First 150 years of catatonia: Looking back at its complicated history and forward to the road ahead.

Karl Ludwig Kahlbaum (1828-1899) was the first to conceptualize and describe the main clinical features of a novel psychiatric illness, which he termed catatonia in his groundbreaking monograph published 150 years ago. Although Kahlbaum postulated catatonia as a separate disease entity characterized by psychomotor symptoms and a cyclical course, a close examination of his 26 cases reveals that most of them presented with motor symptom complexes or syndromes associated with various psychiatric and medical conditions. In his classification system, Kraepelin categorized catatonic motor symptoms that occur in combination with psychotic symptoms and typically have a poor prognosis within his dementia praecox (schizophrenia) disease entity. Because of the substantial influence of Kraepelin's classification, catatonia was predominantly perceived as a component of schizophrenia for most of the 20th century. However, with the advent of the psychopharmacotherapy era starting from the early 1950s, interest in catatonia in both clinical practice and research subsided until the early 2000s. The past two decades have witnessed a resurgence of interest in catatonia. The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition, marked a paradigmatic shift by acknowledging that catatonia can occur secondary to various psychiatric and medical conditions. The introduction of an independent diagnostic category termed "Catatonia Not Otherwise Specified" significantly stimulated research in this field. The authors briefly review the history and findings of recent catatonia research and highlight promising directions for future exploration.

An Evidence-Based Update on Anticholinergic Use for Drug-Induced Movement Disorders.

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.

The Clinician's Tardive Inventory (CTI): A New Clinical Tool for Documenting and Rating Tardive Dyskinesia.

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.

Catatonia: "Fluctuat nec mergitur".

In the beginning of the 1900s, the prevalence of catatonia in inpatient samples was reported to be between 19.5% and 50%. From the mid-1900s, most clinicians thought that catatonia was disappearing. Advances in medical sciences, particularly in the field of neurology, may have reduced the incidence of neurological diseases that present with catatonic features or mitigated their severity. More active pharmacological and psychosocial treatment methods may have either eliminated or moderated catatonic phenomena. Moreover, the relatively narrow descriptive features in modern classifications compared with classical texts and ascribing catatonic signs and symptoms to antipsychotic-induced motor symptoms may have contributed to an apparent decline in the incidence of catatonia. The application of catatonia rating scales introduced in the 1990s revealed significantly more symptoms than routine clinical interviews, and within a few years, the notion of the disappearance of catatonia gave way to its un-expected resurgence. Several systematic investigations have found that, on average, 10% of acute psychotic patients present with catatonic features. In this editorial, the changes in the incidence of catatonia and the possible underlying causes are reviewed.

Impact of possible tardive dyskinesia on physical wellness and social functioning: results from the real-world RE-KINECT study.

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.

Caregiver-Reported Burden in RE-KINECT: Data From a Prospective Real-World Tardive Dyskinesia Screening Study.

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.

Treatment of schizophrenia with catatonic symptoms: A narrative review.

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.

A new era in the diagnosis and treatment of tardive dyskinesia.

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.

Catatonia during pregnancy and the postpartum period.

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.

Intravenous dantrolene in hypermetabolic syndromes: a survey of the U.S. Veterans Health Administration database.

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 pO2 (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.

Risk of Drug-induced Movement Disorders with Newer Antipsychotic Agents.

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.

Antipsychotics for schizophrenia spectrum disorders with catatonic symptoms.

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.

ANTECEDENTES: Aunque los antipsicóticos son la base del tratamiento de los trastornos del espectro de la esquizofrenia, ha habido numerosos intentos de identificar biomarcadores que puedan predecir la respuesta al tratamiento. Un posible marcador podrían ser las anomalías psicomotoras, incluidos los síntomas catatónicos. Los estudios más antiguos indican que los síntomas catatónicos predicen una respuesta deficiente al tratamiento, mientras que se han alegado informes anecdóticos de eventos adversos poco frecuentes contra los antipsicóticos. La eficacia y la seguridad de los antipsicóticos en el tratamiento de este subtipo de esquizofrenia rara vez se han estudiado en ensayos controlados aleatorizados (ECA). OBJETIVOS: Comparar los efectos de cualquier fármaco antipsicótico único con otro antipsicótico o con otros agentes farmacológicos, terapia electroconvulsiva (TEC), otras terapias de neuromodulación no farmacológicas (p. ej., estimulación magnética transcraneal) o placebo para el tratamiento de los síntomas positivos, negativos y catatónicos en personas que presentan trastornos del espectro de la esquizofrenia con síntomas catatónicos. MÉTODOS DE BÚSQUEDA: El 19 de septiembre de 2021 se realizaron búsquedas en el registro de ensayos basados en estudios del Grupo Cochrane de Esquizofrenia (Cochrane Schizophrenia Group), que se basa en CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, PubMed, ClinicalTrials.gov, el registro ISRCTN y la ICTRP de la OMS. No hubo limitaciones de idioma, fecha, tipo de documento o estado de publicación para la inclusión de los registros en el registro. También se realizaron búsquedas manuales en las listas de referencias de los estudios incluidos y se estableció contacto con los autores de los estudios cuando fue pertinente. CRITERIOS DE SELECCIÓN: Todos los ECA que compararan cualquier fármaco antipsicótico único con otro antipsicótico o con otros agentes farmacológicos, TEC, otras terapias de neuromodulación no farmacológicas o placebo en personas que presentan trastornos del espectro de la esquizofrenia con síntomas catatónicos. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión inspeccionaron de forma independiente las citas, seleccionaron los estudios, extrajeron los datos y evaluaron la calidad de los estudios. Para los desenlaces binarios se planeó calcular las razones de riesgos y sus intervalos de confianza (IC) del 95% sobre la base de la intención de tratar. Para los desenlaces continuos se planeó calcular las diferencias de medias entre los grupos y sus IC del 95%. Se evaluó el riesgo de sesgo de los estudios incluidos y se creó una tabla de resumen de los hallazgos. Sin embargo, no se evaluó la certeza de la evidencia mediante el método GRADE porque no hubo evidencia cuantitativa en el estudio incluido. RESULTADOS PRINCIPALES: De los 53 informes identificados, un ECA que incluyó a 14 adultos hospitalizados con esquizofrenia y síntomas catatónicos cumplió con los criterios de inclusión de la revisión. El estudio, realizado en la India y que sólo duró tres semanas, comparó la risperidona con la TEC en personas que no respondieron a una prueba inicial con lorazepam. No se informaron datos utilizables sobre los desenlaces principales de eficacia de cambios clínicamente importantes en los síntomas positivos, negativos o catatónicos. Aunque ambos grupos del estudio mejoraron en las puntuaciones de catatonia en la Bush­Francis Catatonia Rating Scale (BFCRS), el grupo de TEC mostró una mejoría significativamente mayor en el desenlace a las tres semanas (media +/­ desviación estándar estimada; 0,68 +/­ 4,58; n = 8) que el grupo de risperidona (6,04 +/­ 4,58; n = 6; p = 0,035 de un análisis de varianza (ANOVA) de dos vías para medidas repetidas realizado originalmente en el ensayo). Asimismo, ambos grupos mejoraron en las puntuaciones de la Positive and Negative Syndrome Scale (PANSS) a las tres semanas, pero la TEC mostró una mejoría significativamente mayor en las puntuaciones de los síntomas positivos en comparación con la risperidona (p = 0,04). Sin embargo, los datos sobre las puntuaciones de la BFCRS en el grupo de TEC parecieron estar sesgados, y no se informaron las puntuaciones medias de la PANSS, lo que impidió realizar más análisis de los datos de la BFCRS y la PANSS según el protocolo. Aunque no se informaron casos de síndrome neuroléptico maligno, en tres casos del grupo de risperidona se notificaron síntomas extrapiramidales como un desenlace principal de seguridad. Por el contrario, en las personas que recibieron TEC se informó cefalea (n = 6), pérdida de memoria (n = 4) y una convulsión prolongada. Estos efectos adversos, que se evaluaron como específicos de los antipsicóticos y de la TEC, respectivamente, fueron los únicos efectos adversos notificados en el estudio. Sin embargo, el número exacto de participantes con eventos adversos no se informó claramente en ambos grupos, lo que impidió realizar un análisis más profundo. Los resultados de esta revisión se basaron en un solo estudio con un tamaño muestral muy pequeño, una duración corta del tratamiento, un riesgo de sesgo incierto o alto debido a métodos de asignación al azar poco claros, un posible desequilibrio en las características iniciales, datos sesgados y un informe selectivo. No se informaron datos sobre los desenlaces de funcionalidad general, estado global, calidad de vida ni uso de los servicios, así como tampoco datos sobre la fenomenología específica ni la duración de los síntomas catatónicos. CONCLUSIONES DE LOS AUTORES: Solo se encontró un ensayo pequeño, a corto plazo, que indica que la risperidona podría mejorar las puntuaciones de la escala de síntomas catatónicos y positivos entre las personas con trastornos del espectro de la esquizofrenia y síntomas catatónicos, pero que la TEC podría producir una mayor mejoría en las primeras tres semanas de tratamiento. Debido al pequeño tamaño muestral, las deficiencias metodológicas y la breve duración del estudio, así como el riesgo de sesgo, la evidencia de esta revisión es de calidad muy baja. No hay confianza en que estos efectos sean verdaderos, lo que limita cualquier conclusión que se pueda sacar a partir de la evidencia. No se notificaron casos de síndrome neuroléptico maligno, pero no se puede descartar el riesgo de este u otros eventos adversos poco frecuentes en muestras poblacionales más grandes. Aún se necesitan ensayos de calidad alta para diferenciar los tratamientos en las personas con síntomas de catatonia en los trastornos del espectro de la esquizofrenia. La falta de consenso sobre la psicopatología de la catatonia todavía es un obstáculo para definir los tratamientos para las personas con esquizofrenia. Un mejor conocimiento de la eficacia y la seguridad de los antipsicóticos podría aclarar el tratamiento de este subtipo único de esquizofrenia.

Commentary on the Continued Investigational Status of DBS for Psychiatric Indications.

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.

Defining utility values for patients with tardive dyskinesia.

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.

An Experimental Study to Assess the Professional and Social Consequences of Tardive Dyskinesia.

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.

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.

Effect of Varenicline on Tardive Dyskinesia: A Pilot Study.

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.

Drug-induced Hyperthermic Syndromes in Psychiatry.

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.

Recent Advances in the Pharmacology of Tardive Dyskinesia.

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.