Neurological Perspectives Should Be Integrated Into the Management of Tardive Dyskinesia—Expert Opinions and Proposed Educational Initiatives in Asia
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Tardive dyskinesia (TD) is a movement disorder that has a range of clinical manifestations and is a side effect of treatment with dopamine receptor-blocking agents, primarily antipsychotic drugs (APDs) [1,2]. Therefore, the management of TD involves multiple disciplines-specifically, psychiatry and neurology. In practice, this can result in a gap in disease management, whereby patients receive only one aspect of what should ideally be multidisciplinary care. Psychiatrists will naturally focus on controlling patients’ challenging psychotic symptoms and may not be trained to evaluate the abnormal movements that are a core manifestation of TD [3,4]. As a result, neurologists may only encounter TD patients when the condition has become severe. Indirect evidence supporting this finding has been reported in the psychiatry curriculum for neurology residents, which was developed in collaboration with the Consortium of Neurology Program Directors and the American Association of Directors of Psychiatric Residency Training, approved by the American Academy of Neurology’s (AAN) Graduate Education Subcommittee (https://www.aan.com/tools-resources/academic-core-curricula). In this curriculum, TD is mentioned only once in the topic related to the evaluation and management of neurological side effects of medications used for psychiatric purposes. Therefore, it can be hypothesized that any lack of exposure to TD management among neurologists after their initial residency is likely to extend into their later clinical practice. We challenge the conventional practice whereby TD management is primarily psychiatrist-led, and we propose that integrative management between neurologists and psychiatrists is essential for optimal patient outcomes. This collaborative approach needs to be based on education and should reflect the perspectives of both psychiatrists and neurologists [5].
To evaluate this issue in Asia, a focus group was established. The focus group comprised seven movement disorder neurologists with a special interest in TD representing six Asian countries (Thailand, China, Japan, South Korea, Malaysia, and India). The group performed a systematic literature review on TD and its management in Asia to better understand the current situation across the region [6]. Based on the findings of the review, the neurologists aimed to determine how the management of TD can be improved in Asia by narrowing the current gap between the psychiatry and neurology disciplines. This article summarizes their insights and provides proposals for focused educational initiatives that could be incorporated into future courses.
An initial online meeting was held in April 2023 to discuss the scope of the project, available data on TD in Asia, each member’s personal experience with TD treatment, and their insights regarding the overall situation in their country based on their national-level experience. A 15-item questionnaire about TD and its management was developed by R.B. and O.P. based on domains related to TD in clinical practice, including its prevalence, its potential contributing factors, patient types, and the usual clinical pathways and treatment practices in each of the countries represented (Supplementary Material in the online-only Data Supplement). The questionnaire was completed by all participants, and the responses were combined and analyzed at a second online meeting, which was held in August 2023. The experts’ feedback is summarized in Table 1.
Summary of focus group questionnaire responses
APD use is known to be associated with an increased risk of developing TD; specifically, the use of first-generation APDs, the use of high doses and long-term treatment are strong risk factors for TD [7,8]. Several non-APD drug classes have also been shown to be associated with the development of TD-like syndromes, including some antiemetics, calcium channel blockers and, more rarely, anticholinergics and anticonvulsants [9,10]. Unsurprisingly, the experiences of the focus group members were consistent with these global literature reports. The calcium channel blocker flunarizine and the combination therapy of flupentixol (an APD) plus melitracen (a tricyclic antidepressant), which is used in some countries for the treatment of mood disorders, were reported to be common causes of TD in Asia. Reports in the literature indicate that female sex (40% of respondents) and older age (60% of respondents) are associated with a risk of developing TD [11,12]. The number of comorbid conditions, including previous stroke, small vessel disease, psychiatric disorders, brain damage, dementia, drug addiction and gastrointestinal motility disorders, has also been shown to be associated with the risk of developing TD. The experts’ experiences reflected both Western literature [8,13] and observations from studies in Asia [14] indicating that that off-label use of APDs is common and likely impacts the prevalence of TD. It was suggested that any observed increase in the prevalence of TD may be due to improved awareness among neurologists, the availability of newer drugs, and the increased number of patients seeking treatment. An important observation was that in some Asian countries, there may be differences in TD prevalence between rural and urban areas, possibly due to inequalities in drug availability.
The responses to the questionnaire indicated that the usual number of TD patients that the experts saw in their clinical practice was relatively low, at 2–10 per month (mean: 4 patients/month), with a total of between 20–100 over the previous year (mean: 38.33 patients/year). The majority of their TD patients (60%–100%) had a documented history of APD use, and 0%–40% had a documented history of using other dopamine receptor blocking agents (DRBAs). According to the experts’ opinions, a high proportion of patients (30%–80%) felt that their condition had a significant negative impact on their daily lives, including their physical, cognitive, and psychosocial functioning, and that this negative impact becomes stronger as the duration of APD exposure, the duration of symptoms, age, and the duration of work increases. This finding aligns with a recent survey undertaken in the USA, which revealed that TD imposes a substantial burden on patients’ physical, psychological, social, and professional lives and impacts the management of their underlying psychotic condition [15]. Consensus recommendations now suggest that the impact of TD should be assessed routinely in clinical care, particularly in the key domains of social, physical, vocational, and psychological functioning [16]. The experts suggested that tracking patients’ APD exposure over time would be useful but would be a challenge in clinical practice since many patients are unaware of what particular drugs they are taking, and clinicians may not maintain a good history or may be using them off-label. According to the experts’ clinical experience, patients are often unaware that the drugs they are taking may contribute to abnormal movements, assuming that they are part of their underlying condition, so they may not report them.
In 2013, the AAN developed evidence-based guidelines for the treatment of tardive syndromes [17], which were updated in 2018 [18]. The initial approach when TD occurs is to adjust the dosage of the causative agent and change the medication, if possible, before considering specific treatments. The questionnaire responses revealed that most Asian countries do not have specific national TD management guidelines, and it is not clear whether existing international guidelines, such as those of the AAN, have been adopted in clinical practice in Asian regions. Moreover, many patients in Asia use complementary medicines to manage their TD, and these complementary medicines are not included in such guidelines. Thailand commonly uses the AAN guidelines, but this may reflect the fact that the primary author of this practice parameter is from Thailand (R.B.) and received some neurology training in the USA. As he now uses these guidelines in his current practice in Thailand, he has some influence on local education and guideline adoption.
A wide range of different approaches, including both pharmacological and nonpharmacological approaches, are used for the management of TD in Asian countries (Table 2). All six countries examined herein use GABAergic compounds and amantadine, but the availability of other therapies varies. Complementary, alternative and traditional therapies, such as Ginkgo biloba leaves [19], are commonly used in Asia. These treatments are often employed despite limited evidence for their efficacy, although Ginkgo biloba leaves have level B evidence for improving TD according to AAN treatment guidelines [18]. Further studies are needed to determine the efficacy of various complementary, alternative, and traditional therapies for the treatment of TD in well-controlled clinical trials involving Asian patients. The new vesicular monoamine transporter 2 (VMAT2) inhibitors valbenazine and deutetrabenazine are recommended as TD treatments in the updated version of the AAN practice parameter based on Level A evidence [18]. These data are available for only three of the Asian countries studied herein, i.e., Thailand, Japan, and China (Table 2). Therefore, wider access is necessary. The older VMAT2, tetrabenazine, is available in South Korea, Malaysia, India, and Thailand (as an orphan drug). Based on promising initial results, experts believe that neurostimulation treatments, transcranial direct current stimulation and repetitive transcranial magnetic stimulation are of interest for TD management [20,21].
Use of pharmacological and nonpharmacological therapies for the management of tardive dyskinesia in the six Asian countries represented by the neurology experts
The experts estimated that once appropriate medication was prescribed, approximately 50%–80% of their TD patients were able to achieve symptom relief; however, patients were generally referred to them only when TD was severe and impacted their daily functioning. Earlier referral and prompt treatment of less severe TD might provide better outcomes; however, there is currently no published evidence supporting this approach. However, experts reported that 50%–70% of their TD patients were unaware of their condition before being referred for evaluation, which is consistent with reports in the literature regarding subjective awareness of TD [22]. This is an important issue since a lack of awareness results in patients not discussing their symptoms with their psychiatrist, thereby delaying referral to a neurologist. Generally, the main reasons that trigger referral are when TD symptoms start interfering with the patient’s daily life despite a reduction in the dose of causative medication or the use of alternative therapy. Ideally, a referral should be made as soon as abnormal involuntary movements are observed.
A broad range of challenges were highlighted by the focus group regarding the management of TD in Asian countries. Some of these issues are related to access to effective drugs and lack of funding, which need to be addressed at the national governmental and health care system level. For example, new VMAT2 inhibitors are not always reimbursed by health authorities, and access to second-generation APDs may be limited in certain regions or may depend on what is reimbursed in that country, thereby impacting the number of patients who develop TD. Other challenges relate to the delivery of clinical care in terms of knowledge and awareness of TD, gaps in the management pathway, and the need for more collaboration between the neurology and psychiatry disciplines. Under recognition of TD symptoms by psychiatrists is also a potential issue that could impact the reported prevalence [23,24]. The low referral rates observed in our survey could reflect a lack of awareness of the condition among psychiatrists or the low priority given to managing these abnormal movements. However, TD has a significant negative impact on patients’ quality of life, which can be counteracted by aggressive and prompt treatment. Educational initiatives will play a vital role in this process and will ultimately improve the management of TD. Initiatives should target all clinical personnel involved in the care of TD patients, including general and nurse practitioners, neurologists, and psychiatrists. Some interventions are also appropriate for patients and their caregivers, particularly interventions related to the recognition of TD symptoms. To achieve these aims, a range of focused educational initiatives was proposed herein. The initiatives address three main topics based on the focus group’s insights: 1) understanding who is at risk of developing TD, 2) correctly diagnosing TD and assessing its impact on patients, and 3) selecting the right treatment based on local availability and ensuring adequate follow-up as part of a collaborative care pathway (Figure 1). These interventions can be delivered in the form of seminars, educational materials, online courses, and social media communications, depending on the target audience.
Proposed topics, learning objectives and strategies for the development and communication of educational initiatives regarding tardive dyskinesia and its management in Asia. TD, tardive dyskinesia; APDs, antipsychotic drugs; AIMS, Abnormal Involuntary Movement Scale.
This survey-based project has certain limitations. The proposals were based on the opinions and insights of a limited number of experts. However, these experts were carefully selected because they had extensive experience in both TD management and TD research in their respective countries in Asia. We acknowledge the limitations regarding generalizing the results for each individual country and the whole region; however, the aim of convening the focus group of experts was to provide an overview of the TD situation in their country. Therefore, this article aims to raise important issues for further discussion and debate.
Our findings highlighted the challenges in the clinical management of TD in Asia and proposed some practical initial steps to address these challenges. In particular, education should be a priority within the region. These proposals are based on the viewpoints from seven experts about the practical reality of TD management in major countries in Asia and the challenges that the experts face. The proposals are not based on specific original research on this topic with robust analytical methods. While the focus group questionnaire used in the current study is far from the perfect solution to the challenges identified, we feel it is an important initiative that would benefit from more widespread communication. We hope that raising this issue will encourage collaboration and facilitate graduate progress toward better TD education in Asia.
There are few formal relationships between psychiatrists and neurologists in the Asian region to ensure multidisciplinary management of TD. Similarly, there are no established care pathways for TD in Asia, nor are there any collaborative clinics that allow for the exchange of ideas between neurologists and psychologists. Clinical experience from the countries examined in our analysis, which compose the majority of Asia, suggests that most TD clinics in the region are structured as solo practices that focus on a single specialty (e.g., psychiatry). It is necessary to improve care pathways and communication between psychiatrists and neurologists in order to ensure early detection and adequate treatment of TD. Educational interventions at both the medical school level and the professional level will lead to increased awareness among neurologists and psychiatrists regarding the benefits of collaboration. As DRBAs and other agents known to be associated with TD are also prescribed by clinicians in other disciplines, it might be valuable to expand these educational initiatives beyond neurology and psychiatry. Reaching these objectives can be supported by the gradual adoption of focused, patient-centered educational activities to bridge the current gaps in patient care.
Notes
Ethics Statement
Ethical approval was not required for this manuscript. Informed patient consent was not necessary or acquired for this work.
Supplementary Materials
The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.24068.
Notes
Conflicts of Interest
The authors have no financial conflicts of interest.
Funding Statement
Focus Group Meetings held to discuss the data and content of this article and subsequent development of the manuscript were supported by an unrestricted educational grant from Teva Pharmaceutical Industries Ltd. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.
Roongroj Bhidayasiri is supported by the Senior Research Scholar Grant (RTA6280016) of the Thailand Science Research and Innovation (TSRI), and Centre of Excellence grant of Chulalongkorn University (GCE 61009300041), Bangkok, Thailand. Editorial assistance for the development of the manuscript was provided by Dr Karen Wolstencroft, Bluewolf Communications Ltd, UK.
Author Contributions
Conceptualization: Roongroj Bhidayasiri. Data curation: Onanong Phokaewvarangkul. Formal analysis: Roongroj Bhidayasiri, Onanong Phokaewvarangkul. Funding acquisition: Roongroj Bhidayasiri. Methodology: Roongroj Bhidayasiri, Onanong Phokaewvarangkul. Project administration: Roongroj Bhidayasiri, Onanong Phokaewvarangkul. Resources: Roongroj Bhidayasiri. Supervision: Roongroj Bhidayasiri. Validation: Roongroj Bhidayasiri. Visualization: Roongroj Bhidayasiri, Onanong Phokaewvarangkul. Writing—original draft: Roongroj Bhidayasiri, Onanong Phokaewvarangkul. Writing—review & editing: all authors.
Acknowledgements
None