2023 Impact Factor
2023 Impact Factor
Tardive dyskinesia and tardive dystonia are intractable extrapyramidal symptoms induced by antipsychotic drugs. It has been reported that tardive dyskinesia occurs in 15 to 20% and tardive dystonia in 1 to 2% of the patients using antipsychotic drugs [1,2]. A 10-year follow-up study of 92 patients taking antipsychotic medications found that as many as 42.4% experienced at least one tardive syndrome (defined as tardive dyskinesia, tardive dystonia, tardive akathisia, tardive tremor, tardive myoclonus, tardive parkinsonism, tardive tics, tardive sensory syndrome) and one in 4 patients showed no improvement [3]. Common risk factors include long-term use of antipsychotics and use of typical antipsychotics [4,5]. Tardive dyskinesia and tardive dystonia are associated with patient distress, decreased quality of life, and increased mortality [6,7]. Patients with tardive dyskinesia and tardive dystonia are also more likely to suffer from occupational and social stigmas [8].
Japanese guidelines for the pharmacotherapy of schizophrenia recommend reducing the dose of the causative agent when tardive dyskinesia or tardive dystonia develops, temporarily discontinuing the causative agent, and switching to another antipsychotic in severe cases [9]. This change has been recommended by other studies as well [6,10-12]. Moreover, Kremens [10] reported that clinicians should try to withdraw dopamine receptor-blocking agents if possible. However, there is no conclusive evidence that reducing or discontinuing antipsychotic medication is effective for antipsychotic-induced tardive dyskinesia or tardive dystonia. In addition, reduction of the antipsychotic medication dose may worsen tardive dyskinesia, tardive dystonia, and psychiatric symptoms [12,13].
Furthermore, even after the offending drug is removed, tardive dyskinesia or tardive dystonia tends to persist for years or decades in most patients [12,14]. Other treatment options include vesicular monoamine transporter 2 (VMAT2) inhibitors valbenazine and deutetrabenazine for tardive dyskinesia and botulinum toxin, baclofen, anticholinergic drugs, benzodiazepines, and the VMAT2 inhibitor tetrabenazine for tardive dystonia [11,15,16]. However, at least 10 to 30% of patients with tardive dyskinesia [17] and 50% of patients with tardive dystonia reported no improvement even with adequate treatment [13]. Therefore, a new, highly effective treatment method is desired.
Electroconvulsive therapy (ECT) is a treatment option for tardive dyskinesia and dystonia [18,19]. In a retrospective chart review, Yasui-Furukori et al. [20] reported that 39% of patients with tardive dyskinesia or tardive dystonia responded to ECT completely, while 61% responded partially. Systematic reviews have been reported by Hay et al. [21] in 1990 and Peng et al. [19] in 2013. Although cases have been previously reported, recent reports have not been investigated [18,21,22]. Furthermore, although valbenazine has recently been released and proven to be effective, there have been a few cases wherein no improvement has been achieved. Moreover, there have been no case reports on the improvement of tardive dyskinesia refractory to valbenazine with ECT.
Although the efficacy of valbenazine for tardive dyskinesia is well proven, we present a case of valbenazine-resistant tardive dyskinesia that responded to ECT. In addition, we reviewed previous studies of ECT for tardive dyskinesia and tardive dystonia to evaluate its safety and efficacy.
The patient was a 25-year-old female. One year and four months prior, she had been diagnosed with a major depressive episode of bipolar disorder at a psychiatric clinic. She was prescribed up to 300 mg/day of quetiapine. She was switched from 300 mg quetiapine to 60 mg lurasidone 11 months previously due to an inadequate response. Nine months prior, dystonia on the right side of the neck appeared. Four months before, dyskinesia on the right upper arm and oral cavity was noted. Antipsychotic medication was discontinued immediately after that, but the extrapyramidal symptoms did not im-prove. Various therapies, including valbenazine 80 mg, were administered for tardive dyskinesia and tardive dystonia, but little improvement was achieved. The patient was admitted to our hospital for ECT due to tardive dyskinesia and tardive dystonia (day 0). At the initial examination, the patient was diagnosed with dystonia on the right side of the neck and dyskinesia of the upper limbs and lips, including twisting and splaying of the right upper limb, pouting and pursing the mouth, and protruding and retracting the tongue. She had an Abnormal Involuntary Movement Scale (AIMS) score of 10. During hospitalization, the patient was given biperiden (6 mg), lorazepam (1 mg), valbenazine (80 mg), and tocopherol acetate (600 mg). The patient and her family were informed regarding ECT, and consent was obtained from both parties. ECT was performed twice a week for a total of 12 times. Tardive dyskinesia and tardive dystonia improved to an AIMS score of 2 points on ECT (day 45). She was eventually discharged and is currently attending a clinic to which she was referred (further details about drug treatment of the case and ECT are provided in the Supplementary Appendix; available online.).
We reviewed previous studies to investigate the efficacy and safety of ECT in tardive dyskinesia and tardive dystonia.
A PubMed search was performed on October 31, 2023, with the combination of ([“Dystonia” OR “Dyskinesia”] AND “Electroconvulsive therapy”) in the MeSH term. The search yielded 221 studies, and 4 more were obtained from secondary sources (Fig. 1). Methods are detailed in the Supplementary Appendix. Studies published that met the following criteria were included: (a) patients with drug-induced tardive dyskinesia or tardive dystonia; (b) patients with tardive dyskinesia or tardive dystonia treated with ECT; and (c) studies detailing the following information on cases of ECT for tardive dystonia or tardive dyskinesia (age, sex, and response after ECT). Finally, 18 articles on tardive dyskinesia and ECT and 13 on tardive dystonia and ECT were included. Furthermore, we obtained consent from the patient for the case report and evaluated ethical considerations.
As a result of the search, 27 articles were finally selected, including 50 patients [18-44]. In addition, our case was added (Table 1 and Supplementary Appendix). In all reports, there was a reference to previous treatment with psychotropic medications, confirming that the patient had drug-induced tardive dystonia and tardive dyskinesia. For antipsychotics listed in the table, the medications immediately before the start of ECT were noted. For cases in which AIMS scores were recorded, the mean and SD of cases before and after ECT were calculated. The results were 19.1 ± 6.2 before and 8.6 ± 4.4 after implementation.
A literature review reported that 32 patients had undergone ECT, and 84% (27/32) of them showed partial response or response. Two patients demonstrated no change [24]. In addition, 9% (3/32) of patients had worsening symptoms after ECT. Among the three patients, one showed no improvement in tardive dyskinesia 1 month after the end of ECT [27], one had tardive dyskinesia that shifted from the extremities to the face and tongue [30], and one had incomplete details [24].
A literature review reported that 22 patients underwent ECT, and 91% (20/22) of them showed partial response or response. One patient demonstrated no change [44]. In addition, 5% (1/22) of the patients had worsening symptoms after ECT, but the patient was subsequently treated with 50 mg of zuclopenthixol and 150 mg of tetrabenazine, and the symptoms improved after 3 months [36]. In this case, it was reported that other adverse events included dysphagia and worsening of tics.
This case is the first where ECT was effective not only for tardive dystonia but also for tardive dyskinesia refractory to valbenazine. ECT was effective without inducing severe adverse events. Moreover, this literature review provided updates on previous studies on ECT for tardive dyskinesia and tardive dystonia.
Approximately 80 to 90% of patients with tardive dyskinesia or tardive dystonia showed either partial response or response of symptoms with ECT, while less than 10% of patients worsened. Hanin et al. [36] reported worsening of tardive dystonia during ECT but did not specify whether it was because the ECT was ineffective. Furthermore, all psychotropic medications had been discontinued immediately before ECT. Therefore, they did not clearly indicate whether the worsening of tardive dystonia was directly causally related to ECT as they could not rule out a worsening associated with the sudden discontinuation of psychotropic medications. Other adverse events observed were postoperative dysphagia and tic. Apart from these, no other adverse events were reported. However, because ECT is associated with a high frequency of adverse events, such as increased blood pressure, tachycardia, and headache, the fact that few adverse events were reported in previous studies may have been due to bias [45,46].
Although VMAT2 inhibitors are an effective treatment for tardive dyskinesia and tardive dystonia [11,15,47], ECT may have a role in patients with drug-resistant tardive dyskinesia and dystonia who have severe symptoms. Notably, our literature review revealed that 84% of cases of tardive dyskinesia and 91% of cases of tardive dystonia had a partial response or response to ECT. However, the duration of symptom improvement after ECT varies from a few weeks to several years. Moreover, even in cases with a long duration of improvement after ECT, it cannot be concluded that this is solely due to the ECT and could be influenced by concomitant use of other therapeutic agents, change or discontinuation of the causative agent, or other factors. Furthermore, in < 10% of cases, tardive dystonia or tardive dyskinesia worsened after ECT. However, when reporting side effects, there is a bias in case reports, which may understate the reality. One study reported worsening of other extrapyramidal symptoms that had been present before ECT [20]. In addition, pre-existing tardive dystonia and dyskinesia have been reported to be further exacerbated by ECT. Although this has been pointed out as a short-duration side effect, attention should be paid to the worsening caused by ECT.
As a result of our research, five previous papers reported a small number of cases in which dyskinesia or dystonia was newly observed immediately after administered ECT to patients with severe psychiatric symptoms [48,49]. As these are only case reports, it is difficult to conclude whether ECT causes new extrapyramidal symptoms or worsens existing extrapyramidal symptoms in patients with tardive dystonia or tardive dystonia. In addition to ECT, factors such as drug use, age, sex, and comorbidities should be considered. Further evidence is needed.
It remains unclear whether the effects of ECT on tardive dyskinesia and tardive dystonia persist. Previous studies have reported that the effects of ECT last for several years or more. However, it cannot be ruled out that this was due solely to the ECT and could have been influenced by the concomitant use of other therapeutic agents or change or discontinuation of the causative agent. Others have reported that the improvement was temporary, lasting from a few days to a few months [22,40-42]. One case has been reported in which maintenance ECT was performed [22]. Therefore, even after improvement with ECT, patients should be alert for worsening symptoms and consider treatment for tardive dyskinesia and tardive dystonia.
The mechanism underlying the effect of ECT on tardive dyskinesia and tardive dystonia remains unclear. Although the details of the pathophysiology of tardive dyskinesia have not been fully elucidated, it is thought to involve postsynaptic dopamine supersensitivity in the dopamine pathway of the striatum in the brain, caused by long-term blockade of dopamine D2 receptors with antipsychotic drugs [16]. Other theories have also been reported, including the gradual progression of gamma-aminobutyric acid (GABA)ergic neuronal metamorphosis and desensitization of the striatum, deficiency of the acetylcholine system, neurotoxicity and oxidative stress, and changes in synaptic plasticity [50-52]. The pathophysiology of tardive dystonia is similarly not well understood, and it has been postulated that hypersensitivity of the striatal dopamine D2 receptors in the brain, as in tardive dyskinesia, is a contributing factor; however, it has also been suggested that the pathogenesis may be different from that of tardive dyskinesia [11]. ECT has been shown to be effective in the treatment of tardive dyskinesia and tardive dystonia, wherein it may improve the motor symptoms by increasing the GABA concentration in the striatum [33], which is thought to be the pathogenesis of dystonia and by preventing postsynaptic dopamine receptor supersensitivity [53]. The specific mechanism underlying the therapeutic efficacy of ECT against tardive dyskinesia and tardive dystonia remains to be elucidated, and further neurobiological studies are needed to elucidate the specific mechanisms by which it exerts its therapeutic effects.
This study had some limitations. First, this case report had a short follow-up period, and the persistence of ECT effects or adverse events over time could not be assessed. Second, caution should be exercised in interpreting the results of this study, as many of the definitions of outcomes from previous studies included in the literature review are not presented. Third, only a few patients were included in this literature review. Fourth, all previous studies were case reports or case series, which may have a case selection bias. Fifth, when using ECT for tardive dyskinesia and tardive dystonia, it may cause exacerbation or other side effects. Therefore, clinicians should reconsider ECT as a treatment option for severe tardive extrapyramidal symptoms that do not improve even after discontinuing the causative drug or drug therapy and the symptoms are severe, particularly when tardive dyskinesia and tardive dystonia coexist, weighing its pros and cons.
In conclusion, this case was the first in which ECT was effective for tardive dyskinesia and tardive dystonia refractory to valbenazine treatment. Improvements in motor symptoms have opened new therapeutic intervention options beyond conventional pharmacotherapy. However, no randomized controlled trials have examined the efficacy and safety of ECT for delayed extrapyramidal symptoms. Future trials are required to test its usefulness for treatment-resistant delayed extrapyramidal symptoms. Furthermore, our findings may enrich the discussion on the effectiveness of ECT in patients with tardive dyskinesia or tardive dystonia. However, further studies are warranted.
The authors would like to express their gratitude to all those who have contributed to this work.
No potential conflict of interest relevant to this article was reported.
Conceptualization: Keisuke Irinaka, Yu Itoh, Masahiro Takeshima, Masaya Ogasawara, Kazuhisa Yoshizawa. Data acquisition: Keisuke Irinaka, Yu Itoh, Naoko Ayabe, Masaya Ogasawara, Kazuhisa Yoshizawa. Formal analysis: Keisuke Irinaka, Yu Itoh. Supervision: Masahiro Takeshima, Kazuo Mishima. Writing—original draft: Keisuke Irinaka, Yu Itoh. Writing—review & editing: Keisuke Irinaka, Yu Itoh, Masahiro Takeshima.
Fig. 1. Literature search method.
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Author ORCID Information Keisuke Irinaka Yu Itoh Kazuhisa Yoshizawa Masaya Ogasawara Naoko Ayabe Kazuo Mishima Masahiro Takeshima |
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