Management Of Tardive Dyskinesia Research Articles

Neurological perspectives should be integrated into the management of tardive dyskinesia - expert opinion and proposed educational initiatives in Asia.

Neurological perspectives should be integrated into the management of tardive dyskinesia - expert opinion and proposed educational initiatives in Asia.

Bacillus Calmette-Guérin Vaccine Attenuates Haloperidol-Induced TD-like Behavioral and Neurochemical Alteration in Experimental Rats.

Tardive dyskinesia (TD) is a hyperkinetic movement disorder that displays unusual involuntary movement along with orofacial dysfunction. It is predominantly associated with the long-term use of antipsychotic medications, particularly typical or first-generation antipsychotic drugs such as haloperidol. Oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis are major pathophysiological mechanisms of TD. The BCG vaccine has been reported to suppress inflammation, oxidative stress, and apoptosis and exert neuroprotection via several mechanisms. Our study aimed to confirm the neuroprotective effect of the BCG vaccine against haloperidol-induced TD-like symptoms in rats. The rats were given haloperidol (1 mg/kg, i.p.) for 21 days after 1 h single administration of the BCG vaccine (2 × 107 cfu). Various behavioral parameters for orofacial dyskinesia and locomotor activity were assessed on the 14th and 21st days after haloperidol injection. On the 22nd day, all rats were euthanized, and the striatum was isolated to estimate the biochemical, apoptotic, inflammatory, and neurotransmitter levels. The administration of the BCG vaccine reversed orofacial dyskinesia and improved motor function in regard to haloperidol-induced TD-like symptoms in rats. The BCG vaccine also enhanced the levels of antioxidant enzymes (SOD, GSH) and reduced prooxidants (MDA, nitrite) and pro-apoptotic markers (Cas-3, Cas-6, Cas-9) in rat brains. Besides this, BCG treatment also restored the neurotransmitter (DA, NE, 5-HT) levels and decreased the levels of HVA in the striatum. The study findings suggest that the BCG vaccine has antioxidant, antiapoptotic, and neuromodulatory properties that could be relevant in the management of TD.

Zolpidem dependence for self-medication in the management of tardive dyskinesia

Zolpidem dependence for self-medication in the management of tardive dyskinesia

Telehealth for Assessing and Managing Tardive Dyskinesia: Expert Insights from a Cross-Disciplinary Virtual Treatment Panel.

Introduction: Publications on the integration of telehealth in the care of patients with movement disorders are increasing, but little has been presented regarding its use in tardive dyskinesia (TD), a drug-induced movement disorder associated with prolonged exposure to dopamine receptor blocking agents. This study was conducted to address that knowledge gap, based on insights from a panel of TD experts. Methods: In 2020, six neurologists, three psychiatrists, and three psychiatric nurse practitioners participated in individual semistructured interviews about in-person and virtual TD assessment and management in their practices. Two virtual roundtables were then conducted to consolidate findings from these interviews. Results: The panel agreed that despite the challenges of virtual TD assessment (e.g., technology issues, difficulty observing entire body, inability to conduct thorough neurological examinations), telehealth can offer benefits (e.g., fewer missed appointments, reduced time/cost, easier access to family/caregiver feedback). The panel also agreed that telehealth should be combined with periodic in-person visits, and they recommended an in-person TD assessment within 6 months before the first virtual visit and at least one in-person assessment every 6 months thereafter. Additional best practices for TD telehealth included implementing video, involving family/caregivers, and providing preappointment instructions to help patients prepare their technology and environment. Conclusions: Telehealth is not a substitute for in-person visits but can be a helpful complement to in-person clinical care. Clinicians can optimize virtual visits in patients at risk of TD by using targeted questions to identify TD and evaluate its impact and by providing education about approved TD treatments.

Filgrastim, a Recombinant Form of Granulocyte Colony-stimulating Factor, Ameliorates 3-nitropropionic Acid and Haloperidol-induced Striatal Neurotoxicity in Rats.

Striatal neurotoxicity is the pathological hallmark for a heterogeneous group of movement disorders like Tardive dyskinesia (TD) and Huntington's disease (HD). Both diseases are characterized by progressive impairment in motor function. TD and HD share common features at both cellular and subcellular levels. Filgrastim, a recombinant methionyl granulocyte colony-stimulating factor (GCSF), shows neuroprotective properties in in-vivo models of movement disorders. This study seeks to evaluate the neuroprotective effect of filgrastim in haloperidol and 3-NP-induced neurotoxicity in rats. The study was divided into two: in study one, rats were administered with haloperidol for 21days, filgrastim at the dose of (20, 40, 60µg/kg,s.c.) was administered once a day before haloperidol treatment and the following parameters (orofacial movements, rotarod, actophotometer) were performed to assess TD. Similarly, in the second study, rats were administered with 3-NP for 21days, filgrastim at a dose of (20 and 40µg/kg, s.c.) was administered, and the following parameters (rotarod, narrow beam walk, and open field test) were assessed for HD. On the 22nd day, animals were sacrificed and cortex and striatum isolated for oxidative stress (LPO, GSH, SOD, catalase, and nitrate) marker assessment. Results revealed that haloperidol and 3-NP treatment significantly impaired motor coordination, and oxidative defense inducing TD and HD-like symptoms. Treatment with filgrastim significantly averted haloperidol and 3-NP-induced behavioral and biochemical alterations. Conclusively, the neuroprotective effect of filgrastim is credited to its antioxidant properties. Hence, filgrastim might be a novel therapeutic candidate for the management of TD and HD.

Once-Daily Valbenazine Is Effective for Tardive Dyskinesia in Elderly Patients (>=65 Years)

<h3>Introduction</h3> Valbenazine is a selective and potent vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics or other dopamine-receptor blocking agents (DRBAs). Valbenazine is the only approved TD medication with once-daily dosing and no requirements or cautions for dosing based on age. Older adults (≥55 years) have an increased risk for TD after a shorter duration of treatment with DRBAs, and previous analyses have shown that valbenazine is effective and well tolerated in this population (Sajatovic et al, Int J Geriatr Psychiatry 2020). The current presentation includes findings from the first analyses to evaluate the effects of an approved TD medication in an elderly population, using the more conventional age cutoff of ≥65 years. <h3>Methods</h3> Data from two long-term studies (KINECT 3-extension, KINECT 4) of participants receiving up to 48 weeks of once-daily treatment with valbenazine (40 mg or 80 mg) were pooled and analyzed by age (≥65 and <65 years). Analyses included mean change from baseline (CFB) to Week 48 in Abnormal Involuntary Movement Scale (AIMS) total score. AIMS response at Week 48 was also assessed as follows: clinically meaningful response (≥30% improvement from baseline); protocol-defined response (≥50% improvement from baseline). Additional analyses included response thresholds for Clinical Global Improvement-Tardive Dyskinesia (CGI-TD) and Patient Global Impression of Change (PGIC) as follows: rating of "minimally improved" or better (score ≤3) at Week 48 (CGI-TD≤3, PGIC≤3); rating of "much improved" or "very much improved" (score ≤2) at Week 48 (CGI-TD≤2, PGIC≤2). Treatment-emergent adverse events (TEAEs) were also monitored. <h3>Results</h3> Treatment outcomes were generally robust and comparable between the age subgroups. Pooled AIMS results indicated substantial improvements in TD movements were found in both age subgroups with valbenazine 40 mg (≥65 years, n=8; <65 years, n=46) and 80 mg (≥65 years, n=20; <65 years, n=105): mean CFB (≥65 years, -6.4 and -9.8 [for 40 and 80 mg, respectively]; <65 years, -5.5 and -8.3); clinically meaningful ≥30% response (≥65 years, 75% and 95%; <65 years, 61% and 80%); and protocol-defined ≥50% response (≥65 years, 75% and 85%; <65 years, 50% and 70%). CGI-TD and PGIC response rates indicated that clinician- and patient-reported global improvements were also substantial in both age subgroups: CGI-TD≤3 (≥65 years, 88% and 100% [for 40 and 80 mg, respectively]; <65 years, 89% and 97%); CGI-TD≤2 (≥65 years, 88% and 95%; <65 years, 62% and 83%); PGIC≤3 (≥65 years, 88% and 100%; <65 years, 89% and 94%); PGIC≤2 (≥65 years, 75% and 90%; <65 years, 77% and 80%). Analyses of TEAEs indicated no statistically significant differences between age subgroups for the incidence of any TEAEs (≥65 years, 73%; <65 years, 72%) or any serious TEAEs (≥65 years, 18%; <65 years, 17%). However, discontinuations due to TEAEs were significantly more common in elderly participants (≥65 years, 26%; <65 years, 13%; <i>P</i><0.05). <h3>Conclusions</h3> These analyses, which are the first to evaluate any approved TD medication in patients ≥65 years, indicate that long-term treatment with once-daily valbenazine is appropriate and beneficial for this age group. Elderly study participants had clinically meaningful and substantial improvements in TD that were comparable to (or better than) those in the younger cohort. These results may provide clinicians with important information about the management of TD in elderly patients. <h3>This research was funded by</h3> Neurocrine Biosciences, Inc.

Tardive Dyskinesia in Older Persons Taking Antipsychotics.

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.

Tardive Dyskinesia: Spotlight on Current Approaches to Treatment

Tardive dyskinesia (TD) is a debilitating, iatrogenic, and potentially severe movement disorder characterized by involuntary, repetitive, purposeless movements that are present throughout the body. The authors present a review of studies of past, current, and possible future treatment approaches to the management of TD; consider the phenomenology, assessment, and putative pathophysiological mechanisms of TD, early pharmacological trials, a focus on the newer vesicular monoamine transporter 2 inhibitors, and other evidence-based approaches, such as clozapine; and present preliminary evidence for newer approaches, such as deep brain stimulation and repetitive transcranial magnetic stimulation. On the basis of the evidence presented here, the authors highlight the importance of early recognition and assessment of TD, as well as how to best approach management of these often incapacitating symptoms.

A Focused Update on Tardive Dyskinesia.

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication following chronic exposure to centrally acting dopamine receptor antagonists, mainly of the class of antipsychotics drugs. New generations of antipsychotic drugs reduced its mean prevalence to 20%, but it continues to mar the drug experience and social integration in a significant fraction of patients. The underlying molecular cascade remains elusive, explaining in part why TD management is so often difficult. Protocol variations between experimental laboratories and inter-species differences in the biological response to antipsychotic drugs have added layers of complexity. The traditional dopamine D2 receptor supersensitivity hypothesis was revisited in an experimental nonhuman primate model. Findings in the striatum revealed a strong upregulation of D3, not D2, receptors specific to dyskinetic animals, and indirect evidence suggestive of a link between overactivation of glycogen synthase kinase-3β signaling and TD. New effective vesicular monoamine transporter type 2 inhibitors alleviating TD have been approved in the USA. They were integrated to an emerging stepwise treatment algorithm for troublesome TD, which also includes consideration for changes in the current antipsychotic drug regimen and recognition of potentially aggravating factors such as anticholinergic co-medications. These advances may benefit TD.

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

The purpose of this review is to summarize the current evidence for valbenazine and deutetrabenazine use for the treatment of tardive dyskinesia (TD). 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. 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.

Tardive dyskinesia: Prevention and newer management strategies

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.

Role of Vesicular Monoamine Transporter 2 Inhibitors in Tardive Dyskinesia Management.

Tardive dyskinesia (TD) is a distressing and disabling movement disorder that occurs with the use of chronic neuroleptic medications. TD is defined as involuntary athetoid or choreiform movements of head, trunk or limbs. Tongue, lower face, jaw, and extremities are commonly involved but pharyngeal, diaphragmatic, or truncal muscles are also sometimes involved affecting breathing, swallowing, speech, posture, gait, and mobility of an individual.TD is a debilitating movement disorder that requires timely intervention. Subtle tongue movements, tic-like facial movements or increased blink frequency could be some of the initial manifestations of TD. Our article is focused on the new advents in treating TD, their efficacy, and tolerability with emphasizing their side effect profile. The implication of a genetic marker vesicular monoamine transporter 2 (VMAT2), helped in investigating VMAT2 inhibitors for alleviating TD. Among the modalities tested, only VMAT2 inhibitors reported efficacy. However, the outcome of long-term use and its side effect profile can only be determined with longer studies utilizing large set data. More clinical trials are required to explore individual drug efficacy and their long-term adverse effects.We aim to provide an overview of TD management, illustrating the priority of VMAT2 inhibitors and to determine the importance of selecting an optimal medication. A search through PubMed with terms "Tardive dyskinesia" and "VMAT2 inhibitors" was carried out. Several treatment modalities were tested to control the symptoms of TD with limited benefit. However, VMAT2 inhibitors showed improvement in the Abnormal Involuntary Movement Scale (AIMS) rating scale for TD. Valbenazine and deutetrabenazine (d-TBZ) were recently approved by the Food and Drug Administration (FDA) for treating TD in adults.

Hospital utilization rates following antipsychotic dose reductions: implications for tardive dyskinesia

BackgroundData are limited on the benefits and risks of dose reduction in managing side effects associated with antipsychotic treatment. As an example, antipsychotic dose reduction has been recommended in the management of tardive dyskinesia (TD), yet the benefits of lowering doses are not well studied. However, stable maintenance treatment is essential to prevent deterioration and relapse in schizophrenia.MethodsA retrospective cohort study was conducted to analyze the healthcare burden of antipsychotic dose reduction in patients with schizophrenia. Medical claims from six US states spanning a six-year period were analyzed for ≥10% or ≥ 30% antipsychotic dose reductions compared with those from patients receiving a stable dose. Outcomes measured were inpatient admissions and emergency room (ER) visits for schizophrenia, all psychiatric disorders, and all causes, and TD claims.ResultsA total of 19,556 patients were identified with ≥10% dose reduction and 15,239 patients with ≥30% dose reduction. Following a ≥ 10% dose reduction, the risk of an all-cause inpatient admission increased (hazard ratio [HR] 1.17; 95% confidence interval [CI] 1.11, 1.23; P < 0.001), and the risk of an all-cause ER visit increased (HR 1.09; 95% CI 1.05, 1.14; P < 0.001) compared with controls. Patients with a ≥ 10% dose reduction had an increased risk of admission or ER visit for schizophrenia (HR 1.27; 95% CI 1.19, 1.36; P < 0.001) and for all psychiatric disorders (HR 1.16; 95% CI 1.10, 1.23; P < 0.001) compared with controls. A dose reduction of ≥30% also led to an increased risk of admission for all causes (HR 1.23; 95% CI 1.17, 1.31; P < 0.001), and for admission or ER visit for schizophrenia (HR 1.31; 95% CI 1.21, 1.41; P < 0.001) or for all psychiatric disorders (HR 1.21; 95% CI 1.14, 1.29; P < 0.001) compared with controls. Dose reductions had no significant effect on claims for TD.ConclusionPatients with antipsychotic dose reductions showed significant increases in both all-cause and mental health–related hospitalizations, suggesting that antipsychotic dose reductions may lead to increased overall healthcare burden in some schizophrenia patients. This highlights the need for alternative strategies for the management of side effects, including TD, in schizophrenia patients that allow for maintaining effective antipsychotic treatment.

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.

Treatment of tardive dyskinesia with tetrabenazine or valbenazine: a systematic review

Up to 30% of patients taking antipsychotics may develop tardive dyskinesia (TD). Recent evidence-based recommendations demonstrate an unmet need for effective TD management. This systematic review was designed to update the evidence for TD treatment, comparing two vesicular monoamine transporter 2 (VMAT2) inhibitors, tetrabenazine and valbenazine. Of 487 PubMed/Embase search results, 11 studies met the review criteria. Valbenazine efficacy was demonstrated in rigorously designed clinical trials that meet the guidelines for AAN Class I evidence. Due to differences in study designs and a lack of standardized and controlled trials with tetrabenazine, a formal meta-analysis comparing the agents was not possible. However, valbenazine appears to have fewer side effects and a more favorable once-daily dosing regimen for the treatment of TD.

Systematic review of interventions for treating or preventing antipsychotic-induced tardive dyskinesia.

Antipsychotic medication can cause tardive dyskinesia (TD) - late-onset, involuntary, repetitive movements, often involving the face and tongue. TD occurs in > 20% of adults taking antipsychotic medication (first-generation antipsychotics for > 3 months), with this proportion increasing by 5% per year among those who continue to use these drugs. The incidence of TD among those taking newer antipsychotics is not different from the rate in people who have used older-generation drugs in moderate doses. Studies of TD have previously been found to be limited, with no treatment approach shown to be effective. To summarise the clinical effectiveness and safety of treatments for TD by updating past Cochrane reviews with new evidence and improved methods; to undertake public consultation to gauge the importance of the topic for people living with TD/the risk of TD; and to make available all data from relevant trials. All relevant randomised controlled trials (RCTs) and observational studies. Cochrane review methods, network meta-analysis (NMA). Systematic reviews, patient and public involvement consultation and NMA. Any setting, inpatient or outpatient. For systematic reviews, adults with TD who have been taking a stable antipsychotic drug dose for > 3 months. Any, with emphasis on those relevant to UK NHS practice. Any measure of TD, global assessments and adverse effects/events. We included 112 studies (nine Cochrane reviews). Overall, risk of bias showed little sign of improvement over two decades. Taking the outcome of 'TD symptoms improved to a clinically important extent', we identified two trials investigating reduction of antipsychotic dose [n = 17, risk ratio (RR) 0.42, 95% confidence interval (CI) 0.17 to 1.04; very low quality]. Switching was investigated twice in trials that could not be combined (switching to risperidone vs. antipsychotic withdrawal: one RCT, n = 42, RR 0.45, 95% CI 0.23 to 0.89; low quality; switching to quetiapine vs. haloperidol: one RCT, n = 45, RR 0.80, 95% CI 0.52 to 1.22; low quality). In addition to RCTs, six observational studies compared antipsychotic discontinuation with decreased or increased dosage, and there was no clear evidence that any of these strategies had a beneficial effect on TD symptoms (very low-quality evidence). We evaluated the addition to standard antipsychotic care of several treatments, but not anticholinergic treatments, for which we identified no trials. We found no clear effect of the addition of either benzodiazepines (two RCTs, n = 32, RR 1.12, 95% CI 0.6 to 2.09; very low quality) or vitamin E (six RCTs, n = 264, RR 0.95, 95% CI 0.89 to 1.01; low quality). Buspirone as an adjunctive treatment did have some effect in one small study (n = 42, RR 0.53, 95% CI 0.33 to 0.84; low quality), as did hypnosis and relaxation (one RCT, n = 15, RR 0.45, 95% CI 0.21 to 0.94; very low quality). We identified no studies focusing on TD in people with dementia. The NMA model found indirect estimates to be imprecise and failed to produce useful summaries on relative effects of interventions or interpretable results for decision-making. Consultation with people with/at risk of TD highlighted that management of TD remains a concern, and found that people are deeply disappointed at the length of time it has taken researchers to address the issue. Most studies remain small and poorly reported. Clinicians, policy-makers and people with/at risk of TD are little better informed than they were decades ago. Underpowered trials of limited quality repeatedly fail to provide answers. TD reviews have data from current trials extracted, tabulated and traceable to source. The NMA highlights one context in which support for this technique is ill advised. All relevant trials, even if not primarily addressing the issue of TD, should report appropriate binary outcomes on groups of people with this problem. Randomised trials of treatments for people with established TD are indicated. These should be large (> 800 participants), necessitating accrual through accurate local/national registers, including an intervention with acceptable treatments and recording outcomes used in clinical practice. This study is registered as PROSPERO CRD4201502045. The National Institute for Health Research Health Technology Assessment programme.

Angiotensin II type 1/adenosine A2A receptor oligomers: a novel target for tardive dyskinesia

Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2Rs). Striatal D2R functioning may be finely regulated by either adenosine A2A receptor (A2AR) or angiotensin receptor type 1 (AT1R) through putative receptor heteromers. Here, we examined whether A2AR and AT1R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT1R-A2AR interaction in cultured cells. Interestingly, by protein-protein docking and molecular dynamics simulations, we described that a stable heterotetrameric interaction may exist between AT1R and A2AR bound to antagonists (i.e. losartan and istradefylline, respectively). Accordingly, we subsequently ascertained the existence of AT1R/A2AR heteromers in the striatum by proximity ligation in situ assay. Finally, we took advantage of a TD animal model, namely the reserpine-induced vacuous chewing movement (VCM), to evaluate a novel multimodal pharmacological TD treatment approach based on targeting the AT1R/A2AR complex. Thus, reserpinized mice were co-treated with sub-effective losartan and istradefylline doses, which prompted a synergistic reduction in VCM. Overall, our results demonstrated the existence of striatal AT1R/A2AR oligomers with potential usefulness for the therapeutic management of TD.

Resolution of Tardive Dyskinesia with Clozapine: A Case Report

Tardive dyskinesia is an extrapyramidal side effect that can occur after a prolonged use of antipsychotic medication, it appears to be about 0.4% to 4% worldwide. Prior reports suggest that clozapine may be effective in the management of tardive dyskinesia. We present the case of a patient with tardive dyskinesia induced by antipsychotics. After treatment failure with other psychotropic medications, clozapine medication was initiated; we used the "evaluation of tardive dyskinesia" scale to assess severity of tardive dyskinesia. We noticed a significant improvement in tardive dyskinesia from the fifth week of treatment with clozapine at the dose of 250 mg per day with a decrease in the scale score for "evaluation of tardive dyskinesia" from 70 to 22. Clozapine appears to be efficacious in the management of tardive dykinesia. Larger, randomized, blinded, and controlled prospective studies are needed to confirm these findings and to determine optimal dosage.

Conservative Approach to Tardive Dyskinesia–Induced Neck and Upper Back Pain

The management of schizophrenia typically involves the use of antipsychotics (neuroleptics). Use of such medications, however, can result in tardive dyskinesia, or the involuntary contracture of muscles, and associated symptomatic somatic dysfunction. The authors present a case of a 29-year-old woman who presented to a family medicine clinic for ongoing management of schizophrenia with noticeable tardive dyskinesia and complaints of neck and upper back pain. Conventional management of tardive dyskinesia involves either a change in or reduction of the offending antipsychotic. In the present case, the patient received osteopathic manipulative treatment in addition to conventional care for the management of her neck and upper back pain. Although not curative, osteopathic manipulative treatment can provide palliative relief for patients with tardive dyskinesia.

Rapid improvement of tardive dyskinesia with tetrabenazine, clonazepam and clozapine combined: a naturalistic long-term follow-up study

Tardive dyskinesia (TD) is a complex involuntary movement disorder affecting about 23% of neuroleptic-treated patients. Our objective was to retrospectively analyze a combination of tetrabenazine (TBZ), clonazepam (CLONAZ) and clozapine (CLOZ) used simultaneously for TD in psychotic patients. Six patients with severe, unsuccessfully controlled TD were referred for treatment (mean age 51.5 years; three male; four schizophrenics; one bipolar disease; one borderline personality disorder). They were being treated with neuroleptics (classic, three; risperidone, two; olanzapine, one) and developed severe neck and buccolingual dyskinesias. At our clinic, all of them were treated simultaneously with TBZ (mean dose 141.6mg); CLONAZ (mean dose 4.3mg); and CLOZ (mean dose 125mg). In parallel, we stopped the offending medication. With 1week, we observed a very impressive improvement in symptoms and within 1month all the patients were free of symptoms. The mean observation period was 4years. The combination of TBZ, CLONAZ and CLOZ is a rapid and beneficial option for the management of TD. An augmentation effect probably played a role in the rapid alleviation of symptomatology.