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.

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.

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.

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.

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.

Correlates of the Abnormal Involuntary Movement Scale in Veterans With Tardive Dyskinesia.

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 ß 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.

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

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

RE-KINECT: A Prospective Study of the Presence and Healthcare Burden of Tardive Dyskinesia in Clinical Practice Settings.

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.

Revisiting amantadine as a treatment for drug-induced movement disorders.

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.

Hospital utilization rates following antipsychotic dose reduction in mood disorders: implications for treatment of tardive dyskinesia.

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.

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

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 and Metabolic Risk in Veterans with Serious Mental Illness.

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.

A Validation Study of the International Consensus Diagnostic Criteria for Neuroleptic Malignant Syndrome.

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.

The cyclical revival of psychedelics in psychiatric treatment.

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.

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.

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.

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.