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Next, let’s look at a 2019 review on tardive dyskinesia and its treatment. This is a review by movement disorder specialists, psychiatrists, and psychopharmacologists with particular expertise in the use antipsychotics from the Canadian Journal of Psychiatry.
How common is tardive dyskinesia? Are the second-generation antipsychotics really better? Well, the article cites a 2017 meta-analysis of 41 different studies by Maren Carbon and colleagues from the Zucker Hillside Hospital in New York. Again, this is a citation within the article I’m reviewing here but just to look at that prevalence rate, and it’s so interesting. A significantly lower tardive prevalence rate for patients receiving second-generation than first-generation antipsychotics, 20% vs 30%. Dr. Carbon and colleagues point out that all of the studies included a systemic screening, including relatively mild cases. So, 20% and 30% are kind of on the high side compared to severe tardive dyskinesia. They also point out that rare, life-threatening TD has been reported for the first-generation but not for second-generation antipsychotics. Second-generation antipsychotics are better, but 20% tardive dyskinesia rate is still a concern.
Let’s look at this new review from the Canadian Journal of Psychiatry in terms of what can be done about tardive dyskinesia. The first strategy is using a lower dose, but that’s not really evidence based. It’s just kind of pleasing, theoretically, in that we should’ve been using the lowest possible effective dose all along. They emphasized that as a first strategy, all the way along use a lower dose as opposed to lowering it once TD has shown up.
Secondly, they note that if the TD occurs on a first-generation antipsychotic, you could switch to a second-generation one. Interestingly, they did single out quetiapine as an alterative to which to switch because of its lower D2-receptor occupancy. Have we actually established that quetiapine has lower tardive dyskinesia rate than other antipsychotics? In that meta-analysis by Carbon, et al., only 4 of the 41 studies that they meta-analyzed actually reported rates on individual antipsychotics. So, we actually don’t have the data to say quetiapine really is better. They noted that there are lots of confounds in terms of exposures to previous antipsychotics that were difficult to control. We still don’t have evidence that would put quetiapine ahead of everybody else in terms of lower tardive dyskinesia risk.
The third strategy that was discussed by Ricciardi and colleagues in this Canadian Journal of Psychiatry review was use of anticholinergics. Is that part of the problem? When we’re treating EPS, is the anticholinergic to which we might turn actually part of causing tardive dyskinesia, or is it just a co-traveler? The answer is, in a separate Cochrane review, that there is no evidence to support that anticholinergics themselves are causing tardive dyskinesia; so, removing them wouldn’t help.
Then we’re heading almost directly to these new monoamine transport inhibitors, the VMAT inhibitors. But before we get there, let’s look at everything else that was considered here in this review. That would be the GABA agonists, including baclofen and divalproex and even levetiracetam. Interestingly, the review says evidence of no effect. Meaning, we have evidence that these don’t work as opposed to, for example, benzodiazepines, where there is no evidence of benefit not so directly studied. Then there’s a large miscellaneous category also dismissed by the reviewers for evidence of no effect, and that includes piracetam, melatonin, lithium, ritanserin, selegiline, estrogen, and even diltiazem. All have evidence of no effect.
By contrast, for vitamin B6, there was a separate Cochrane review of 3 studies that did find efficacy greater than placebo, but the doses were in the range of 400 mg to 1200 mg per day. Doses of 1000 mg per day can cause a severe sensory neuropathy. Overall, the current Canadian Journal of Psychiatry reviewers found that the evidence here was too weak to support vitamin B6. They said it might be considered for nonresponders, where you’re still looking for a solution, but they point out that the dose and duration for optimal benefits while maintaining safety hasn’t been established. This did strike me as like the typical problem: Cheap solutions don’t have funding for adequate study. So, vitamin B6 is not ruled off the list yet.
By comparison, vitamin E “does not lead to clinically important improvements in TD once it is established, but it may protect against deterioration of TD symptoms.” So, you wouldn’t get better, but you might be able to keep things from getting worse using vitamin E. Lastly, they even included deep brain stimulation of the globus pallidus, which did help, but, obviously, that’s not a simple, widely applicable solution.
That brings us to the vesicular monoamine transporters, the VMAT inhibitors, reminding briefly that VMAT is a neuron membrane protein that packages and releases dopamine and other monoamines. The authors of this review looked at these agents and concluded that they work. The evidence for benefit is much clearer than anything else in the literature. Of the 3, tetrabenazine has more side effects, including a higher incidence of drowsiness and parkinsonism at 39% and 27%, respectively, meaning significant. Compare that to valbenazine, where the side effects of fatigue and akathisia were seen about 10% of the time, and deutetrabenazine, where somnolence was seen at 14%. Clearly, tetrabenazine [is] falling behind the others in terms of causing more side effects. As a result, the review lists both valbenazine and deutetrabenazine as the first-line agents for TD.
Was there pharmaceutical company influence among the authors? Most of them had not received any pharma funding. Among the 4 that did, only 1 had grant money from Neurocrine Biosciences or Teva, the makers of valbenazine and deutetrabenazine, respectively.
In conclusion, even though the new agents are more expensive and have more company money behind their study, in this review—I think a neutral review—they clearly stood out relative to all other solutions as first-line agents for tardive dyskinesia.
Abstract
Treatment Recommendations for Tardive Dyskinesia
Lucia Ricciardi, Tamara Pringsheim, Thomas R.E. Barnes, Davide Martino, David Gardner, Gary Remington, Donald Addington, Francesca Morgante, Norman Poole, Alan Carson, Mark Edwards
Background: Tardive dyskinesia is a movement disorder characterised by irregular, stereotyped, and choreiform movements associated with the use of antipsychotic medication. We aim to provide recommendations on the treatment of tardive dyskinesia.
Methods: We performed a systematic review of studies of the treatment of tardive dyskinesia. Studies were rated for methodological quality using the American Academy of Neurology Risk of Bias Classification system. Overall level of evidence classifications and grades of recommendation were made using the Scottish Intercollegiate Guidelines Network framework.
Results: Preventing tardive dyskinesia is of primary importance, and clinicians should follow best practice for prescribing antipsychotic medication, including limiting the prescription for specific indications, using the minimum effective dose, and minimising the duration of therapy. The first-line management of tardive dyskinesia is the withdrawal of antipsychotic medication if clinically feasible. Yet, for many patients with serious mental illness, the discontinuation of antipsychotics is not possible due to disease relapse. Switching from a first-generation to a second-generation antipsychotic with a lower D2 affinity, such as clozapine or quetiapine, may be effective in reducing tardive dyskinesia symptoms. The strongest evidence for a suitable co-intervention to treat tardive dyskinesia comes from tests with the new VMAT inhibitors, deutetrabenazine and valbenazine. These medications have not been approved for use in Canada.
Conclusion: Data on tardive dyskinesia treatment are limited, and the best management strategy remains prevention. More long-term safety and efficacy data are needed for deutetrabenazine and valbenazine, and their routine availability to patients outside of the USA remains in question.
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Reference
Ricciardi, L., Pringsheim, T., Barnes, T., Martino, D., Gardner, D., Remington, G., Addington, D., Morgante, F., Poole, N., Carson, A., & Edwards, M. (2019). Treatment Recommendations for Tardive Dyskinesia. Canadian Journal of Psychiatry, 64(6), 388–399.
