Tardive Dyskinesia

Tardive dyskinesia is a persistent, involuntary hyperkinetic movement disorder, usually orofacial (lip smacking, tongue protrusion, chewing), caused by prolonged exposure to dopamine receptor blocking drugs. It appears after at least 3 months of exposure (1 month in people over 60 years) and may persist after the drug is stopped.

It affects about 20 to 30% of people taking first generation antipsychotics for long periods, and about 7 to 20% of those taking second generation drugs. The risk rises by about 4 to 5% each year of exposure, and is greater in older adults, women, those with mood disorders and those with diabetes.

Causes. Antipsychotics, metoclopramide, prochlorperazine and other dopamine blockers; antidepressants and antiepileptics rarely.

Course. Mild in most. About one third remit over years, particularly after stopping the drug early; others persist and may impair eating, speech, breathing and social function.

Pathophysiology.

Chronic D2 blockade leads to dopamine receptor supersensitivity in the striatum, together with oxidative stress, GABAergic dysfunction and changes in striatal plasticity.

Differences in D2 receptor affinity and the CYP2D6 genotype influence the risk.

• Choreiform or stereotyped movements of lips, tongue and jaw; limb chorea or athetosis; truncal rocking and respiratory dyskinesia.
• Tardive dystonia, tardive akathisia and tardive tics in some.
• Worsening with stress and during dose reduction (withdrawal emergent dyskinesia); improvement with sleep.
• Dental problems, speech and swallowing difficulty, weight loss and social embarrassment.

Red flags.

• Dysphagia, respiratory dyskinesia or airway compromise.
• Severe dystonia, falls or injury.
• Depression or suicidal thoughts.
• Fever and rigidity (neuroleptic malignant syndrome).

• Clinical diagnosis from the movement pattern, exposure to a dopamine blocker and exclusion of other causes.
• Structured rating of severity at baseline and every 6 to 12 months in people on antipsychotics.
• Investigations to exclude other causes: thyroid function, glucose, calcium, copper studies in young patients, and MRI if features are atypical.
• Review of all drugs, including anti-nausea drugs.
• Assess mood and suicidal thoughts before starting vesicular monoamine transporter 2 inhibitors.

Differential diagnosis. Huntington disease, Sydenham chorea, Wilson disease, neuroacanthocytosis, ill fitting dentures, edentulous dyskinesia, spontaneous orofacial dyskinesia in older adults, stereotypies, hyperthyroidism and levodopa induced dyskinesia.

• Review the need for the dopamine blocker with the prescribing team; use the lowest effective dose, or switch to an agent with a lower risk. Do not withdraw an antipsychotic without psychiatric advice.
• Valbenazine, first line: 40 mg orally once daily for 1 week, then 80 mg once daily. Maximum 80 mg daily. Reduce to 40 mg daily in moderate to severe hepatic impairment, in CYP2D6 poor metabolisers and with strong CYP3A4 inhibitors. Monitor mood and suicidal thoughts, somnolence, QT interval and parkinsonism. Avoid in congenital long QT syndrome, arrhythmia and untreated depression; no dose adjustment for mild renal impairment; avoid in severe renal impairment.
• Deutetrabenazine: 6 mg orally twice daily with food, increased by 6 mg each day every week to the lowest effective dose. Maximum 48 mg daily (36 mg daily with strong CYP2D6 inhibitors). Monitor depression, suicidal thoughts, somnolence, QT interval and akathisia. Contraindicated in hepatic impairment, untreated depression and with monoamine oxidase inhibitors, reserpine and valbenazine; avoid in pregnancy unless benefit outweighs risk.
• Tetrabenazine as an alternative: 12.5 mg orally once daily, increased by 12.5 mg each week to a usual 25 to 75 mg daily in 2 to 3 divided doses. Maximum 100 mg daily without CYP2D6 genotyping. Monitor depression, suicidal thoughts, parkinsonism and QT interval. Contraindicated in depression with suicidal thoughts, hepatic impairment and with monoamine oxidase inhibitors; avoid in pregnancy.
• Botulinum toxin for focal tardive dystonia.
• Deep brain stimulation of the globus pallidus internus for severe, refractory cases.
• Avoid anticholinergic drugs, which can worsen tardive dyskinesia.
• Dental and speech therapy review.

Monitoring. Review at 4 to 8 weeks after starting treatment, then every 3 months; repeat severity rating and mood assessment.

Referral and escalation. Neurology or psychiatry for treatment choice; urgent review for airway or swallowing compromise or suicidal thoughts.

Special groups. Older adults: higher risk, so review antipsychotic need every 6 months. Women of childbearing potential: counsel on pregnancy and drug choice.