Valbenazine-associated acute extrapyramidal symptoms during treatment of tardive dyskinesia: A case series

Tardive dyskinesia (TD) is a potentially irreversible movement disorder that emerges in a proportion of schizophrenia patients who are prescribed antipsychotic medications. These movements affect mostly the orofacial regions, but may also affect the limbs and other body areas, resulting in significant functional impairment and decreased quality of life. While uncertainty about the pathophysiology of TD persists, studies on families support a genetic component. Over the years, a number of genes have emerged as potential candidates for TD, but evidence supporting their involvements remain inconclusive. Here, we performed a literature search for articles related to genetics of TD from 2015 to 2025 on PubMed and Scopus and reviewed the progress in TD genetic research over the past decade.

Tardive dyskinesia (TD) is a common, often underrecognized movement disorder resulting from long-term antipsychotic use, yet its detection in routine mental health care remains inconsistent despite the availability of structured rating scales. This study evaluated the performance of an artificial intelligence-powered, video-based model for detecting abnormal movements associated with TD using the Clinician's Tardive Inventory (CTI) dataset. We compare automated assessments of videos from the CTI dataset with previously completed clinician-rated Abnormal Involuntary Movement Scale (AIMS) and CTI scores for the dataset's videos to determine the model's reliability and the accuracy of its assessment conclusions relative to expert raters. In total, 69 videos with corresponding AIMS and CTI ratings were analyzed using the visual transformer algorithm model called TDtect reported previously. The dataset included single-video assessments per participant, with varied instructions and movement types. The relationship between automated predictions and clinician ratings was assessed using Pearson correlation, and predictive accuracy was evaluated using area under the curve (AUC) metrics. The model showed a strong correlation with AIMS total scores (r=0.717) and high diagnostic accuracy (AUC 0.854), which improved further at an optimized threshold (AUC 0.900). Performance differed across anatomical regions, with the tongue, lips, and jaw displaying the highest predictive reliability. Functional CTI components had weaker correlations (r=0.27-0.63), as expected due to the subjective nature of these measures. These findings provide preliminary evidence that an artificial intelligence-driven TD detection model can generalize across video protocols, suggesting potential for broader clinical applicability, although further validation is needed. Future refinements and fine-tuning are expected to enhance accuracy, particularly in predicting functional impact.

Lumateperone, a novel atypical antipsychotic, has emerged as an illuminating hope for patients with schizophrenia and bipolar disorder. While prior studies have employed spontaneous reporting databases and identified over 100 novel adverse events associated with lumateperone, the differences in these adverse events across subgroups remain unclear. This study provides a comprehensive evaluation of the adverse event profile of lumateperone using the Food and Drug Administration Adverse Event Reporting System database, focusing on the potential differences in reporting adverse events across subgroups. Based on the results of clinical characteristics and signal detection, the potential differences in reporting lumateperone-associated adverse events across specific subgroups regarding report year, reporter type, sex, age, outcome, indication, and concomitant drug were analyzed using the ROR algorithm and Fisher's exact test with Bonferroni correction. The observed differences were further validated using sensitivity analyses, stratified analyses, and comparative analyses. This study identified 1762 reports and 5074 adverse events associated with lumateperone. Notably, females had a higher frequency of reporting nervous system disorders. Tardive dyskinesia was more frequently resulted in serious consequences. Moreover, bipolar disorder patients more frequently reported nervous system disorders, while schizophrenia patients more frequently reported psychiatric disorders. This study underscores the need for future confirmatory studies into the potential sex, outcome and indication differences in adverse events associated with lumateperone. The findings should be considered preliminary and require further validation.

BackgroundNeurological presentations of pediatric intussusception lead to delayed diagnosis, higher rates of surgical intervention, and worse outcomes compared with classic presentations. These atypical manifestations, including lethargy, altered mental status, and rarely movement disorders, may predominate and redirect evaluation toward primary neurological etiologies, delaying recognition of this reversible surgical emergency.Case PresentationA previously healthy 2-year-old boy presented with clustered orofacial dyskinesias and irregular upper-extremity jerks without exposure to dopamine-receptor antagonists. He was initially misdiagnosed with tardive dyskinesia and treated with biperiden without improvement. Neurologic examination and brain magnetic resonance imaging were normal. During observation, he developed bilious vomiting. Abdominal imaging revealed ileocolic intussusception. Pneumatic reduction was unsuccessful, and surgical exploration demonstrated an invaginated Meckel diverticulum with ischemic bowel requiring resection. Abnormal movements resolved completely following surgery.MethodsWe conducted a systematic case-based review of published pediatric cases of intussusception presenting with neurological manifestations.ResultsNeurological symptoms-most commonly lethargy and altered mental status-frequently dominated the initial presentation and contributed to significant diagnostic delay (median 12 hours vs 5 hours in classic presentations, P < 0.001). Critically, patients with neurological presentations required surgical intervention in 60% of cases compared with 18% of classic presentations (P < 0.001), with approximately one-quarter of surgical patients requiring bowel resection, reflecting more advanced disease at diagnosis.ConclusionIntussusception should be considered in infants and young children with unexplained acute neurological symptoms, particularly when initial neurologic evaluation is unrevealing. Early abdominal imaging may prevent diagnostic delay in this reversible surgical emergency.

Drug-induced acute dystonia is an adverse drug reaction that is concerning in pediatric patients but resolves rapidly with appropriate treatment. In children, data on risky drugs, clinical patterns, and the management of dystonia in the emergency department are limited. This study aimed to evaluate the demographic and clinical findings and treatment outcomes of children presenting to the pediatric emergency department with drug-induced acute dystonia. This retrospective observational study includes children aged 1 month to 18 years who were diagnosed with acute dystonia in a tertiary pediatric emergency department between October 2022 and March 2025. The diagnosis was made by a pediatric emergency subspecialist based on clinical findings. Patients were classified according to clinical phenotype as focal/segmental dystonia (group I) and multifocal/generalized dystonia (group II). Demographic data, drug exposures, clinical characteristics, and treatment responses were analyzed. A total of 79 patients were included in the study. The median age was 11 years (IQR: 7 to 16) in group I and 10 years (IQR: 6 to 16) in group II. The most commonly associated drug groups were antipsychotics (55.6%), antiemetics (26.6%), and psychostimulants (20.3%). Focal dystonia is the most common clinical pattern, affecting the head and neck muscles in 61% of cases. The use of metoclopramide was significantly higher in group I (OR: 0.21; 95% CI: 0.04-0.99). All patients were treated with parenteral biperiden. Antipsychotics and antiemetics are the main triggers of drug-induced acute dystonia in children. Dystonia usually appears within the first 72 hours after starting the drug. It can develop even at therapeutic doses. Dystonias associated with antiemetic drugs often show focal or segmental distribution. Parenteral biperiden is a fast and effective treatment option. Acute dystonia can mimic serious etiologies in the emergency department. Obtaining a detailed drug history can facilitate the diagnostic process.

Measuring What Matters: Further Validation for the Tardive Dyskinesia Impact Scale, a Novel Patient-Reported Outcome Measure in Valbenazine Clinical Trials.

Efficacy and safety of different pharmacological interventions in the treatment of tardive dyskinesia: a systematic review and network meta-analysis.

Dystonia is a movement disorder (MD), which is the third most common MD after Parkinson's disease and essential tremor. Although drugs are one of the main risk factors for dystonia, they are often not fully recognized. This study aims to identify drugs related to dystonia and explore the potential molecular mechanism of drug-induced dystonia. We used disproportionality analysis to analyze the data of the FDA Adverse Event Reporting System (FAERS) to identify risk drugs associated with dystonia. The molecular target information of these drugs comes from the DrugBank database. In order to explore the causal relationship, we integrated proteomics data from deCODE research and the UK Biobank Pharma Proteomics Project with the genome-wide association study data from FinnGen to carry out proteome-wide Mendelian randomization (MR) analysis. The application of Bayesian colocalization analysis enhances the reliability of causal inference. In addition, we have built a protein-protein interaction (PPI) network to examine the relationship between dystonia-related proteins and drug target genes. We found that in the reports of 18,286 cases of dystonia, 84 drugs showed continuous positive pharmacovigilance signals. The top 30 drugs are mainly antipsychotics and antidepressants. Metoclopramide has the strongest correlation, followed by prochlorperazine, haloperidol, and ziprasidone. MR and colocalization analysis identified 58 proteins related to susceptibility to dys-tonia, of which 6 were verified in different cohorts. PPI analysis revealed that 21 dystonia-related genes interacted with 22 drug target genes, which are enriched in neuronal signaling pathways, metabolic regulation, and xenobiotic metabolism. This integrated framework transcends traditional pharmacovigilance because it combines real-world drug safety data with causal inference of proteogenomics. For the first time, we have constructed a proteogenomic map of drug-induced dystonia. Starting from the drug-disease relationship, we deeply explored the causal mechanisms, such as dopamine-cholinergic imbalance, thus providing mechanism-level insights for drug-induced susceptibility. Our study highlights risk drugs for dystonia and their molecular mechanisms and provides evidence for the safer and more individualized use of antipsychotics, antidepressants, and other drugs related to dystonia.

Adjunctive cerebellar anodal transcranial direct current stimulation for tardive dyskinesia in patients with SchIzophrenia: An open-label pilot study.

Tardive dyskinesia and cognitive performances in late-life depression: a sex-stratified analysis.

Drug-induced dystonia is a serious, potentially disabling adverse event (AE) associated with certain medications. Despite its clinical relevance, the existing literature is largely limited to case reports or analyses of individual drugs, and a systematic evaluation of medications implicated in dystonia remains lacking. This study undertook one of the first comprehensive screenings and risk signal rankings of drugs linked to dystonia using data from the FDA adverse event reporting system (FAERS), aiming to inform clinical drug safety. Reports of dystonia-related AEs from Q1 2004 to Q3 2024 were retrieved from FAERS using standardized MedDRA queries. Disproportionality analyses were conducted using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) methods to identify potential drug-dystonia signals. The Kaplan-Meier method was applied to assess the time to dystonia onset after drug exposure. Sensitivity analyses using the Ω shrinkage estimator were performed to explore potential drug-drug interactions. A total of 27,618 patients with 28,938 dystonia reports were included. Metoclopramide (7178 reports) and aripiprazole (1595 reports) were most frequently reported. Among the top 50 drugs, metoclopramide showed the strongest disproportionality signal, followed by prochlorperazine and haloperidol. Notably, dystonia was not listed in the package inserts of eight identified drugs, including certain antiepileptics, antidepressants, and antiparkinsonian agents. Most events occurred within 0-30 days of drug initiation. The combination of aripiprazole and risperidone was frequently reported and showed notable interaction signals. Metoclopramide and several antipsychotics were strongly associated with reported drug-induced dystonia. These findings highlight the need for cautious prescribing and close monitoring, particularly with antipsychotic combinations, and may support improved risk awareness and labeling.

The clinical evidence for antipsychotic (AP) therapeutic drug monitoring (TDM) in evaluating AP-related movement disorders and cardiometabolic side-effects remains inconsistent. This study evaluates how AP plasma concentrations associate with movement disorders and cardiometabolic side-effects over time, and compares its predictive value to prescription dose in first-episode psychosis (FEP) patients. We included 200 remitted FEP patients from the HAMLETT trial. AP plasma concentrations were standardized using robust z-scores to accommodate different AP types. The St. Hans Rating Scale and Barnes Akathisia Rating Scale assessed movement disorders. Cardiometabolic indices included body mass index, waist circumference, blood pressure, glucose, triglycerides, and cholesterol. We evaluated longitudinal associations between plasma concentrations, movement disorders and cardiometabolic side-effects using two-part and linear mixed-effects models, and compared its predictive value to prescription dose using Bayesian Information Criterion (ΔBIC). Over a median 6-month follow-up (range = 0-48), AP plasma concentrations were positively associated with odds for parkinsonism (OR = 1.81, 95 % CI 1.27, 2.57, p = 0.001). No associations were found with tardive dyskinesia, akathisia, tardive dystonia, or cardiometabolic indices. AP plasma concentrations predicted parkinsonism better than prescription dose (ΔBIC = -2.95), but showed lower predictive value for waist circumference (ΔBIC = 3.22), total cholesterol (ΔBIC = 3.70), low-density-lipoprotein cholesterol (ΔBIC = 2.14) and non-high-density-lipoprotein cholesterol (ΔBIC = 5.46). These findings suggest that in remitted FEP patients, AP TDM may be more useful than dose in evaluating parkinsonism, likely because plasma concentrations more closely reflect free drugs at striatal dopamine receptors, but it does not appear useful for cardiometabolic side-effects.

The American Society of Clinical Psychopharmacology convened a 45-member international expert task force to identify circumstances supporting the deprescribing of core psychotropic medications for major depressive disorder (MDD) and bipolar disorders. Three Delphi survey rounds plus a selective literature review identified points of consensus (predefined as ≥75% agreement) about when antidepressant, antipsychotic, mood stabiliser and sedative-hypnotic deprescribing is warranted. Twenty out of 32 statements (63%) achieved consensus across seven thematic areas. In MDD, panellists favoured discontinuing antidepressants when mechanisms of action are duplicative, adequate trials produce ≤25% improvement or loss of prior efficacy cannot be regained through dose increases or augmentations. Indefinite antidepressant maintenance in MDD was favoured after three or more lifetime episodes. In bipolar disorder, antidepressant deprescribing was favoured in the setting of rapid cycling, mixed features or emerging mania/hypomania symptoms; and discouraged if prior antidepressant cessation led to relapse. In nonpsychotic mood disorders, panellists favoured deprescribing antipsychotics that caused significant weight gain or tardive dyskinesia over adding pharmacological antidotes. Deprescribing to achieve an eventual medication-free status was considered inappropriate, in bipolar type 1, but not necessarily bipolar type 2 disorder. Although individualised circumstances necessarily inform psychopharmacology management, clinical presentations that misalign with existing pharmacotherapies may signal the desirability of cautious deprescribing.

Background: Tardive dyskinesia is a debilitating hyperkinetic movement disorder characterized by repetitive involuntary movements involving the orofacial musculature. The disorder most commonly arises following exposure to dopamine receptor–blocking medications and reflects dysfunction within cortico-basal ganglia-thalamocortical motor circuits¹. Structural brain lesions may further destabilize motor network function and contribute to abnormal movement patterns. Cerebral arteriovenous malformations (AVMs) are congenital vascular anomalies that typically present with intracranial hemorrhage, seizures, headaches, or progressive neurological deficits². Movement disorders associated with AVMs are rare. Case Description: We report a case of severe refractory oro-buccal dyskinesia in a patient with a cerebral AVM and seizure disorder. Neuroimaging demonstrated a left posterior temporal arteriovenous malformation located near the temporoparietal junction. Despite withdrawal of the offending medication and trials of tetrabenazine and botulinum toxin injections, the dyskinesia persisted. The patient underwent microsurgical AVM excision, which resulted in angiographic cure and seizure control but did not resolve the abnormal movements. Because of persistent disabling dyskinesia, the patient subsequently underwent bilateral globus pallidus internus deep brain stimulation (GPi-DBS). Intraoperative microelectrode recordings confirmed appropriate pallidal neuronal activity. An implantable pulse generator was implanted during the same procedure and stimulation was activated immediately in the recovery period, resulting in rapid suppression of dyskinetic movements. Conclusion: This case highlights the complex interaction between structural cerebrovascular pathology and dysfunctional basal ganglia circuitry. Successful treatment required a staged neurosurgical strategy combining vascular and functional neurosurgery. Immediate activation of pallidal stimulation produced dramatic clinical improvement and demonstrates the therapeutic role of neuromodulation in refractory dyskinetic disorders.

Drug-induced dystonia and dyskinesia are associated with increased all-cause mortality, with limited data on cause-specific mortality. We aim to confirm mortality risk and cause-specific mortality in drug-induced acute dystonia or tardive dyskinesia. From Taiwan's National Health Insurance Database (2015-2021), we identified adults with ≥2 psychiatrist- or neurologist-confirmed diagnoses of drug-induced acute dystonia or tardive dyskinesia, and created 1:4 age- and sex-matched population controls and an unaffected sibling cohort. Outcomes included all-cause, natural-cause, and unnatural-cause mortality expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). Multivariable Cox models were adjusted for sex, age, urbanization, socioeconomic status, and comorbidities. A total of 2862 patients and 11 448 matched controls were identified. Mean age was 64.6years, 67.2% female, mean follow-up duration was 4.5years. Drug-induced acute dystonia or tardive dyskinesia was associated with significant excess risk of all-cause (HR = 1.51, 95% CI 1.36-1.67), natural-cause (1.39, 1.25-1.55), and unnatural-cause (3.67, 2.42-5.54) mortality. For natural-cause mortality, mortality risk was elevated for endocrine, nutritional, and metabolic diseases; mental and behavioral disorders; nervous, circulatory, and respiratory system diseases; but reduced for neoplasms. For unnatural-cause mortality, both accidents and suicides revealed higher mortality risks. Results were similar across age groups and ten psychiatric comorbidities. Sex subgroup analysis revealed higher suicide mortality risk in females than males. Drug-induced acute dystonia and tardive dyskinesia are associated with elevated all-cause, natural-cause, unnatural-cause, and cause-specific mortalities, highlighting the need for targeted interventions to prevent these specific causes of deaths.

Schizophrenia is a severe mental health condition affecting up to 1.2% of the US population, resulting in an estimated economic burden of approximately $343 billion in 2019. Traditional treatments primarily target dopamine receptors and include first- and second-generation antipsychotics, which are associated with chronic adverse events (AEs) (eg, severe movement disorders, metabolic syndrome). Management of these AEs entails considerable clinical implications and economic burden, leading to increased health care expenditures for patient care and symptom control. Recently, the US Food and Drug Administration (FDA) approved xanomeline and trospium chloride (X/T), a novel treatment targeting muscarinic rather than dopaminergic receptors. X/T has demonstrated efficacy in reducing both positive and negative symptoms of schizophrenia, with a more tolerable AE profile than traditional standard of care. To estimate the budget impact of incorporating X/T in a hypothetical 1 million-member US health plan, with Medicare, Medicaid, and commercial coverage, to treat adults with schizophrenia. A 3-year budget impact model was developed in Microsoft Excel to estimate the number of schizophrenia patients eligible for second-line treatment within a health plan and the total treatment-related costs. The 10 largest first- and second-generation antipsychotic treatments by market share across payer type were the comparators included in the base case analysis. The model captured drug acquisition, administration, and treatment-emergent AE management costs to estimate the budget impact on a total per year and per member per month (PMPM) basis. Introducing X/T as a second-line treatment for adults with schizophrenia to a 1 million-member health plan results in a PMPM budget impact ranging from $0.0177 in year 1 to $0.1006 in year 3. The total annual budget impact is estimated to be between $212,479 and $1,219,085 in year 1 and year 3, respectively. X/T also results in reduced AE management costs over 3years ($11,336 692 vs $11,276,020) driven by lower rates of tardive dyskinesia and metabolic syndrome associated with X/T use. Sensitivity and scenario analyses demonstrated minimal budget impact sensitivity to parameter variations, with results most sensitive to the cost of X/T and inputs used to estimate the size of the eligible patient population. The safety and tolerability profile of X/T, coupled with its minimal PMPM budget impact of $0.0177 in year 1 up to $0.1006 in year 3, based on market uptake of 1%, 2%, and 3% in years 1, 2, and 3, respectively, supports the inclusion of X/T on the formularies of third-party US health care plans for adults with schizophrenia.

After a brief overview of tardive dyskinesia, this targeted narrative review will examine the psychosocial consequences of tardive dyskinesia on patients' daily lives, including stigma, social withdrawal, and quality of life, as well as impact on physical functioning. The extant literature on the impact of tardive dyskinesia on patients and their caregivers is described and summarized, including how patients with tardive dyskinesia perceive the severity and impact of their motor symptoms and whether this aligns with clinical observations by their treaters.

A woman with complex psychiatric illness and substance use disorder presented with nausea, vomiting, and episodes of oculogyric crisis. A medication review suggested drug-induced acute dystonia, likely triggered by metoclopramide. Other symptoms were possibly related to cumulative anticholinergic effects. Fluoxetine, a potent CYP2D6 inhibitor, may have increased exposure to metoclopramide and promethazine. This case report demonstrates that pharmacological insight and deprescribing can improve symptoms and support rational pharmacotherapy in vulnerable psychiatric patients.

Bilateral nucleus Accumbens–Anterior limb of the internal capsule stimulation combined with medial globus pallidus stimulation for the treatment of Obsessive‑Compulsive disorder with tardive Dyskinesia: A case report and therapeutic Exploration