The role of glutamate receptors and their interactions with dopamine and other neurotransmitters in the development of tardive dyskinesia: preclinical and clinical results.

Tardive dyskinesia is a serious, disabling, movement disorder associated with the ongoing use of antipsychotic medication. Current evidence regarding the pathophysiology of tardive dyskinesia is mainly based on preclinical animal models and is still not completely understood. The leading preclinical hypothesis of tardive dyskinesia development includes dopaminergic imbalance in the direct and indirect pathways of the basal ganglia, cholinergic deficiency, serotonin receptor disturbances, neurotoxicity, oxidative stress, and changes in synaptic plasticity. Although, the role of the glutamatergic system has been confirmed in preclinical tardive dyskinesia models it seems to have been neglected in recent reviews. This review focuses on the role and interactions of glutamate receptors with dopamine, acetylcholine, and serotonin in the neuropathology of tardive dyskinesia development. Moreover, preclinical and clinical results of the differentiated effectiveness of N-methyl-D-aspartate (NMDA) receptor antagonists are discussed with a special focus on antagonists that bind with the GluN2B subunit of NMDA receptors. This review also presents new combinations of drugs that are worth considering in the treatment of tardive dyskinesia.

Abnormal involuntary movement scale in tardive dyskinesia: Minimal clinically important difference.

BACKGROUND: A minimal clinically important difference has not been established for the Abnormal Involuntary Movement Scale in patients with tardive dyskinesia. Valbenazine is a vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia in adults. Efficacy in randomized, double-blind, placebo-controlled trials was defined as the change from baseline in Abnormal Involuntary Movement Scale total score (sum of items 1-7). OBJECTIVES: To estimate an minimal clinically important difference for the Abnormal Involuntary Movement Scale using valbenazine trial data and an anchor-based method. METHODS: Data were pooled from three 6-week double-blind, placebo-controlled trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), and KINECT 3 (NCT02274558). Valbenazine doses were pooled for analyses as follows: "low dose," which includes 40 or 50 mg/day; and "high dose," which includes 75 or 80 mg/day. Mean changes from baseline in Abnormal Involuntary Movement Scale total score were analyzed in all participants (valbenazine- and placebo-treated) with a Clinical Global Impression of Change-Tardive Dyskinesia or Patient Global Impression of Change score of 1 (very much improved) to 3 (minimally improved). RESULTS: The least squares mean improvement from baseline to week 6 in Abnormal Involuntary Movement Scale total score was significantly greater with valbenazine (low dose: -2.4; high dose: -3.2; both, P < 0.001) versus placebo (-0.7). An minimal clinically important difference of 2 points was estimated based on least squares mean changes in Abnormal Involuntary Movement Scale total score in participants with a Clinical Global Impression of Change-Tardive Dyskinesia score ≤3 at week 6 (mean change: -2.2; median change: -2) or Patient Global Impression of Change score ≤3 at week 6 (mean change: -2.0; median change: -2). CONCLUSIONS: Results from an anchor-based method indicate that a 2-point decrease in Abnormal Involuntary Movement Scale total score may be considered clinically important. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Characteristics of Patients Experiencing Extrapyramidal Symptoms or Other Movement Disorders Related to Dopamine Receptor Blocking Agent Therapy.

PURPOSE/BACKGROUND: Dopamine receptor blocking agents (DRBAs), also known as antipsychotics, are medications widely used to treat a growing number of mental health diagnoses. However, their utility is limited by the potential to cause serious adverse movement reactions. Akathisia, dystonia, parkinsonism, and tardive dyskinesia (collectively known as extrapyramidal symptoms or EPSs) are associated with reduced social and occupational functioning, negative patient attitudes toward treatment, and nonadherence to pharmacotherapy. Neuroleptic malignant syndrome is a life-threatening reaction that can result from DRBA use and cause musculoskeletal dysfunction. The aim of this study is to profile patients who have developed DRBA-related movement adverse effects and identify risk factors significantly associated with each subtype of EPSs or other movement disorders (OMDs) such as neuroleptic malignant syndrome. METHODS/PROCEDURES: A report of all potential DRBA-related EPSs or OMDs occurrences within a large community hospital network was generated using International Classification of Diseases, Ninth Revision (ICD-9) and 10th Revision (ICD-10) billing codes. Each patient encounter was manually reviewed to confirm that a documented case of DRBA-related EPSs or OMDs had indeed occurred and subsequently determine the likely causative agent(s). FINDINGS/RESULTS: The resultant cohort of 148 patients experiencing unique DRBA-related EPS or OMD events was analyzed. The average patient was female, middle-aged, and overweight. The most common DRBAs precipitating EPSs or OMDs were haloperidol and quetiapine. In the population studied, age was significantly associated with the subtype of EPSs experienced such that those patients with akathisia and dystonia tended to be younger, whereas those with tardive dyskinesia tended to be older. Body mass index (BMI) category was also negatively correlated with the incidence of dystonia. In addition, it was observed that exposure to specific DRBAs, classes, and routes of administration significantly affected the risk of developing different subtypes of EPSs or OMDs in the study population. IMPLICATIONS/CONCLUSIONS: To our knowledge, this is the first study to describe an association between age and BMI with the risk of akathisia and dystonia, respectively, in patients taking DRBAs. Other trends observed with age and BMI in patients developing DRBA-related EPSs support previously reported findings. Expanding the knowledge base of individual characteristics associated with the risk of developing different subtypes of EPSs or OMDs can help providers and patients anticipate and attempt to mitigate these reactions, and may ultimately improve adherence to DRBA therapy.

A Phase 3, 1-Year, Open-Label Trial of Valbenazine in Adults With Tardive Dyskinesia.

PURPOSE/BACKGROUND: Valbenazine is approved to treat tardive dyskinesia (TD) in adults. KINECT 4 (NCT02405091) was conducted to explore the long-term effects of once-daily valbenazine in patients with TD. METHODS/PROCEDURES: The study included a 48-week, open-label treatment period and 4-week washout. Dosing was initiated at 40 mg/d, with escalation to 80 mg/d at week 4 based on efficacy and tolerability. Standard safety methods were applied, including treatment-emergent adverse event (TEAE) reporting. Valbenazine effects on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD, and Patient Global Impression of Change. FINDINGS/RESULTS: After week 4, <15% of all participants had a serious TEAE (13.7%) or TEAE leading to discontinuation (11.8%). Participants experienced TD improvements during long-term treatment as indicated by mean change from baseline to week 48 in AIMS total score (sum of items 1-7, evaluated by site raters) with valbenazine 40 mg/d (-10.2 [n = 45]) or 80 mg/d (-11.0 [n = 107]). At week 48, most participants had ≥50% improvement from baseline in AIMS total score (40 mg/d, 90.0%; 80 mg/d, 89.2%), Clinical Global Impression of Change-TD rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 95.9%), and Patient Global Impression of Change rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 89.2%). No dose effects were apparent by week 36. Week 52 results indicated some loss of effect after washout. IMPLICATIONS/CONCLUSIONS: Valbenazine was generally well tolerated, and no new safety concerns were detected. Substantial clinician- and patient-reported improvements were observed in adults with TD who received once-daily valbenazine for up to 48 weeks.

A Review of Differences in Clinical Characteristics between Tardive Syndrome Induced or Improved by Aripiprazole Treatment.

INTRODUCTION: Tardive syndrome is a troublesome complication secondary to the long-term usage of antipsychotic medication. At present, there is a lack of effective treatment for tardive syndrome. Aripiprazole has been used in the treatment of tardive syndrome, with some reports of a good response. However, other reports have suggested that tardive syndrome can actually be induced by aripiprazole. The aim of current study was to investigate whether aripiprazole is beneficial or harmful for the treatment of tardive syndrome in specific patients. METHOD: We performed a thorough literature search via PubMed. We included all of the studies discussing the relationship between tardive syndrome and aripiprazole, either with regards to "inducing" or "improving" the disease. RESULT: None of the included studies were well-designed clinical trials, and all were case reports or case series. A total of 26 articles were included in which aripiprazole induced tardive syndrome, and another 24 in which tardive syndrome was improved by aripiprazole treatment. In the "improved" group, there were significantly more cases of schizophrenia than in the "induced" group (p=0.002). However, there were significantly more cases with other miscellaneous diagnoses in the "induced" group than in the "improved" group (p=0.003). In addition, the cases in the "induced" group had a significantly longer duration of aripiprazole usage than those in the "improved" group (p=0.001). CONCLUSION: Current study is important for clinicians to pay attention to the risk of tardive syndrome when prescribing aripiprazole in patients with a diagnosis other than a psychiatric illness or in the long-term administration of aripiprazole.

Adult-onset stereotypical motor behaviors.

Stereotypies have been defined as non-goal-directed movement patterns repeated continuously for a period of time in the same form and on multiple occasions, and which are typically distractible. Stereotypical motor behaviors are a common clinical feature of a variety of neurological conditions that affect cortical and subcortical functions, including autism, tardive dyskinesia, excessive dopaminergic treatment of Parkinson's disease and frontotemporal dementia. The main differential diagnosis of stereotypies includes tic disorders, motor mannerisms, compulsion and habit. The pathophysiology of stereotypies may involve the corticostriatal pathways, especially the orbitofrontal and anterior cingulated cortices. Because antipsychotics have long been used to manage stereotypical behaviours in mental retardation, stereotypies that present in isolation tend not to warrant pharmacological intervention, as the benefit-to-risk ratio is not great enough.

[Idiopathic (Oral) and Tardive Dyskinesia: Pathogenesis, Epidemiology, and Treatment].

Etymologically, dyskinesia is a combination of the prefix "dys-," which means 'abnormality' and the suffix "-kinesia," which means 'movement.' In a broad sense, dyskinesia indicates hyperkinetic involuntary movements. In a narrow sense, as a general term, dyskinesia refers to combinations of one or more of the following movements: chorea, dystonia, tremor, ballism, athetosis, tics, and myoclonus. In this article, we describe the pathogenesis, epidemiology, and treatment of idiopathic (oral) and tardive dyskinesia.

Sex difference in association between tardive dyskinesia and cognitive deficits in patients with chronic schizophrenia.

BACKGROUND: Tardive dyskinesia (TD), a side effect due to long-term use of antipsychotic medication, is associated with cognitive impairment. Several studies have found sex differences in cognitive impairment in schizophrenia patients, while whether there are sex differences in cognitive performance in schizophrenia patients with TD has not been reported. METHODS: A total of 496 schizophrenia inpatients and 362 healthy controls were recruited for this study. We used the Positive and Negative Syndrome Scale (PANSS) to assess patients' psychopathological symptoms and the Abnormal Involuntary Movement Scale (AIMS) to assess the severity of TD. Cognitive function was measured in 313 of these inpatients and 310 of healthy controls using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). RESULTS: Patients with schizophrenia performed worse in all cognitive domains than healthy controls(all p < 0.001). Compared to patients without TD, patients with TD had higher PANSS total, PANSS negative symptom subscale and AIMS scores (all p < 0.001), while RBANS total, visuospatial/constructional and attention subscale scores were significantly lower (all p < 0.05). In addition, the visuospatial/constructional and attention indices remained significantly lower in male patients with TD than those without TD (both p < 0.05), but these results were not observed in female patients. Moreover, visuospatial/constructional and attention indices were negatively correlated with total AIMS scores only in male patients (both p < 0.05). CONCLUSION: Our results suggest that there may be sex differences in cognitive impairment in schizophrenia patients with comorbid TD, indicating that female gender may have a protective effect on cognitive impairment in schizophrenia patients caused by TD.

Revisiting Tardive Dyskinesia: Focusing on the Basics of Identification and Treatment.

The use of second-generation antipsychotics has not eliminated tardive dyskinesia (TD), and the prevalence of the disorder is higher than commonly realized. The involuntary movements of TD can decrease patients' quality of life, cause embarrassment, and lead to social withdrawal. Clinicians must evaluate patients taking DRBAs for TD risk factors and regularly screen them for TD using a rating scale. Familiarity with tools and diagnostic criteria will enable clinicians to conduct a differential diagnosis. Once a diagnosis is made, medications approved by the US Food and Drug Administration can be used to treat the condition. These medications are effective, but clinicians should be aware of key differences. A baseline assessment and regular follow-up evaluations will allow the clinician to monitor the patient's progress and make adjustments to meet treatment goals.​.

A preliminary exome sequence in three patients with tardive dystonia.

Tardive dystonia is one of the most serious adverse events that can be caused by antipsychotic treatment, but few studies have examined the etiology of tardive dystonia, and no genetic study using a next-generation sequencing technique has been performed to date. We conducted exome sequencing in three subjects with severe tardive dystonia. We analyzed the results focusing on candidate genes of primary dystonia, for example, TOR1A, GCH1, TH, THAP1, and SGCE. There were no single-nucleotide polymorphisms of these dystonia genes that were commonly shared among our subjects. Instead, the results revealed the presence of rare mutations (minor allele frequency <0.01) on the ZNF806 and SART3 genes in all three patients. This is the first study to analyze whole-exonic regions of the genomes of patients with tardive dystonia. These results were only preliminary, but they suggest that subjects presenting with tardive dystonia induced by antipsychotic treatment can have a genetic predisposition to tardive dystonia.

Health Care Resource Utilization and Costs for Patients with Tardive Dyskinesia.

BACKGROUND: Tardive dyskinesia (TD) is an often-irreversible movement disorder affecting any part of the body. Patients experience debilitating symptoms that lower quality of life and increase mortality. Prolonged exposure to dopamine antagonists, which are frequently prescribed for psychiatric disorders as neuroleptic (antipsychotic) drugs, is a common cause of TD. The estimated prevalence of TD is 20%-50% among patients on antipsychotics, and the reported incidence of TD ranges from < 1% to 42%, depending on the antipsychotics studied. However, there are few real-world studies examining health care utilization and the economic burden of TD. OBJECTIVE: To assess health care utilization and costs in a sample of patients with TD from the commercially insured and Medicare supplemental U.S. METHODS: A retrospective analysis was conducted using Truven MarketScan Commercial and Medicare administrative claims data. Patients were included in the TD group if they had the first TD diagnosis (index date) between January 1, 2008, and September 30, 2014, with ≥ 1 inpatient or ≥ 2 outpatient nondiagnostic claims for TD (ICD-9-CM code 333.85). Patients without TD were randomly assigned an index date. Further inclusion criteria for all patients were ≥ 12 months of pre- and post-index medical and pharmacy continuous enrollment and no evidence of TD claims during the pre-index period. Patients with TD were directly matched to patients without TD within subgroups for schizophrenia, major depressive disorder, bipolar disorder, and other psychiatric disorders and propensity matched on other demographic and clinical factors. Descriptive statistics on the incidence of resource utilization and costs of health care were reported. RESULTS: Of 3,397 patients with TD, 834 met the selection criteria and were matched to 834 non-TD controls. Patients with TD generally had significantly greater utilization during the 12 months after TD diagnosis than in the 12 months before TD diagnosis. Their rates for health care utilization and costs were also substantially higher than for those without TD. During the post-TD-diagnosis time, inpatient admissions (55.5% vs. 26.1%; P < 0.001) and emergency room visits (61.5% vs. 50.6%; P < 0.001) occurred more for patients with TD than for patients without TD. Total health care costs were significantly greater for patients with TD than for those without TD ($54,656 vs. $28,777; P < 0.001). CONCLUSIONS: Patients diagnosed with TD demonstrate significantly higher health care utilization and costs compared with non-TD patients. DISCLOSURES: This study was funded by Teva Pharmaceuticals (Petach Tikva, Israel). Truven Health Analytics, an IBM Watson Health Company, received payment from Teva Pharmaceuticals for the analysis in this study. Carroll is employed by Teva Pharmaceuticals and Irwin is employed by Truven Health Analytics, an IBM Watson Health Company.

What You Should Know About Tardive Dyskinesia: Screening, Causes, and New Treatment Options.

Do you know which of your patients are at risk for developing tardive dyskinesia? Watch this Webcast to learn about how to prevent tardive dyskinesia in your patients and new treatment strategies for your patients who have already been diagnosed.

Tardive Dyskinesia Associated with Atypical Antipsychotics: Prevalence, Mechanisms and Management Strategies.

All antipsychotics, including the atypical antipsychotics (AAPs), may cause tardive dyskinesia (TD), a potentially irreversible movement disorder, the pathophysiology of which is currently unknown. The prevention and treatment of TD remain major challenges for clinicians. We conducted a PubMed search to review the prevalence and etiology of and management strategies for TD associated with AAPs. TD prevalence rates varied substantially between studies, with an estimated prevalence of around 20% in patients using AAPs. The risk of TD is lower with AAPs than with typical antipsychotics (TAPs) but remains a problem because AAPs are increasingly being prescribed. Important risk factors associated with TD include the duration of antipsychotic use, age, and ethnicity other than Caucasian. Theories about the etiology of TD include supersensitivity of the dopamine receptors and oxidative stress, but other neurotransmitters and factors are probably involved. Studies concerning the management of TD have considerable methodological limitations. Thus, recommendations for the management of TD are based on a few trials and clinical experience, and no general guidelines for the management of TD can be established. The best management strategy remains prevention. Caution is required when prescribing antipsychotics, and regular screening is needed for early detection of TD. Other strategies may include reducing the AAP dosage, switching to clozapine, or administering vesicular monoamine transporter (VMAT)-2 inhibitors. In severe cases, local injections of botulinum toxin or deep brain stimulation may be considered. More clinical trials in larger samples are needed to gather valid information on the effect of interventions targeting TD.

Decreased Gray Matter Volume of Cuneus and Lingual Gyrus in Schizophrenia Patients with Tardive Dyskinesia is Associated with Abnormal Involuntary Movement.

Tardive dyskinesia (TD) is a devastating motor disorder associated with the etiological process of schizophrenia or antipsychotic medication treatments. To examine whether cerebral morphological changes may manifest in TD, we used voxel-based morphometry to analyze high-resolution T1-weighted brain structural magnetic resonance images from 32 schizophrenics with TD (TD group), 31 schizophrenics without TD (non-TD group), and 32 healthy controls (HC group). We also assessed psychopathological symptoms with the Positive and Negative Syndrome Scale (PANSS), and TD severity with the Abnormal Involuntary Movement Scale (AIMS). We compared gray matter volumes (GMVs) among groups, and tested for correlations between GMV changes and psychopathological symptoms or TD severity. The results showed significant differences in GMV in the frontal and temporal cortices, insula and cerebellum among the three groups. Brainstem and inferior frontal and precentral gyri GMVs were significantly larger, whereas cuneus and lingual gyrus GMVs were significantly smaller in the TD group as compared to non-TD group. Further, the cuneus and lingual gyrus GMVs were positively correlated with AIMS scores in the TD group. The current results suggest that TD may be associated with the alterations in GMV that are different from that of schizophrenics without TD. Further studies are needed to confirm and to examine the functional significance of these structural findings.

Tardive Dyskinesia: A Historical Perspective.

The goal of this column is to provide historical context on tardive dyskinesia (TD) to help the reader understand how the concept was studied and evolved over time. Psychiatrists today should understand this history and consider it in combination with more recent data on the neurobiology of TD, including data from animal studies. This combination of classic data with modern science can help readers develop a more complete understanding and lead to a more judicious use of the term TD, after consideration of all of the alternative causes of abnormal movements, including spontaneous dyskinesia (SD). We advocate that clinicians use the term SD when in doubt about the cause of a movement disorder in a given patient, as TD is never distinguishable from SD in a given patient but is instead an issue of a statistical odds ratio.

Association between DBH 19bp insertion/deletion polymorphism and cognition in schizophrenia with and without tardive dyskinesia.

Long-term antipsychotic treatment for schizophrenia is associated with the development of tardive dyskinesia (TD), which is involved in increased cognitive impairment. Dopamine beta-hydroxylase (DBH) gene associated with dopamine and norepinephrine systems influences cognition. Schizophrenia with TD have higher DBH activity than those without TD. This study examined whether DBH5'-insertion/deletion (-Ins/Del) polymorphism could influence cognitive function in schizophrenia with and without TD. The presence of DBH5'-Ins/Del polymorphism was determined in 345 schizophrenia with TD and 397 schizophrenia without TD. The Abnormal Involuntary Movement Scale and Repeatable Battery for Assessment of Neuropsychological Status (RBANS) were used to assess TD severity and cognition. The allele and genotype frequencies of DBH5'-Ins/Del polymorphism did not differ between patients with and without TD (both p>0.05). RBANS total score and subscales did not differ by DBH5'-Ins/Del genotype groups in patients with TD (all p>0.05). However, attention score significantly differed by DBH5'-Ins/Del genotype groups in those without TD (p<0.05). Patients without TD who were Del homozygous had significantly lower attention score than those without TD who were Ins alleles (p<0.05). Immediate memory and attention scores were lower in patients with TD than without TD (both p<0.05). This study indicated that DBH5'-Ins/Del polymorphism may not play a role in the susceptibility to TD and cognitive deficits in schizophrenia with TD, but it may influence cognitive function in schizophrenia with non-TD. Moreover, schizophrenia with TD experienced greater cognitive deficits than those with non-TD, especially in immediate memory and attention.

Antipsychotic-induced Tardive dyskinesia: from biological basis to clinical management.

INTRODUCTION: Tardive dyskinesia (TD) is a chronic and disabling movement disorder with a complex pathophysiological basis. A significant percentage of patients does not receive correct diagnosis, resulting in delayed or inaccurate treatment and poor outcome. Therefore, there is a critical need for prompt recognition, implementation of efficacious treatment regimens and long-term follow up of patients with TD. Areas covered: The current paper provides an overview of emerging data concerning proposed pathophysiology theories, epidemiology, risk factors, and therapeutic strategies for TD. Expert commentary: Despite considerable research efforts, TD remains a challenge in the treatment of psychosis as the available strategies remain sub-optimal. The best scenario will always be the prophylaxis or prevention of TD, which entails limiting the use of antipsychotics.

[Antipsychotic-induced tardive syndromes]. / Antipsychotikainduzierte tardive Syndrome.

Tardive dyskinesia (TD) remains a relevant clinical problem despite the increasing use of new-generation antipsychotics. Antipsychotic-induced tardive syndromes are difficult to treat and have a low tendency of remission. Therefore, prophylaxis is of utmost importance, with the responsible use of antipsychotics as a prime desideratum. With respect to managing tardive dyskinesia, discontinuing the antipsychotic, if possible, albeit not backed up by unequivocal evidence, is still the main recommendation. If this is not possible, the switch to an antipsychotic with a lower TD risk is the next-preferred option. Other symptomatic treatments have been explored, but clinical trials have provided inhomogeneous results and only very few compounds are approved for the treatment of tardive dyskinesia. This manuscript summarizes the current evidence with respect to the phenomenology, course, prevention and treatment of tardive syndromes.