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Stanley N Caroff Corporal Michael J Crescenz VA Medical Center, and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Abstract: Tardive dyskinesia (TD) is a heterogeneous syndrome of involuntary hyperkinetic movements that is often persistent and occurs belatedly during treatment with antipsychotics. Recent approval of two dopamine-depleting analogs of tetrabenazine based on randomized controlled trials offers an evidence-based therapeutic approach to TD for the first time. These agents are optimally used within the context of a comprehensive approach to patient management that includes a practical screening and monitoring program, sensitive and specific criteria for the diagnosis of TD, awareness of the severity and impact of the disorder, informed discussions with patients and caregivers, and a rational basis for prescribing decisions about continued antipsychotic and adjunctive agents. Areas of limited or inconclusive data, bias and misunderstandings about key aspects, and neglect of training about TD in recent years contribute to barriers in providing effective care and promoting patient safety. Keywords: tardive dyskinesia, valbenazine, deutetrabenazine, tetrabenazine vesicular monoamine transporter inhibitors, antipsychotics, schizophrenia, bipolar disorder, major depressive disorder, drug-induced movement disorders

Background and Objectives: Vertical rhythmic dyskinetic movements that are primarily drug-induced and affect solely the jaw, mouth, and lips without involving the tongue have been historically described as "rabbit" syndrome (RS). Evidence on the unique features and implications of this disorder remains limited. This literature review aims to evaluate the clinical-epidemiological profile, pathological mechanisms, and management of this movement disorder. Materials and Methods: Two reviewers identified and assessed relevant reports in six databases without language restriction published between 1972 and 2024. Results: A total of 85 articles containing 146 cases of RS were found. The mean frequency of RS among adults in psychiatric hospitals was 1.2% (range 0-4.4%). The mean age of affected patients was 49.2 (SD: 17.5), and 63.6% were females. Schizophrenia was the most frequent comorbidity found in 47.6%, followed by bipolar disorder (17.8%), major depressive disorder (10.3%), and obsessive-compulsive disorder (3.7%). Five cases were idiopathic. The most common medications associated with RS were haloperidol (17%), risperidone (14%), aripiprazole (7%), trifluoperazine (5%), and sulpiride (5%). The mean duration of pharmacotherapy before RS was 21.4 weeks (SD: 20.6). RS occurred in association with drug-induced parkinsonism (DIP) in 27.4% and with tardive dyskinesia (TD) in 8.2% of cases. Antipsychotic modification and/or anticholinergic drugs resulted in full or partial recovery in nearly all reported cases in which they were prescribed. Conclusions: RS occurs as a distinct drug-induced syndrome associated primarily but not exclusively with antipsychotics. Distinguishing RS from TD is important because the treatment options for the two disorders are quite different. By contrast, RS may be part of a spectrum of symptoms of DIP with similar course, treatment outcomes, and pathophysiology.

There is an increasing demand for effective treatments for depression, particularly for individuals grappling with treatment-resistant depression. Over recent years, a surge of interest has focused on exploring the safety and efficacy of psilocybin as a potential treatment for depression. However, preliminary findings from phase 2 studies have been inconclusive, prompting critical examination of issues such as maintaining blinding and the role of adjunctive psychotherapy. The maintenance of double-blinding and the role of adjunctive psychotherapy introduce biases that complicate the attainment of conclusive results in clinical research. Examining historical data reveals a recurrent pattern linked to the use of psychoactive substances, which starts with an excess of optimism and ends with general addictive behaviors and a heightened risk of serious public health problems. Considering these findings, a cautious and measured approach is imperative, given that the efficacy and safety of psilocybin treatment have yet to be unequivocally established. The potential for excessive optimism among researchers is a notable concern, as unwarranted enthusiasm may inadvertently facilitate the widespread adoption of this treatment without sufficient empirical support. In navigating the complexities of depression treatment, it is necessary to strike a balance between innovation and prudence to ensure evidence-based advancement of therapeutic approaches.

Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are drug-induced parkinsonism (DIP), dystonia, akathisia, and tardive dyskinesia (TD). Although rare, neuroleptic malignant syndrome (NMS) is a potentially life-threatening consequence of DRBA exposure. Recommendations for anticholinergic use in patients with DIMDs were developed on the basis of a roundtable discussion with healthcare professionals with extensive expertise in DIMD management, along with a comprehensive literature review. The roundtable agreed that "extrapyramidal symptoms" is a non-specific term that encompasses a range of abnormal movements. As such, it contributes to a misconception that all DIMDs can be treated in the same way, potentially leading to the misuse and overprescribing of anticholinergics. DIMDs are neurobiologically and clinically distinct, with different treatment paradigms and varying levels of evidence for anticholinergic use. Whereas evidence indicates anticholinergics can be effective for DIP and dystonia, they are not recommended for TD, akathisia, or NMS; nor are they supported for preventing DIMDs except in individuals at high risk for acute dystonia. Anticholinergics may induce serious peripheral adverse effects (e.g., urinary retention) and central effects (e.g., impaired cognition), all of which can be highly concerning especially in older adults. Appropriate use of anticholinergics therefore requires careful consideration of the evidence for efficacy (e.g., supportive for DIP but not TD) and the risks for serious adverse events. If used, anticholinergic medications should be prescribed at the lowest effective dose and for limited periods of time. When discontinued, they should be tapered gradually., (© 2024. The Author(s).)

Objective: Current clinician-rated tardive dyskinesia (TD) symptom scales have not addressed the expanding clinical signs and functional impact of TD. The study objective was to develop and test the reliability of a new integrated instrument., Methods: A movement disorder neurologist devised the outline of the rating scale. A Steering Committee (5 neurologists and 2 psychiatrists) provided revisions until consensus was reached. The Clinician's Tardive Inventory (CTI) assesses abnormal movements of the eye/eyelid/face, tongue/mouth, jaw, and limb/trunk; complex movements defined as complicated movements different from simple patterned movements or postures; and vocalizations. The CTI rates frequency of symptoms from 0 to 3 (ranging from absent to constant). Functional impairments, including activities of daily living (ADL), social impairment, symptom distress, and physical harm, are rated 0-3 (ranging from unawareness to severe impact). The CTI underwent interrater and test-retest reliability testing between February and June 2022 based on videos and accompanying vignettes, which were reviewed by 2 movement disorder specialists to determine adequacy. Four clinicians rated each video/vignette. Interrater agreement was analyzed via 2-way random-effects intraclass correlation (ICC), and test-retest agreement was assessed utilizing the Kendall tau-b., Results: Forty-five video/vignettes were assessed for interrater reliability and 16 for test-retest reliability. The most prevalent movements were those of the tongue and mouth (77.8%) and jaw (55.6%). ICCs for movement frequency for anatomic symptoms were as follows: anatomic symptom summary score 0.92, abnormal eye movement 0.89, abnormal tongue/mouth movement 0.91, abnormal jaw movement 0.89, abnormal limb movement 0.76, complex movement 0.87, and abnormal vocalization 0.77; ICCs for functional impairments were as follows: total impairment score 0.92, physical harm 0.82, social embarrassment 0.88, ADLs 0.83, and symptom bother 0.92; Retests were conducted a mean (SD) of 15 (3) days later with correlation coefficients ranging from 0.66 to 0.87., Conclusions: The CTI is a new integrated instrument with proven reliability in assessing TD signs and functional impacts. Future validation study is warranted., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

While the psychopathology of mental disorders during pregnancy and the postpartum period is a growing area of research, the prevalence and significance of catatonic symptoms has been relatively neglected. To address this gap in knowledge, a systematic review of articles on catatonia occurring during pregnancy and the postpartum period was conducted. PubMed, Excerpta Medica, (later EMBASE) databases were queried for articles published in English from their inception in 1966 and 1946, respectively to May 31. 2022 using the terms "catatonia", AND "perinatal", "puerperal", "postpartum", "antepartum" "lactation" "pregnancy" or "pregnancy-related", supplemented by a manual search of references. This review failed to identify any well-designed, prospective, or controlled studies addressing the subject of catatonia during pregnancy or the postpartum period; only one retrospective chart review, a single small case series, and twenty single case reports were found. The limited literature suggests that the clinical presentation and treatment response during pregnancy and after childbirth are similar to catatonia observed in other contexts. Catatonic signs and symptoms could affect physical and mental health, markedly compromising a mother's ability to take care of and bond with her infant. Further studies are needed to advance understanding of the role of catatonia in the pathogenesis, diagnosis and treatment of perinatal mental disorders., Competing Interests: Declaration of competing interest Dr. Caroff received research grants for unrelated projects from Neurocrine Biosciences and Eagle Pharmaceuticals and served as consultant for Neurocrine Biosciences and Adamas Pharmaceuticals. The other authors have no declarations of interest to report., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Catatonia is a neuropsychiatric syndrome consisting of psychomotor abnormalities caused by a broad range of disorders affecting brain function. While the nosological status of catatonia is no longer restricted to a subtype of schizophrenia in standardized diagnostic systems, the character, course, and clinical significance of catatonia in people with schizophrenia remain unclear. Evidence suggests that catatonia could be a nonspecific state-related phenomenon, a fundamental core symptom dimension of schizophrenia, or a subcortical variant of schizophrenia. Either way, the validity of catatonia in schizophrenia is clinically significant only insofar as it predicts prognosis and response to treatment. Most contemporary clinical trials of antipsychotics have targeted schizophrenia as an overly broad unitary psychosis neglecting any differential response defined by phenomenology or course. However, early naturalistic studies showed that catatonia predicted poor response to first-generation antipsychotics in chronic schizophrenia and case reports cautioned against the risk of triggering neuroleptic malignant syndrome. More recent studies suggest that second-generation antipsychotics, particularly clozapine, may be effective in schizophrenia with catatonic symptoms, while small randomized controlled trials have found that the short-term response to ECT may be faster and more significant. Based on available data, conclusions are limited as to whether antipsychotics are as effective and safe in acute and chronic schizophrenia with catatonic symptoms compared to other treatments and compared to schizophrenia without catatonia. Further studies of the pathophysiology, phenomenology, course and predictive value of catatonia in schizophrenia are worthwhile., Competing Interests: Declaration of competing interest Stanley N. Caroff reports a relationship with Neurocrine Biosciences Inc. that includes: consulting or advisory. Stanley N. Caroff reports a relationship with Adamas Pharmaceuticals Inc. that includes: consulting or advisory. Stanley N. Caroff reports a relationship with Neurocrine Biosciences Inc. that includes: funding grants. Stanley N. Caroff reports a relationship with Eagle Pharmaceuticals Inc. that includes: funding grants., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: RE-KINECT (NCT03062033), a real-world study of possible tardive dyskinesia (TD) in antipsychotic-treated patients, included a questionnaire to assess the effects of patients' abnormal involuntary movements on caregivers., Aims: To capture the experiences of caregivers who assisted individuals with abnormal involuntary movements that were confirmed by clinicians as being consistent with TD., Methods: Qualified (nonpaid) caregivers were invited to complete a questionnaire that included the following: caregivers' sociodemographic characteristics, their perceptions about the impact of abnormal involuntary movements on patients, and the impact of these movements on themselves (caregivers)., Results: Of the 41 participating caregivers, 25 (61.0%) were women, 20 (48.8%) were employed full time or part time, and 35 (85.4%) were family members or friends. Based on responses from caregivers who noticed patients' abnormal involuntary movements and were caring for individuals who also noticed those movements, 48.0% of patients had "a lot" of severity in ≥1 body region and 76.0% had abnormal involuntary movements in ≥2 regions. Caregiver ratings were significantly correlated with patient ratings (but not with clinician ratings) for maximum severity of abnormal involuntary movements and the number of affected regions (both p <.05). Based on their own judgments and perceptions, caregivers reported that the patient's movements had "some" or "a lot" of impact on their (caregiver's) ability to continue usual activities (50.0%), be productive (58.3%), socialize (55.6%), or take care of self (50.0%)., Conclusions: Caregivers as well as patients are negatively affected by TD, and the impact of TD on caregivers' lives should be considered when determining treatment options.

Tardive dyskinesia (TD) is a heterogeneous, hyperkinetic movement disorder induced by dopamine-receptor blocking agents that presents a unique challenge in the treatment of psychosis. Although acceptance of TD as a serious consequence of antipsychotic treatment was resisted initially, subsequent research by many investigators in psychopharmacology contributed to a rich store of knowledge on many aspects of the disorder. While basic neuroscience investigations continue to deepen our understanding of underlying motor circuitry, past trials of potential treatments of TD focusing on a range of theoretical targets were often inconclusive. Development of newer antipsychotics promised to reduce the risk of TD compared to older drugs, but their improved tolerability unexpectedly enabled an expanding market that paradoxically both increased the absolute number of patients at risk and diminished attention to TD which was relegated to legacy status. Fortunately, development and approval of novel vesicular monoamine transporter inhibitors offered evidence-based symptomatic treatment of TD for the first time and rekindled interest in the disorder. Despite recent progress, many questions remain for future research including the mechanisms underlying TD, genetic predisposition, phenomenological diversity, whether new cases are reversible, how to implement best practices to prevent and treat TD, and whether the development of novel antipsychotics free of the risk of TD is attainable. We owe our patients the aspirational goal of striving for zero prevalence of persistent symptoms of TD in anyone treated for psychosis.

Background: Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with antipsychotic use. Data from RE-KINECT, a real-world study of antipsychotic-treated outpatients, were analyzed to assess the effects of possible TD on patient health and social functioning., Methods: Analyses were conducted in Cohort 1 (patients with no abnormal involuntary movements) and Cohort 2 (patients with possible TD per clinician judgment). Assessments included: EuroQoL's EQ-5D-5L utility (health); Sheehan Disability Scale (SDS) total score (social functioning); patient- and clinician-rated severity of possible TD ("none", "some", "a lot"); and patient-rated impact of possible TD ("none", "some", "a lot"). Regression models were used to analyze the following: associations between higher (worse) severity/impact scores and lower (worse) EQ-5D-5L utility (indicated by negative regression coefficients); and associations between higher (worse) severity/impact scores and higher (worse) SDS total score (indicated by positive regression coefficients)., Results: In Cohort 2 patients who were aware of their abnormal movements, patient-rated TD impact was highly and significantly associated with EQ-5D-5L utility (regression coefficient: - 0.023, P < 0.001) and SDS total score (1.027, P < 0.001). Patient-rated severity was also significantly associated with EQ-5D-5L utility (- 0.028, P < 0.05). Clinician-rated severity was moderately associated with both EQ-5D-5L and SDS, but these associations were not statistically significant., Conclusions: Patients were consistent in evaluating the impacts of possible TD on their lives, whether based on subjective ratings ("none", "some", "a lot") or standardized instruments (EQ-5D-5L, SDS). Clinician-rated severity of TD may not always correlate with patient perceptions of the significance of TD., (© 2023. The Author(s).)

Background: Intravenous dantrolene is often prescribed for hypermetabolic syndromes other than the approved indication of malignant hyperthermia (MH). To clarify the extent of and indications for dantrolene use in conditions other than MH, we sought to document current practices in the frequency, diagnoses, clinical characteristics and outcomes associated with dantrolene treatment in critical care settings., Methods: Inpatients receiving intravenous dantrolene from October 1, 2004 to September 30, 2014 were identified retrospectively in the U.S. Veterans Health Administration national database. Extracted data included; diagnoses of hypermetabolic syndromes; triggering drugs; dantrolene dosages; demographics; vital signs; laboratory values; in-hospital mortality; complications; and lengths of stay. Frequency and mortality of patients who did not receive dantrolene were obtained in selected diagnoses for exploratory comparisons., Results: Dantrolene was administered to 304 inpatients. The most frequent diagnoses associated with dantrolene treatment were neuroleptic malignant syndrome (NMS; N = 108, 35.53%) and sepsis (N = 47, 15.46%), with MH accounting for only 13 (4.28%) cases. Over half the patients had psychiatric comorbidities and received psychotropic drugs before dantrolene treatment. Common clinical findings in patients receiving dantrolene included elevated temperature (mean ± SD; 38.7 ± 1.3 °C), pulse (116.33 ± 22.80/bpm), respirations (27.75 ± 9.58/min), creatine kinase levels (2,859.37 ± 6,646.88 IU/L) and low pO 2 (74.93 ± 40.16 mmHg). Respiratory, renal or cardiac failure were common complications. Mortality rates in-hospital were 24.01% overall, 7.69% in MH, 20.37% in NMS and 42.55% in sepsis, compared with mortality rates in larger and possibly less severe groups of unmatched patients with MH (5.26%), NMS (6.66%), or sepsis (41.91%) who did not receive dantrolene., Conclusions: In over 95% of cases, dantrolene administration was associated with diagnoses other than MH in critically-ill patients with hypermetabolic symptoms and medical and psychiatric comorbidities. Exploratory survey data suggested that the efficacy and safety of dantrolene in preventing mortality in hypermetabolic syndromes other than MH remain uncertain. However, randomized and controlled studies using standardized criteria between groups matched for severity are essential to guide practice in using dantrolene., (© 2022. The Author(s).)

Background: Whilst antipsychotics are the mainstay of treatment for schizophrenia spectrum disorders, there have been numerous attempts to identify biomarkers that can predict treatment response. One potential marker may be psychomotor abnormalities, including catatonic symptoms. Early studies suggested that catatonic symptoms predict poor treatment response, whilst anecdotal reports of rare adverse events have been invoked against antipsychotics. The efficacy and safety of antipsychotics in the treatment of this subtype of schizophrenia have rarely been studied in randomised controlled trials (RCTs)., Objectives: To compare the effects of any single antipsychotic medication with another antipsychotic or with other pharmacological agents, electroconvulsive therapy (ECT), other non-pharmacological neuromodulation therapies (e.g. transcranial magnetic stimulation), or placebo for treating positive, negative, and catatonic symptoms in people who have schizophrenia spectrum disorders with catatonic symptoms., Search Methods: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, PubMed, ClinicalTrials.gov, the ISRCTN registry, and WHO ICTRP, on 19 September 2021. There were no language, date, document type, or publication status limitations for inclusion of records in the register. We also manually searched reference lists from the included studies, and contacted study authors when relevant., Selection Criteria: All RCTs comparing any single antipsychotic medication with another antipsychotic or with other pharmacological agents, ECT, other non-pharmacological neuromodulation therapies, or placebo for people who have schizophrenia spectrum disorders with catatonic symptoms., Data Collection and Analysis: two review authors independently inspected citations, selected studies, extracted data, and appraised study quality. For binary outcomes, we planned to calculate risk ratios and their 95% confidence intervals (CI) on an intention-to-treat basis. For continuous outcomes, we planned to calculate mean differences between groups and their 95% CI. We assessed risk of bias for the included studies, and created a summary of findings table; however, we did not assess the certainty of the evidence using the GRADE approach because there was no quantitative evidence in the included study., Main Results: Out of 53 identified reports, one RCT including 14 hospitalised adults with schizophrenia and catatonic symptoms met the inclusion criteria of the review. The study, which was conducted in India and lasted only three weeks, compared risperidone with ECT in people who did not respond to an initial lorazepam trial.   There were no usable data reported on the primary efficacy outcomes of clinically important changes in positive, negative, or catatonic symptoms. Whilst both study groups improved in catatonia scores on the Bush-Francis Catatonia Rating Scale (BFCRS), the ECT group showed significantly greater improvement at week 3 endpoint (mean +/- estimated standard deviation; 0.68 +/- 4.58; N = 8) than the risperidone group (6.04 +/- 4.58; N = 6; P = 0.035 of a two-way analysis of variance (ANOVA) for repeated measures originally conducted in the trial). Similarly, both groups improved on the Positive and Negative Syndrome Scale (PANSS) scores by week 3, but ECT showed significantly greater improvement in positive symptoms scores compared with risperidone (P = 0.04). However, data on BFCRS scores in the ECT group appeared to be skewed, and mean PANSS scores were not reported, thereby precluding further analyses of both BFCRS and PANSS data according to the protocol.  Although no cases of neuroleptic malignant syndrome were reported, extrapyramidal symptoms as a primary safety outcome were reported in three cases in the risperidone group. Conversely, headache (N = 6), memory loss (N = 4), and a prolonged seizure were reported in people receiving ECT. These adverse effects, which were assessed as specific for antipsychotics and ECT, respectively, were the only adverse effects reported in the study. However, the exact number of participants with adverse events was not clearly reported in both groups, precluding further analysis.  Our results were based only on a single study with a very small sample size, short duration of treatment, unclear or high risk of bias due to unclear randomisation methods, possible imbalance in baseline characteristics, skewed data, and selective reporting. Data on outcomes of general functioning, global state, quality of life, and service use, as well as data on specific phenomenology and duration of catatonic symptoms, were not reported., Authors' Conclusions: We found only one small, short-term trial suggesting that risperidone may improve catatonic and positive symptoms scale scores amongst people with schizophrenia spectrum disorders and catatonic symptoms, but that ECT may result in greater improvement in the first three weeks of treatment. Due to small sample size, methodological shortcomings and brief duration of the study, as well as risk of bias, the evidence from this review is of very low quality. We are uncertain if these are true effects, limiting any conclusions that can be drawn from the evidence. No cases of neuroleptic malignant syndrome were reported, but we cannot rule out the risk of this or other rare adverse events in larger population samples.  High-quality trials continue to be necessary to differentiate treatments for people with symptoms of catatonia in schizophrenia spectrum disorders. The lack of consensus on the psychopathology of catatonia remains a barrier to defining treatments for people with schizophrenia. Better understanding of the efficacy and safety of antipsychotics may clarify treatment for this unique subtype of schizophrenia., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: The last decade has seen development of numerous novel antipsychotic drugs with unique mechanisms including long-acting formulations for clinical use. A comparative assessment of these new drugs with each other and previous antipsychotics have not been performed with regards to risk for drug-induced movement disorders (DIMD)., Methods: Medline was searched from January 2010 to February 2022 for primary research articles and review articles in English using the search terms "extrapyramidal" and "tardive" with individual drug names of novel antipsychotics., Results: We identified articles describing the risk of DIMD with 6 novel antipsychotics, 4 novel formulations, and 3 experimental antipsychotics. Both short- and long-term data generally showed comparable to lower risk of DIMD with novel antipsychotics and recent long-acting formulations compared to previously marketed antipsychotics., Discussion: Several novel antipsychotics, particularly lumateperone and pimavanserin, show promise in being able to treat psychosis while reducing the risk of DIMD. Long-acting paliperidone may reduce risk of DIMD while other long-acting injectable formulations of SGA have similar risk of DIMD compared to oral formulations. New drug targets for treating psychosis without dopamine blockade also show promise., Competing Interests: Dr. George T. Kannarkat serves as a consultant for Guidepoint Global. Dr. Stanley Caroff served as consultant for Neurocrine Biosciences and Adamas Pharmaceuticals and received research grants from Neurocrine Biosciences and Eagle Pharmaceuticals unrelated to the current manuscript. Dr. James Morley has served as a consultant to GE Healthcare and received funding from the Department of Defense and the Department of Veteran Affairs unrelated to this review., (Copyright: © 2022 The Author(s).)

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.

Objective: To measure health state preferences and estimate utility values for tardive dyskinesia (TD) from the perspective of the US general population, accounting for factors affecting quality of life (QOL)., Methods: Participants from the general population were recruited and asked to watch and assess videos of professional actors simulating nine health states, including psychiatric disorders with/without TD and moderate-to-severe TD without any underlying disease. Time tradeoff (TTO) methods were used to elicit utility values, which ranged from -1 (worse than death) to +1 (perfect health) and represented individual preferences for avoiding specific health states associated with TD. Lower TTO utility values indicated individuals' willingness to give up more years of life to avoid living in each health state., Results: Based on TTO responses ( n  = 157), mean ± standard deviation utility for TD alone was 0.59 ± 0.38. Mean utilities for schizophrenia with negative symptoms (without TD: 0.43; with TD: 0.29) and positive symptoms (without TD: 0.44; with TD: 0.30) were generally lower than those for bipolar disorder (without TD: 0.59; with TD: 0.46) and major depressive disorder (without TD: 0.60; with TD: 0.44). According to utility decrements associated with TD (0.13-0.16), respondents were willing to give up 1.3 to 1.6 years during a 10-year lifespan to avoid living with TD., Conclusions: Utility decrements for TD in this study were slightly larger than previously reported values, potentially due to incorporation of QOL and social consequences in TD health state descriptions. An important limitation of this analysis is that participants' willingness to trade future years of healthy life may not indicate actual willingness to accept the life decrement. These findings can be leveraged to improve cost-effectiveness analyses used to assess the value of treatments for TD.

Objective: Antipsychotic medications may cause tardive dyskinesia (TD), an often-irreversible movement disorder characterized by involuntary movements that are typically stereotypic, choreiform, or dystonic and may impair quality of life. This study evaluated others' perceptions of abnormal TD movements in professional and social situations., Methods: This was an experimental, randomized, blinded, digital survey in a general population sample. Participants were randomized 1:1 into a test or control group to view a video of a professional actor simulating TD movements or no TD movements prior to completing surveys on employment, dating, and friendship domains. Assessments for mild-to-moderate and moderate-to-severe TD movements were conducted separately. Authenticity of abnormal movements and Abnormal Involuntary Movement Scale (AIMS) scores were evaluated by physician experts., Results: Surveys were completed by 2,400 participants each for mild-to-moderate and moderate-to-severe TD. In all domains, participants responded significantly less favorably to persons with TD movements (both mild-to-moderate and moderate-to-severe) than those without TD movements. Fewer participants in the test versus control group for mild-to-moderate and moderate-to-severe TD, respectively, considered the candidate as a potential employee (29.2% and 22.7% fewer), found him/her attractive (20.5% and 18.7% fewer), and were interested in becoming friends with him/her (12.3% and 16.5% fewer)., Conclusion: Professional actors simulating TD movements were perceived more negatively than those without TD movements in employment, dating, and friendship domains. To our knowledge, this is the first randomized study to quantify professional and social stigma associated with TD movements that may reduce opportunities for gainful employment, marital status, and an effective support system.

Behavioral disorders exact a tragic toll on patients, families, and society. Consequently, the search for better treatments is a public health priority. Recent research promises to lead to advances in psychiatric treatment that may include implantation of deep brain stimulation (DBS) devices. In this commentary, the authors discuss how promising results from initial pilot studies of DBS in treatment-resistant depression (TRD) were not validated in 2 randomized, controlled, multicenter trials. Reliance on pilot data may have contributed to the selection of primary efficacy endpoints that were not achieved, and to the underestimation of adverse events and device-related complications. Published data on the population prevalence of affective disorders also may have led sponsors to overestimate the number of patients with TRD who were candidates for DBS therapy. Consequently, a more complete discussion of certain aspects of the depression trials may allow a realistic appraisal of the clinical and ethical situation of DBS therapy for TRD in a US regulatory context. A US regulatory perspective also may clarify the clinical research and reimbursement consequences of the Humanitarian Device Exemption (HDE) approval status of DBS for obsessive-compulsive disorder (OCD). Retrospective analyses akin to failure modes and effects analysis in engineering may clarify unexpected results in the DBS depression trials. Recent research suggests that subject selection in future trials may be augmented by advanced neuroimaging methods. For the present, the noncommercial research status of DBS to treat depression and the HDE status for OCD appear likely to remain in place., (© 2022 S. Karger AG, Basel.)

Objective: Although evidence implicates striatal cholinergic impairment as a mechanism underlying tardive dyskinesia, trials of nonspecific cholinergic agents have been inconclusive. As a partial agonist at specific nicotinic receptor subtypes, varenicline reduces drug-induced dyskinesias in animal models suggesting promise as a treatment for tardive dyskinesia., Methods: Three schizophrenia patients with tardive dyskinesia who were smokers underwent an open trial of varenicline. After a 2-week baseline, subjects received varenicline 1 mg twice daily. Changes from baseline on the Abnormal Involuntary Movement Scale were measured after a 4-week varenicline stabilization period, and 6 weeks after the smoking quit date in one patient., Results: Varenicline had no effect on mean Abnormal Involuntary Movement Scale scores after 4 weeks. Although smoking decreased after 4 weeks on varenicline and diminished further in one patient after 10 weeks, this also appeared to have no effect on ratings of tardive dyskinesia., Conclusion: In contrast to animal models, no significant change in tardive dyskinesia occurred in response to varenicline replacement in three schizophrenia patients. Further investigations of cholinergic mechanisms in tardive dyskinesia are worthwhile as agents for specific cholinergic targets become available for treatment. In addition, treatment trials of tardive dyskinesia should control for smoking status, while patients on antipsychotics receiving nicotine replacement therapies for smoking should be studied further for changes in movement.

Hyperthermia, or extreme elevations in body temperature, can be life-threatening and may be caused by prescription drugs or illegal substances acting at a number of different levels of the neuraxis. Several psychotropic drug classes and combinations have been associated with a classic clinical syndrome of hyperthermia, skeletal muscle hyper-metabolism, rigidity or rhabdomyolysis, autonomic dysfunction and altered mental status ranging from catatonic stupor to coma. It is critical for clinicians to have a high index of suspicion for these relatively uncommon drug-induced adverse effects and to become familiar with their management to prevent serious morbidity and mortality. Although these syndromes look alike, they are triggered by quite different mechanisms, and apart from the need to withdraw or restore potential triggering drugs and provide intensive medical care, specific treatments may vary. Clinical similarities have led to theoretical speculations about common mechanisms and shared genetic predispositions underlying these syndromes, suggesting that there may be a common "thermic stress syndrome" triggered in humans and animal models by a variety of pharmacological or environmental challenges.

Tardive dyskinesia (TD) is a syndrome of abnormal involuntary movements that follows treatment with dopamine D2-receptor antagonists. Recent approval of vesicular monoamine transporter-2 (VMAT2) inhibitors offers hope for reducing the impact of TD. Although these drugs represent a significant advance in patient care and a practical step forward in providing relief for patients with TD, understanding of the pharmacology of TD that could inform future research to prevent and reverse TD remains incomplete. This review surveys evidence for the effectiveness of VMAT2 inhibitors and other agents in the context of theories of pathogenesis of TD. In patients for whom VMAT2 inhibitors are ineffective or intolerable, as well as for extending therapeutic options and insights regarding underlying mechanisms, a review of clinical trial results examined as experimental tests of etiologic hypotheses is worthwhile. There are still compelling reasons for further investigations of the pharmacology of TD, which could generate alternative preventive and potentially curative treatments. Finally, benefits from novel drugs are best realized within an overall treatment strategy addressing the condition and needs of individual patients.

Tardive syndromes (TDS) are a group of hyperkinetic and hypokinetic movement disorders that occurs after exposure to dopamine receptor blocking agents such as antipsychotic and antiemetic drugs. The Abnormal Involuntary Movement Scale (AIMS) is a widely used instrument that has become the standard for assessment of tardive dyskinesia (TDD), the most common form of TDS. However, the AIMS has a number of clinimetric limitations and was designed primarily to assess the anatomic distribution and severity of involuntary movements without regard to phenomenology. To build on recent advances in understanding and treatment of TDS, re-evaluation and revision of the AIMS that could aid both clinical practice and research may be worthwhile. Challenges, such as retaining the efficiency of the current AIMS, incorporating evaluation of impairment in daily activities, and re-training clinicians for a revised examination procedure and rating instrument, are very likely surmountable., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Amantadine, an aliphatic primary amine with complex actions on neurotransmitter systems in the basal ganglia, is approved for treating Parkinson's disease and drug-induced movement disorders (DIMDs). These disorders have a significant impact on clinical outcomes and quality of life in patients receiving antipsychotic treatment., Methods: We searched PubMed up to June 1, 2019 to identify relevant studies. The following search terms were used: "amantadine" AND "dystonia," "parkinsonism, " "akathisia," "tardive dyskinesia," "catatonia," "neuroleptic malignant syndrome." Reference lists were reviewed for additional material., Results: Evidence from multiple, small, controlled trials supports the efficacy of amantadine as a treatment for drug-induced parkinsonism. Studies show amantadine has a more favorable tolerability profile than anticholinergic medications in these patients. Clinical evidence from observational studies and case reports suggests that further trials might be warranted to support use of amantadine in select patients for preventing dystonic reactions and as a second-line agent for treating catatonia, neuroleptic malignant syndrome, and tardive dyskinesia. Evidence is lacking on the use of amantadine specifically for akathisia relative to other treatments., Conclusions: Amantadine is an evidence-based pharmacologic strategy for treating drug-induced parkinsonism and might be an alternative treatment for other DIMDs in select patients. Additional randomized controlled trials are needed.

Background: The relative benefits and risks of long-term maintenance treatment with antipsychotics have not been well studied in patients with bipolar disorder and major depressive disorder. For example, while antipsychotic dose reduction has been recommended in the management of serious side effects associated with antipsychotics, there is limited evidence on the impact of lowering doses on the course of underlying mood disorders., Methods: This retrospective cohort study analyzed the impact of antipsychotic dose reduction in patients with bipolar disorder or major depressive disorder. Medical claims from six US states over a 6-year period were analyzed for patients with ≥10% or ≥ 30% reductions in antipsychotic dose (cases) and compared using survival analyses with matched controls receiving a stable dosage. Outcomes included hospitalizations for disease-specific mood disorders, other psychiatric disorders and all-cause emergency room visits, and claims for tardive dyskinesia., Results: A total of 23,992 patients with bipolar disorder and 17,766 with major depressive disorder had a ≥ 10% dose reduction, while 19,308 and 14,728, respectively, had a ≥ 30% dose reduction. In multivariate analyses, cases with a ≥ 10% dose reduction had a significantly increased risk of disease-specific admission (bipolar disorder: hazard ratio [95% confidence interval], 1.22 [1.15-1.31]; major depressive disorder: 1.22 [1.11-1.34]), other psychiatric admission (bipolar disorder: 1.19 [1.13-1.24]; major depressive disorder: 1.17 [1.11-1.23]), all-cause admission (bipolar disorder: 1.17 [1.12-1.23]; major depressive disorder: 1.11 [1.05-1.16]), and all-cause emergency room visits (bipolar disorder: 1.09 [1.05-1.13]; major depressive disorder: 1.07 [1.02-1.11]) (all P <  0.01). Similar results were observed following an ≥30% dose reduction. Dose reduction was not associated with decreased claims for tardive dyskinesia., Conclusions: Patients with mood disorders who had antipsychotic dose reductions showed small but statistically significant increases in all-cause and mental health-related hospitalizations, which may lead to increased healthcare costs. These results highlight the need for additional long-term studies of the necessity and safety of maintenance antipsychotic treatment in mood disorders.

Purpose/background: To add to limited evidence on the Abnormal Involuntary Movement Scale (AIMS) as a measure of tardive dyskinesia (TD) in clinical practice settings, the characteristics and correlates of AIMS scores were assessed., Methods/procedures: Veterans with schizophrenia/schizoaffective, bipolar, or major depressive disorders receiving antipsychotics and at least 1 AIMS score during October 1, 2014, to September 30, 2015, were identified. Tardive dyskinesia was determined by the International Classification of Diseases, Ninth Revision, Clinical Modification, codes. Correlates of AIMS scores were examined using χ or t tests. Odds ratios and β parameters with 95% confidence intervals for categorical and continuous variables associated with AIMS scores were derived from a multivariate logistic and linear regression, respectively., Findings/results: Among 7985 veterans receiving antipsychotics, only 4706 (58.9%) had at least 1 AIMS examination. Of these, 229 (4.9%) were diagnosed with possible TD. The mean total AIMS scores and AIMS awareness/incapacitation scores were significantly higher for patients with TD (both P < 0.0001). Comparing diagnostic threshold criteria of AIMS ratings, only 17.5% to 37.1% of veterans with TD were successfully identified. Among TD patients, 21.4% had a total score of moderate-severe and 15.3% had ratings of at least mild movements in 2 or more body regions. In the regression analyses, being older, African-American, having schizophrenia/schizoaffective disorder, and receiving antipsychotics or benztropine significantly increased the severity of AIMS scores. Higher AIMS scores were not predictive of outcomes other than marital status in socioeconomic or healthcare domains., Implications/conclusions: Although the AIMS is essential for TD research, its value in clinical practice without training and oversight remains unclear. Efforts to adapt screening procedures to clinical needs may be worthwhile.

Objective: Vesicular monoamine transporter-2 (VMAT2) inhibitors have been proven to be effective for the treatment of tardive dyskinesia and their use is likely to increase. The evidence base of published clinical reports was reviewed to evaluate the possible risk of neuroleptic malignant syndrome (NMS) with these drugs., Methods: Pubmed, Embase, Web of Science and PsycINFO databases were queried for all years using terms for "neuroleptic malignant syndrome", "hyperthermia" AND "vesicular monoamine transporter inhibitors", "reserpine", "tetrabenazine", "valbenazine" or "deutetrabenazine"., Results: Thirteen clinical cases, ten of which involved tetrabenazine, were identified in which VMAT2 inhibitors were prescribed in patients with current or past NMS episodes. In most cases, the association was confounded by limited reporting of clinical data, variable temporal correlation with VMAT2 inhibitors, polypharmacy with antipsychotics, and uncertain differential diagnoses., Conclusion: While rare cases of NMS meeting consensus criteria have been reported primarily with tetrabenazine, the risk with recently developed VMAT2 inhibitors may be even less. Evidence of causality of NMS with VMAT2 inhibitors is confounded by concomitant treatment with antipsychotics and diagnostic uncertainties in patients susceptible to basal ganglia dysfunction. Nevertheless, clinicians should remain vigilant for early signs of NMS in all patients treated with any drugs that affect brain dopamine activity.

Purpose/background: RE-KINECT (NCT03062033) was designed to assess the presence and impact of possible tardive dyskinesia (TD) in antipsychotic-treated outpatients., Methods/procedures: The study included adults with 3 or more months of lifetime antipsychotic exposure and 1 or more psychiatric disorder. Based on clinician observation and assessment, patients were assigned to cohort 1 (without involuntary movements or with non-TD involuntary movements) or cohort 2 (with involuntary movements confirmed by clinician as possible TD). Baseline assessments included the following: patient characteristics; location/severity of involuntary movements; and impact of possible TD on health-related quality of life, including the EuroQoL 5-Dimensions 5-Level questionnaire., Findings/results: Of 739 eligible patients, 204 (27.6%) had clinician-confirmed possible TD (cohort 2). Compared with cohort 1, patients in cohort 2 were significantly older (P < 0.0001), more likely to have schizophrenia or schizoaffective disorder (P < 0.0001) and longer lifetime exposure to antipsychotics (P < 0.0001), and less likely to be working or studying, based on clinician perception (P = 0.0010). Clinician- and patient-rated severity of possible TD movements was significantly correlated in each of 4 body regions (head/face, neck/trunk, upper extremities, lower extremities), for maximum severity in any region, and for total number of affected regions (P < 0.001 for all correlations). For the patient-rated EuroQoL 5-Dimensions 5-Level, the health state visual analog scale score was significantly lower (worse) in cohort 2 versus cohort 1 (66.8 vs 69.7; P = 0.0002), as was the utility index score (0.71 vs 0.76; P < 0.0175)., Implications/conclusions: Results from this real-world population indicate that TD occurs frequently and can significantly reduce quality of life in patients with a psychiatric disorder.

Objective: A nominal group process followed by a modified Delphi method was used to survey expert opinions on best practices for tardive dyskinesia (TD) screening, diagnosis, and treatment and to identify areas lacking in clinical evidence., Participants: A steering committee of 11 TD experts met in nominal group format to prioritize questions to be addressed and identify core bibliographic materials and criteria for survey panelists. Of 60 invited experts, 29 (23 psychiatrists and 6 neurologists) agreed to participate., Evidence: A targeted literature search of PubMed (search term: tardive dyskinesia) and recommendations of the steering committee were used to generate core bibliographic material. Inclusion criteria were as follows: (1) review articles, meta-analyses, guidelines, or clinical trials; (2) publication in English between 2007 and 2017; (3) > 3 pages in length; and (4) publication in key clinical journals with impact factors ≥ 2.0. Of 29 references that met these criteria, 18 achieved a score ≥ 5 (calculated as the number of steering committee votes multiplied by journal impact factor and number of citations divided by years since publication) and were included., Consensus Process: Two survey rounds were conducted anonymously through electronic media from November 2017 to January 2018; responses were collected, collated, and analyzed. Respondent agreement was defined a priori as unanimous (100%), consensus (75%-99%), or majority (50%-74%). For questions using a 5-point Likert scale, agreement was based on percentage of respondents choosing ≥ 4 ("agree completely" or "agree"). Round 1 survey included questions on TD screening, diagnosis, and treatment. Round 2 questions were refined per panelist feedback and excluded Round 1 questions with < 25% agreement and > 75% agreement (unless feedback suggested further investigation)., Conclusions: Consensus was reached that (1) a brief, clinical assessment for TD should be performed at every clinical encounter in patients taking antipsychotics; (2) even mild movements in 1 body area may represent possible TD; (3) management requires an overall evaluation of treatment, including reassessment of antipsychotics and anticholinergics as well as consideration of vesicular monoamine transporter 2 (VMAT2) inhibitors; and (4) informed discussions with patients/caregivers are essential., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

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 β 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 (β = 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.

Background: Data 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., Methods: A 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., Results: A 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., Conclusion: Patients 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.

Socioeconomic disparities were assessed in predicting metabolic risk among veterans with serious mental illness. Veterans with schizophrenia, schizoaffective, or bipolar disorders were identified in VISN 4 facilities from 10/1/2010 to 9/30/2012. Differences between patients with and without metabolic syndrome were compared using t-tests, Chi square tests and multivariate logistic regressions. Among 10,132 veterans with mental illness, 48.8% had metabolic syndrome. Multivariate logistic regression analysis confirmed that patients with metabolic syndrome were significantly more likely to be older, male, African-American, married, and receiving disability pensions but less likely to be homeless. They were more likely to receive antipsychotics, antidepressants, or anticonvulsants. Bivariate cross-sectional analysis revealed that patients with metabolic syndrome had higher rates of coronary artery disease, cerebrovascular disease, and mortality, and that metabolic syndrome was more often associated with emergency visits and psychiatric or medical hospitalizations. Demographics, socioeconomic status and medications are independent predictors of metabolic syndrome and should be considered in broader screening of risk factors in order to provide preventive interventions for metabolic syndrome.

Tardive dyskinesia (TD) is a persistent hyperkinetic movement disorder associated with dopamine receptor blocking agents including antipsychotic medications. Although uncertainty and concern about this drug side effect have vacillated since its initial recognition 60 years ago, recent commercial interest in developing effective treatments has rekindled scientific and clinical interest after a protracted period of neglect. Although substantial research has advanced knowledge of the clinical features and epidemiology of TD, many fundamental questions raised by early investigators remain unresolved. In this paper, we review the early clinical reports that led to the acceptance of TD as an iatrogenic disorder and the lingering controversies that emerged thereafter. Continued research on TD as a serious adverse reaction to treatment may not only enhance patient outcomes and recovery efforts but may also provide insights into both the mechanism of action of antipsychotic drugs and the nosology and pathophysiology of idiopathic psychomotor disorders., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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.

Introduction: Tardive dyskinesia (TD) occurs in patients receiving antipsychotic treatment with dopamine receptor antagonists. Despite the prevalence of TD and its negative impact on patients' lives, there has been a lack of approved treatments and limited evidence from controlled trials of pharmacological treatment. Areas covered: PubMed was searched for English-language papers published during 2007-2016 using terms 'tardive dyskinesia' or 'drug-induced movement disorder', and 'treatment'. Studies evaluating pharmacological agents for the treatment of TD were selected. A total of 26 studies (five meta-analyses, twelve randomized controlled trials, and nine open-label observational studies) are reviewed. Expert commentary: Treatment of TD necessitates a stepwise approach. Optimization of antipsychotic therapy should be considered before initiation of antidyskinetic therapies. Data from some recent studies indicate possible improvements in TD after switching antipsychotics or with the use of amantadine, levetiracetam, piracetam, zonisamide, propranolol, vitamin B 6 , or certain unregulated herbal medicines; although significance of these improvements is unclear and require further investigation in randomized controlled trials. By contrast, recent evidence from Phase III trials of novel vesicular monoamine transporter-2 inhibitors demonstrates they could have a significant effect on TD symptom severity and suggests these agents may have the potential to transform treatment of TD in coming years.

Background: Neuroleptic malignant syndrome requires prompt recognition for effective management, but there are no established diagnostic criteria. This is the first validation study of recently published international expert consensus (IEC) diagnostic criteria, which include priority points assigned on the basis of the importance of each criterion for making a diagnosis of neuroleptic malignant syndrome., Methods: Data were extracted from 221 archived telephone contact reports of clinician-initiated calls to a national telephone consultation service from 1997 to 2009; each case was given a total priority point score on the basis of the IEC criteria. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, (DSM-IV-TR) research criteria, in original form and modified to accept less than "severe" rigidity, served as the primary diagnostic reference standard. Consultants' diagnostic impressions were used as a secondary reference standard. Receiver operating characteristic curve analysis was used to optimize the priority point cutoff score with respect to the reference standards., Results: Area under the receiver operating characteristic curve ranged from 0.715 (95% confidence interval, 0.645-0.785; P = 1.62 × 10) for consultant diagnoses to 0.857 (95% confidence interval, 0.808-0.907; P < 5 × 10) for modified DSM-IV-TR criteria. The latter was associated with 69.6% sensitivity and 90.7% specificity., Conclusions: Agreement was best between IEC criteria with a cutoff score of 74 and modified DSM-IV-TR criteria (sensitivity, 69.6%; specificity, 90.7%); this cutoff score demonstrated the highest agreement in all comparisons. Consultant diagnoses showed much better agreement with modified, compared with original, DSM-IV-TR criteria, suggesting that the DSM-IV-TR criterion of "severe" rigidity may be more restrictive than what most knowledgeable clinicians use in practice.