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 he 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 ailability to patients outside of the USA remains in question.
Keywords: tardive dyskinesia, evidence-based medicine, antipsychotics
Abstract Contexte :La dyskinésie tardive (DT) est un trouble moteur caractérisé par des mouvements irréguliers, stéréotypés et choréiformes associés à l’utilisation de médicaments antipsychotiques. Nous voulons présenter des recommandations sur le traitement de la dyskinésie tardive.
Méthodes :Une revue systématique des études sur le traitement de la dyskinésie tardive a été menée. La qualité méthodologique des études a été évaluée à l’aide du système de classification du risque de biais de l’Académie américaine de neurologie. Le niveau général des classifications des données probantes et des cotes des recommandations a été établi grâce au cadre du réseau Scottish Intercollegiate Guidelines.
Résultats :La prévention de la DT est d’une importance primordiale, et les cliniciens devraient suivre les pratiques exemplaires en matière de prescription d’antipsychotiques, soit limiter la prescription aux indications spécifiques, utiliser la dose efficace minimale et la durée la plus courte de la thérapie. La prise en charge de première intention de la DT est le sevrage d’antipsychotique si c’est cliniquement faisable, mais pour de nombreux patients souffrant de maladie mentale gre, l’interruption des antipsychotiques n’est pas possible en raison de la rechute de la maladie. Passer d’un antipsychotique de première génération à un autre de deuxième génération ayant une affinité moindre au récepteur D2, comme la clozapine ou la quétiapine, peut être efficace pour réduire les symptômes de la DT. Les données probantes les plus fortes en feur des co-interventions pour traiter la DT prônent les nouveaux inhibiteurs des VMAT, la deutétrabénazine et la valbénazine. Ces médicaments n’ont pas été approuvés au Canada.
Conclusion :Les données sur le traitement de la DT sont limitées et la meilleure stratégie de prise en charge demeure la prévention. Des données à plus long terme sur l’innocuité et l’efficacité sont nécessaires pour la deutétrabénazine et la valbénazine, dont la disponibilité régulière pour les patients hors des États-Unis demeure en question.
IntroductionTardive 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 he 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 movements1,2.
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 he 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 medications5–7.
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. Hing 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 ethnicity5,6.
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 disturbances12,13. SGAs were expected to he 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 he 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 he 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 ailable therapeutic options, and to make evidence-based recommendations for TD treatment for practicing clinicians.
MethodsA 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 topic17–26, 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 ailable 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, ailability, 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 he 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 populationTriple 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 presentedAll 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 characteristicsA 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. Open in a new tabaNumbers 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 EVIDENCE1++ High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias1+ Well conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias1− Meta-analyses, systematic reviews, or RCTs with a high risk of bias2++ 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 causal2+ Well conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal2− Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal3 Non-analytic studies, e.g. case reports, case series4 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; orA 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; orExtrapolated 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; orExtrapolated 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 Open in a new tabResults 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 relapse16,30,31. 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 remission32–35.
Several studies he 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 SymptomsVarious older small studies evaluated the effect of using high doses of haloperidol or other antipsychotics to mask TD36–41. 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 MedicationsSeveral studies he 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