Treatment of tardive dyskinesia: A systematic review (1997-2011)

M. Alimi^*,**; P. Gaillard^*,***; V. Camus^*,*** and W. El-Hage^*,***

^*Clinique Psychiatrique Universitaire, CHRU de Tours. France
^**Centre Hospitalier Esquirol, CHU de Caen. France
^***Inserm U930 ERL, Université François Rabelais de Tours. France

Correspondence

ABSTRACT

Background and Objectives: Tardive dyskinesia (TD) is a frequent and incapacitating side effect of first-generation antipsychotics. Although second-generation antipsychotics (SGAs) seem to be associated with a decreased risk of TD, it remains a severe, unresolved iatrogenic condition. Moreover, there is no commonly accepted effective treatment for TD.
We conducted a systematic review of the literature to assess evidence regarding the effectiveness of different therapeutic interventions for TD.
Methods: We performed a systematic review focussing exclusively on randomised controlled trials (RCTs). We searched the MEDLINE database (1997 to 2011) using the keyword "tardive dyskinesia" within the "title" search field. Twenty-six RCTs were included. Based on the evidence from RCTs, we built a decision tree that healthcare professionals can use to choose an effective therapeutic intervention for TD.
Results: Four therapeutic interventions were found to be effective in TD (vitamin B6, ginkgo biloba, branched-chain amino acids, and piracetam).
Conclusions: Patients with TD could benefit from the therapeutic interventions supported by the data accumulated from RCTs.

Key words: Tardive dyskinesia; Antipsychotics; Neuroleptic-induced movement disorders.

Tardive dyskinesia (TD) causes severe social and physical disability. TD is characterised by abnormal involuntary movements of the tongue, jaw, trunk, or extremities that persist for at least 4 weeks. The symptoms appear during neuroleptic treatment or within 4 weeks after discontinuing neuroleptic treatment that has been administered for at least 3 months. The annual incidence of TD varies between 4 and 5% in patients using first-generation antipsychotics (FGAs)¹. The use of second-generation antipsychotics (SGAs) is associated with a reduced rate of TD², with an estimated incidence ranging from 2.1 to 4.9%^3,4.

Primary prevention that prevents the disease from occurring remains the best strategy. In the case of TD, the lowest effective dose should be used^5,6 for the shortest amount of time possible⁷. There is also a class effect: SGAs cause fewer cases of dyskinesia⁴, and clozapine has not shown any correlation to TD⁸. Moreover, prescribing anticholinergic therapy in patients with acute extrapyramidal symptoms is a risk factor for TD⁷.

Currently, there is no evidence supporting the effectiveness of any therapeutic intervention for this illness⁹. Nevertheless, several publications have reported an alleviating effect of some treatments for TD symptoms. This review aims to determine the effectiveness and safety of using these proposed therapeutic interventions for TD.

Objectives

This review aims to determine the effects of any intervention for neuroleptic-induced TD in people with schizophrenia or other chronic mental illness.

Methods

Criteria for considering studies for this review

Types of participants. We included people suffering from schizophrenia or chronic mental illness, irrespective of diagnosis criteria used, who required neuroleptic medications and developed neuroleptic-induced TD.

Types of interventions. We included trials whose aim was to assess any type of intervention in neuroleptic induced TD.

Types of outcome measures. This paper reviewed four health outcome measures that were commonly used in the selected RCTs to assess changes in patients. To determine clinical relevance, we defined significant change using the original cut-off point chosen by the authors.

- Tardive dyskinesia: No significant change in TD score; average endpoint TD score; average change in TD score.

- Mental state: No significant change in mental state; average endpoint mental state score; average change in mental state score.

- Adverse effects: Clinically important adverse effects; any adverse effect.

- Leaving the study early for general reasons.

Search method for identification of studies

Data collection and analysis

Selection of studies. Two of the authors (MA, WEH) independently and manually inspected the search results to retrieve those studies that were likely relevant. Where disagreement existed, we tried to resolve it by discussion. If a disagreement could not be resolved, we included the trial with a description of the ambiguity in the results section.

Data extraction and management. Two authors (MA, WEH) extracted data independently. In cases of disagreement, we tried to achieve resolution via discussion. If doubt persisted, we did not use the data and mentioned the lack of information. We assessed outcomes using quantitative (i.e., TD score change) or qualitative data (no significant change or significant change in TD score). When it was possible, we used binary data. Participants were divided into "clinically improved" or "not clinically improved" according to the primary cut-off point presented by the authors.

Assessment of risk of bias in included studies

The various risks of bias were evaluated as low, high, or uncertain, using the tool published in the Cochrane Collaboration Handbook¹⁰. For assessing the risk of bias, this tool recommends that evaluators pay attention to the sequence generation, the allocation concealment, the blinding of participants, the completeness of information, and the risk of selective reporting.

Measures of treatment effect

For continuous data, we calculated the effect size and the 95% confidence interval according to Hedges and Olkin's formula¹¹. When binary data were presented, we calculated a relative risk and its 95% confidence interval¹². When results were significant, we used the tool provided in Grade Profiler 3.6 software (ims.cochrane.org) to determine the absolute risk reduction (ARR) and its 95% confidence interval. The number needed to treat (NNT) and its 95% confidence interval were calculated as the inverse of the ARR.

Unit of analysis issues

Some studies used randomisation by clusters, leading to a significant risk of type I error, reducing the level of evidence provided by the test. In crossover trials, there is a risk of a persistent effect between the two phases despite the wash-out period. This risk is reasonable in the case of chronic patients in stable condition, in an attempt to reduce variance and to increase effective sample size.

The rate of loss affects the credibility of published data. We excluded data from studies where more than 50% of the participants in any group were lost to follow-up.

Results

Selected references

Our search of the MEDLINE database returned 81 references; among these, only 41 articles described therapeutic interventions for symptoms of TD. After controlling for the inclusion criteria, this review included a total of 26 references. We excluded 15 studies due to a lack of randomisation protocol.

Design. Fourteen trials used a crossover design; 12 were conducted in parallel groups.

Study location. Most of the studies were carried out exclusively among inpatients (17 trials).

Outcomes. The studies often reported outcomes in the form of scale-derived scores. TD was assessed using three different scales: the Abnormal Involuntary Movement Scale (AIMS)¹³, the dyskinesia subscale of the Extrapyramidal Symptom Rating Scale (ESRS)¹⁴, and the Maryland Psychiatric Research Center Involuntary Movement Scale (MPRC)¹⁵. Other extrapyramidal symptoms were assessed using the ESRS, the Simpson-Angus Scale (SAS)¹⁶, and the Barnes Akathisia Rating Scale (BARS)¹⁷. Mental state was assessed using the Brief Psychiatric Rating Scale (BPRS)¹⁸ and the Positive and Negative Syndrome Scale (PANSS)¹⁹. Other tests used included the Global Assessment of Functioning scale (GAF)²⁰, the Mini Mental State Examination (MMSE)²¹, the Auditory Verbal Learning Test²², the Continuous Performance Test²³, and the Stroop test²⁴.

Risk of bias in included studies

Among the selected RCTs, only three studies^29,46,55 concealed the patient allocation. Two active trials had a single-blind design^41,42; the remaining studies used a double-blind design, although their methods were not always described. The data from the studies often allowed us to calculate the relative risk of leaving the study early. We were not able to use data from two of the studies due to poor presentation^30,32.

Effects of interventions

The efficacy of the different interventions in treating the symptoms of TD is summarised in Tables 2 and 3. Three studies supported the efficacy of vitamin E^26,27,29. We found evidence for a modest efficacy of vitamin E in the TD scores (five trials, n = 249, Hedge's g effect size (ES) = -0.30, 95% CI = -0.54 to -0.05). We did not find any evidence supporting the efficacy of amantadine, phenylalanine, melatonin, naltrexone, eicosapentanoic acid, donepezil, or levetiracetam in the TD scores. The published data concerning mianserin and trazodone were poorly presented and unusable. We found a significant difference in the average endpoint TD scores for acetazolamide, thiamine, vitamin B6, branched-chain amino acids, galantamine, piracetam, and ginkgo biloba.

Three trials assessed the action of SGAs in TD. Risperidone was compared to a placebo⁴⁰ and olanzapine⁴², and quetiapine was compared to haloperidol⁴¹. We found a significant difference between the average endpoint AIMS scores of risperidone and placebo (ES = -1.09, 95% CI = -0.39 to -0.96). Risperidone and olanzapine had significantly different effects (p = 0.55), but they did not produce different clinical improvements in TD (RR = 0.84, 95% CI = 0.55 to 1.30). Quetiapine did not show a clinical improvement compared with haloperidol (RR = 0.64, 95% CI = 0.31 to 1.32).

One study evaluated the efficacy of bilateral pallidal stimulation in resistant TD⁵⁰. The two conditions of stimulation (on-off) were applied to patients over 2 days under double-blind conditions. The authors did not publish the results obtained for blind conditions.

Mental state. Mental state was evaluated by the BPRS in five studies^{28,30,40,42,45}, the PANSS in three studies^41,44,49, and the MMSE in one study⁴⁵. This review did not find any significant results from additional treatments on psychiatric symptomatology.

Adverse effects. Extrapyramidal symptoms were evaluated by the BARS in two studies^28,45, the SAS in three studies^28,33,45, and the ESRS in four studies^37,38,40,46. The improvement in parkinsonism was significant for vitamin B6 at doses of 400 mg (ES = -1.58, 95% CI = -2.36 to -0.73)³⁷ and 1200 mg (ES = -7.61, 95% CI = -9.13 to 5.83)³⁸. There was a significant worsening of extrapyramidal symptoms with galantamine (ES = 3.33, 95% CI = 2.50 to 4.08). There was no difference in akathisia scores (ES = 0, 95% CI = -0.52 to 0.52). In all other cases, the extrapyramidal symptomatology remained unchanged. No other severe adverse effects were found in this review.

Leaving the study early. The risk of leaving the study early was noted in most articles included in this review. This risk was not significantly different among the groups included in each trial.

Discussion

Summary of main results

This review suggests that there are scant evidence-based data supporting the efficacy of pharmacological or non-pharmacological interventions for treating TD.

By modifying the balance of dopamine and serotonin in the basal ganglia, 5HT2A antagonism is expected to reduce the symptoms of dyskinesia^66,67. SGAs showed superior efficacy to placebos⁴⁰, but not to FGAs, for this indication⁴¹. Moreover, an improvement with risperidone was maintained over a period of 48 weeks under open-label conditions⁵⁴.

We found a positive effect of branched-chain amino acids in one study⁴³. This intervention appears safe but is supported by low-quality evidence.

We found evidence for the efficacy of piracetam for TD and parkinsonian symptoms in one study⁴⁶. We assessed the evidence provided by this study as low quality. Thus, piracetam, whose safety is well established, might be a reasonable treatment for TD.

Two trials reported the efficacy of vitamin B6 in reducing the symptoms of TD^37,38. At a dose of 1200 mg/day, the results were significant, regardless of the threshold used (AIMS score improvement of 60%, 40%, or 20%). The NNT to obtain an improvement of 60% was estimated at 2.88. Therefore, vitamin B6 appears to be a treatment supported by low-quality evidence.

Ginkgo biloba was found to be effective in treating the symptoms of TD in one study⁴⁹ with medium-quality evidence. The NNT to obtain greater than 30% symptomatic improvement was calculated at 2.16 subjects. Thus, ginkgo biloba offers a positive benefit-to-risk ratio in TD.

Only a modest benefit of vitamin E in TD has been shown, with contradictory results from different studies. Furthermore, a previous review did not find a clinically significant improvement in patients treated with vitamin E⁶⁸. Thus, we are not able to recommend the use of vitamin E for TD.

Melatonin was not found to be effective at a dose of 2 mg/day and provided ambiguous results at 10 mg/day. In our opinion, the data provided do not support a positive effect of melatonin on TD.

One study found a modest efficacy of galantamine for TD⁴⁵, which was offset by its deleterious effect on extrapyramidal symptoms. Galantamine does not present a positive benefit-to-risk ratio in TD.

Vitamin B6, ginkgo biloba, piracetam, and branched-chain amino acids have shown significantly greater improvement than placebos in RCTs. The use of ginkgo biloba is supported by medium-quality evidence, while the level of evidence supporting branched-chain amino acids, piracetam, and vitamin B6 is low.

Treatment strategy for tardive dyskinesia

In light of the data reported above, a medical decision-making pattern can be proposed. It seems necessary to reassess the indications of drug prescriptions and the risk-benefit ratios in the context of iatrogenic disease. Several guidelines recommend the reduction of antipsychotics^1,69,70, though this strategy has not been proven effective in TD⁷¹. When antipsychotic drugs are definitively indicated, a treatment that is less likely to induce TD should be chosen as the first-line treatment. Risperidone and olanzapine showed comparable efficacy in this indication^40,42,54. Quetiapine did not demonstrate significantly greater efficacy than haloperidol⁴¹. Clozapine remains a second-line treatment due to the lack of RCTs.

Four treatments evaluated in this review in addition to antipsychotic medications have shown relative efficacy for the symptoms of TD. Vitamin B6, ginkgo biloba, piracetam, and branched-chain amino acids can all be used in cases of persistent dyskinesia after a disabling relay by SGAs or neuroleptic discontinuation.

In cases of insufficient effects of one or more of these treatments, other therapeutic options that have not been evaluated in RCTs are available. Tetrabenazine, which is already used for several movement disorders, and clozapine are commonly used by physicians in clinical practice. Some uncontrolled studies have reported the efficacy of tetrabenazine in TD⁷³.

Considering the data presented in this review, we propose a decision tree to help clinicians choose a treatment for patients suffering from TD.

Limitations

Since the description of TD in 1957⁷⁴, no effective treatment has been clearly identified. This problem remains important despite the prescription of SGAs at lower doses. The studies included in this review provide a level of evidence that is low to moderate, and they suffer from crucial limitations and imprecision. Each trial included only a small number of participants, and their results have not been reproduced.

Many treatments used experimentally in TD have not been evaluated by RCTs. The use of clozapine and tetrabenazine is based on empirical data and consistent aetiopathogenic hypotheses. These treatments, prescribed by many physicians in cases of TD, have not yet been evaluated by RCTs. Despite the fact that the neuropathology of TD remains complex and has not been fully elucidated, several theories have been proposed⁷⁵ that could lead to the development of new compounds useful in the treatment of TD.

Future research on these treatments, including clozapine and tetrabenazine, could bring about significant changes in TD treatment strategies.

Conclusion

This systematic review of the literature has identified several interventions that could be useful in the treatment of antipsychotic-induced TD. SGAs appear to be a consistent first-line intervention for patients requiring long-term antipsychotic treatment. However, no study has demonstrated their superiority compared to FGAs in TD. Several additional treatments can benefit patients with TD (vitamin B6, piracetam, branched-chain amino acids, ginkgo biloba). In view of these results, it seems reasonable to offer symptomatic treatment to patients suffering from TD. Future research will be necessary to confirm these results and to evaluate other compounds already prescribed by physicians for TD.

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Correspondence:
Dr Michael Alimi
Clinique Psychiatrique Universitaire
CHRU de Tours
Tours, France
E-mail: michael.alimi@ymail.com