Antipsychotic-Induced Tardive Dyskinesia

Update on Epidemiology and Management

Christian G. Widschwendter; Alex Hofer

Disclosures

Curr Opin Psychiatry. 2019;32(3):179-184. 

In This Article

Management

The initial step in managing tardive dyskinesia is to recognize and characterize its full spectrum of subjective and objective manifestations by visual inspection and questioning the patient.[2,30] Screening for tardive dyskinesia can generally be done without the use of a specific rating scale, however, the Abnormal Involuntary Movement Scale[31] has been recommended for this purpose. As tardive dyskinesia can vary during the course of a day and can worsen with emotional stress, repeated examinations at different time points can be helpful. The American Psychiatric Association recommends a frequency for monitoring tardive dyskinesia in patients with schizophrenia every 3–12 months, depending on the type of antipsychotic drug prescribed and the patient's personal risk factors.[32] As a next step in the management of tardive dyskinesia, any anticholinergic medication to address drug-induced Parkinsonian symptoms should be discontinued, as it may worsen current symptoms.[33] However, the correlation of anticholinergic medication use with the occurrence of tardive syndromes remains vague.[24]

Although dose reduction or tapered withdrawal of an antipsychotic drug seems to be a logical approach in the management of tardive dyskinesia, this is clinically not always feasible because of the risk of exacerbation of psychotic symptoms. Moreover, data on stopping[34] or reducing the dose[35] of the antipsychotic medication associated with tardive dyskinesia do not provide clear evidence or benefit. Earlier studies have shown that withdrawal of antipsychotics led to an initial worsening of tardive dyskinesia in 33–53% of patients, whereas symptomatology eventually improved in 36–55% of patients.[36] However, the best chances for remission of tardive dyskinesia after stopping antipsychotic treatment may exist in younger patients.[37]

In patients on antipsychotic maintenance therapy, for whom drug withdrawal or dose reduction may be destabilizing, data on the effects of switching from one antipsychotic to another have yielded mixed evidence.[38,39] The effects of switching antipsychotic medication, including a switch to clozapine, have been reported in earlier studies.[40–45] Empirical evidence is controversial; however, some open-label trials have demonstrated a significant benefit in reducing tardive dyskinesia symptom severity associated with switching to alternative NGA.[46–52]

A plethora of specific substances for managing tardive dyskinesia has come and gone because of insufficient or conflicting data to support or refute. Evidence on effectiveness for most of these agents remains preliminary and inconclusive and managing tardive dyskinesia therefore remains a significant unmet need.

Specific Antidyskinetic Drugs

Vesicular monoamine transporter-2 inhibitors. At present, there are three commercially available VMAT2 inhibitors: tetrabenazine, deutetrabenazine, and valbenazine. Based on open-label observational studies, tetrabenazine is generally regarded as efficacious for the treatment of moderate-to-severe tardive dyskinesia symptoms.[53]

A recent review updating the American Academy of Neurology (AAN), tardive dyskinesia treatment guidelines downgraded tetrabenazine from a Level B (probably improves tardive dyskinesia and should be considered as treatment) to a Level C compound (might be considered as tardive dyskinesia treatment; possibly effective, based on at least one class II study and two consistent class III studies) option.[34] Its short half-life and its relatively poor tolerability profile has led to drug development efforts and has resulted in two new VMAT2 inhibitors which are approved for the treatment of tardive dyskinesia in adults by the US Food and Drug Administration: valbenazine and deutetrabenazine. Recent high-standard RCT have provided robust evidence on their efficacy and tolerability[54–57] and they are recommended as established and efficient by a review updating the AAN guidelines (Level A; strongest recommendation, established as effective, based on at least two consistent class I studies).[34] Compared with deutetrabenazine, valbenazine appears to have fewer side-effects and a more favorable once-daily dosing regimen for the treatment of tardive dyskinesia. However, although these two VMAT2 inhibitors offer clear evidence of efficacy in reducing the severity of tardive dyskinesia in patients continuing antipsychotic treatment, their impact on long-term outcomes in real-world settings remains to be investigated.

Benzodiazepines. A recent review revealed evidence of very low quality on the effect of benzodiazepines as a treatment strategy for antipsychotic-induced tardive dyskinesia.[58] However, the AAN ranks clonazepam as a treatment option that probably improves tardive dyskinesia (Level B; probably effective treatment, derived from at least one class I study or two consistent class II studies) and should therefore be considered for pharmacological management. Importantly, tolerance to its antidyskinetic effect can develop in the long-term extension. Accordingly, it should solely be considered for short-term tardive dyskinesia treatment (i.e., for approximately 3 months).[59] Next to the risk of addiction the risks of deterioration of cognitive status, sedation, and ataxia have also to be mentioned.

Amantadine. Amantadine is considered as a Level C therapy option by the AAN. A small double-blind RCT in patients with schizophrenia under antipsychotic treatment showed a modest improvement in the average Abnormal Involuntary Movement Scale total score.[60] Minor side-effects such as insomnia, dizziness, and constipation were reported.

Extract of gingko biloba. Three 12-week, placebo-controlled RCT of gingko biloba in patients with schizophrenia and tardive dyskinesia[61] were meta-analyzed demonstrating a significant beneficial effect of extract of gingko biloba vs. placebo. Moreover, gingko biloba was well tolerated. The AAN ranked gingko biloba as a Level B treatment option.

Vitamin B6 and E. Vitamin B6 was investigated in patients with tardive dyskinesia and schizophrenia or schizoaffective disorder and has been associated with a significant decrease of tardive dyskinesia.[62] However, the quality of evidence may be considered low because of the small sample sizes and the short follow-up examination. On the other hand, no clear difference between vitamin E and placebo for the outcome of tardive dyskinesia was found.[63] However, small trials of limited quality suggest that vitamin E may protect against deterioration of tardive dyskinesia.[63] According to insufficient evidence, there is no recommendation to support or refute vitamin B6 and E treatment (Level U) by the AAN.

Chinese Herbal Medicine

The traditional Chinese herbal medicines Yi-gan san and Kamishoyosan were tested in prospective observational open-label studies in small samples of patients with schizophrenia for 12 and 16 weeks, respectively. Both led to a significant improvement of tardive dyskinesia.[64,65] However, there is insufficient evidence to support or refute tardive dyskinesia treatment by Chinese herbal medicine (Level U).

Other Pharmacological Agents

A number of potential tardive dyskinesia treatments have very limited or conflicting evidence bases, including calcium channel blockers, other VMAT inhibitors such as reserpine, cholinergic and anticholinergic drugs, and levetiracetam.[38,66,67]

Botulinum Toxin A, Surgical Approaches

No convincing evidence was found to support the use of botulinum toxin A injections in patients showing orofacial dyskinesia, although evidence suggests that it may be useful for focal dystonia.[68] As a last resort for patients who fail to respond to pharmacological treatment options or develop resistance to botulinum toxin type A, pallidal deep brain stimulation may improve tardive dyskinesia and might be considered as a treatment for intractable tardive dyskinesia (Level C).[69,70]

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