presented All relevant baseline characteristics are presented and substantially equivalent across treatment groups (or treatment order groups for crossover trials, or there is appropriate statistical adjustment for differences). Masked or objectiveb outcome assessment

Class III

Controlled studies (including studies with external controls such as well-defined natural history controls) Crossover trial missing both of the following 2 criteria:  a. Period and carryover effects  b. Presentation of baseline characteristics A description of major confounding differences between treatment groups that could affect outcomeb Outcome assessment performed by someone who is not a member of the treatment team

Class IV

Studies not meeting Class I, II or III criteria.

^aNumbers i–iii in Class Ie are required for Class II in equivalence trials. If any 1 of the 3 is missing, the class is automatically downgraded to Class III.

^bObjective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Table 2.

Scottish Intercollegiate Guidelines Network Framework.

LEVELS OF EVIDENCE 1++ High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias 1+ Well conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias 1− Meta-analyses, systematic reviews, or RCTs with a high risk of bias 2++ High quality systematic reviews of case control or cohort studies, or High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal 2+ Well conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal 2− Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal 3 Non-analytic studies, e.g. case reports, case series 4 Expert opinion

GRADES OF RECOMMENDATION Note: The grade of recommendation relates to the strength of the evidence on which the recommendation is based. It does not reflect the clinical importance of the recommendation.

A At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or A body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results

B A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+

C A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 2++

D Evidence level 3 or 4; or Extrapolated evidence from studies rated as 2+

GOOD PRACTICE POINTS Recommended best practice based on the clinical experience of the guideline development group

Results

Modification of Antipsychotic Medication as a Treatment for TD (Level of Evidence 1−)

One strategy for the treatment of TD includes modification of the antipsychotic medication regimen, such as dose reduction, cessation, switching from one antipsychotic medication to another, or using higher doses to mask TD symptoms. Individuals with psychotic disorders usually require long-term antipsychotic therapy to maintain a remission of their symptoms; the discontinuation of antipsychotic medication is associated with a worsening of symptoms over time and high rates of relapse^16,30,31. Thus, in such patients, discontinuing the medication is precluded and dosage changes or switching to another antipsychotic drug should be undertaken with caution. In patients where antipsychotics are prescribed without an approved indication or for indications other than a primary psychotic disorder, attempts to withdraw the causative drug may be more feasible; however, in some cases, patients experience withdrawal dyskinesia and low rates of remission^32–35.

Several studies have evaluated the effect of modifying an existing antipsychotic therapy for the treatment of TD. A Cochrane review, published in 2006¹⁷, included 5 RCTs. We reviewed the results of the Cochrane review, as well as studies that were excluded by the Cochrane review, and searched for additional studies published after the review that addressed antipsychotic dose reduction, cessation, or switching, or the use of higher doses to mask TD symptoms. Most studies were included in the American Academy of Neurology guideline on the management of tardive syndromes²⁷. As the studies included in the Cochrane review did not provide enough data to support a recommendation, these studies are summarised in Appendix 3.

Using Higher Doses of Antipsychotic Medications to Mask TD Symptoms

Various older small studies evaluated the effect of using high doses of haloperidol or other antipsychotics to mask TD^36–41. Although some of these studies reported an improvement in TD symptoms, this practice is now seldom employed, as the benefits are short lived, and TD symptoms inevitably return in most individuals. Furthermore, higher doses of antipsychotics may lead to worsening of the drug-induced parkinsonism or akathisia.

Switching Antipsychotic Medication: From First-Generation to Second-Generation Antipsychotic Medications

Several studies have evaluated the effect of switching from an FGA to risperidone to treat TD. Bai and colleagues⁴² performed an RCT of 44 patients with schizophrenia and severe TD. All participants were taking FGAs at baseline. After a 4-week wash-out, patients were randomised to receive risperidone or a placebo. After 12 weeks of treatment, there was a significantly greater decrease in the mean AIMS score in the risperidone group (mean [SD] −5.5 [3.8]) than in the placebo group (−1.1 [4.8]) (P = 0.001) when compared with the baseline⁴². Forty participants were followed in a 36-week, extended, open-label study (Class IV)⁴³. All participants received 2 to 6 mg risperidone daily. At week 48, the total AIMS score decreased in 35 participants (87.5%), with a mean change of –6.1 [3.5] points.

Chouinard⁴⁴ performed a post hoc analysis on data from patients with TD from a clinical trial that had compared 4 doses of risperidone, haloperidol, or a placebo. In this class II RCT, 135 hospitalised patients with chronic schizophrenia and who were poor responders to FGAs, were randomly allocated to 2, 6, 10, or 16 mg/day risperidone; 20 mg/day haloperidol; or placebo for 8 weeks. The post hoc analysis included 48 participants with moderately severe TD. Participants randomised to 6 mg/day risperidone had a mean 1.2-point decrease in the total Extrapyramidal Symptom Rating Scale (ESRS) dyskinesia score from baseline to their worst score on double-blind treatment, which was statistically significant compared with both the placebo and haloperidol-treatment groups (P < 0.05).

Another RCT compared the effect of risperidone and olanzapine in 60 patients with TD⁴⁵. All participants entered a washout period of 3 to 7 days before randomisation, during which time all previously used FGAs and other psychotropic medications were stopped. Participants were randomised to receive risperidone or olanzapine for 24 weeks. After 24 weeks of treatment, both groups had a significant improvement in AIMS total scores compared with baseline (risperidone: −7.4 [6.9], P < 0.0001; olanzapine: −6.2 [8.0], P = 0.0002), with no significant difference between risperidone and olanzapine. After an initial worsening in AIMS scores during the washout period, AIMS scores steadily decreased in both groups from baseline to week 24.

Kinon and coworkers⁴⁶ performed a class III study evaluating the effect of olanzapine on TD. They enrolled 95 participants with persistent TD: 42 were taking FGAs and 53 were treated with SGAs. Following medication withdrawal, patients were treated with a placebo washout period. All participants then received 5 to 20 mg olanzapine daily for 8 months. During this period, they underwent 1 or 2 dose-reduction periods under blinded conditions. During the 2-week dose-reduction period, the patients experienced an approximately 75% reduction in the dose that they had received immediately before the reduction period. Fifty-five patients (58%) completed the 8-month study. There was an overall improvement in the AIMS total score from 12.0 at baseline to 6.4 at endpoint (P < 0.001); 70% of patients no longer met the criteria for persistent TD after 8 months of treatment. No significant rebound worsening of TD was found during either of the blinded dose-reduction periods.

Brar et al.⁴⁷ compared the effect of olanzapine on TD v. continuing FGA therapy in a comparative study (class IV) of 63 patients. Consecutive patients with schizophrenia, schizoaffective disorder, or bipolar I disorder, who were initiated on olanzapine by their physician, were compared with patients admitted during the same time period who continued to receive FGAs. There was no difference in the AIMS scores at baseline between the 2 groups. At 8 weeks and 6 months, participants treated with olanzapine had a significant reduction in AIMS scores compared with those who continued on FGAs.

A recent review evaluated studies assessing the effect of clozapine on tardive syndromes⁴⁸. The review described 2 RCTs comparing clozapine and haloperidol, and their effects on TD symptoms. In the first study, 32 patients with schizophrenia and TD initially treated with haloperidol were randomised to clozapine plus placebo or haloperidol plus benztropine for 1 y⁴⁹. There was a significant difference in TD severity over the course of the treatment period (P < 0.05), with a decrease in TD scores in the clozapine group commencing after 4 months of treatment. In the second study, 423 hospitalised patients with refractory schizophrenia were randomised to haloperidol plus benztropine or clozapine plus placebo for 1 y⁵⁰. The baseline AIMS scores for TD severity were similar between the 2 treatment groups (clozapine, 5.9; haloperidol, 5.8). After 1 y of treatment, clozapine use was associated with markedly greater reductions in the AIMS scores over time, with mean scores of 3.6 for clozapine v. 5.2 for haloperidol (P = 0.005) at follow up.

Recommendations (Grade B)

1. For individuals who develop TD, do not have a psychotic disorder, and are able to stop their antipsychotic therapy without the risk of worsening their mental health condition, slow and gradual tapering of the medication can be attempted over a period of weeks or months, depending on the condition treated and history of relapse.

2. In most patients with schizophrenia, stopping antipsychotic therapy is not an option for the treatment of TD due to the increased risk of relapse.

3. Patients must be warned that TD symptoms may worsen transiently as medication dosages are lowered (withdrawal emergent dyskinesias). In some cases, the signs of TD may take months or years to remit once antipsychotic medication has stopped and may never completely resolve.

4. Although the use of high doses of antipsychotic medication may transiently mask TD, this practice is not recommended.

5. There is insufficient evidence to recommend dose reduction as a treatment for TD. Targeting the low end of the recommended dose range throughout treatment is recommended to limit the risk of developing TD.

6. Switching from an FGA, particularly haloperidol, to an SGA with a lower D2 affinity, such as clozapine or quetiapine, may be effective in reducing TD symptoms. All antipsychotic medications are associated with a risk of TD; though, the available evidence suggests that the risk may be lower with SGAs. Clinicians and patients must be aware that improvement in symptoms may take months or years to occur.

Vitamin E for TD (Level of Evidence 1−) (See Appendix 3)

Recommendation (Grade B)

Vitamin E use does not lead to clinically important improvements in TD once it is established but may protect against deterioration of TD symptoms.

Vitamin B6 and Pyridoxal 5 Phosphate for TD (Level of Evidence 1−)

Pyridoxal 5 phosphate is the metabolically active form of vitamin B6. A Cochrane review²⁴ of 3 RCTs evaluated the effectiveness of pyridoxal 5 phosphate delivered as vitamin B6, pyridoxine, or pyridoxal phosphate in the treatment of TD in patients with psychotic disorders. Risk of bias was low in all 3 studies (Class II). All 3 trials were conducted at the same centre and used a crossover design. The duration of the trials ranged from 9 weeks^51,52 to 26 weeks⁵³. Eighty participants were included, with ages ranging from 18 to 71 y, with slightly more females. Participants received vitamin B6 or placebo in addition to their on-going medications, with the dose ranging from 400 mg to 1200 mg daily.

Clinical efficacy was evaluated by means of the ESRS. Vitamin B6 was clinically efficacious compared with placebo in reducing dyskinesia symptoms (RR, 19.97; 95%CI, 2.87 to 139.19). There was no difference between groups in the rate of discontinuation of treatment or in the deterioration of TD symptoms. Only one study⁵² evaluated the change in psychiatric symptoms and found no difference between vitamin B6 and placebo.

Due to the small number of participants in trials of vitamin B6 for TD and the limited duration of therapy, the long-term safety and usefulness of this intervention is difficult to gauge. Chronic administration (more than 12 months) of vitamin B6, in amounts exceeding 1,000 mg per day, can cause a severe and progressive sensory neuropathy⁵⁴.

Recommendation (Grade B)

In patients failing to respond to more established alternative treatments for TD, such as switching to an SGA or prescribing VMAT-2 inhibitors, short-term treatment with vitamin B6 may be considered. However, the dose and duration for optimal benefits while maintaining safety have not been established.

Benzodiazepines for TD (Level of Evidence 1−) (See Appendix 3)

Recommendation (Grade B)

Currently, there is little evidence to support the beneficial effects of benzodiazepines on reducing TD. Moreover, given the evidence of acute and long-term harm (sedation, worsening of cognitive functions, tolerance, dependence and risk of falls especially in elderly people) from benzodiazepine use in patients with mental health disorders, the routine use of benzodiazepines is discouraged.

Gamma-Aminobutyric Acid (GABA) Agonists for TD (Level of Evidence 1−) (See Appendix 3)

Recommendation (Grade B)

Due to evidence of no effect and to the risk of side effects (ataxia, sedation), non-benzodiazepine GABA agonists (baclofen, gamma-vinyl-GABA, gamma-acetylenic-GABA, progabide, muscimol, sodium valproate, and tetrahydroisoxazolopyridine, piracetam, levetiracetam) are not recommended for the treatment of TD.

Cholinergic Medication for TD (Level of Evidence 1-) (See Appendix 3)

Recommendation (Grade B)

Due to evidence of no effect, cholinergic medications (arecoline, choline, deanol, lecithin, meclofenoxate, physostigmine, RS86, tacrine, metoxytacrine, galantamine, ipidacrine, donepezil, rivastigmine, eptastigmine, metrifonate, xanomeline, cevimeline) are not recommended for the treatment of TD.

Anticholinergic Medication for Antipsychotic-Induced Tardive Dyskinesia (Level of Evidence 1−)

An association between anticholinergic medication and TD has been rather inconsistently observed^55,56. If it requires explanation, one possibility is that it could be an epiphenomenon, in that the appearance of acute EPS early in treatment is not only a risk factor for the later development of TD⁵⁷ but also likely to attract the prescription of an antiparkinsonian (anticholinergic) agent. An alternative explanation is that long-term anticholinergic drug administration is a risk factor for TD, but there is no convincing evidence for this⁵⁸. Nevertheless, for the primary prevention of TD, it is sometimes recommended that anticholinergic agents should be avoided and, further, if anticholinergic agents are co-prescribed with antipsychotic medication in a patient with TD, they should be withdrawn^59–61 on the basis that they may be exacerbating the condition⁶². However, a Cochrane systematic review²⁶ concluded that the currently available evidence did not allow for any confident statement about whether the withdrawal of anticholinergic medication provides any benefit for people with antipsychotic-induced TD and called for further clinical trials to test its effect. There is only one RCT of 10 individuals with schizophrenia and TD on long-term treatment with antipsychotics and anticholinergics in whom controlled discontinuation of anticholinergic medication has been performed⁶³. This Class III study reported a significant decrease in the severity of TD in 9 individuals within 2 weeks of anticholinergic discontinuation (P < 0.001), which was most pronounced in the oral region. Three of the 10 participants had worsening of drug-induced parkinsonism with anticholinergic discontinuation.

Recommendation (Grade C)

Clinicians may consider discontinuation of anticholinergic medications for the treatment of TD, keeping in mind that there is very little evidence to support this course of action, and that drug-induced parkinsonism may worsen.

Miscellaneous Treatments for TD (Level of Evidence 1−) (See Appendix 3)

Recommendation (Grade C)

There is insufficient evidence to recommend the use of ginko biloba, levetiracetam, buspirone, dehydrogenated ergot alkaloids, hypnosis or relaxation, pemoline, promethazine, insulin, branched chain amino acids, or isocarboxazid for the treatment of TD. Due to evidence of no effect, ceruletine, phenylalanine, piracetam, melatonin, lithium, ritanserin, selegiline, oestrogen, gamma-linolenic acid and diltiazem are not recommended for the treatment of TD.

Non-antipsychotic Catecholaminergic Drugs for TD

A Cochrane review was published in 2006 evaluating the effect on TD of pharmacological agents known to influence the catecholaminergic system at various junctures²³. A recent update of this review has been published²². Neither review found any useful information on the treatment of TD using these types of drugs, as most of the identified studies were either excluded, or of low or very low quality. We reviewed the list of excluded studies and searched for additional studies on the use of non-antipsychotic catecholaminergic drugs published after this review.

Amantadine (Level of Evidence 1−)

There are 2 randomised crossover trials^64,65 of amantadine for TD that are of low⁶⁴ (class II) and high⁶⁵ (class III) risk of bias. These trials included a total of 38 individuals with a diagnosis of schizophrenia and TD. Participants were treated with up to 400 mg amantadine daily for 1 or 2 weeks, then crossed over to placebo (or vice versa) after a washout period. Both studies reported a statistically significant benefit with amantadine on symptoms of TD as measured using the AIMS relative to treatment with placebo, though the magnitude of the effect was small in both studies. No serious adverse events were reported, and one study reported no adverse effects on cognitive function with amantadine.

Recommendation (Grade B)

The evidence to support the use of amantadine for TD is extremely limited. Amantadine may be considered for the treatment of TD if more established treatments are contraindicated or ineffective.

VMAT2 Inhibitors

The vesicular monoamine transporter 2 (VMAT2) is an integral membrane protein that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release. There are 3 VMAT2 inhibitors: tetrabenazine, valbenazine and deutetrabenazine.

Valbenazine (Level of Evidence 1+)

Valbenazine selectively inhibits VMAT2, with little to no affinity for VMAT1 or other monoamine receptors. It metabolizes slowly, has less peak-to-trough variations in plasma levels than TBZ, and has a half-life of approximately 20 h, allowing for a once daily administration. Genotyping is not required but dosing adjustments are recommended in the presence of CYP 2D6 or CYP 3A4 modulators.

There are 2 published RCTs of valbenazine^66,67 for the treatment of TD. These trials were rated as having a low risk of bias (class I) and included a total of 339 individuals with a primary diagnosis of schizophrenia, schizoaffective disorder, mood disorder or gastrointestinal disorder with metoclopramide-induced TD. Participants were treated with 25 to 80 mg valbenazine or placebo once daily for 6 weeks. The primary outcome of both studies was the change in the AIMS score from baseline to endpoint. In the flexible-dose study, the mean difference between valbenazine and placebo was −2.4 points (95%CI, −3.7 to −1.1), with a significantly greater proportion of individuals treated with valbenazine reported as much or very much improved⁶⁶. In the fixed-dose study, there was a dose-dependent effect of valbenazine, with the change in the AIMS score from baseline to week 6 of −0.1 with placebo, −1.9 with 40 mg valbenazine (P = 0.002) and −3.2 with 80 mg valbenazine (P < 0.001)⁶⁷. There were no serious adverse effects associated with valbenazine in either study. Fatigue, akathisia and dry mouth were the most common adverse effects, occurring in approximately 10% of participants receiving valbenazine⁶⁸. Long-term safety and efficacy of valbenazine were confirmed by the extension phase of the KINECT 3 trial, where 124 patients who completed the 6-week RCT entered the 42-week extension period receiving 40 mg or 80 mg of valbenazine⁶⁹.

Valbenazine was approved by the US Food and Drug Administration for the treatment of TD in 2017.

Recommendation (Grade A)

There is good evidence to support a favourable benefit-risk ratio for valbenazine as a treatment for TD. Valbenazine should be considered a first-line treatment for TD.

Deutetrabenazine (Level of Evidence 1+)

Deutetrabenazine is an isotopic isomer of tetrabenazine, in which 6 hydrogen atoms have been replaced by deuterium atoms. The incorporation of deuterium slows the rate of drug metabolism, such that less frequent dosing is required, making the drug more tolerable.

There are 2 RCTs of deutetrabenazine for the treatment of TD^70,71. These trials were rated as having a low risk of bias (one class I and one class II) and included a total of 415 individuals with a diagnosis of TD and treated for 12 weeks with deutetrabenazine. One trial was a flexible-dose study, with deutetrabenazine between 12 and 48 mg (v. placebo)⁷⁰; the other trial was a fixed-dose study, with trial participants randomised to placebo, 12, 24 or 36 mg of deutetrabenazine⁷¹. The primary outcome in both trials was the change in the AIMS score from baseline to week 12. In the flexible-dose study, the mean dose used was 38.8 mg. Deutetrabenazine was significantly superior to the placebo, with a mean difference in the change in AIMS score −1.4 points (95%CI −2.6 to −0.2) from baseline to week 12⁷⁰. There was no difference between placebo and deutetrabenazine in the rate of psychiatric adverse effects during the study period (depressed mood or suicidal ideation). Somnolence was the most common adverse effect in both the deutetrabenazine group (13.8%) and in placebo group (10.2%). In the fixed-dose study, both the 24 mg and 36 mg doses were significantly superior to the placebo in the AIMS score change from baseline to week 12. The treatment difference was −1.9 points (95%CI, −3.09 to −0.79) for the 36 mg dose v. placebo, and was −1.8 points (95%CI, −3.00 to −0.63) for the 24 mg dose⁷¹. Deutetrabenazine was efficacious both in patients receiving and those not receiving concomitant dopamine receptor antagonists at baseline, but the improvement was greater in patients not receiving these drugs and in patients with higher AIMS scores. There was no difference between deutetrabenazine and placebo in terms of adverse effects, serious adverse effects, or adverse effects leading to treatment discontinuation. There was no difference between treatment groups in the rate of psychiatric adverse effects. The group receiving 36 mg per day had a slightly higher rate of neurological adverse effects (particularly headache and somnolence). There were no clinically meaningful changes in vital signs or laboratory tests. The incidence of adverse events did not differ based on the concomitant treatment with dopamine receptor antagonists. Deutetrabenazine was approved by the US Food and Drug Administration for the treatment of TD in 2017.

Recommendation (Grade A)

There is good evidence for a favourable benefit-risk ratio for deutetrabenazine as a treatment for TD. Deutetrabenazine should be considered a first-line treatment for TD.

Tetrabenazine (Level of Evidence 1−)

There are 2 Class III studies of tetrabenazine for TD^38,72. These studies included a total of 38 individuals, treated with doses of tetrabenazine up to 200 mg per day. One study³⁸ compared tetrabenazine with haloperidol for 18 weeks and found that 2 of 6 participants treated with tetrabenazine had resolution of their symptoms. The other study⁷² used blinded randomised videotape evaluations to compare patients’ AIMS scores before and after treatment with tetrabenazine for a mean of 20 weeks. Mean scores on the AIMS motor subset improved 54% (P < 0.001), and subjective scores on the AIMS improved 60% (P < 0.001). Side effects included sedation and mild parkinsonism. One class IV study reported a case series of 400 patients treated with tetrabenazine for various hyperkinetic movement disorders. Whereas most of the patients with TD (n = 94) reported a marked reduction in their symptoms, side effects for the entire sample were frequently reported: drowsiness in 37% of the cohort, parkinsonism in 29%, depression in 15%, insomnia in 11%, anxiety in 10%, and akathisia in 10%.

Recommendation (Grade B)

There is limited evidence for the use of tetrabenazine for the treatment of TD. The current available evidence suggests that, while tetrabenazine may be helpful for TD, its use is associated with more adverse effects than valbenazine and deutetrabenazine. Given the higher-quality evidence in support of the other VMAT2 inhibitors with fewer adverse effects, valbenazine and deutetrabenazine should be preferred over tetrabenazine for the treatment of TD.

Reserpine and Alpha Methyldopa (Level of Evidence 1−) (See Appendix 3)

Recommendation (Grade B)

Given the very limited and low-quality evidence for alpha methyldopa and reserpine as treatments for TD, the use of other dopamine depleters (valbenazine and deutetrabenazine) is advised.

Deep Brain Stimulation (DBS) for TD (Level 2+) (See Appendix 3)

Recommendation (Grade C)

There is limited evidence for the use of globus pallidus interna deep brain stimulation (GPi-DBS) in the treatment of TD. The current available evidence suggests that GPi-DBS could be considered in select cases where TD symptoms are severe and distressing and not responsive to medical treatment, and where psychiatric conditions are stabilised.

Summary and Conclusions

TD is a relatively common and potentially disabling condition. Although the incidence and prevalence of TD seems to be lower with SGAs, TD is still commonly seen in clinical practice, possibly reflecting the increased use of these medications for different indications. The prevention and treatment of TD remain important concerns in current clinical practice. The prevention of TD is of primary importance, and clinicians should follow best practice guidance for the prescription of antipsychotic medication; this includes limiting prescription to specific indications, using the minimum effective dose, and minimising the duration of therapy.

The first-line management of TD is the withdrawal of antipsychotic medication, if clinically feasible. Yet, for many patients, this course of action is not possible as it worsens the underlying psychiatric disorder. Alternatively, if the patient develops TD while taking an FGA, it is reasonable to switch them to an SGA with a lower D2 affinity.

Other than ceasing or switching antipsychotic medication, the strongest current evidence for TD treatment is the use of the VMAT inhibitors, deutetrabenazine and valbenazine. These 2 new inhibitors appear to be effective and have considerably more favourable side effects than tetrabenazine⁷³. However, given the lack of their widespread use, scanty long-term safety data are available, and knowledge of any potential side effects (<1:10,000) is rare at this time. Further studies are needed to clarify the long-term safety and efficacy of these new drugs. At present, valbenazine and deutetrabenazine are approved only for the treatment of TD in the USA; Canadian physicians wishing to prescribe either medication can make a Special Access Request to Health Canada’s Special Access Program.

TD is a very disabling clinical disorder that is often hard to manage and treat. Clinicians should be aware of the potential risk of developing TD in patients on long-term treatment with antipsychotics and should carefully assess patients to recognize TD for its prompt management.