Once thought untreatable, we now have two FDA-approved medications for TD and a handful of off-label options. More in this research update.
When the second-generation antipsychotics were first released in the 1990s there was optimism that these agents might eliminate-or even treat-tardive dyskinesia (TD). They were, after all, derived from clozapine, which remains the antipsychotic with the lowest risk of TD. That hope has not stood the test of time. Judging from a recent meta-analysis, you can expect that 1 in 4 patients will develop TD after 10 years on a second-generation antipsychotic.† That’s lower than the rate with first-generation antipsychotics, which is 1 in 2, but is still concerning.1 There are ways to lower the risk of TD and treat it when it comes up, and I will review them here.
†Based on an annualized incidence of 2.6% for second-generation and 6.5% for first-generation antipsychotics1
The risk of TD starts to climb after age 50. Older adults develop TD at more than double the rate for younger adults: 7% vs. 2.6% per year on second-generation antipsychotics.1,2 Mood disorders also raise the risk approximately two-fold.3 Other signs that your patient is vulnerable to TD include: early extrapyramidal side effects (EPS), diabetes, history of substance abuse, HIV+, brain injury, female gender, and African-American race.4
Duration and dose are two of the biggest risk factors for TD. Use the lowest effective dose. That is usually in the low range for bipolar and unipolar depression (eg, quetiapine 150 mg to 300 mg qhs); medium for mania and mixed states (eg, quetiapine 400 mg to 600 mg qhs, sometimes 800 mg); and higher for schizophrenia (eg, quetiapine 400 mg to-800 mg qhs, usually closer to 800 mg). If the patient already has TD, it is likely to improve with either dose-reduction or discontinuation of the antipsychotic.
TD is a delayed reaction to antipsychotics, and the risk increases with each year of exposure.4 While it may be unwise to taper off an antipsychotic in schizophrenia, it is a move worth considering when the antipsychotic is used for augmentation in a mood disorder. After a patient recovers from bipolar disorder or depression with antipsychotic augmentation, I will attempt to wean the antipsychotic if a patient has remained well for at least 6 months. I will lower the dose slowly, every 1 to 2 weeks. This strategy worked well in a randomized-controlled trial of 159 patients in recovery from a manic episode. Those who weaned off the antipsychotic augmentation agent after 6 months did just as well as those who stayed on it for a year.5
Here is a common error to avoid: benztropine for TD. This anticholinergic relieves antipsychotic-induced Parkinsonism, but it worsens TD.4 It also causes significant cognitive problems, which can be more troublesome than muscle stiffness. Parkinsonism can resemble TD, and it is a risk factor for TD-but it is not treated in the same way.
If the antipsychotic cannot be stopped, treatment may be in order. Severe TD can be painful and stigmatizing, with impairments in eating, speaking, and even breathing. The two FDA-approved medications for TDâvalbenazine (Ingrezza) and deutetrabenazine (Austedo)âhave similar risks and benefits. Both are derived from tetrabenazine, a VMAT2 inhibitor which has been used to treat TD since the early 1970s. A reasonable trial of these agents is 6 weeks after reaching the therapeutic dose. If it works, the VMAT2 inhibitor will likely need to be continued as long as the antipsychotic is in place. Otherwise, the TD tends to return within a month of discontinuation.6
VMAT2 inhibitors address one mechanism behind TD: dopaminergic hypersensitivity at the D2 receptors. Basic science supports other pathways to TD, and there are evidence-based therapies that address several of these. The options with the best evidence are listed above. They target glutamatergic hyperactivity (amantadine), neurotoxicity (ginkgo), or stabilize dopamine vesicles (levetiracetam).7 Amantadine has the additional benefit of weight loss when taken with antipsychotics.8 Levetiracetam is not as well studied as the others, but I have had good success with it.
Clozapine has the lowest risk of TD, but the second place spot is up for debate. Most papers cite quetiapine, but this recommendation is based on theory. Quetiapine resembles clozapine in its low level of D2 occupancy and low rate of EPS-both of which are risk factors for TD. However, a recent meta-analysis of 52 head-to-head trials casts doubt on that idea. They found that quetiapine had the highest risk of TD among the second-generation antipsychotics, while the lowest risk, after clozapine, was with aripiprazole and then olanzapine.9 That is enough to give one pause before prescribing quetiapine for primary insomnia.
TD is insidious and easy to miss. Patients often deny it even when it’s clearly visible to others. Regular testing with the Abnormal Involuntary Movement Scale (AIMS) is the best way to catch it early, and early intervention is the best way to keep this neurotoxic side effect from turning into a permanent, refractory state.
1. Carbon M, Kane JM, Leucht S, et al. Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis. World Psychiatry. 2018;17:330-340.
2. O'Brien A. Comparing the risk of tardive dyskinesia in older adults with first-generation and second-generation antipsychotics: a systematic review and meta-analysis. Int J Geriatr Psychiatry. 2016;31:683-693.
3. Kane JM. Tardive dyskinesia in affective disorders. J Clin Psychiatry. 1999;60(Suppl 5):43-47.
4. Correll CU, Kane JM, Citrome LL. Epidemiology, prevention, and assessment of tardive dyskinesia and advances in treatment. J Clin Psychiatry. 2017;78:1136-1147.
5. Yatham LN, Beaulieu S, Schaffer A, et al. Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial. Mol Psychiatry. 2016;21:1050-1056.
6. Citrome L. Clinical management of tardive dyskinesia: Five steps to success. J Neurol Sci. 2017;383:199-204.
7. Lin CC and Ondo WG. Non-VMAT2 inhibitor treatments for the treatment of tardive dyskinesia. J Neurol Sci. 2018;389:48-54.
8. Graham KA, Gu H, Lieberman JA, et al. Double-blind, placebo-controlled investigation of amantadine for weight loss in subjects who gained weight with olanzapine. Am J Psychiatry. 2005;162:1744-1766.
9. Carbon M, Kane JM, Leucht S, et al. Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis. World Psychiatry. 2018;17:330-340.