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Kaplan-Meier curves of time to TD diagnosis. Estimated TD incidence rate within 7 years after antipsychotic drug initiation were stratified by index psychiatric disorder diagnosis. TD, tardive dyskinesia
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Abstract Background Tardive dyskinesia (TD) is a serious, often irreversible movement disorder caused by prolonged exposure to antipsychotics; identifying patients at risk for TD is critical to preventing it. Predictive models for the occurrence of TD can improve patient monitoring and inform implementation of counteractive interventions. This stud...
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Purpose of Review
Tardive dyskinesia (TD) is caused by exposure to medications with dopamine antagonism, mainly antipsychotics. It often distresses individuals, physically and emotionally and affects their quality of life. We evaluated peer-reviewed recently published articles with a goal of providing a critically appraised update on the latest adv...
![Figure 1. Management Scheme of Tardive Dyskinesia [45,53]](profile/Marianto-Marianto/publication/354828125/figure/fig1/AS:1071823655534593@1632554081565/Management-Scheme-of-Tardive-Dyskinesia-45-53_Q320.jpg)
![Risk Factors for TD [13,15,21]](profile/Marianto-Marianto/publication/354828125/figure/tbl1/AS:1071823655555073@1632554081591/Risk-Factors-for-TD-13-15-21_Q320.jpg)
![Differences between Drug-Induced Parkinsonism and Tardive Dyskinesia [41]](profile/Marianto-Marianto/publication/354828125/figure/tbl2/AS:1071823655559168@1632554081610/Differences-between-Drug-Induced-Parkinsonism-and-Tardive-Dyskinesia-41_Q320.jpg)
Drug-induced movement disorders could be classified into acute, subacute, and chronic based on the time of occurrence. Tardive dyskinesia (TD) is one of the most frequent long-term drug-induced movement disorders. Delay in treatment often caused TD to be irreversible. In this review, we will discuss TD in-depth to enhance clinician knowledge regard...
Citations
... It has been demonstrated that the risk of TD is elevated in older patients relative to younger patients (Sajatovic et al., 2022). This finding is consistent with the epidemiologic profile of TD, and previous studies have shown that female sex and advanced age are risk factors for TD (Solmi et al., 2018;Patterson-Lomba et al., 2019;Saklad, 2020). The metabolism and excretion of drugs are slowed in elderly patients, resulting in the accumulation of the drug in the body and an increased risk of adverse events (Akinosoglou et al., 2023). ...
Background
Deutetrabenazine is a widely used drug for the treatment of tardive dyskinesia (TD), and post-marketing testing is important. There is a lack of real-world, large-sample safety studies of deutetrabenazine. In this study, a pharmacovigilance analysis of deutetrabenazine was performed based on the FDA Adverse Event Reporting System (FAERS) database to evaluate its relevant safety signals for clinical reference.
Methods
Adverse events (AEs) of FAERS with deutetrabenazine as the primary suspect drug were collected from the first quarter (Q1) of 2017 to Q1 of 2024. Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) were used to mine AEs risk signals of deutetrabenazine. AEs were standardized and classified using the System Organ Class (SOC) and Preferred Terms (PTs) from Medical Dictionary for Regulatory Activities (MedDRA) version 23.0.
Results
A total of 3,583 AEs with deutetrabenazine as the primary suspect drug were collected in this study. We found that these AEs involved 23 SOCs, and the positive signals were mainly concentrated in systemic disease and various reactions at the site of administration (n = 1816, ROR = 1.23, PRR = 1.18, IC = 0.24, EBGM = 1.18), neurological disorders (n = 1736, ROR = 3.02, PRR = 2.60, IC = 1.38, EBGM = 2.60) and psychiatric disorders (n = 1,659, ROR = 4.15, PRR = 3.52, IC = 1.82, EBGM = 3.52). We eventually identified 100 valid PTs that met the criteria of the four algorithms. Drug ineffective, dyskinesia, depression, somnolence, suicidal ideation were considered to be the common PTs of deutetrabenazine. Tongue thrust (n = 4, ROR 253.47, PRR 253.35, IC 7.88, EBGM 235.95), grunting (n = 5, ROR 78.49, PRR 78.45, IC 6.26, EBGM 76.71) and drooling (n = 17, ROR 13.21, PRR 13.19, IC 3.72, EBGM 13.14) were not mentioned in the specification, but the high signal intensity suggested that they may be the potential adverse reactions.
Conclusion
The efficacy of deutetrabenazine may be accompanied by some potential adverse effects in several systems. Adverse events in psychiatric, neurologic, gastrointestinal and respiratory need to be monitored in clinical practice.
... First-generation antipsychotics are more likely to cause NMS than second-generation antipsychotics [13]. Neuroleptic malignant syndrome is a rare, but potentially life-threatening adverse event associated with the use In this life-threatening manifestation of NMS, the patient presents with "leadpipe" muscle rigidity, autonomous instability, hyperpyrexia of more than 40 degrees Celsius, altered mental status, leucocytosis, and elevated serum creatinine kinase [18,19]. ...
A male in his early 20's presented to the ED of a district hospital within the West Midlands following an intentional mixed overdose of prescribed medications; Citalopram, Chlorpromazine, and Diazepam. Following ingestion of an unknown quantity of these medications at around 2 PM, he was found an hour later in an unresponsive state by family members. The patient reported a separation from their partner preceding the event and had a history of PTSD and extreme anxiety.
... 2,3 Several risk factors for TD have been identified, including older age, female gender, longer use of antipsychotics, higher dosages of antipsychotics, a history of extrapyramidal symptoms (EPSs), and the use of first-generation antipsychotics (FGAs). [4][5][6][7][8][9][10] Although the risk of TD with second-generation antipsychotics (SGAs) is lower compared with FGAs, 11 it still exsists. 12 In addition, polypharmacy, or the use of more than two antipsychotics over a prolonged period, increases the risk of TD and EPS due to higher dosages and use of anticholinergic drugs. ...
... 12 In addition, polypharmacy, or the use of more than two antipsychotics over a prolonged period, increases the risk of TD and EPS due to higher dosages and use of anticholinergic drugs. 13 Furthermore, patients with mood disorders who receive antipsychotics are at increased risk for TD 7,14 and up to half of patients with bipolar disorder receive antipsychotics. 15 However, there is limited evidence about TD in Japan. ...
Aim The aim of this study is to summarize the spontaneous reports of tardive dyskinesia (TD) and extrapyramidal symptoms (EPSs) that occurred in Japan over the past decade.
Methods The study analyzed TD and EPS cases reported in the Japanese Adverse Drug Event Report database between April 2011 and March 2021. The cases were stratified by the diagnoses of schizophrenia, bipolar disorders, and depressive disorders.
Results In total, 800 patients including a total of 171 TD cases and 682 EPS cases were reported in the JADER database across psychiatric diagnosis. The cases were caused by first‐generation antipsychotics (FGA, TD: n = 105, EPS: n = 245) and second‐generation antipsychotics (SGA, TD: n = 144, EPS: n = 598). The SGA were categorized based on Neuroscience‐based Nomenclature (NbN) regarding pharmacological domain and mode of action, which were reported evenly as the offending agents. Among reported treatment and outcome in TD cases ( n = 67, 37.6%) and EPS cases ( n = 405, 59.3%), the relatively limited number of TD cases were reported as recovered/improved was also limited ( n = 32, 47.8%) compared to those of EPS cases ( n = 266, 65.7%). Some cases still had residual symptoms or did not recover fully (TD: n = 21, 31.3%, EPS: n = 77, 19.0%).
Conclusion
Tardive dyskinesia and EPS have been widely reported in Japan over the past decade across psychiatric diagnoses and antipsychotic classes.
Limitations
It is important to acknowledge the presence of reporting bias and the lack of comparators to accurately assess risks. Owing to the nature of spontaneous reporting, the estimation of prevalence is not feasible.
... 66,67 For the majority of pharmacological treatments, higher doses tend to increase the risk of most adverse drug reactions; 68 this is also reported to be the case with antipsychotics. 46,69 Interestingly, a recent retrospective data analysis reported an increased risk of TD with a dose equivalent to ⩽ 100 mg/day chlorpromazine but not with a dose equivalent to > 100 mg/day; 70 this could be attributed to the increased dose of antipsychotic masking the symptoms of TD. 46 Diabetes mellitus has been suggested as an independent risk factor for TD, [70][71][72] although other studies have failed to corroborate this association. 61,73,74 The link between diabetes and TD is influenced by certain treatments for symptoms of diabetes, which are known to increase the risk of TD (e.g. ...
Tardive dyskinesia (TD) is a movement disorder that can develop with the use of dopamine receptor-blocking agents and is most commonly caused by antipsychotics. The use of antipsychotics is expanding, which may lead to an increased number of patients experiencing TD. To summarise the current knowledge of the epidemiology and risk factors for TD in Japan, we reviewed articles related to the current state of knowledge around TD identified through a PubMed search, and held a roundtable discussion of experts in Japan on 9 September 2021 to form the basis of the opinion presented within this review. The true prevalence of TD among patients treated with antipsychotics is not well characterised; it is reported to be between 15% and 50% globally and between 6.5% and 7.7% in Japan. Potential barriers to timely treatment of TD include the stigma surrounding mental health issues and the lack of data regarding TD in Asian patients. This review summarises the current knowledge of the epidemiology, challenges to TD diagnosis and risk factors for TD in Japan. Recent strategies for symptom monitoring and early diagnosis, as well as consensus recommendations are included. Achieving a high level of awareness of TD among physicians who treat patients with psychiatric disorders is of great importance and physicians should ensure that patients with psychiatric disorders receiving antipsychotics are proactively monitored for signs of TD.
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Visual Summary ( In Japanese )
... Advancing age is the strongest predictor of TD, such that antipsychotics should be prescribed cautiously in people 45 years or older. [44][45][46][47][48] The incidence and prevalence of TD among older adults may reach 15% to 30% annually and 50% to 60%, respectively. 44,49 Sex, race, and ethnicity are less consistent risk factors as contrasting prescribing practices affecting demographic groups may be one of many confounding variables. ...
... 44,49 Sex, race, and ethnicity are less consistent risk factors as contrasting prescribing practices affecting demographic groups may be one of many confounding variables. [45][46][47][50][51][52][53] Schizophrenia, which like aging predisposes to spontaneous dyskinesias, 7,54-58 confers a high risk of TD. Severity of positive, negative, and cognitive symptoms has been associated independently with TD, 45,46,59 although confounded by higher dosing and longer use of potent agents with frequent noncompliance in patients with more severe symptoms of chronic schizophrenia. ...
... [60][61][62] But more women and older patients with depression who receive intermittent treatment with antipsychotics during episodic relapses may confound the association with mood disorders. 6,46,47,62,63 TD is associated with medical co-morbidities as well. 58 In particular, diabetes has been implicated in increasing the risk of TD in some but not all studies. ...
Tardive dyskinesia (TD) is a heterogeneous, hyperkinetic movement disorder induced by dopamine-receptor blocking agents that presents a unique challenge in the treatment of psychosis. Although acceptance of TD as a serious consequence of antipsychotic treatment was resisted initially, subsequent research by many investigators in psychopharmacology contributed to a rich store of knowledge on many aspects of the disorder. While basic neuroscience investigations continue to deepen our understanding of underlying motor circuitry, past trials of potential treatments of TD focusing on a range of theoretical targets were often inconclusive. Development of newer antipsychotics promised to reduce the risk of TD compared to older drugs, but their improved tolerability unexpectedly enabled an expanding market that paradoxically both increased the absolute number of patients at risk and diminished attention to TD which was relegated to legacy status. Fortunately, development and approval of novel vesicular monoamine transporter inhibitors offered evidence-based symptomatic treatment of TD for the first time and rekindled interest in the disorder. Despite recent progress, many questions remain for future research including the mechanisms underlying TD, genetic predisposition, phenomenological diversity, whether new cases are reversible, how to implement best practices to prevent and treat TD, and whether the development of novel antipsychotics free of the risk of TD is attainable. We owe our patients the aspirational goal of striving for zero prevalence of persistent symptoms of TD in anyone treated for psychosis.
... 17 Similarly, patients with BD-I subtype are more likely to use antipsychotics as antimanic mood stabilizers, especially in the presence of psychotic features. 1,11,18 In this line, although not significant, history of psychosis was more common in TD+ participants, which might suggest an increased exposure to antipsychotics. Although less consistently reported, female sex has been associated with more frequent and more severe TD. 19 Although African ancestry has been reported as a risk factor for TD, we did not find a significant difference in TD by ancestry. ...
... Given the small sample size, deeper assessments of genetic risk for TD+, such as DRD2 polymorphisms, were not conducted nor were analysis of nonmodifiable environmental risk factors. 20 Antipsychotic dosage, in addition to class, has been associated with a significant increase in risk of TD. 18,19 A retrospective data analysis in a large cohort of US psychiatric patients (n = 189,415) reported an overall average daily dose of antipsychotic, converted to HALeq, of 4.2 ± 3.8 mg in BD (n = 66,723) and 5.6 ± 4.6 mg in TD+ BD (n = 381; 24.2%). 18 The mean antipsychotic dose reported in our TD+ cohort (5.96 ± 3.5 mg) is similar to the larger cohort TD+ group. ...
... 20 Antipsychotic dosage, in addition to class, has been associated with a significant increase in risk of TD. 18,19 A retrospective data analysis in a large cohort of US psychiatric patients (n = 189,415) reported an overall average daily dose of antipsychotic, converted to HALeq, of 4.2 ± 3.8 mg in BD (n = 66,723) and 5.6 ± 4.6 mg in TD+ BD (n = 381; 24.2%). 18 The mean antipsychotic dose reported in our TD+ cohort (5.96 ± 3.5 mg) is similar to the larger cohort TD+ group. For instance, a previous study assessing antipsychotic use patterns in an inpatient BD cohort (n = 139) from South Korea, reported an overall HALeq dose of more than 13 mg 2 . ...
Purpose:
Recognizing the negative impact that antipsychotic-induced movement disorders have on the quality of life and treatment outcomes in bipolar disorder (BD), this study aimed to assess clinical correlates and antipsychotic use patterns of tardive dyskinesia (TD+) in BD.
Materials and methods:
Participants with and without TD were included. Clinical variables were compared using t-test and χ2 test. Antipsychotic use patterns in TD+, including number of trials, mean doses, and estimated cumulative exposure, were assessed in a case-only analysis.
Results:
The prevalence rate of TD was 5.1%. In comparison to the TD- group (n = 1074), TD+ participants (n = 58) were older, more likely to be female and have type I bipolar illness. There were 60.3% of the TD+ group that continued using antipsychotics at study entry and had a mean cumulative exposure to antipsychotics of 18.2 ± 15.6 years. Average dose, in haloperidol equivalents, was 5.9 ± 3.5 mg and 77.7% of the trials were second-generation antipsychotics.
Conclusions:
This study confirms previously identified TD risk factors, such as age, sex, and bipolar subtype in a large BD cohort. Limitations included a cross-sectional design and the lack of tardive illness severity assessment. As atypical antipsychotics continue to be primary mood stabilization treatment, attempting to harmonize large data sets to identify additional biomarkers of tardive risk will optimize individualized care for patients with BD.
... The results are conflicting regarding the impact of duration and the dosage of the antipsychotic therapy on TD risk. A retrospective study suggested that the dose of antipsychotics was associated with high TD risk in patients with schizophrenia (Patterson-Lomba et al., 2019). In contrast, a meta-analysis of 26 studies (Takeuchi et al., 2020) and a review of 13 RCTs (Bergman et al., 2018) did not confirm this association. ...
Tardive dyskinesia is a severe motor adverse event of antipsychotic medication, characterized by involuntary athetoid movements of the trunk, limbs, and/or orofacial areas. It affects two to ten patients under long-term administration of antipsychotics that do not subside for years even after the drug is stopped. Dopamine, serotonin, cannabinoid receptors, oxidative stress, plasticity factors, signaling cascades, as well as CYP isoenzymes and transporters have been associated with tardive dyskinesia (TD) occurrence in terms of genetic variability and metabolic capacity. Besides the factors related to the drug and the dose and patients’ clinical characteristics, a very crucial variable of TD development is individual susceptibility and genetic predisposition. This review summarizes the studies in experimental animal models and clinical studies focusing on the impact of genetic variations on TD occurrence. We identified eight genes emerging from preclinical findings that also reached statistical significance in at least one clinical study. The results of clinical studies are often conflicting and non-conclusive enough to support implementation in clinical practice.
... Other risk factors include the dopamine-receptor binding affinity of the DRBA in question, female sex, mood disorders, dementia, and prior drug-induced parkinsonism. 4,[30][31][32][33] Smoking and substance abuse may also be associated with a higher risk of developing TD. 33 ...
... As noted, age is a key risk factor for developing TD. 31,34 A study of 404 people aged ≥55 years reported cumulative TD incidences of 26%, 30%, and 60% after the first, second, and third year, respectively, of first-generation AP use. 35 This is considerably higher than that observed in younger people; a meta-analysis of 32 randomized studies that included 10,706 subjects of mixed ages calculated an annualized TD incidence of 6.5% with the use of first-generation APs. ...
Tardive dyskinesia (TD) is a hyperkinetic movement disorder caused by the use of dopamine receptor-blocking agents (DRBAs), a category of medications that includes first- and second-generation antipsychotics (APs) and agents such as metoclopramide that are used for the treatment of nausea and gastrointestinal dysmotility. While TD can affect people of all ages, older age is associated with increased risk of TD and also with the emergence of TD occurring after shorter treatment durations and lower dosages of DRBAs. TD is characterized by involuntary movements that include the face, limbs, and trunk, and is associated with increased comorbidities, social stigmatization, and impaired physical and mental health. Once present, TD tends to persist despite AP dose adjustment or discontinuation. Even with the use of US Food and Drug Administration (FDA)-approved medications for TD, symptoms may persist. Because the leading hypothesis for the pathophysiology of TD has been dysregulation of dopamine transmission due to treatment with DRBAs, APs that avoid postsynaptic dopamine receptor blockade may provide an alternative therapeutic approach for patients who require an AP. In this review, we discuss the risks, burdens, prevention, and management of TD, with a focus on older people.
... [2] It can also be physically disabling, embarrassing, and socially stigmatizing, leading to social alienation, depression, and suicide. [10,17] It can worsen the stigma that patients with mental illness often experience and interferes with treatment adherence. [17] TD has been shown to be associated with poorer quality of life. ...
... [10,17] It can worsen the stigma that patients with mental illness often experience and interferes with treatment adherence. [17] TD has been shown to be associated with poorer quality of life. [18] pathophysiology The cause of these movements has been the subject of debate and a stimulus for continuing research. ...
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.
... Characteristics that have been associated with a higher risk for TD include older age, female sex (with a possible interaction between age and sex), white or black/African-American race, longer illness duration, cognitive disability, schizophrenia or mood disorder diagnosis, treatment with FGAs or SGAs, and longer duration of antipsychotic use. 32 Although higher antipsychotic dosages and FGA use have also been associated with TD, 33 it may be problematic to conclude that patients who take lower doses of adjunctive SGAs (eg, for major depressive disorder) have a lower risk of TD because mood disorders are a risk factor 32 and overall use of SGAs continues to increase. Consistent with some of these risk factors, cohort 2 patients were statistically significantly older than cohort 1 patients and had a longer lifetime exposure to antipsychotics. ...
Purpose/background:
RE-KINECT (NCT03062033) was designed to assess the presence and impact of possible tardive dyskinesia (TD) in antipsychotic-treated outpatients.
Methods/procedures:
The study included adults with 3 or more months of lifetime antipsychotic exposure and 1 or more psychiatric disorder. Based on clinician observation and assessment, patients were assigned to cohort 1 (without involuntary movements or with non-TD involuntary movements) or cohort 2 (with involuntary movements confirmed by clinician as possible TD). Baseline assessments included the following: patient characteristics; location/severity of involuntary movements; and impact of possible TD on health-related quality of life, including the EuroQoL 5-Dimensions 5-Level questionnaire.
Findings/results:
Of 739 eligible patients, 204 (27.6%) had clinician-confirmed possible TD (cohort 2). Compared with cohort 1, patients in cohort 2 were significantly older (P < 0.0001), more likely to have schizophrenia or schizoaffective disorder (P < 0.0001) and longer lifetime exposure to antipsychotics (P < 0.0001), and less likely to be working or studying, based on clinician perception (P = 0.0010). Clinician- and patient-rated severity of possible TD movements was significantly correlated in each of 4 body regions (head/face, neck/trunk, upper extremities, lower extremities), for maximum severity in any region, and for total number of affected regions (P < 0.001 for all correlations). For the patient-rated EuroQoL 5-Dimensions 5-Level, the health state visual analog scale score was significantly lower (worse) in cohort 2 versus cohort 1 (66.8 vs 69.7; P = 0.0002), as was the utility index score (0.71 vs 0.76; P < 0.0175).
Implications/conclusions:
Results from this real-world population indicate that TD occurs frequently and can significantly reduce quality of life in patients with a psychiatric disorder.
