|Year : 2020 | Volume
| Issue : 1 | Page : 10-19
Tardive dyskinesia: Prevention and newer management strategies
Sreelakshmi Vaidyanathan, Suyog Vijay Jaiswal
Department of Psychiatry, All India Institute of Medical Sciences, Nagpur, Maharashtra, India
|Date of Submission||10-Apr-2020|
|Date of Decision||14-May-2020|
|Date of Acceptance||22-May-2020|
|Date of Web Publication||30-May-2020|
Dr. Sreelakshmi Vaidyanathan
Department of Psychiatry, All India Institute of Medical Sciences, Plot No. 2, Sector - 20, MIHAN, Nagpur - 441 108, Maharashtra
Source of Support: None, Conflict of Interest: None
Tardive dyskinesia (TD) is a condition where we have a limited understanding of the cause and of management. The delayed-onset movements can occur due to prolonged exposure to dopamine receptor-blocking agents (DRBAs). They can be physically disabling and lead to ridicule and stigmatization. TD also interferes with treatment adherence. The increased trend of prescriptions for off-label use of various DRBAs, especially antipsychotics, has increased the risk of TD. No currently available antipsychotic is free of the risk of TD, though the atypicals have a lower risk. The Abnormal Involuntary Movements Scale is the most widely used and recommended tool for the assessment and monitoring of TD. Varied treatment strategies have been tried including cessation of the DRBA, switch to a lower potency antipsychotic, and concomitant use of other medications such as clonazepam and Vitamin E. Most of these strategies have minimal evidence. The recent US Food and Drug Administration approval of two VMAT2 inhibitors, deutetrabenazine and valbenazine, for the treatment of TD has brought some relief to these patients. Cost may be a limiting factor in their use. Nonpharmacological treatment such as deep-brain stimulation, botulinum toxin, and electroconvulsive therapy is to be used only in intractable/incapacitating movements. Despite these newer options, the best strategy in the management of TD continues to be prevention. Judicious use of antipsychotics, regular monitoring of patients on DRBAs, and early diagnosis and intervention are strategies that significantly reduce the development of TD and improve the quality of life of patients.
Keywords: Drug-induced dyskinesia, movement disorders, tardive dyskinesia, VMAT2 inhibitors
|How to cite this article:|
Vaidyanathan S, Jaiswal SV. Tardive dyskinesia: Prevention and newer management strategies. Ann Indian Psychiatry 2020;4:10-9
|How to cite this URL:|
Vaidyanathan S, Jaiswal SV. Tardive dyskinesia: Prevention and newer management strategies. Ann Indian Psychiatry [serial online] 2020 [cited 2020 Sep 18];4:10-9. Available from: http://www.anip.co.in/text.asp?2020/4/1/10/285498
| Introduction|| |
The advent of antipsychotics heralded a revolution in the treatment of psychosis, giving patients a better chance at recovery and reintegration into the community. The challenge of delayed-onset, hyperkinetic movements that seemed to persist even after drug withdrawal, soon followed. This phenomenon termed “Tardive Dyskinesia” (TD) by Faurbye  continues to remain a mystery, with limited understanding of etiology, management, and treatment options. This iatrogenic and mostly persistent disorder with possible medicolegal outcomes directed research up until the early 1990s. Second-generation antipsychotics (SGA) or “atypicals” reduced the general risk of movement disorders. This resulted in decreased focus on the management as well as research of TD. The US Food and Drug Administration (FDA) approval of two drugs – valbenazine and deutetrabenazine – in 2017 saw a resurge in TD research. Further, detailed long-term evaluation of the SGAs shows that TD can occur even on these medications, albeit with a lower risk. Thus, it is imperative to revisit this forgotten phenomenon, reviewing the available literature and the latest additions in treatment options.
| Nomenclature|| |
”Tardive” meaning “arriving or coming late” denotes the delay between the initiation of treatment with the drug and onset of the abnormal movements. The term was first used by Faurbye in a review of experience involving patients with chronic psychosis on antipsychotics who developed irreversible bucco–lingual–masticatory dyskinesias. Over time, this term has expanded to include various tardive hyperkinetic movement disorders, leading to confusion in medical literature because of the variable presentation and management. Literature reviews suggest the use of the term “tardive syndrome” when referring to the spectrum of “any combination of hyperkinetic or hypokinetic movement disorders, as well as sensory symptoms that share the etiological background of recent exposure to dopamine receptor-blocking agents (DRBAs).” Tardive syndrome encompasses the following:
TD (oro–buccal–lingual, plus choreiform movements in any other body parts)
- Tardive stereotypy
- Tardive akathisia
- Tardive dystonia
- Tardive myoclonus
- Tardive tremor
- Tardive tics (Tourette like)
- Tardive pain (chronic oral/genital pain/dysesthesia)
- Withdrawal-emergent dyskinesia.
| Comparative Nosology|| |
There are multiple diagnostic criteria ,, for TD in various classification systems [Table 1]. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition definition of TD is restrictive in view as it covers only TD caused by neuroleptics, although other medications could be the causative agents. The Schooler and Kane's criteria (RD–TD) is widely used as the standard diagnostic criteria. Comparisons of the assessments over time can provide valuable insight into the course of the movements and the effect of factors such as medication changes on the severity.
For clinical understanding, TD can be defined as delayed-onset, abnormal, choreoathetoid involuntary movements, typically involving the orofacial musculature (tongue, jaw, and lips), with or without the involvement of peripheral musculature (trunk, limbs, pharyngeal, and diaphragmatic), attributed to prolonged exposure to a DRBA.
| Prevalence and Impact of Tardive Dyskinesia|| |
Most studies in the Western population estimate the prevalence rate of 20%–30% for TD in patients on neuroleptics, with an increase in prevalence with age.,,, Similar prevalence rate is reported in Indian studies as well,,, though few of them report the prevalence to be lower than that in Western countries.,
TD can lead to adverse medical outcomes such as fractures due to falls, stridor, or choking, when affecting the central musculature and possible death. It can also be physically disabling, embarrassing, and socially stigmatizing, leading to social alienation, depression, and suicide., It can worsen the stigma that patients with mental illness often experience and interferes with treatment adherence. TD has been shown to be associated with poorer quality of life.
| Pathophysiology|| |
The cause of these movements has been the subject of debate and a stimulus for continuing research. The earliest theories were related to upregulation and supersensitivity of postsynaptic dopaminergic D2 receptors, though this failed to explain how the symptoms persisted despite cessation of the causative drug. Several other theories have come to light over the years. [Figure 1] shows some of the proposed mechanisms of induction of TD. Latest evidence focuses on disordered synaptic plasticity and an imbalance in flow between striatal pathways. Genetic vulnerability to TD is also an area of significant interest. One of the largest genome-wide association studies (TD GWAS) showed significant GWAS locus for TD, suggesting an inherent vulnerability that may be precipitated by the long-term antipsychotic use. In addition, several pathways in this pointed to DNA damage and immune responses, warranting further research in this direction. A detailed discussion of various theories is beyond the scope of this review. For further details of pathophysiology, one may refer to some of the relevant articles.,,,
| Medications With the Potential to Cause Tardive Dyskinesia|| |
When we think of TD, it is almost always antipsychotics that come to mind. There are other medications, including commonly used antiemetics, which have the potential to cause TD [Table 2].
TD was initially thought to be absent with SGAs. However, long-term evaluation has found the incidence of TD with these medications as well, though the risk is lesser than that with the older generation. Carbon et al. in a meta-analysis found that “the annualized TD incidence across first generation antipsychotics arms was 6.5% (95% CI: 5.3%-7.8%) vs. 2.6% (95% CI: 2.0%-3.1%) across second generation antipsychotics arms.” Thus, all the currently available antipsychotics have an associated risk of TD.
| Risk Factors for Tardive Dyskinesia|| |
The occurrence of TD in an individual is based on various factors such as age, gender,, and duration of exposure,, to name a few [Table 3]. Studies show that over the last 10 years, there is an increasing trend of prescriptions for off-label uses of DRBAs, including prokinetic drugs such as metoclopramide. Such long-term use of these medications, such as antipsychotics, for the management of insomnia and disruptive behavior in nonpsychotic disorders, may increase the risk of TD. Antipsychotic polypharmacy implicates higher cumulative receptor blockade with an increased risk of TD. This area is relatively unexplored with sparse literature to conclude a definitive relationship between the two.
| Diagnosis and Clinical Features|| |
Any voluntary muscle and group of muscles can be affected by TD and due to the varied combinations of movements, there can be a diverse array of presentations. Eighty percent of cases present with predominant orofacial involvement, whereas 20% with predominant peripheral symptoms involving trunk/limbs. A combination of the two is also often seen. [Figure 2] illustrates the key clinical features of TD. The person is often initially unaware of the movements, and caregivers are the first ones to notice. As the intensity and frequency of the movements increase gradually, they may attempt to cover or disguise the movements, though they are often unsuccessful in doing so. The onset of these symptoms may occur during exposure to the medication, i.e., treatment – emergent or after cessation of medication or reduction in dose, i.e., withdrawal emergent. The latter is seen more often in children and usually resolves over a few weeks or months.
| Differential Diagnosis|| |
There is a wide array of differentials to be considered in a person with movement disorder [Table 4]. A detailed history, with specific focus on the history of treatment with any DRBAs and a careful neurological examination, rules out most of the other differentials.
Wilson's disease is likely if there is jaundice with hepatomegaly associated with the choreiform movements. Slit-lamp examination for Kayser–Fleischer ring and serum ceruloplasmin levels will clinch the diagnosis. Those with Huntington's have greater difficulty in gait and coordination, cognitive decline, and positive family history. Genetic testing can be done to detect the abnormal gene, and neuroimaging will show degenerative changes in basal ganglia region. Sydenham's chorea is usually seen in children or adolescents with a history of sore throat (Group A Streptococcal infection). Metabolic causes such as hyper- or hypoglycemia and hyperthyroidism can be diagnosed by blood investigations. Spontaneous dyskinesias may be seen in up to 4% of first-episode patients of schizophrenia and up to 40% in patients ≥60 years of age. Psychogenic movements have an abrupt onset, spontaneous remissions, and disability that is usually out of proportion to examination findings. The movements tend to be inconsistent, likely to disappear with distraction or appear on suggestion. These could be due to an underlying psychiatric illness or malingering.
Dealing with the elderly could be more complex as it becomes difficult to pinpoint the diagnosis and many may have associated comorbidities. Up to 16% of edentulous persons can have spontaneous movements. People with ill-fitting dentures could also have similar movements.
| Management of Tardive Dyskinesia|| |
In most cases, as mentioned previously, a detailed history of prolonged DRBA use [refer the medications mentioned in [Table 2] steers us toward diagnosis. In the absence of any associated comorbidity, laboratory investigations in TD will be normal. The neural changes or findings primarily due to the long-standing psychosis for which the patient is taking antipsychotics are difficult to clearly distinguish from those related to TD. Certain studies have reported changes in the form of significantly smaller volumes of caudate nuclei in magnetic resonance imaging (MRI) and left lenticular nucleus neural damage on proton magnetic resonance spectroscopy in patient groups with TD.
When faced with conditions that may resemble TD [as in [Table 4], laboratory studies and neural imaging as follows may be required to obtain a clearer picture:
- Slit-lamp examination for KF ring, liver function tests, serum ceruloplasmin, and urine and serum copper in suspected cases of Wilson's disease
- Thyroid function tests (T3, T4, and thyroid-stimulating hormone [TSH] and/or anti-TPO antibodies) to rule out thyroid dysfunction
- Genetic testing and caudate nucleus atrophy on MRI in Huntington's disease
- Autoimmune disorder test battery to rule out disorders such as systemic lupus erythematosus
- Electroencephalography if seizures are suspected
- Neuroimaging (computed tomography/MRI) to rule out infarct and/or neoplasm
Using the above-mentioned investigation arsenal as required on a case-to-case basis combined with good clinical judgment, other differentials of TD can be excluded.
Assessment of tardive dyskinesia
There are standardized assessment scales for the quantification and monitoring of progress of movements in TD. These scales are not diagnostic instruments. They provide a “snapshot” of the occurring movements, but do not provide details related to the cause. To get a complete picture, the information from the scale needs to be taken in the context with factors such as treatment history (medications – history, dosage, and changes in dose) and neurological or other causes. Repeated ratings over several days help monitor the movements and chart their progression. The common scales for the assessment of TD are given in [Table 5].,,,,,
The Abnormal Involuntary Movements Scale (AIMS) is the most widely used clinician-rated scale for the assessment of severity of TD. It has been extensively used in clinical trials of antipsychotic medications to assess TD. Its simplicity, availability in public domain, and short assessment time (around 10 min) make it a highly recommended tool in routine clinical evaluation as well. It provides a step-by-step detailed examination procedure, which ensures standardization of the process. It is a 12-item scale that assesses abnormal involuntary movements in the following three regions:
- Orofacial (four items: muscle of facial expression, lips and perioral area, jaw, and tongue)
- Extremity movements (two items: upper – arms, wrists, hands, and fingers; lower – legs, knees, ankles, and toes) and
- Truncal (one item: neck, shoulder, and hips).
The items are rated on a 5-point scale of 0 (none) to 4 (severe). One point is to be subtracted if the movements are observed to occur only on activation and not spontaneously. Three items titled global judgment (each on a 5-point scale) score the overall severity of movements, incapacitation due to movements, and patient's awareness of the movements.
The scale ends with two items on the dental status of the patient, which help account for one of the most common differentials for TD movements in the orofacial area. The scale provides a total score (items 1–7). The severity item score can be used in isolation., The AIMS is a simple and time-efficient standardized tool for the screening as well as monitoring of TD.
All available scales are essential to assess and record the movements of TD. There are currently no instruments that specifically measure patient awareness, burden, and the functional impact of TD.
A plethora of treatment strategies have been proposed over the years to treat TD, with only few managing to hold their ground in terms of evidence. Until recently, there were hardly any medications or other treatment modalities with high level of evidence for use in TD. Through this myriad of interventions, one strategy that has stood the test of time is the early recognition and regular monitoring for TD using one of the standardized instruments/scales. This should be included as an essential part of patient follow-up for every patient on any DRBA.
The various options for treatment of TD are as follows:
Pharmacological management [Table 6],
Increase in dose of antipsychotic
Increasing the dose of the antipsychotic was thought to be effective in controlling the TD. The rationale being that on increasing the dosage, the further blockade of the supersensitized dopamine receptors will lead to suppression of the movements. The same effect can also be obtained by switching to a higher potency antipsychotic. This strategy may help in reducing the movements for a brief period, but additional side effects due to increased dosage and eventual supersensitization of the remaining receptors with worsening of TD are definite limiting factors.
Dose reduction/cessation/switching of antipsychotic
This is one of the most used initial strategies to combat TD. Dose reduction or cessation can be the option if the mental state of the patient permits the same. The rationale is that stopping the DRBA will allow the dopamine receptor hypersensitivity to gradually normalize. If the patient has been prescribed the antipsychotics for conditions other than psychosis, for example, mood disorders, insomnia, or behavioral issues, gradual dose reduction and cessation of the drug with the use of other appropriate medications such as mood stabilizers or SSRIs is the optimal course. If the patient of psychosis is stable without any symptoms for some years, dose reduction can be considered. It must be done very cautiously with a gradual reduction in dose over several weeks. There is a definite risk of relapse and hence, regular follow-ups with monitoring of mental status is paramount. If patient is symptomatic and has residual symptoms or any recent relapse history, switching of the antipsychotic is preferable. Most research till date supports shifting to SGAs such as clozapine or quetiapine, due to the relatively lower risk of TD., Preliminary evidence suggests reduction in TD movements with these drugs, but prospective randomized controlled trials are lacking to substantiate these existing recommendations. Another strategy recommended for the switch is to gradually shift to a medication with lower potency and wider receptor binding profile, for example, haloperidol to olanzapine or clozapine and risperidone to aripiprazole to treat TD. This too carries with it the inherent risk of a relapse. As there is some evidence of worsening of the dyskinetic movements due to anticholinergics, they should be stopped.,
Vesicular monoamine transporter 2 inhibitors
Vesicular monoamine transporters (VMAT) are responsible for the transport of cytoplasmic monoamines into presynaptic vesicles for storage and release on stimulation. Targeting these transporters directly “may allow for the modulation of neurotransmission while maintaining the proper kinetics of exocytotic (dopamine) release and termination of the signal,” avoiding an increased risk of compensatory mechanisms. Inhibition of VMAT reduces presynaptic storage of monoamines such as dopamine, thereby reducing the amount released into the synaptic cleft. Lesser dopamine in the synapse will result in lesser stimulation of the supersensitized receptors, leading to a reduction in the movements  [Figure 3]. VMAT 1 is present in central as well as peripheral nervous system, whereas VMAT 2 is only centrally located. Tetrabenazine, deutetrabenazine, and valbenazine are selective reversible VMAT2 inhibitors.
|Figure 3: Mechanism of action of VMAT2 inhibitors. (a) Entry of dopamine into the synaptic vesicle for storage occurs via VMAT2. On stimulation of the neuron, the stored dopamine is released into the synaptic cleft. Dopamine that remains in the cytoplasm is degraded by monoamine oxidase. (b) VMAT2 inhibitors prevent dopamine entry into synaptic vesicle → reduce the amount of dopamine released into the synaptic cleft → lesser stimulation of the super sensitized receptors → reduction of the movements|
Click here to view
Tetrabenazine was introduced around the 1960s, initially for the treatment of psychoses. It was quickly displaced by better drugs such as phenothiazines. Over the last two decades, it has been used off label for treating TD and other movement disorders. It has a high first-pass metabolism, giving rise to α-dihydrotetrabenazine (active metabolite with 4–8 h half-life) and β-dihydrotetrabenazine (biochemically inert with 2–4 h half-life). It is prescribed 50–100 mg/day in three divided doses.
Replacing the hydrogen atoms on the two methoxy groups of tetrabenazine gave us deutetrabenazine, while valbenazine is the purified patent prodrug of (+)– isomer of α-dihydrotetrabenazine.,, Deutetrabenazine has a half-life of 9–10 h with a dose range of 24–48 mg/day in two divided doses, whereas valbenazine has a half-life of 15–22 h with a dose range of 40–80 mg once a day. Ease of dosing of these agents promises a better treatment adherence profile than tetrabenazine. Both these drugs were US FDA approved in 2017 following results from pivotal trials (ARM–TD  and AIM–TD  for deutetrabenazine and KINECT– 2 and KINECT–3 for valbenazine).
The likely adverse effects with this group of drugs include psychiatric (sedation/somnolence, fatigue, insomnia, depression, suicidality, and anxiety); neurological (akathisia, Parkinsonism More Details, and headache/migraine); and gastrointestinal (dry mouth, nausea/vomiting, and weight gain). Prolongation of QTc interval has also been seen in some patients, especially those with congenital QT syndrome or concomitantly on other medications, which may prolong QTc interval. These side effects are more severe and common with tetrabenazine and least with valbenazine due to its high VMAT2 specificity. Both tetrabenazine and deutetrabenazine come with a black box warning for depression and suicidality and are contraindicated in those with untreated or inadequately treated depression or in suicidal patients., In addition, in case of both these medications, hepatic impairment is a contraindication, and CYP2D6 genotyping is to be considered at higher doses. Limited data is available at present on their use in pregnancy or lactation, but due to certain animal studies finding increased rates of still born and postnatal deaths, they are to be avoided.
Studies with these medications indicate effective management of TD even with continuation of antipsychotic drugs., These are currently the medications with high level of evidence for use in TD. Though long-term studies on benefits and safety as well as head-on comparisons among the various VMAT2 inhibitors are awaited, current evidence has shown promising results and is a ray of hope for patients suffering from TD. Cost of treatment may prove to be a limiting factor in usage. At present, only tetrabenazine is available in the Indian market and its cost of treatment ranges between $40 and 100 per day at the time of writing this article. Valbenazine and deutetrabenazine are not yet available in Indian markets.
Several other medications have been tried in the treatment of TD though only a couple have shown some evidence for use. Most of the studies reported are small trials or case series with insufficient evidence. Large-scale RCTs are required to establish further evidence. [Table 6] gives a summary of these medications.,,,
There is no evidence that calcium channel blockers, baclofen, other vitamins and antioxidants, acetazolamide, levetiracetam, melatonin, etc., are beneficial in TD (Level U).,
These treatment modalities are recommended only in incapacitating, intractable or life-threatening cases of TD.,,, Given the invasive nature of the procedures and lack of controlled trials, these are not recommended routinely in the treatment of TD. Anesthetists and/or neurologists will be required as part of the treating team.
- Deep-brain stimulation
- Globus pallidus interna is to be the focus
- Some case series and reports have shown >50% long-term improvement of symptoms  (Level U)
Electroconvulsive therapy (ECT)
- Only few case series or retrospective reports (Level U)
- Use in TD purely empirical
- Possibly best used only in patients who otherwise also have indications for ECT
- Small reports have described improvements in tongue movements and oro–bucco–lingual stereotypies in TD ,,
- Absence of controlled trials (Level U)
- [Figure 4] summarizes the management of a patient of TD.
Most drug-induced movement disorders, for example, dystonia and parkinsonism, tend to reverse on cessation of the offending drug. TD is one syndrome that is notorious for its persistence despite discontinuation of the drug. Remission rates from available data range from 0% to 73%. Most studies report rates of around 25% only. A study by Zutshi et al. in patients with TD with follow-up of up to approximately 3 years after DRBA discontinuation reported that only 2% had spontaneous remission and only 13% had remission with specific treatments. Many of the patients are required to continue the DRBAs in order to prevent relapse or worsening of the underlying psychiatric illness. There is some promising data for valbenazine and deutetrabenazine at present. Both KINECT trials showed a great percentage of patients achieving 50% or more reduction in AIMS score at 6 weeks compared to placebo. The trials for deutetrabenazine showed similar results at 12 weeks.,,,, Long-term effects and head-to-head comparisons are yet to be seen.
With limited options for treatment at our disposal and low remission rates even with the available specific interventions, prevention is of great importance. A prudent clinical policy with prevention as the treatment modality is the need of the hour.
A model borrowed from community psychiatry, Gardos and Cole years ago, recognized TD as a public health issue and conceptualized its prevention into primary, secondary, and tertiary levels.
It focuses mainly on addressing the causative factors to prevent the emergence of TD in the first place. Judicious use of antipsychotics and other DRBA is the key. Wherever possible, the agents with relatively lesser risk, such as SGAs, should be preferred, and the dosing should be kept to optimum clinical utility levels. The prescription of multiple antipsychotics increases the cumulative risk of TD and therefore is best avoided whenever possible. Due caution needs to be taken while prescribing DRBAs in high-risk populations, for example, elderly.
Early recognition and early interventions increase the chances of remission. Routine monitoring of patients who are on antipsychotics, especially those with known risk factors, must be done so that the movements are detected as early as possible. The recommended duration for monitoring is every 6 months for first-generation antipsychotics (FGA) and annually for SGA. In case of high-risk patients, frequent monitoring is recommended – every 3 months for FGA and every 6 months for SGA.
The focus of tertiary prevention is on improving the quality of life and minimizing the impact of the movements. If psychiatric status permits, taper and stop the antipsychotic or use at the lowest possible dose. Switching the antipsychotic or the use of other pharmacological options to minimize severity and improve functionality of the patient can also be considered.
Until robust evidence on the newer available treatment modalities gives us a clear choice in the treatment of TD, the principle of “Prevention is better than cure” is the path to follow.
With the false sense of security provided by the decreased risk of TD in SGAs, subtle initial movements in patients are often left out and come to notice only after they are significant and disabling, by when the chances of remission are significantly reduced. In order to ensure early recognition and intervention, it is imperative that the medical fraternity is sensitized and trained in the identification and monitoring of TD with a regular screening protocol in place.,,
Clarity on the etiology of TD is still a work in progress, and there is a definite scope for improving our understanding of the same. This will help us develop better, effective, and more focused treatment strategies. Furthermore, most of the work on TD thus far focuses on the movements and their quantification and monitoring as well as treatment aspects. There is not enough evidence to substantiate the claim of efficacy for agents apart from VMAT2 inhibitors, and the psychological impact of the disorder is less studied. Whether any therapy or behavioral modifications will help reduce the severity or at least help cope with the condition in a better way, especially in those with severe or intractable movements, is yet unexplored.
| Conclusion|| |
TD is very much in existence. It is a physically disabling and socially stigmatizing condition that impacts the patient's quality of life and interferes with treatment adherence. All antipsychotics have a variable risk of TD, with FGAs having a higher risk. Even after the offending drug has been stopped, remission rates are low. We still do not have a clear understanding of the pathophysiology which makes the development of treatment strategies a difficult task. Various medications as well as nonpharmacological strategies have been tried, but most have had limited success and lack concrete evidence. We have new medications in the picture (deutetrabenazine and valbenazine), which bring some hope. Lack of robust evidence in favor of these newer agents and cost of treatments are the limiting factors in the wide adaptation of these in regular clinical practice. Hence, the best strategy available is “prevention.” Judicious use of antipsychotics with lesser risk of TD and at minimal effective doses, avoidance of polypharmacy, awareness of risk factors, regular monitoring for TD using standardized instruments, early recognition of the movements, and timely management will help prevent this difficult-to-treat condition. In our regular practice, all of us need to be aware and alert for the symptoms of TD.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Faurbye A, Rasch PJ, Petersen PB, Brandborg G, Pakkenberg H. Neurological symptoms in pharmacotherapy of psychoses. Acta Psychiatr Scand 1964;40:10-27.
Owens DC. Tardive dyskinesia update: The syndrome. BJPsych Adv 2019;25:57-69.
Carbon M, Kane JM, Leucht S, Correll CU. Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: A meta-analysis. World Psychiatry 2018;17:330-40.
Waln O, Jankovic J. An update on tardive dyskinesia: From phenomenology to treatment. Tremor Other Hyperkinet Mov (N
Y) 2013;3. pii: tre-03-161-4138-1.
Aquino CC, Lang AE. Tardive dyskinesia syndromes: Current concepts. Parkinsonism Relat Disord 2014;20 Suppl 1:S113-7.
American Psychiatric Association. DSM-5 Diagnostic Classification. In: Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association; 2013.
American Psychiatric Association. Mental, Behavioral and Neurodevelopmental Disorders (F01-F99). ICD-10-CM 2017: The Complete Official Codebook. American Psychiatric Association; 2016.
Schooler NR, Kane JM. Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry 1982;39:486-7.
Kalachnik JE. Applied monitoring for tardive dyskinesia and other extrapyramidal side effects. Ment Health Clin 2012;1:159-63.
Caroff SN. Overcoming barriers to effective management of tardive dyskinesia. Neuropsychiatr Dis Treat 2019;15:785-94.
Cornett EM, Novitch M, Kaye AD, Kata V, Kaye AM. Medication-Induced Tardive Dyskinesia: A Review and Update. Ochsner J 2017;17:162-74.
Kane JM, Smith JM. Tardive dyskinesia: Prevalence and risk factors, 1959 to 1979. Arch Gen Psychiatry 1982;39:473-81.
Achalia RM, Chaturvedi SK, Desai G, Rao GN, Prakash O. Prevalence and risk factors associated with tardive dyskinesia among Indian patients with schizophrenia. Asian J Psychiatr 2014;9:31-5.
Doongaji DR, Jeste DV, Jape NM, Sheth AS, Apte JS, Vahia VN, et al
. Tardive dyskinesia in India: A prevalence study. J Clin Psychopharmacol 1982;2:341-4.
Bhatia T, Sabeeha MR, Shriharsh V, Garg K, Segman RH, Uriel HL, et al
. Clinical and familial correlates of tardive dyskinesia in India and Israel. J Postgrad Med 2004;50:167-72.
] [Full text]
Pandurangi AK, Aderibigbe YA. Tardive dyskinesia in non-western countries: A review. Eur Arch Psychiatry Clin Neurosci 1995;246:47-52.
Patterson-Lomba O, Ayyagari R, Carroll B. Risk assessment and prediction of TD incidence in psychiatric patients taking concomitant antipsychotics: A retrospective data analysis. BMC Neurol 2019;19:174.
Browne S, Roe M, Lane A, Gervin M, Morris M, Kinsella A, et al
. Quality of life in schizophrenia: Relationship to sociodemographic factors, symptomatology and tardive dyskinesia. Acta Psychiatr Scand 1996;94:118-24.
Owens DC. Tardive dyskinesia update: Treatment and management. BJPsych Adv 2019;25:78-89.
Lim K, Lam M, Liu J, Lee J. Genome-wide association of tardive dyskinesia. Eur Neuropsychopharmacol 2019;29:S944.
Margolese HC, Chouinard G, Kolivakis TT, Beauclair L, Miller R. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 1: Pathophysiology and mechanisms of induction. Can J Psychiatry 2005;50:541-7.
Margolese HC, Chouinard G, Kolivakis TT, Beauclair L, Miller R, Annable L. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 2: Incidence and management strategies in patients with schizophrenia. Can J Psychiatry 2005;50:703-14.
Niemann N, Jankovic J. Treatment of tardive dyskinesia: A general overview with focus on the vesicular monoamine transporter 2 inhibitors. Drugs 2018;78:525-41.
Frei K. Tardive dyskinesia: Who gets it and why. Parkinsonism Relat Disord 2019;59:151-4.
Miller DD, Caroff SN, Davis SM, Rosenheck RA, McEvoy JP, Saltz BL, et al
. Extrapyramidal side-effects of antipsychotics in a randomised trial. Br J Psychiatry 2008;193:279-88.
Olfson M, Blanco C, Liu SM, Wang S, Correll CU. National trends in the office-based treatment of children, adolescents, and adults with antipsychotics. Arch Gen Psychiatry 2012;69:1247-56.
Gallego JA, Nielsen J, De Hert M, Kane JM, Correll CU. Safety and tolerability of antipsychotic polypharmacy. Expert Opin Drug Saf 2012;11:527-42.
Koller WC. Edentulous orodyskinesia. Ann Neurol 1983;13:97-9.
Fenton WS. Prevalence of spontaneous dyskinesia in schizophrenia. J Clin Psychiatry 2000;61 Suppl 4:10-4.
Pontone GM. Comorbid movement and psychiatric disorders: assessment and treatment. Psychiatric Times 2013;30:35.
Mion CC, Andreasen NC, Arndt S, Swayze VW, Cohen GA. MRI abnormalities in tardive dyskinesia. Psychiatry Res 1991;40:157-66.
Ando K, Takei N, Matsumoto H, Iyo M, Isoda H, Mori N. Neural damage in the lenticular nucleus linked with tardive dyskinesia in schizophrenia: A preliminary study using proton magnetic resonance spectroscopy. Schizophrenia Res 2002;57:273-9.
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rev Rockville Md.: U.S. Dept. of Health Education and Welfare Public Health Service Alcohol Drug Abuse and Mental Health Administration National Institute of Mental Health Psychopharmacology Research Branch; 1976.
Chouinard G, Margolese HC. Manual for the extrapyramidal symptom rating scale (ESRS). Schizophr Res 2005;76:247-65.
Sprague RL, Kalachnik JE. Reliability, validity, and a total score cut off for the dyskinesia identification system: Condensed user scale (DISCUS) with mentally ill and mentally retarded populations. Psychopharmacol Bull 1991;27:51-8.
Simpson GM, Lee JH, Zoubok B, Gardos G. Rating scale for tardive dyskinesia. Psychopharmacology 1979;64:171-9.
Smith RC, Allen R, Gordon J, Wolff J. Rating scale for tardive dyskinesia and Parkinsonian symptoms. Psychopharmacol Bull 1983;19:266-76.
Gervin M, Barnes TR. Assessment of drug-related movement disorders in schizophrenia. Adv Psychiatr Treat 2000;6:332-41.
Bhidayasiri R, Fahn S, Weiner WJ, Gronseth GS, Sullivan KL, Zesiewicz TA, et al
. Evidence-based guideline: Treatment of tardive syndromes: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2013;81:463-9.
Elkurd MT, Bahroo L. Keeping up with the clinical advances: Tardive dyskinesia. CNS Spectr 2019;24:70-81.
Fernandez HH, Factor SA, Hauser RA, Jimenez-Shahed J, Ondo WG, Jarskog LF, et al
. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study. Neurology 2017;88:2003-10.
Anderson KE, Stamler D, Davis MD, Factor SA, Hauser RA, Isojärvi J, et al
. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry 2017;4:595-604.
Hauser RA, Factor SA, Marder SR, Knesevich MA, Ramirez PM, Jimenez R, et al
. KINECT 3: A phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry 2017;174:476-84.
Soares-Weiser K, Maayan N, Bergman H. Vitamin E for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev. 2018;1(1):CD000209. Published 2018 Jan 17. doi:10.1002/14651858.CD000209.pub3.
Li CR, Chung YC, Park TW, Yang JC, Kim KW, Lee KH, et al
. Clozapine-induced tardive dyskinesia in schizophrenic patients taking clozapine as a first-line antipsychotic drug. World J Biol Psychiatry 2009;10 (4 Part 3):919-24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19995222
[Last accessed on 2020 Apr 09].
Traynor K. FDA advisers wary of expanding quetiapine use: Clinicians air concerns about metabolic effects, tardive dyskinesia. Am J Health Syst Pharm 2009;66:880, 882. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19420301
[Last accessed on 2020 Apr 09].
Pardis P, Remington G, Panda R, Lemez M, Agid O. Clozapine and tardive dyskinesia in patients with schizophrenia: A systematic review. J Psychopharmacol (Oxford, England) 2019;33:1187-98. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31347436
[Last accessed on 2020 Apr 05].
Bernstein AI, Stout KA, Miller GW. The vesicular monoamine transporter 2: An underexplored pharmacological target. Neurochem Int 2014;73:89-97. Available from: http://www.ncbi.nlm.nih.gov/pu bmed/24398404
[Last accessed on 2020 Apr 05].
Jankovic J. Dopamine depleters in the treatment of hyperkinetic movement disorders. Expert Opin Pharmacother 2016;17:2461-70.
Caroff SN, Ungvari GS, Cunningham Owens DG. Historical perspectives on tardive dyskinesia. J Neurol Sci 2018;389:4-9.
Seeberger LC, Hauser RA. Valbenazine for the treatment of tardive dyskinesia. Expert Opinion Pharmacother 2017;18:1279-87.
Factor S, Hauser R, Mandri D, Castro-Gayol J, Jimenez R, Siegert S, et al
. A phase 2 study of valbenazine (NBI-98854) for treatment of tardive dyskinesia: KINECT 2. Neurology. 2016;86 (16 Supplement):S27.007.
Touma KTB, Scarff JR. Valbenazine and deutetrabenazine for tardive dyskinesia. Innov Clin Neurosci 2018;15:13-6.
Citrome L. Valbenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication-What is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2017;71:10.1111/ijcp.12964. doi:10.1111/ijcp.12964.
Pouclet-Courtemanche H, Rouaud T, Thobois S, Nguyen JM, Brefel-Courbon C, Chereau I, et al
. Long-term efficacy and tolerability of bilateral pallidal stimulation to treat tardive dyskinesia. Neurology 2016;86:651-9.
Jankovic J. An update on new and unique uses of botulinum toxin in movement disorders. Toxicon 2018;147:84-8.
Morigaki R, Mure H, Kaji R, Nagahiro S, Goto S. Therapeutic perspective on tardive syndrome with special reference to deep brain stimulation. Front Psychiatry 2016;7:207.
Vijayakumar D, Jankovic J. Drug-induced dyskinesia, part 2: Treatment of tardive dyskinesia. Drugs 2016;76:779-87.
Vinuela A, Kang UJ. Reversibility of tardive dyskinesia syndrome. Tremor Other Hyperkinetic Move (New York, NY) 2014;4:282.
Zutshi D, Cloud LJ, Factor SA. Tardive syndromes are rarely reversible after discontinuing dopamine receptor blocking agents: Experience from a university-based movement disorder clinic. Tremor Other Hyperkinet Mov (N
Gardos G, Cole JO. Overview: Public health issues in tardive dyskinesia. Am J Psychiatry 1980;137:776-81.
Marder SR, Essock SM, Miller AL, Buchanan RW, Casey DE, Davis JM, et al
. Physical health monitoring of patients with schizophrenia. Am J Psychiatry 2004;161:1334-49.
Kalachnik JE, Sprague RL, Slaw KM. Training clinical personnel to assess for tardive dyskinesia. Prog Neuropsychopharmacol Biol Psychiatry 1988;12:749-62.
Barnes TR, Trauer T. Reliability and validity of a tardive dyskinesia videotape rating technique. Br J Psychiatry 1982;140:508-15.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]