Medication Summary
Tardive dystonia may improve or, rarely, resolve, after discontinuation of neuroleptics; however, the condition is often permanent. Medications used for treatment include dopamine-depleting agents, dopamine receptor blocking agents, and anticholinergics. Local botulinum toxin injections have been useful for well-chosen focal dystonias.
Dopamine-depleting agents
Class Summary
The most effective medications are those that deplete catecholamines (eg, reserpine, tetrabenazine). A study by Kang et al in 1988 showed a 63% response to at least one of these drugs. [7] Effective doses of reserpine were 2-9 mg/d. Significant adverse effects were parkinsonism, dizziness, lethargy, depression, headache, GI upset, and hallucination. Effective doses of tetrabenazine were 12.5-250 mg/d. Most patients required >100 mg/d. Adverse effects include parkinsonism, depression, lethargy, euphoria, hallucinations, confusion, dizziness, vomiting, and unilateral leg tremor. Tetrabenazine (not available in United States) has minimal risk of tardive dyskinesia, which is an advantage compared to other antidopaminergic drugs.
Tetrabenazine (Xenozine)
Tetrabenazine is a presynaptic dopamine antagonist with minimal risk of tardive dystonia. It is designated as an orphan drug in the United States.
Atypical antipsychotics (serotonin dopamine receptor antagonists)
Class Summary
Atypical (or second generation) antipsychotics (eg, clozapine, risperidone, olanzapine) bind to dopamine D2 receptors and may improve tardive dystonia when lower doses are used. Trials have shown that they not only may cause or aggravate tardive dystonia but ultimately may prove to be highly useful therapeutic agents to treat dystonias. Long-term safety is not fully established for this indication.
Clozapine (Clozaril)
Clozapine binds to dopamine D2 receptor with 20 times lower affinity than for serotonin-2 receptor.
Anticholinergic agents
Class Summary
Anticholinergic therapy (eg, trihexyphenidyl, ethopropazine) has been used. Kang et al reported a 38% response to trihexyphenidyl alone and 44% when combined with other medications. [7] Effective doses were 10-32 mg/d. Severe adverse effects (eg, drowsiness, confusion, hallucinosis, memory difficulties) occurred at 60-100 mg/d. Ethopropazine showed 27% improvement when administered alone and 42% as adjuvant therapy. Doses were 100-450 mg/d. Adverse effects included confusion, forgetfulness, GI problems, dizziness, blurry vision, dry mouth, urinary retention, lethargy, palpitations, and sleep disturbances. Diphenhydramine, an anticholinergic with H1 antagonist properties, also has antidystonic effects.
Trihexyphenidyl (Artane)
This agent is a central inhibitor of the parasympathetic nervous system, resulting in diminished muscle spasms. It is often the drug of choice for young persons with generalized, multifocal, or segmental dystonia, especially with lower extremities and trunk involvement.
Acetylcholine receptor inhibitors
Class Summary
The most promising development for treating tardive dystonia and all other forms of dystonia has been botulinum toxin type A (BTTA). BTTA produces neuromuscular blockade by inhibiting the calcium ion–mediated release of acetylcholine at the motor nerve terminals. This results in diminished endplate potential and subsequent flaccid paralysis of the affected muscles. The paralysis persists until new nerve terminals form, usually within 2-3 months.
BTTA is effective in treating focal dystonias, including blepharospasm, oromandibular dystonia, spasmodic torticollis, spasmodic dysphonia (especially the adductor form), and some cases of focal limb dystonia. Injections are well tolerated. Systemic complications are not evident, although single-fiber electromyelogram studies show mild distant effects. Following administration, the onset of effect is apparent within a few days. Peak effects are evident within the first few weeks and wear off over 2-4 months.
Typical adverse effects are excessive weakness with inadvertent IM injection (eg, ptosis with eyelid injection, dysphagia in spasmodic torticollis). Treatment with large or frequent doses may prompt the development of antibodies to the toxin and may correlate with loss of the original benefit. Development of less antigenic forms of type A toxin or use of other botulinum toxin strains (ie, strains B or F) may overcome this problem. Patients should be advised that botulinum toxin is not curative but offers nonimmediate temporary improvement.
OnabotulinumtoxinA (BOTOX®)
Neurotoxins produced by Clostridium botulinum exert paralytic effects at the neuromuscular junction by inhibiting the release of acetylcholine, thus, inhibiting impulse transmission in neuromuscular tissue. It has become a mainstay of therapy for focal and segmental dystonia, including tardive dystonia.
Benzodiazepines
Class Summary
Benzodiazepines bind to a specific benzodiazepine receptor on GABA receptor complex, thereby increasing GABA affinity for its receptor. They also increase the frequency of chlorine channel opening in response to GABA binding. GABA receptors are chlorine channels that mediate postsynaptic inhibition, resulting in postsynaptic neuron hyperpolarization. The final result is a sedative-hypnotic effect. Benzodiazepines may provide additional benefit. Clonazepam is effective for blepharospasm and myoclonic dystonia.
Clonazepam (Klonopin)
Clonazepam is a long-acting benzodiazepine that increases presynaptic GABA inhibition and reduces monosynaptic and polysynaptic reflexes. It has multiple indications, including suppression of myoclonic, akinetic, or petit mal seizure activity and focal or generalized dystonias (eg, tardive dystonia).
