Tardive Dyskinesia

Tardive dyskinesia, a result of long-term anti-dopaminergic medication use, is treated by discontinuing the causative agent, switching to safer antipsychotics, and using VMAT2 inhibitors, botulinum toxin, benzodiazepines, anticholinergics, or amantadine. Deep brain stimulation is considered for severe, treatment-resistant cases.

Overview of Tardive Dyskinesia:

Tardive dyskinesia is a hyperkinetic movement disorder which occurs after prolonged use of anti- dopaminergic agents, such as, metoclopramide, chlorpromazine olanzapine and haloperidol. It may manifest as chorea, athetosis, dystonia and stereotyped behaviours.

Prevention and Initial Treatment Approaches:

The treatment of tardive dystonia is difficult and it frequently shows refractoriness to treatments. So, prevention and discontinuation of the causative agent are important. Also, switching from first to second generation antipsychotic drug, such as, risperidone (0.25mg twice daily) or clozapine (25 mg PO daily) is another strategy.

Pharmacological Interventions for Tardive Dyskinesia:

Additional pharmacologic interventions include the use of Vesicular monoamine transporter- 2 (NMAT2), botulinum toxin injections (if focal), benzodiazepines, anticholenergic agents and amantadine. Deep brain stimulation (DBS) is reserved to severe and refractory cases. (1, 2, 3)

Vesicular Monoamine Transporter-2 (VMAT2) Inhibitors:

VMAT2 including valbenazine (40 mg daily), deutetrabenazine (6 mg twice daily) and tetrabenazine at 12.5 mg daily are effective for short term tardive dyskinesia. However, with their long term use, patients frequently experience somnolence, depression up to suicide. Also, VMAT2 may lead to QT prolongation and neuroleptic malignant syndrome. (4)

Botulinum Toxin Injections for Focal Tardive Dyskinesia:

Botulinum toxin injection including onabotulinumtoxin -A (Botox) at 150-300 units or rimabotulinumtoxin-B (Myobloc) 2,500 to 5,000 units seems effective especially for focal cases although the evidence is limited. In a multicenter study, botulinum toxin produced significant improvement in 29 out of 34 patients with tardive dyskinesia. (5)

Benzodiazepines for Tardive Dyskinesia:

Benzodiazepine, such as, clonazepam (0.5 mg daily to be titrated by 0.5 mg every 5 days to a maximum of 3mg/day) was effective as per phase 3 trials.

Use of Anticholinergic Drugs:

Anticholinergic drugs, such as, trihexyphenidyl 1mg twice daily to be titrated to a maximum dose of 6mg daily, is suggested for severe and more generalised tardive dyskinesia refractory to above interventions. (7)

Role of Amantadine in Tardive Dyskinesia:

Amantadine (300 mg/day) with antipsychotic drugs may also help severe tardive dyskinesia. (8)

Deep Brain Stimulation (DBS) in Refractory Cases:

Additionally, DBS of the globus pallidus is suggested to treat severe refractory tardive dyskinesia. (9)

References

1-Hauser RA, Factor SA, Marder SR, et al. KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Valbenazine for Tardive Dyskinesia. Am J Psychiatry 2017; 174:476.

2- Bhidayasiri R, Fahn S, Weiner WJ, et al. Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2013; 81:463.

3-Emsley R, Turner HJ, Schronen J, et al. A single-blind, randomized trial comparing quetiapine and haloperidol in the treatment of tardive dyskinesia. J Clin Psychiatry 2004; 65:696

3- Spivak B, Mester R, Abesgaus J, et al. Clozapine treatment for neuroleptic-induced tardive dyskinesia, parkinsonism, and chronic akathisia in schizophrenic patients. J Clin Psychiatry 1997; 58:318.

4-Fernandez HH, Factor SA, Hauser RA, et al. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study. Neurology 2017; 88:2003.

5-Tarsy D, Kaufman D, Sethi KD, et al. An open-label study of botulinum toxin A for treatment of tardive dystonia. Clin Neuropharmacol 1997; 20:90.

6- Shapleske J; Mickay AP; Mckenna PJ: Successful treatment of tardive dystonia with clozapine and clonazepam. Br J Psychiatry. 1996; 168(4):516-8.

7-Suzuki T, Hori T, Baba A, et al. Effectiveness of anticholinergics and neuroleptic dose reduction on neuroleptic-induced pleurothotonus (the Pisa syndrome). J Clin Psychopharmacol 1999; 19:277.

8-Tammenmaa-Aho I, Asher R, Soares-Weiser K, Bergman H. Cholinergic medication for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev 2018; 3:CD000207.

9-Gruber D, Trottenberg T, Kivi A, et al. Long-term effects of pallidal deep brain stimulation in tardive dystonia. Neurology 2009; 73:53.