Evidence-Based Reviews

Is there a rational management strategy for tardive dyskinesia?

Current Psychiatry. 2011 October;10(10):22-32

References

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Clinical Point

One theory proposes that TD results from damage to striatal cholinergic neurons, which suggests that cholinergic agonists may suppress TD

Apart from short-term suppression of TD symptoms, the advantage of switching to lower-potency antipsychotics or other SGAs would be to increase the odds of eventual TD resolution. Although there has been speculation that in contrast to high-potency FGAs, SGAs may increase the possibility of remission by actively reversing TD or by passively allowing time for TD to resolve, existing data are inconclusive as to whether treatment with SGAs or FGAs results in true recovery rather than symptom suppression. To distinguish remission from suppression, a few studies discontinued SGAs. Some reported continued absence of TD,^27,28 but others found unmasking and reappearance of TD.^29-31

Clinical Point

Data on whether high-potency FGAs suppress TD symptoms more than low-potency drugs or SGAs are limited and inconsistent

Adjunctive antidyskinetic drugs. Agents that have been tested off-label for antidyskinetic effects could be considered if symptoms of TD remain problematic despite optimization of antipsychotic treatment, although none have been confirmed as uniformly effective in randomized controlled trials replicated by different investigators.^13,17,22 These include dopamine-depleting agents, dopamine agonists, noradrenergic agonists and antagonists, GABAergic drugs (benzodiazepines, valproate, levetiracetam), lithium, calcium channel blockers, serotonergic drugs, antioxidants (vitamin E and B6), branched-chain amino acids, neuropeptides, cholinergic precursors, and cholinesterase inhibitors. Electroconvulsive therapy and botulinum toxin or surgical intervention (for tardive dystonia) also may be considered.

Clinical Point

Dopamine-depleting agents, GABAergic drugs, and cholinesterase inhibitors have been tested off-label for antidyskinetic effects

Hypotheses proposed to explain TD pathophysiology and thereby justify trials of specific antidyskinetic agents include dopamine receptor hypersensitivity, GABA insufficiency, and structural damage resulting from increased catecholamine metabolism and oxidative free radical production.³² Another hypothesis proposes that TD results from damage to striatal cholinergic interneurons due to loss of dopamine-mediated inhibition.³³ If correct, this implies that cholinesterase inhibitors or cholinergic agonists may suppress TD by directly enhancing post-synaptic cholinergic activity, thereby compensating for the loss of pre-synaptic cholinergic neurons. Several preliminary trials that explored the use of cholinesterase inhibitors had mixed results.^34-36 However, this hypothesis is supported by evidence from animal and human studies that correlated antipsychotic-induced changes in cholinergic activity with the delay in onset, irreversibility, and age-related risk of TD, the worsening of symptoms due to anticholinergic drugs, and the reduced liability of SGAs for causing TD. These findings suggest that further investigation of cholinergic mechanisms underlying TD may be worthwhile.³⁵

Algorithm: Proposed treatment algorithm for tardive dyskinesia
Source: Reprinted from Caroff SN, Hurford I, Lybrand J, et al. Movement disorders induced by antipsychotic drugs: implications of the CATIE Schizophrenia Trial. Neurol Clin. 2011;29:127-148 with permission from Elsevier

Figure: Adjusted^a repeated measures model of change in total AIMS scores for patients with tardive dyskinesia at baseline in CATIE
^a Model adjusted for baseline AIMS, baseline PANSS, and duration of illness. Adjusted P value for reduction in total AIMS score from baseline for all patients: P < .001. Treatment differences between the second-generation antipsychotics during the trial: P = .811
AIMS: Abnormal Involuntary Movement Scale; CATIE: Clinical Antipsychotic Trials of Intervention Effectiveness; PANSS: Positive and Negative Syndrome Scale
Source: Reprinted from Caroff SN, Davis VG, Miller DD, et al; for the CATIE Investigators. Treatment outcomes of patients with tardive dyskinesia and chronic schizophrenia. J Clin Psychiatry. 2011;72(3):295-303 with permission from Physician Postgraduate Press, Inc.Related Resources

National Institute of Neurological Disorders and Stroke. NINDS Tardive Dyskinesia Information Page. www.ninds.nih.gov/disorders/tardive/tardive.htm.
WE MOVE (Worldwide Education and Awareness for Movement Disorders). www.wemove.org.

Drug Brand Names

Botulinum toxin • Botox, Dysport, others
Clonidine • Catapres
Clozapine • Clozaril
Haloperidol • Haldol
Levetiracetam • Keppra
Levodopa • Dopar, Larodopa
Lithium • Lithobid, Eskalith, others
Nifedipine • Adalat, Afeditab CR, others
Olanzapine • Zyprexa
Phenytoin • Dilantin
Quetiapine • Seroquel
Reserpine • Serpasil
Risperidone • Risperdal
Tetrabenazine • Xenazine
Valproate • Depakote
Ziprasidone • Geodon

Disclosures

Drs. Caroff, Dhopesh, and Campbell report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Miller receives research/grant support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Ortho-McNeil-Janssen, and Pfizer Inc. and is a consultant to GlaxoSmithKline and Otsuka.