Cumulative Burden of Illness in Veterans With Tardive Dyskinesia and Serious Mental Disorders.

PURPOSE/BACKGROUND: To inform cost-benefit decisions for veterans, the risk of tardive dyskinesia (TD) and its impact on comorbidities and outcomes were assessed. METHODS/PROCEDURES: In a retrospective study, veterans with schizophrenia/schizoaffective, and bipolar and major depressive disorders receiving antipsychotics during the period October 1, 2014, to September 30, 2015, were identified. Tardive dyskinesia was determined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Correlates of TD were examined using χ or t tests. Odds ratios (ORs) and ß parameters with 95% confidence intervals (CIs) for categorical and continuous variables associated with TD were derived from a multivariate logistic and linear regression, respectively. FINDINGS/RESULTS: Among 7985 veterans, 332 (4.2%) were diagnosed as having possible TD. The odds of having TD were higher for older veterans (OR, 1.04; 95% CI, 1.03-1.05; P < 0.0001) and veterans with schizophrenia/schizoaffective disorder (OR, 1.54; 95% CI, 1.23-1.91; P < 0.0001) or diabetes (OR, 1.64; 95% CI, 1.30-2.06; P < 0.0001). Veterans with TD received more antipsychotic prescriptions (mean ± SD, 18.4 ± 30.3 vs 13.3 ± 26.4; P = 0.003) and days of supply (233.9 ± 95.4 vs 211.4 ± 102.0; P < 0.0001). They were more likely to have received 2 or more antipsychotics (27.1% vs 19.7%, P = 0.0009) and benztropine (OR, 2.25: 95% CI 1.73-2.91; P < 0.0001). Veterans with TD had a higher Charlson Comorbidity Index score (ß = 0.32; SE, 0.09; 95% CI, 0.14-0.49; P = 0.0003) and higher odds of any medical hospitalization (OR, 1.45; 95% CI, 1.07-1.95; P = 0.001). IMPLICATIONS/CONCLUSIONS: The diagnosis of possible TD was associated with older age, schizophrenia/schizoaffective disorder, medical comorbidity, and hospitalization. Tardive dyskinesia may be a marker for patients at risk of adverse health care outcomes and diminished quality of life.

Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia.

OBJECTIVE: To evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD). METHOD: Patients with TD who completed the 12 week, phase 3, placebo-controlled trials were eligible to enter this open-label, single-arm study. The open-label study consisted of a 6 week dose-escalation phase and a long-term maintenance phase (clinic visits at Weeks 4, 6 and 15, and every 13 weeks until Week 106). Patients began deutetrabenazine at 12 mg/day, titrating up to a dose that was tolerable and provided adequate dyskinesia control, based on investigator judgement, with a maximum allowed dose of 48 mg/day (36 mg/day for patients taking strong cytochrome P450 2D6 (CYP2D6) inhibitors). Safety measures included incidence of adverse events (AEs) and scales used to monitor parkinsonism, akathisia/restlessness, anxiety, depression, suicidality and somnolence/sedation. Efficacy endpoints included the change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 to 7) from baseline and the proportion of patients rated as 'Much Improved' or 'Very Much Improved' on the Clinical Global Impression of Change. RESULTS: A total of 343 patients enrolled in the extension study, and there were 331 patient-years of exposure in this analysis. The exposure-adjusted incidence rates of AEs with long-term treatment were comparable to or lower than those observed in the phase 3 trials. The mean (SE) change in AIMS score was -4.9 (0.4) at Week 54 (n = 146), - 6.3 (0.7) at Week 80 (n = 66) and -5.1 (2.0) at Week 106 (n = 8). CONCLUSIONS: Overall, long-term treatment with deutetrabenazine was efficacious, safe, and well tolerated in patients with TD. TRIAL REGISTRATION NUMBER: NCT02198794.

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.

Repetitive transcranial magnetic stimulation for treatment of tardive syndromes: double randomized clinical trial.

Tardive syndromes (TDS) typically manifest 3 months or later after exposure to antipsychotic drugs, and unfortunately have no satisfactory medical treatment. We explored the possibility of using therapeutic repetitive transcranial magnetic stimulation (rTMS). Twenty-six patients were allocated to receive real or sham rTMS over the hand/arm area of motor cortex (M1). Each received a daily total of 2000 rTMS pulses (20 Hz at 100% rMT: 1000 stimuli per hemisphere) for 10 consecutive days. Outcome was assessed using the Abnormal Involuntary Movement Scale (AIMS) and TMS measures of M1 excitability. Three patients in the sham group failed to complete the study. At baseline, there was no significant difference between the groups in age, sex distribution, duration of illness, AIMS score and drug treatment. rTMS improved symptoms in both groups. However, there was a greater reduction in the AIMS score of the real rTMS group compared with the sham group (real, 8.3 ± 1.7 points; sham 1.2 ± 3.3; repeated measure analysis ANOVA Time X Group interaction P = 0.001). The same trends were observed in the clinical subscales. Following treatment, MEP amplitudes at higher intensities (140, and 150%) increased more in the real treatment group than in the sham group. This is the first clinical trial study of bilateral hemispheric rTMS in patients with TDS and suggests that 20 Hz rTMS might be a feasible treatment option in patients unresponsive to "first-line" treatment.Clinical trial registration ClinicalTrials.gov Identifier: NCT03145311.

VMAT2 Inhibitors: New Drugs for the Treatment of Tardive Dyskinesia.

OBJECTIVE: To provide a review of tardive dyskinesia (TD) symptoms, etiology, pathophysiology, and treatments. DATA SOURCES: PubMed, Web of Science, ClinicalTrials. gov, and Google Scholar were searched for relevant literature using a combination of the following terms: tardive dyskinesia, treatment, management, guidelines, tetrabenazine, deutetrabenazine, and valbenazine. Sources were limited to human data. STUDY SELECTION/DATA EXTRACTION: Articles were reviewed for relevance to TD therapy. Reference lists were manually searched for other relevant articles. Selected literature was published between 1968 and 2017. DATA SYNTHESIS: This article reviews treatment options available for patients with TD. Many agents have been tried off-label to manage symptoms, with limited evidence of benefit. The Food and Drug Administration approved the first drug to treat TD valbenazine on April 11, 2017. CONCLUSION: TD is largely iatrogenic. Valbenazine's approval by the Food and Drug Administration was followed by the approval of deutetrabenazine, a drug with similar mechanism of action. Further data from postmarketing studies will be needed to verify that valbenazine's adverse effect profile is different from the profiles of tetrabenazine and deutetrabenazine.

Neuronal traffic signals in tardive dyskinesia: not enough "stop" in the motor striatum.

Tardive dyskinesia is a disturbance in the balance between dopamine receptor stimulation and dopamine receptor blockade in the motor striatum, with hypothetically too much stimulation of supersensitive D2 receptors, resulting in "don't stop" signaling to motor output.

Deep brain stimulation of the internal globus pallidus for disabling haloperidol-induced tardive dystonia. Report of two cases.

AIM: Tardive dystonia (TD) represents a side effect of prolonged intake of neuroleptic drugs. TD can be a disabling movement disorder persisting despite available medical treatment. Deep brain stimulation (DBS) has been reported successful in this condition although the number of treated patients with TD is still limited to small clinical studies or case reports. In this study, we present 2 additional cases of patients after bilateral globus pallidus internus (GPi) stimulation. METHODS: The formal assessment included the Burke-Fahn-Dystonia Rating Scale (BFMDRS). The preoperative and postoperative functional and motor parts of this scale were compared in each patient. The postoperative assessments were done every 6 months. RESULTS: Both patients underwent successful bilateral GPi DBS for TD. The postoperative motor score improved by 78% at 24 months in patient 1 and 69% at 12 months in patient 2. There were no surgical or hardware-related complications over follow-up period. CONCLUSION: Our experience indicates that bilateral GPi DBS can be an effective treatment for disabling TD. The response of TD to bilateral GPi DBS is very rapid and occurs within days after the procedure.

Co-treatment with imipramine averted haloperidol-instigated tardive dyskinesia: Association with serotonin in brain regions.

Outcome of imipramine (IMI) treatment was scrutinized on progression of haloperidol instigated tardive dyskinesia (TD). 0.2 mg/kg/rat dosage of haloperidol provided orally to rats for 2 weeks enhanced vacuous chewing movements that escalated when the process proceeded for 5 weeks. Following 2 weeks co-injection 5 mg/kg dosage of IMI was diminished haloperidol-instigated VCMs and fully averted following five weeks. The potency of 8-OH-DPAT-instigated locomotor activity exhibited higher in saline+haloperidol treated rats while not observed in IMI+ haloperidol treated rats. 8-OH-DPAT-instigated low 5-hydroxytryptamine (5-HT; serotonin) metabolism was higher in saline+ haloperidol treated rats when compare to IMI+ haloperidol treated rats in both regions of brain (striatum and midbrain). It is recommended that IMI possibly competent in averting TD, in cases receiving treatment to antipsychotics.

Abnormal functional connectivity of motor circuit in the schizophrenic patients with tardive dyskinesia: A resting-state fMRI study.

BACKGROUND: Animal and neuroimaging studies suggest that the volume of the motor-circuit region decreases in tardive dyskinesia (TD). This study examined the differences in functional connectivity within the motor circuit of patients with schizophrenia with and without TD to further clarify how the dysfunction is related to the pathogenesis of TD. METHODS: Functional magnetic resonance images were taken of 56 schizophrenic patients with TD (TD group), 64 without TD (non-TD group), and 68 healthy controls (HC group). The motor-circuit area was selected as the seed region for a whole brain resting-state functional connectivity (rsFC) analysis. Psychopathological symptoms and TD severity were assessed with the Positive and Negative Syndrome Scale (PANSS) and Abnormal Involuntary Movement Scale (AIMS), respectively. Group differences and correlations among 18 brain regions of interest (e.g., the global strength of connectivity between two regions) were analyzed. RESULTS: The analysis of variance results were as follows: The three groups exhibited rsFC losses in the left primary motor cortex, bilateral parietal cortices, right postcentral gyrus, right putamen, right superior parietal lobule, right supplementary motor area and bilateral thalami (false discovery rate,p < 0.05). The TD group showed a significant rsFC loss between the right postcentral gyrus and the inferior frontal gyrus of the left triangular part when compared with the non-TD group (AlphaSim, p < 0.001), which was negatively correlated with the AIMS total score (r=-0.259, p = 0.03). CONCLUSIONS: These findings may suggest dysfunction of the postcentral and inferior frontal gyri of the triangular part in patients with schizophrenia and TD.

Identifying Tardive Dyskinesia: Risk Factors, Functional Impact, and Diagnostic Tools.

Tardive dyskinesia (TD) is an involuntary movement disorder induced by dopamine-receptor blocking agents (DRBAs), including antipsychotics. Because the introduction of second-generation antipsychotics has reduced but not eliminated the risk for TD as had been hoped, recognizing and treating TD are important skills for clinicians. Many patients rely on DRBAs for chronic conditions. To minimize the risk of patients' involuntary movements becoming permanent, they must be detected early and treated. To improve the early recognition and diagnosis of TD, clinicians must know the risk factors, understand the functional impairment, regularly and systematically assess their patients, and appropriately apply diagnostic criteria.

Valbenazine and deutetrabenazine: Vesicular monoamine transporter 2 inhibitors for tardive dyskinesia.

PURPOSE: The purpose of this review is to summarize the current evidence for valbenazine and deutetrabenazine use for the treatment of tardive dyskinesia (TD). SUMMARY: A literature search was conducted to gather relevant data regarding the use of valbenazine and deutetrabenazine for TD management. PubMed, MEDLINE, and ClinicalTrials.gov were searched using the following keywords and MeSH terms: valbenazine, deutetrabenazine, tardive dyskinesia, VMAT2 inhibitors, and vesicular monoamine transporter 2 inhibitors. Randomized, double-blind, placebo-controlled trials and meta-analyses published in English from April 2015 to August 2019 were included. Valbenazine 40-80 mg and deutetrabenazine 12-36 mg per day have been evaluated for the treatment of TD. Abnormal Involuntary Movement Scale (AIMS) scores decline similarly (by 2-5 points) with use of either agent. AIMS response rates, defined by a 50% decline in symptoms, range from 33% to 50%. Both agents are well tolerated, with somnolence and akathisia reported most frequently (at low rates). Agent selection may be guided by manufacturer labeling recommendations for special populations and cost considerations. CONCLUSIONS: Valbenazine and deutetrabenazine were demonstrated to be effective in decreasing AIMS scores and were well tolerated in randomized controlled trials. These treatments may be considered as a next-line option when traditional strategies are not feasible or are ineffective. Head-to-head studies are warranted to decipher if either agent is preferable in terms of efficacy or tolerability.

The effect of rs1076560 (DRD2) and rs4680 (COMT) on tardive dyskinesia and cognition in schizophrenia subjects.

OBJECTIVE: The aim of the study is to test the association of a functional variant each in DRD2 and COMT genes with schizophrenia and its endophenotypes. BASIC METHODS: Effect of two functional variants rs1076560 in DRD2 and rs4680 in COMT on (1) schizophrenia (502 cases, 448 controls) diagnosed by Diagnostic and Statistical Manual of Mental Disorders-IV criteria and in subsets with (2) tardive dyskinesia (80 positive, 103 negative), assessed by Abnormal Involuntary Movement Scale (AIMS), positive and negative symptoms assessed by Positive and Negative Syndrome Scale (PANSS) and (3) cognition (299 cases, 245 controls), estimated by Penn Computerized Neurocognitive Battery, were analysed either using analysis of variance (ANOVA) or regression analysis. MAIN RESULTS: No association of two SNPs with schizophrenia, but association of rs4680 (P < 0.05) with tardive dyskinesia was observed. On ANOVA, main effect of smoking [F(2,148) = 16.3; P = 3.9 × 10]; rs4680 [F(2,148) = 3.3; P = 0.04] and interaction effect of tardive dyskinesia-status*Smoking [F(2,148) = 5.4, P = 0.006]; Smoking*rs1076560 [F(3,148) = 3.6; P = 0.01]; Smoking*rs4680 [F(4,148) = 5.3; P = 4.7 × 10] were significant with AIMS tardive dyskinesia score. The main effect of rs1076560 [F(2,148) = 4.5; P = 0.013] and rs4680 [F(2,148) = 4.0; P = 0.02] were significant with limb truncal tardive dyskinesia. Allelic/genotypic (P = 0.004/P = 0.01) association of rs1076560 with negative scale of PANSS in tardive dyskinesia-negative; diminished expression factor of PANSS in tardive dyskinesia-negative subcohort (allelic/genotypic P = 3.3 × 10/6.6 × 10) and tardive dyskinesia cohorts (P = 0.003/0.002); genotypic association (P = 0.05) with disorganised/concrete factor in tardive dyskinesia-positive subcohorts were observed by regression analysis using gPLINKv2.050. Further allelic/genotypic (P = 0.02) association of rs4680 with depressed factor of PANSS in tardive dyskinesia cohort was observed. Allelic/genotypic association of rs1076560 with abstraction and mental flexibilityaccuracy (P = 0.03/0.04), abstraction and mental flexibilityefficiency (P = 0.01/0.02); allelic association with spatial abilityprocessing speed (P = 0.03), emotionefficiency (P = 0.05); and with spatial abilityefficiency (genotypic, P = 0.05) in healthy controls and allelic association of rs4680 with emotionefficiency in cases with schizophrenia (P = 0.04) were notable. PRINCIPAL CONCLUSION: Dopaminergic genes seem to contribute to tardive dyskinesia and cognition warranting replication.

Copulatory Dyskinesia: Pathognomonic Manifestation of Tardive Dyskinesia.

Background: Copulatory or pelvic thrusting dyskinesia is a subtype of tardive dyskinesia (TD) which is caused by exposure to dopamine blocking agents. Phenomenology shown: A man exhibiting rhythmic, stereotypical pelvic thrusting movements. Educational value: Recognition of copulatory dyskinesia as a distinctive iatrogenic disorder helps prevent unnecessary investigations and guides the implementation of corrective strategies.

Genetic study of neuregulin 1 and receptor tyrosine-protein kinase erbB-4 in tardive dyskinesia.

OBJECTIVES: Tardive dyskinesia (TD) is a movement disorder that may develop as a side effect of antipsychotic medication. The aetiology underlying TD is unclear, but a number of mechanisms have been proposed. METHODS: We investigated single-nucleotide polymorphisms (SNPs) in the genes coding for neuregulin-1 and erbB-4 receptor in our sample of 153 European schizophrenia patients for possible association with TD. RESULTS: We found the ERBB4 rs839523 CC genotype to be associated with risk for TD occurrence and increased severity as measured by the Abnormal Involuntary Movement Scale (AIMS) (P = .003). CONCLUSIONS: This study supports a role for the neuregulin signalling pathway in TD, although independent replications are warranted.

Haloperidol-Induced Preclinical Tardive Dyskinesia Model in Rats.

Haloperidol is a first-generation antipsychotic used in the treatment of psychoses, especially schizophrenia. This drug acts by blocking dopamine D2 receptors, reducing psychotic symptoms. Notwithstanding its benefits, haloperidol also produces undesirable impacts, in particular extrapyramidal effects such as tardive dyskinesia (TD), which limit the use of this and related drugs. TD is characterized by repetitive involuntary movements occurring after chronic exposure therapy with haloperidol. Symptoms most commonly manifest in the orofacial area and include involuntary movements, tongue protrusion, pouting lips, chewing in the absence of any object to chew, and facial grimacing. The most serious aspect of TD is that it may persist for months or years after drug withdrawal and is irreversible in some patients. This unit, aimed at facilitating the study of TD, describes methods to induce TD in rats using haloperidol, as well as procedures for evaluating the animals's TD-related symptoms. © 2019 by John Wiley & Sons, Inc.

VMAT2 Inhibitors for Tardive Dyskinesia-Practice Implications.

Tardive dyskinesia is a potentially irreversible, debilitating, hyperkinetic movement disorder that can result from dopamine receptor antagonists. Prompt recognition and resolution of symptoms are instrumental in preventing disease irreversibility, though current treatment options have fallen short of robust, effective, and long-term symptom control. In April 2017, the Food and Drug Administration (FDA) approved 2 new vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for chorea related to Huntington's disease and tardive dyskinesia, respectively. These agents were pharmacologically modified from tetrabenazine, a VMAT2 inhibitor used off-label in the treatment of tardive dyskinesia. Despite FDA-labeled indications of deutetrabenazine and valbenazine, each agent was explored as a treatment option for those with tardive dyskinesia. In this study, the pharmacologic modifications of the 2 new VMAT2 inhibitors are described, with detailed explanation as to how these may impact clinical practice. The associated case series, observational studies, and clinical trials exploring their use in the treatment of tardive dyskinesia are reported with expert opinion on practice implication.

Tardive Syndromes.

PURPOSE OF REVIEW: This article reviews the history, nosology, clinical features, epidemiology, and treatment of tardive syndromes. RECENT FINDINGS: The major advance in the field of tardive syndromes has been the development and US Food and Drug Administration (FDA) approval of two vesicular monoamine transporter type 2 inhibitors, valbenazine and deutetrabenazine, for treating tardive syndromes. These medications are derivatives of tetrabenazine and reduce dyskinetic movements by reducing dopamine stimulation. Treatment is not curative, and the medications reduce, or "mask," symptoms but presumably without adding to the long-term risk of increased involuntary movements believed to accrue from suppressive treatment with dopamine receptor-blocking drugs. A confounding advance has been the accumulation of data finding that second-generation antipsychotics, also known as atypical antipsychotics, may not be safer than first-generation antipsychotics in causing tardive syndromes. The public health risk of tardive syndromes may actually have increased as some second-generation antipsychotics, widely promoted to both doctors and patients, are increasingly used as antidepressants. SUMMARY: Tardive syndromes remain a public health risk. Second-generation antipsychotics have not been proven to have less risk than first-generation drugs in causing tardive syndromes and are nevertheless being used more widely to treat depression, bipolar disease, and insomnia. Symptomatic treatment for tardive syndromes is available, although expensive.

Setting the record straight: The nosology of tardive syndromes.

We propose the use of the term tardive dyskinesia to refer to the original description of repetitive and complex oral-buccal-lingual (OBL) movements and the analogous repetitive movements of the limbs, trunk, or pelvis. The term tardive syndrome is an umbrella term to be used to refer to the spectrum of all persistent hyperkinetic, hypokinetic, and sensory phenomenologies resulting from chronic dopamine receptor blocking agent (DRBA) exposure. TD is a type of TS. The term tardive dystonia (TDyst) should be used when dystonia is the main feature of TS. Retrocollis and oromandibular dystonia appear to be the most common form of Tdyst. Tardive akathisia refers to the inability to remain still with an urge to move, giving the appearance of restlessness. In tardive tourettism, the patient has complex motor and phonic tics associated with premonitory urge and relief of tension after performing the tic behavior, thus resembling Tourette's syndrome. Tardive tremor is composed of mainly postural and kinetic tremors. It differs from the resting tremor seen in drug-induced parkinsonism. Tardive pain occurs in association with chronic use of DRBAs and involves the mouth, tongue, and genital region with no physical findings. In tardive parkinsonism, the patient has persistent parkinsonism even after discontinuation of the DRBA although this diagnosis is in question and may represent DRBA-uncovered idiopathic Parkinson's disease or coincident development of Parkinson's disease while taking DRBAs.