Dopamine Receptor-blocking Agents Research Articles

Clinician Perceptions of the Negative Impact of Telehealth Services in the Management of Drug-Induced Movement Disorders and Opportunities for Quality Improvement: A 2021 Internet-Based Survey.

Tardive dyskinesia (TD) is a drug-induced movement disorder (DIMD) seen in patients taking dopamine-receptor blocking agents (DRBAs). Clinicians should regularly monitor patients with or at risk of developing DIMDs; however, telehealth visits during the COVID-19 pandemic presented several significant challenges related to screening and care of these patients. In this observational survey study, respondents compared in-person with video/telephone visits to determine the impact on the evaluation, diagnosis, and monitoring of patients with DIMDs. The online survey was conducted (May 14-June 21, 2021) with qualified clinicians who prescribed a vesicular monoamine transporter 2 inhibitor or benztropine for DIMDs in the past 6 months, spent ≤70% of their professional time in the clinic, and conducted telehealth visits with ≥15% of their patients between December 2020 and January 2021. The questionnaire probed clinicians about their ability to evaluate, diagnose and monitor (hereinafter referred to as manage) patients with DIMDs via telehealth. Survey respondents included 277 clinicians from psychiatry (n = 168) and neurology (n = 109) practices. Certain signs and symptoms (visual cues) used for diagnosis of DIMDs were not observable through telehealth and evaluation was comparatively more difficult with phone visits than video visits. Patients without caregivers and lower-functioning patients were at higher risk of missed diagnosis of DIMDs and were also difficult to monitor via telehealth. Limited access to computers or telephones and patients living alone were among the top socioeconomic barriers limiting clinicians' ability to diagnose DIMDs. Patients without a regular caregiver were also more difficult for clinicians to evaluate and monitor adequately. Further, most clinicians received no training related to evaluation of DIMDs via telehealth or engaging caregivers as health care partners. Our study highlights specific limitations and challenges and provides considerations to help clinicians better manage DIMDs in the context of telehealth services.

Severe tongue protrusion dyskinesia after dental extractions

A 63-year-old woman with a history of postnatal infectious encephalopathy was referred for an evaluation of sustained involuntary tongue protrusion and copious drooling. The tongue dyskinesia had increased in the past 5 months since the extraction of her remaining mandibular teeth (Figure, A) and substantially decreased when a grape was inserted in the mouth (Figure, B) (see video in supplemental material). The patient had epilepsy, severe intellectual disability, and episodes of aggressiveness, secondary to the encephalopathy. To control her irritability, the patient had been undergoing therapy for the past 6 years with periciazine, a first-generation neuroleptic of the phenothiazine family (not marketed in the United States), whose mechanism of action is that of a dopamine receptor blocking agent (DRBA). A routine biochemical blood test was requested as well as a peripheral blood smear, serum ceruloplasmin level, urine copper titers, and brain magnetic resonance imaging (MRI), the results of which were normal. Dr. Diniz Freitas is an adjunct professor of Special Care Dentistry, Medical-Surgical Dentistry Research Group, Health Research Institute of Santiago de Compostela, University of Santiago de Compostela, Santiago de Compostela, Spain. Dr. Diz Dios is a professor of Special Care Dentistry, Medical-Surgical Dentistry Research Group, Health Research Institute of Santiago de Compostela, University of Santiago de Compostela, Santiago de Compostela, Spain. Dr. Fernández Feijoo is an associate professor of Special Care Dentistry, Medical-Surgical Dentistry Research Group, Health Research Institute of Santiago de Compostela, University of Santiago de Compostela, Santiago de Compostela, Spain. Dr. Limeres Posse is an associate professor of Special Care Dentistry, Medical-Surgical Dentistry Research Group, Health Research Institute of Santiago de Compostela, University of Santiago de Compostela, Santiago de Compostela, Spain. Dr. Outumuro Rial is an adjunct professor of Special Care Dentistry, Medical-Surgical Dentistry Research Group, Health Research Institute of Santiago de Compostela, University of Santiago de Compostela, Santiago de Compostela, Spain.

Late-Onset Dyskinesia Occurring During Antipsychotic Treatment for Schizophrenia: Management of Tardive Dyskinesia Based on the Latest Knowledge

Tardive dyskinesia is a drug-induced involuntary movement related to long-term use of dopamine receptor-blocking agents. If there is no improvement upon discontinuation or change in the causative drug, treatment needs to be initiated. The most effective drug is the vesicular monoamine transporter 2 selective inhibitor. Other drugs, such as clonazepam, amantadine, yokukansan, and Ginkgo biloba extract, may be effective in some patients. Botulinum toxin treatment and deep brain stimulation are potential treatment options for patients with tardive dyskinesia that is refractory to the aforementioned agents. Optimal treatment should be selected while monitoring for mental illnesses.

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.

Free Papers Compiled

BACKGROUND:Antipsychotic medications are used to treat and manage symptoms for several psychiatric disorders and are commonly categorised into two classes namely first generation and second generation antipsychotics. Extrapyramidal motor symptoms are major adverse effects of antipsychotics mediated by blockade of dopamine signalling in the nigrostriatal dopamine system. First generation antipsychotics exhibit a narrow therapeutic window compared to second generation antipsychotics with respect to these Extrapyramidal side effects. The risk factors for EPS are complicated and are related to a lot of factors including demographics, antipsychotic dosage, duration of treatment and so forth.AIM OF THE STUDY:The aim of the study is to profile patients who have developed, extrapyramidal adverse effects and identify risk factors significantly associated with each subtype of extrapyramidal effects and to compare the risk factors between first and second generation antipsychotics.MATERIALS AND METHODS:A retrospective cross sectional study was conducted using case records of patients, who were treated as inpatients in IMH, Kilpauk from July 2021 to September 2021. Descriptive statistics was used to analyse patient characteristics, including age, gender, BMI category, specific antipsychotics, dosage, daily chlorpromazine equivalents and the presence of antipsychotics overdose with respect to first generation and second generation antipsychotics and the results were compared.RESULTS:There was a male preponderance among the study participants. In our study population, the most common antipsychotics precipitating EPSs were Haloperidol and Risperidone. There was significant association between gender and the type of EPS, tremors were significantly higher among females whereas hypersalivation and bradykinesia was more common among males in both first and second generation antipsychotics. There was no significant association between diagnosis and the type of EPS.REFERENCES:Musco S, Ruekert L, Myers J, Anderson D, Welling M, Cunningham EA. Characteristics of Patients Experiencing Extrapyramidal Symptoms or Other Movement Disorders Related to Dopamine Receptor Blocking Agent Therapy. J Clin Psychopharmacol. 2019 Jul/Aug;39(4):336-343. doi: 10.1097/JCP.0000000000001061. PMID: 31205194; PMCID: PMC6594730.Krause M, Huhn M, Schneider-Thoma J, Bighelli I, Gutsmiedl K, Leucht S. Efficacy, acceptability and tolerability of antipsychotics in patients with schizophrenia and comorbid substance use. A systematic review and meta-analysis. Eur Neuropsychopharmacol. 2019 Jan;29(1):32-45. doi: 10.1016/j.euroneuro.2018.11.1105. Epub 2018 Nov 22. PMID: 30472164.

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.

Akathisia and Restless Legs Syndrome

Akathisia is an urgent need to move that is associated with treatment with dopamine receptor blocking agents (DRBAs) and with restless legs syndrome (RLS). The pathogenetic mechanism of akathisia has not been resolved. This article proposes that it involves an increased presynaptic dopaminergic transmission in the ventral striatum and concomitant strong activation of postsynaptic dopamine D1 receptors, which form complexes (heteromers) with dopamine D3 and adenosine A1 receptors. It also proposes that in DRBA-induced akathisia, increased dopamine release depends on inactivation of autoreceptors, whereas in RLS it depends on a brain iron deficiency–induced down-regulation of striatal presynaptic A1 receptors.

Differentiating tardive dyskinesia: a video-based review of antipsychotic-induced movement disorders in clinical practice.

Accurate diagnosis and appropriate treatment of tardive dyskinesia (TD) are imperative, as its symptoms can be highly disruptive to both patients and their caregivers. Misdiagnosis can lead to incorrect interventions with suboptimal or even deleterious results. To aid in the identification and differentiation of TD in the psychiatric practice setting, we review its clinical features and movement phenomenology, as well as those of other antipsychotic-induced movement disorders, with accompanying links to illustrative videos. Exposure to dopamine receptor blocking agents (DRBAs) such as antipsychotics or antiemetics is associated with a spectrum of movement disorders including TD. The differential diagnosis of TD is based on history of DRBA exposure, recent discontinuation or dose reduction of a DRBA, and movement phenomenology. Common diagnostic challenges are the abnormal behaviors and dyskinesias associated with advanced age or chronic mental illness, and other movement disorders associated with DRBA therapy, such as akathisia, parkinsonian tremor, and tremor related to use of mood stabilizing agents (eg, lithium, divalproex). Duration of exposure may help rule out acute drug-induced syndromes such as acute dystonia or acute/subacute akathisia. Another important consideration is the potential for TD to present together with other drug-induced movement disorders (eg, parkinsonism, parkinsonian tremor, and postural tremor from mood stabilizers) in the same patient, which can complicate both diagnosis and management. After documentation of the phenomenology, severity, and distribution of TD movements, treatment options should be reviewed with the patient and caregivers.

Clinical Spectrum of Drug-Induced Movement Disorders: A Study of 97 Patients.

Background:Drug-induced movement disorders (DIMDs) are commonly encountered, but an often-under-reported subgroup of movement disorders.Objectives:We aimed to highlight the spectrum of DIMDs in patients taking different groups of drugs at our movement disorder center.Methods:It is a cross-sectional descriptive study including 97 consecutive DIMDs patients diagnosed over the past two years (2017–2019).Results:The mean ± standard deviation (SD) age of our study population was 35.89 ± 17.8 years (Range-2–80 years). There were 51 males and 46 females. Different DIMDs observed included tardive dystonia (n = 41; 42.2%), postural tremor (n = 38; 39.2%), parkinsonism (n = 32; 33%), tardive dyskinesia (n = 21; 21.6%), acute dystonia (n = 10; 10.3%), neuroleptic malignant syndrome (NMS) (n = 2; 2.1%), and others [(n = 10; 10.30%) including chorea and stereotypy each in 3; acute dyskinesia in 2; and myoclonic jerks and acute akathisia each in 1 patient]. Of these 97 patients, 49 had more than one type of DIMDs while 48 had a single type of DIMDs. In our study 37 (38%) patients had received non-dopamine receptor blocking agents (non-DRBA), 30 (31%) patients had received dopamine receptor blocking agents (DRBA), and 30 (31%) patients had received both DRBA and non-DRBA.Conclusions:Tardive dystonia was the most common DIMDs observed in our study. Our DIMDs patients were younger than other reported studies. We observed a significant number of non-DRBA drugs causing DIMD in our study as compared to previous studies. Drug-induced parkinsonism (DIP) was the most common DIMDs in the DRBA group. Tardive dystonia was the most common DIMDs seen in DRBA + non-DRBA group and the second most common in the DRBA and non-DRBA group. The postural tremor was the most common DIMDs in the non-DRBA group.

Real-world evaluation of patient characteristics and disease management in long-term valbenazine treatment in adults with Tardive dyskinesia

Objectives: Tardive dyskinesia (TD) is a persistent and often disabling involuntary movement disorder that is associated with long-term exposure to dopamine receptor blocking agents (DRBAs) such as antipsychotics. The long-term efficacy of INGREZZA® (valbenazine) capsules, which was approved in 2017 for treating TD in adults, has been demonstrated in several prospective clinical trials. This multi-center, retrospective chart review will assess the clinical characteristics and overall disease management of adult patients receiving long-term valbenazine treatment for TD in a real-world setting.

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.

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.

Treatment Strategies for Tardive Dyskinesia.

Tardive dyskinesia (TD), a condition of potentially irreversible abnormal involuntary movements that is associated with dopamine receptor blocking agents (DRBAs), produces significant impairment of functioning and quality of life for patients. Contrary to expectations, TD has not vanished despite the introduction of SGAs. Instead, changing prescription practices and increased off-label prescription of DRBAs have placed more patients than ever at risk of this potentially dangerous and disabling condition. This activity provides an overview of treatment strategies for TD as part of an individualized management plan, including DRBA medication adjustment and antidyskinetic treatment.

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

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. 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). 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. 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.

Current treatment of tardive dyskinesia

Tardive dyskinesia (TD) is a common, iatrogenic movement disorder affecting many individuals treated with dopamine-receptor blocking agents (DRBAs). Studying treatment of TD can be complex, as the symptoms can be affected by changes in either dosage or type of DRBA, as well as by the variable natural course of the disease. Historically many pharmacological therapies have been studied in TD, finding varying degrees of treatment success. Most recently, the VMAT2 inhibitors valbenazine and deutetrabenazine were rigorously studied in TD in large, phase III clinical trials, and were shown to be beneficial in this population. In this article, we will review various treatments of TD, including manipulation of the offending agent, VMAT2 inhibitors, other non-VMAT2-inhibiting medications, and non-pharmacological approaches.

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.

Tardive dyskinesia: Who gets it and why

Tardive dyskinesia (TD) is a potentially permanent movement disorder resulting from chronic use of dopamine receptor blocking agents (DRBA). Identified risk factors include the type of antipsychotic agent, being greater for those of first generation antipsychotics (FGA), the duration of illness and cumulative dose of DRBA and advanced age. Female sex and African and Caucasian ethnicity are additional potential risk factors. Because only a subset of people taking DRBA's develops TD, genetics may play a role. Susceptibility gene candidates include those involved in DRBA metabolism and the targets or receptors of DRBA's. Although met with conflicting data, the following genes may be involved with TD development: the cytochrome P450 gene CYP2D6, involved with metabolism of most antipsychotics, Dopamine D2 and D3 receptor genes, serotonin 2A and 2C receptor genes, vesicular monoamine transporter 2 (VMAT 2) gene, involved with intracellular neurotransmitter packaging, and the manganese superoxide dismutase (MnSOD) gene, an antioxidant enzyme. Heparan sulfate proteoglycan 2 (HSPG 2) gene is another potential gene involved with development of TD. The pathogenesis of TD is unknown, however there are three main theories proposed: dopamine receptor supersensitivity resulting from chronic dopamine receptor blockade, oxidative stress and maladaptive synaptic plasticity each of which is discussed further in this article.Tardive dyskinesia (TD) is a potentially permanent and disabling adverse effect from certain medications. By definition TD is the insidious onset of rhythmic, repetitive, stereotypic movements of the face, mouth and tongue, often with involvement of the trunk and extremities that occur as a result of dopamine receptor blocking agents (DRBA) [1]. The term tardive refers to the delayed onset of the disorder. The mean prevalence of TD is estimated to be 25.3% in psychiatric patients taking antipsychotics [2]. Compared to the number of people taking these drugs, TD represents a minority. TD is a potentially permanent condition; stopping the offending agent does not always alleviate the condition. Therefore, prevention of TD by avoiding DRBA's if at all possible is ideal. However, there is no apparent way to predict who will develop TD and there are some cases in which DRBA's are necessary for treatment of chronic conditions. As TD has been present since the development of DRBA's, possible risk factors for its development have been studied. Solmi et al. (2018) [3] have written a comprehensive review on this subject.

Treatment of Tardive Dyskinesia: A General Overview with Focus on the Vesicular Monoamine Transporter 2 Inhibitors.

Tardive dyskinesia (TD) encompasses the spectrum of iatrogenic hyperkinetic movement disorders following exposure to dopamine receptor-blocking agents (DRBAs). Despite the advent of atypical or second- and third-generation antipsychotics with a presumably lower risk of complications, TD remains a persistent and challenging problem. Prevention is the first step in mitigating the risk of TD, but early recognition, gradual withdrawal of offending medications, and appropriate treatment are also critical. As TD is often a persistent and troublesome disorder, specific antidyskinetic therapies are often needed for symptomatic relief. The vesicular monoamine transporter 2 (VMAT2) inhibitors, which include tetrabenazine, deutetrabenazine, and valbenazine, are considered the treatment of choice for most patients with TD. Deutetrabenazine-a deuterated version of tetrabenazine-and valbenazine, the purified parent product of one of the main tetrabenazine metabolites, are novel VMAT2 inhibitors and the only drugs to receive approval from the US FDA for the treatment of TD. VMAT2 inhibitors deplete presynaptic dopamine and reduce involuntary movements in many hyperkinetic movement disorders, particularly TD, Huntington disease, and Tourette syndrome. The active metabolites of the VMAT2 inhibitors have high affinity for VMAT2 and minimal off-target binding. Compared with tetrabenazine, deutetrabenazine and valbenazine have pharmacokinetic advantages that translate into less frequent dosing and better tolerability. However, no head-to-head studies have compared the various VMAT2 inhibitors. One of the major advantages of VMAT2 inhibitors over DRBAs, which are still being used by some clinicians in the treatment of some hyperkinetic disorders, including TD, is that they are not associated with the development of TD. We also briefly discuss other treatment options for TD, including amantadine, clonazepam, Gingko biloba, zolpidem, botulinum toxin, and deep brain stimulation. Treatment of TD and other drug-induced movement disorders must be individualized and based on the severity, phenomenology, potential side effects, and other factors discussed in this review.

The nosology of tardive syndromes

Since the original description of side effects of neuroleptics, different terminologies and definitions for tardive dyskinesia (TD) and tardive syndrome (TS) have been used by different authors, and often these two terms have been used interchangeably. This paper proposes a nosology designed to define and clarify various terms and phenomenologies within the TS spectrum.We propose to use the term tardive dyskinesia to refer to the original description of repetitive and complex oral-buccal-lingual (OBL) movements, as well as to the analogous repetitive movements that can appear in the limbs, trunk, or pelvis. The repetitive, relatively rhythmic nature of the movements is the common denominator of this phenomenologic category.The term tardive syndrome refers to the spectrum of all persistent hyperkinetic, hypokinetic and sensory phenomenologies resulting from chronic dopamine receptor blocking agents (DRBA) exposure. Thus, TS is an umbrella term.When dystonia is the main feature of TS it is considered to be tardive dystonia (TDyst). Retrocollis appears to be the predominant form of cervical dystonia in this condition. Cranial dystonias, particularly oromandibular dystonia, are also common forms of TDyst. Tardive akathisia refers to the inability to remain still with an urge to move, giving the appearance of restlessness. It is a sensory phenomenon and a common and disabling form of TS. Unlike acute akathisia, tardive akathisia tends to occur late and persists after the drug is withdrawn. In tardive tourettism, the patient exhibits the features of Tourette syndrome with complex motor and phonic tics associated with premonitory urge and relief of tension after performing the tic behavior. Tardive tremor differs from the resting tremor seen in drug-induced parkinsonism in that it is mainly a postural and kinetic greater than resting tremor. Tardive pain has been reported in association with chronic use of DRBA's. The pain involved the mouth, tongue and the genital region. The patients tended to obsess over the pain and usually had some other form of motor tardive syndrome, either tardive dyskinesia, tardive akathisia or tardive dystonia. The term tardive parkinsonism has been proposed for those drug induced parkinsonism patients who have persistent symptoms following discontinuation of the DRBA. However, there is a strong possibility that the DRBA may have simply unmasked subclinical parkinsonism or that there is coincident Parkinson disease developing during the period the patient is taking the DRBA.

Deficient striatal adaptation in aminergic and glutamatergic neurotransmission is associated with tardive dyskinesia in non-human primates exposed to antipsychotic drugs

Tardive dyskinesia (TD) is a potentially disabling condition encompassing all delayed, persistent, and often irreversible abnormal involuntary movements arising in a fraction of subjects during long-term exposure to centrally acting dopamine receptor-blocking agents such as antipsychotic drugs and metoclopramide. However, the pathogenesis of TD has proved complex and remains elusive. To investigate the mechanism underlying the development of TD, we have chronically exposed 17 Cebus apella monkeys to typical (11) or atypical (6) antipsychotic drugs. Six additional monkeys were used as controls. Using autoradiography, Western blot and in situ hybridization techniques, we compared neurochemical components of the dopamine, serotonin, and glutamate neurotransmitter systems modulating striatal activity in monkeys chronically exposed to haloperidol and clozapine. Five (5) out of 11 monkeys treated with haloperidol develop TD, whereas none of the monkeys treated with clozapine develop TD. Haloperidol treatment significantly upregulated the levels of serotonin 5-HT2A receptor, NR2A-containing NMDA receptors, and tyrosine hydroxylase contents in the monkey putamen, whereas clozapine regulated putamen NMDA receptor levels and tyrosine hydroxylase contents, and 5-HT2A and dopamine transporter outside the putamen. Comparisons of neurochemical alterations between dyskinetic and non dyskinetic animals within the haloperidol-treated group indicate that modulations of 5-HT2A, metabotropic glutamate type 5, NR2A- and NR2B-containing NMDA receptors, and vesicular monoamine transporter type 2 levels were restricted to the non dyskinetic group. The foregoing results suggest that TD is associated with complex deficient adaptation in aminergic and glutamatergic neurotransmission in the striatum of non-human primates chronically exposed to antipsychotic drugs.