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Background and Purpose: Despite the wide use of dopamine receptor blocking agents (DRBAs) in Huntington disease (HD), neuroleptic malignant syndrome (NMS) is rarely described in this population. The aim of this study was to assess NMS prevalence in a large cohort of HD patients and explore the main associated risk factors., Methods: In 2023, an HD patient was admitted to our neurology department due to NMS. Starting from the case description, we performed a narrative review of the literature of NMS cases in HD, reviewed data from the fifth dataset of the Enroll-HD (a longitudinal, observational, global study of families with HD) study (PDS5) selecting HD patients treated with DRBAs and/or tetrabenazine (TBZ) who presented at least one of the core symptoms of NMS (rigidity and hyperthermia), and collected data to investigate prevalence of NMS and identify risk factors., Results: In the Enroll-HD PDS5 dataset, we identified 5108 of 11,569 HD patients who were undergoing DRBA and/or TBZ treatment. Only one patient, a Caucasian man of 46 years, undergoing clozapine and valproate treatment, had a registered diagnosis of NMS., Conclusions: NMS in HD patients is seldom described. This could be due to an underestimation of this condition. There are no available objective NMS diagnostic criteria at present, and the existence of atypical forms of NMS further complicates diagnosis. Advanced disease stage, rigid-akinetic phenotype, abrupt therapy changes, polytherapy, and dehydration are key risk factors, most of which are preventable through awareness and caution in managing medications in the HD population., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: The incidence of neuroleptic malignant syndrome (NMS), a rare, potentially fatal adverse effect of antipsychotics, among children and youth is unknown. This cohort study estimated NMS incidence in antipsychotic users age 5-24 years and described its variation according to patient and antipsychotic characteristics. Methods: We used national Medicaid data (2004-2013) to identify patients beginning antipsychotic treatment and calculated the incidence of NMS during antipsychotic current use. Adjusted hazard ratios (HRs) assessed the independent contribution of patient and antipsychotic characteristics to NMS risk. Results: The 1,032,084 patients had 131 NMS cases during 1,472,558 person-years of antipsychotic current use, or 8.9 per 100,000 person-years. The following five factors independently predicted increased incidence: age 18-24 years (HR [95% CI] = 2.45 [1.65-3.63]), schizophrenia spectrum and other psychotic disorders (HR = 5.86 [3.16-10.88]), neurodevelopmental disorders (HR = 7.11 [4.02-12.56]), antipsychotic dose >200mg chlorpromazine-equivalents (HR = 1.71 [1.15-2.54]), and first-generation antipsychotics (HR = 4.32 [2.74-6.82]). NMS incidence per 100,000 person-years increased from 1.8 (1.1-3.0) for those with none of these factors to 198.1 (132.8-295.6) for those with 4 or 5 factors. Findings were essentially unchanged in sensitivity analyses that restricted the study data to second-generation antipsychotics, children age 5-17 years, and the 5 most recent calendar years. Conclusion: In children and youth treated with antipsychotics, five factors independently identified patients with increased NMS incidence: age 18-24 years, schizophrenia spectrum and other psychotic disorders, neurodevelopmental disorders, first-generation drugs, and antipsychotic doses greater than 200 mg chlorpromazine-equivalents. Patients with 4 or 5 of these factors had more than 100 times the incidence of those with none. These findings could improve early identification of children and youth with elevated NMS risk, potentially leading to earlier detection and improved outcomes.

Introduction: Long-acting injectable antipsychotics (LAIs) are associated with multiple positive outcomes in psychosis, but it is unclear whether LAIs are associated with worse outcomes if neuroleptic malignant syndrome (NMS), a potentially lethal adverse effect, occurs., Methods: We used nationwide and nationally representative databases of healthcare encounters in Finland to study the incidence and outcome predictors of NMS in patients diagnosed with schizophrenia/schizoaffective disorder between January 01, 1972 and December 31, 2017. Using a nested case-control design, we also explored differences by antipsychotic formulation (LAI vs oral antipsychotic [OAP]) and class (first-generation antipsychotic [FGA] vs second-generation antipsychotic [SGA])., Results: One hundred seventy-two NMS cases and 1441 sex-, age-, and diagnosis-matched controls were included (age = 58.8 ± 13.1 years, males = 59.9%). Incidence of NMS was 1.99 (1.98-2.00) per 10 000 person-years. The likelihood of developing NMS did not differ by antipsychotic formulation (adjusted odds ratio [aOR]: 0.89, 95% confidence intervals [95% CI]: 0.59-1.33, for LAIs vs OAPs) or class (FGA-OAP vs SGA-OAP [aOR: 1.08, 95% CI: 0.66-1.76], FGA-LAI [aOR: 0.89, 95% CI: 0.52-1.53], SGA-LAI [aOR: 1.35, 95% CI: 0.58-3.12]). NMS risk factors included antipsychotic treatment change: increased number (odds ratios [OR]: 5.00, 95% CI: 2.56-9.73); decreased number/switch (OR: 2.43, 95% CI: 1.19-4.96); higher antipsychotic dose (>2DDDs-OR: 3.15, 95% CI: 1.61-6.18); co-treatment with anticholinergics (OR: 2.26, 95% CI: 1.57-3.24), lithium (OR: 2.16, 95% CI: 1.30-3.58), benzodiazepines (OR: 2.02, 95% CI: 1.44-3.58); and comorbid cardiovascular disease (OR: 1.73, 95% CI: 1.22-2.45). Within 30 days, 4.7% of cases with NMS died (15.1% within 1 year) without differences by antipsychotic formulation. NMS reoccurred in 5 of 119 subjects (4.2%), after a median = 795 (range = 77-839) days after rechallenge with antipsychotics., Conclusion: NMS remains a potentially life-threatening risk, yet these results should further contribute to mitigate concerns about LAI safety regarding NMS onset or outcomes, including mortality., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Neuroleptic malignant syndrome (NMS) is a potentially fatal, idiosyncratic reaction to antipsychotics. Due to low incidence of NMS, research on risk factors of mortality associated with NMS is limited., Methods: Two authors independently searched Medline/Embase/Cochrane/CINAHL/PsychINFO databases for case reports with author-defined NMS published in English until 05/30/2020. Demographic, clinical, treatment, and outcome data were independently extracted following PRISMA guidelines. NMS severity was rated using the Francis-Yacoub scale. Mortality risk factors were identified using a multivariable regression analysis including all characteristics that were significantly different between NMS cases resulting vs. not resulting in death., Results: 683 cases with NMS were analyzed (median age = 36 years, males = 62.1%). In a multivariable model, independent predictors of NMS mortality were lack of antipsychotic discontinuation (odds ratio (OR) = 4.39 95% confidence interval (CI) = 2.14-8.99; p < 0.0001), respiratory problems (OR = 3.54 95%CI = 1.71-7.32; p = 0.0004), severity of hyperthermia (Unit-OR = 1.30, 95%CI = 1.16-1.46; p < 0.0001), and older age (Unit-OR = 1.05, 95%CI = 1.02-1.07; p = 0.0014). Even in univariate, patient-level analyses, antipsychotic formulation was not related to death (oral antipsychotic (OAP): n = 39/554 (7.0%) vs. long-acting injectable (LAI): n = 13/129 (10.1%); p = 0.2413). Similarly, death with NMS was not related to antipsychotic class (first-generation antipsychotic: n = 38/433 (8.8%) vs. second-generation antipsychotic: n = 8/180 (4.4%); p = 0.0638). Non-antipsychotic co-treatments were not associated with NMS mortality., Conclusion: Despite reliance on case reports, these findings indicate that presence of respiratory alterations, severity of hyperthermia, and older age should alert clinicians to a higher NMS mortality risk, and that antipsychotics should be stopped to reduce mortality, yet when NMS arises on LAIs, mortality is not increased vs. OAPs., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction : Many drugs are known to induce malignant syndromes. The most common malignant syndromes are induced by the use of antipsychotics and anesthetics and the withdrawal of anti-Parkinson drugs. As the clinical manifestations of antipsychotic malignant syndrome, Parkinson's disease hyperpyrexia syndrome and anesthetic-induced malignant syndrome are very similar, they are easily confused in the clinic. Areas covered : We reviewed articles published between 1960 and April 2021 describing malignant syndromes. This paper provides a detailed literature review of malignant syndromes and important guidance for the diagnosis and treatment of malignant syndromes to clinicians. Expert opinion : Although malignant syndromes are rare conditions with a low incidence, these conditions usually progress rapidly and can endanger patients' lives, meriting attention from clinicians. The typical clinical manifestations of malignant syndromes are hyperpyrexia, muscular rigidity, an altered mental status and increased levels of creatine kinase; however, the pathophysiology, treatment and prognosis of different malignant syndromes are quite different. Prompt diagnosis and treatment may significantly improve the prognosis of patients with malignant syndromes.

Long-acting injectable antipsychotics (LAI-APs) remain underutilized. One reason is the concern that LAI-APs might cause serious adverse events such as neuroleptic malignant syndrome (NMS) and lead to prolonged symptoms compared with oral treatment. Because the risk of NMS associated with LAI second-generation antipsychotics (LAI-SGAs) remains unclear, we compared reporting frequency, time to onset, and mortality of NMS between LAI- and oral SGAs using data from a Japanese spontaneous adverse event reporting database between April 2004 and September 2019. Of 5791 patients reporting adverse events due to LAI-SGAs or the equivalent oral SGAs, 768 (13%) developed NMS. LAI aripiprazole and LAI paliperidone were associated with a significantly lower reporting frequency of NMS than the equivalent oral SGAs (adjusted reporting odds ratio [95% confidence interval]: 0.35 [0.19-0.63] and 0.40 [0.27-0.59], respectively). Between 42% and 62% of the NMS associated with LAI- and oral SGAs other than LAI risperidone occurred within 30 days after initiation. The proportion of mortality due to NMS associated with oral aripiprazole was 13.1% and no deaths occurred in patients with NMS associated with LAI aripiprazole. The proportions of mortality due to NMS associated with oral risperidone/paliperidone, LAI risperidone, and LAI paliperidone were 8.8%, 4.2%, and 3.4%, respectively. Our findings showed that LAI-SGAs were not associated with a higher reporting frequency and mortality of NMS compared with oral SGAs, although clinicians need to closely monitor the occurrence of NMS not only during oral SGA treatment, but also, and in particular, in the early stage of LAI-SGA treatment., Competing Interests: Declaration of competing interest FM has received speaker's honoraria from Sumitomo Dainippon, Eli Lilly, Janssen, Novartis, Otsuka, and Pfizer. YO has received personal fees from MSD K.K., Otsuka Pharmaceutical, Cando, Japan Medical Data Center, and Japan Medical Research Institute. He is also an employee of the Real World Data, Co., Ltd. and a president of the Initiative for Clinical Epidemiological Research. YT has received consultant fees from the Pharmaceuticals and Medical Devices Agency. FY has received speaker's honoraria from Janssen, Novartis, and Otsuka. HT has received speaker's honoraria from EA Pharma, Kyowa, Janssen, Meiji Seika Pharma, Mochida, Otsuka, Sumitomo Dainippon Pharma, and Yoshitomiyakuhin., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Neuroleptic malignant syndrome (NMS) is a rare and acute adverse drug reaction associated with antipsychotic therapy. However, few data on the risk and epidemiology of NMS are available., Objectives: The aim of this study was to ascertain the incidence risk and all-cause mortality of NMS associated with antipsychotic use, and to assess the association of recent antipsychotic exposure and NMS., Methods: We did a population-based study using data from the Hong Kong Hospital Authority's Clinical Data Analysis and Reporting System database. Cases had a first diagnosis of NMS between 1 January 2004 and 30 November 2017. A case-crossover analysis was used to compare antipsychotic exposure 30 days before the diagnosis of NMS (index date) and a reference period 91-120 days before the index date. To adjust for potential time trends in antipsychotic exposure, we sampled from cases to match current cases and future cases, and further adjusted for select medications and acute medical conditions., Results: 297,647 patients were prescribed antipsychotics, and the incidence risk of NMS was 0.11%. Of the 336 cases included in the case-crossover analysis, 20 (6%) died within 30 days after the index date; only one case had NMS recorded as the primary cause of death. When compared with the reference period, cases were more frequently prescribed multiple antipsychotics (15.8% vs 26.8%; standardized mean difference [SMD] 0.27) and short-acting injectable antipsychotics (3.6% vs 13.7%; SMD 0.37) during the 30 days prior to the diagnosis of NMS. Odds ratios for antipsychotic exposure in the case-crossover, case-crossover adjusted for time trend, and case-crossover adjusted for time trend and potential confounders analysis were 8.00 (95% confidence interval 3.42-18.69), 5.88 (2.46-14.04), and 4.77 (1.95-11.66)., Conclusions: Our results suggest that recent use of antipsychotics is associated with NMS. Although a case-only design inherently controls for confounding by time-invariant factors, residual confounding by acute medical conditions with similar presentations to NMS cannot be fully excluded.

Neuroleptic malignant syndrome (NMS) is a rare, but severe adverse drug reaction of drugs with anti-dopaminergic properties. The main symptoms are fever and rigor. In addition, other symptoms such as creatine kinase elevation, alteration of consciousness and various neurological symptoms may occur. A total of 52 NMS cases have been documented in the drug safety program 'Arzneimittelsicherheit in der Psychiatrie' from 1993 to 2015. We calculated incidences and analyzed imputed substances and additional risk factors to study the impact of changing therapy regimes. The overall incidence was 0.16‰. High-potency first-generation antipsychotics (FGAs) had the highest incidences, e.g. flupentixol with 0.61‰. Second-generation antipsychotics (SGAs) had lower incidences. Low-potency FGAs had very low incidences, comparable to SGAs, but in contrast to SGAs, had not been imputed alone in any case of NMS. Preexisting organic pathologies of the central nervous system, lithium treatment, infection/exsiccosis and the withdrawal of medication with anticholinergic properties or alcohol were found to be additional risk factors. With the increasing use of SGAs, one should always be aware of the risk of NMS. Better suited diagnostic criteria for 'atypical NMS' would lead to a better understanding and, therefore, to improved treatment possibilities.

Background: Clozapine is widely prescribed for treatment-refractory schizophrenia, but its use is limited by many potentially life-threatening adverse effects. The risk of rechallenge after these complications has never been comprehensively assessed in controlled studies. Thus, clinical guidelines must rely on the published case reports. The number of such reports is likely to increase over time, and updated analyses of larger samples are needed, as they may lead to changes in clinical guidelines., Study Questions: How safe is the clozapine rechallenge after life-threatening adverse effects?, Study Design: The published case reports of clozapine rechallenge were identified in a MEDLINE search. We added 121 cases reported from 2012 through 2017 to the 138 cases reported from 1972 through 2011 analyzed by us in a previous publication. The 95% confidence intervals (CIs) of the successful rechallenge rate were calculated for each adverse effect with at least 5 published case reports. The rechallenge was considered a valid clinical option when the lower end of the CI range was at least 50%., Results: A successful outcome was documented in 128/203 patients rechallenged after neutropenia (63.0%, CI, 56.0%-69.6%), 3/17 after agranulocytosis (17.7%, CI, 4.7%-44.2%), 11/17 after myocarditis (64.7%, CI, 38.6%-84.7%), and 7/7 after neuroleptic malignant syndrome (100%, CI, 56.1%-100%). Among the 15 patients with other clozapine-induced adverse effects, the rechallenge was successful in those with eosinophilia, cardiac complications other than myocarditis (QTc prolongation, pericarditis, cardiomyopathy, and atrial flutter), and gastrointestinal hypomotility. The rechallenge failed in patients who had developed pancreatitis or renal insufficiency., Conclusion: Clozapine rechallenge is a reasonable clinical option after return to baseline for patients who had developed neutropenia and neuroleptic malignant syndrome, but not after agranulocytosis or myocarditis. Data are insufficient to formulate rechallenge guidelines for any other clozapine-related adverse effects.

Objectives: To measure the incidence of movement side effects of antipsychotic drugs in adults with intellectual disability and compare rates with adults without intellectual disability., Design: Cohort study using data from The Health Improvement Network., Setting: UK primary care., Participants: Adults with intellectual disability prescribed antipsychotic drugs matched to a control group of adults without intellectual disability prescribed antipsychotic drugs., Outcome Measures: New records of movement side effect including acute dystonias, akathisia, parkinsonism, tardive dyskinaesia and neuroleptic malignant syndrome., Results: 9013 adults with intellectual disability and a control cohort of 34 242 adults without intellectual disability together contributed 148 709 person-years data. The overall incidence of recorded movement side effects was 275 per 10 000 person-years (95% CI 256 to 296) in the intellectual disability group and 248 per 10 000 person-years (95% CI 237 to 260) in the control group. The incidence of any recorded movement side effect was significantly greater in people with intellectual disability compared with those without (incidence rate ratio 1.30, 95% CI 1.18 to 1.42, p<0.001, after adjustment for potential confounders), with parkinsonism and akathisia showing the greatest difference between the groups. Neuroleptic malignant syndrome, although occurring infrequently, was three times more common in people with intellectual disability-prescribed antipsychotic drugs (incidence rate ratio 3.03, 95% CI 1.26 to 7.30, p=0.013). Differences in rates of movement side effects between the groups were not due to differences in the proportions prescribed first and second-generation antipsychotic drugs., Conclusions: This study provides evidence to substantiate the long-held assumption that people with intellectual disability are more susceptible to movement side effects of antipsychotic drugs. Assessment for movement side effects should be integral to antipsychotic drug monitoring in people with intellectual disability. Regular medication review is essential to ensure optimal prescribing in this group., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To examine sex and age distributions in neuroleptic malignant syndrome (NMS) patients based on a systematic literature review., Method: EMBASE and PubMed databases were searched to identify any observation of NMS published from January 1, 1998 through November 1, 2014 that was accessible and interpretable (using language translation software). Redundant and equivocal reports were excluded. Sex ratio and age distributions were examined using standard graphical techniques and measures of association., Results: Twenty-eight independent sex ratio estimates were included. Males predominated in most (75%) estimates with an overall median sex ratio of 1.47 (95% CI, 1.20-1.80). NMS incidence peaked at age 20-25 years and declined steadily thereafter, with males consistently outnumbering females at all but the oldest age intervals., Conclusion: NMS patients are 50% more likely to be males, and NMS is most likely to occur in young adulthood., (Published 2017. This article is a U.S. Government work and is in the public domain in the USA.)

There are a few syndromes involving the nonmotor symptoms of Parkinson's disease and other movement disorders that can quickly lead to severe morbidity and mortality, and, as such, need rapid identification and management. Among these are neuroleptic malignant syndrome, serotonin syndrome, dopamine agonist withdrawal syndrome, and dystonic storm. It is important to maintain a high index of suspicion for these disorders as lack of identification can lead to death. Many of these acutely occurring nonmotor syndromes are primarily the result of imbalances in dopaminergic and serotonergic systems due to changes in pharmacologic management of psychiatric disorders or Parkinson's disease. We discuss these acutely occurring nonmotor symptoms in order to raise awareness and also to highlight how these extremes in symptoms may uniquely shed light on the pathophysiology of Parkinson's disease., (© 2017 Elsevier Inc. All rights reserved.)

Background and Purpose: Dementia with Lewy bodies (DLB) is characterised by neuroleptic hypersensitivity. It is unclear, however, whether the neuroleptic hypersensitivity implies an increased incidence of neuroleptic malignant syndrome (NMS) or of akinetic crisis (AC), which are expressions of the same possibly lethal clinical event, and whether AC in DLB can appear independently of neuroleptic treatment. In our prospective study, we assessed the incidence of AC in a cohort of DLB as compared with that in patients with Parkinson disease (PD)., Methods: In total, 614 patients with PD and 236 DLB were recruited and followed during 2005-2013. AC was diagnosed as sudden akinetic state unresponsive to dopaminergic rescue drugs, dysphagia and serological alterations without recovery for 48 h or more requiring hospital admission. Exposure to neuroleptics was specifically evaluated, because of the high implicit risk in DLB., Results: 24 patients with PD (3.9%) and 16 patients with DLB (6.8%) developed AC. 77 (32.6%) DLB and 32 (5.2%) PD were exposed to typical neuroleptics, but only 8 DLB and 3 PD presented with AC. Disease duration before AC was lower in DLB than in PD group (p<0.01). Outcome was fatal in 8 patients with (50%) DLB and 3 (12.5%) PD (p=0.05). When age and use of neuroleptics were adjusted for into a Cox proportional hazards model predicting time to AC, the HR of patients with DLB was 13.0 (95% CI 4.23 to 39.9; p<0.001)., Conclusions: AC in DLB can appear independently of neuroleptic treatment, occurs earlier and is more frequently fatal than in PD., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: Our study objective was to identify real-world rates of complications, mortality, and outcomes in patients with neuroleptic malignant syndrome (NMS) over the last decade in the United States., Methods: A total of 1346 patients were obtained from the nationwide inpatient sample for the years 2002-2011. Common complications known to be associated with NMS were identified. Multivariable regression analyses were used to identify predictors of mortality., Results: The most prevalent complication was rhabdomyolysis (30.1%). Other common complications were acute respiratory failure (16.1%), acute kidney injury (17.7%), sepsis (6.2%), and other systemic infections. Unadjusted mortality rate was 5.6%. Older age, acute respiratory failure, acute kidney injury, sepsis, and comorbid congestive heart failure were significant predictors of mortality. Acute respiratory failure was the strongest independent mortality predictor (p < 0.001)., Conclusion: In our large sample population-based study on NMS, we were able to identify the rates of several preselected complications and the mortality. The identification of independent mortality predictors in this study can guide physicians in the management and prognostication of this rare syndrome.

Background: Neuroleptic malignant syndrome (NMS) is a rare but potentially life-threatening medication-induced syndrome. Core symptoms are hyperthermia, diaphoresis, rigidity, impaired consciousness, and creatinine kinase elevation. Additionally, patients show vegetative dysregulation including blood pressure fluctuations. The purpose of this paper is to summarize current findings, to facilitate diagnostics and to distinguish NMS from other syndromes., Methods: We performed a systematic review of the literature. We included scientific publications, books and guidelines., Results: In this review we summarize the current diagnostic criteria, differential diagnosis, pathogenesis and therapeutic options., Conclusion: Clinical symptoms of NMS are heterogeneous and it is difficult to diagnose early states. Early interventions are important to ensure fast and complete recovery. Since NMS is a rare condition, publications on NMS-therapy are based on single-case reports, meta-analysis or expert opinions. Core symptoms should be considered: Exposure to dopamine-antagonists, hyperthermia, diaphoresis, rigidity, mental status alteration, creatinine kinase elevation, and vegetative dysregulation., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Neuroleptic malignant syndrome (NMS) is a rare, severe, idiosyncratic adverse reaction to antipsychotics. Second-generation antipsychotics (SGAs) were originally assumed to be free from the risk of causing NMS, however several cases of NMS induced by SGAs (SGA-NMS) have been reported., Objectives: The aim of this study was to systematically review available studies and case reports on SGA-NMS and compare the presentation of NMS induced by different SGAs., Data Sources: Citations were retrieved from PubMed up to November 2013, and from reference lists of relevant citations., Study Eligibility Criteria: Eligibility criteria included (a) primary studies reporting data on NMS, with at least 50 % of the sample receiving SGAs; or (b) case reports and case reviews reporting on NMS induced by SGA monotherapy, excluding those due to antipsychotic withdrawal., Study Appraisal and Synthesis Methods: A standardized method for data extraction and coding was developed for the analysis of eligible case reports., Results: Six primary studies and 186 individual cases of NMS induced by SGAs were included. Primary studies suggest that SGA-NMS is characterized by lower incidence, lower clinical severity, and less frequent lethal outcome than NMS induced by first-generation antipsychotics. Systematic analysis of case reports suggests that even the most recently marketed antipsychotics are not free from the risk of inducing NMS. Furthermore, clozapine-, aripiprazole- and amisulpride-induced NMS can present with atypical features more frequently than other SGA-NMS, i.e. displaying less intense extrapyramidal symptoms or high fever., Limitations: Case reports report non-systematic data, therefore analyses may be subject to bias., Conclusions and Implications of Key Findings: Clinicians should be aware that NMS is virtually associated with all antipsychotics, including those most recently marketed. Although apparently less severe than NMS induced by older antipsychotics, SGA-NMS still represent a relevant clinical issue.

Rationale: A substantial overlap exists between catatonic phenomena and features of neuroleptic malignant syndrome., Objectives: The objective of this study is to examine whether catatonia can be distinguished from neuroleptic malignant syndrome and to identify symptoms that may have discriminatory power., Methods: We conducted a literature search to identify relevant studies up to and including the year 2012. A total of 386 studies containing 490 case reports were included. To evaluate the discriminant value of each feature, we performed binominal regression analyses with the diagnosis as the dependent variable. First, all features were entered into the model as independent variables. In a second step, a stepwise backwards analysis was conducted to eliminate criteria with low discriminant value., Results: The most common symptoms in patients with neuroleptic malignant syndrome were fever (87.7 %), rigor (85.9 %), laboratory evidence of muscle injury (70.5 %), and tachycardia (62.1 %) and in patients with catatonia were mutism (78.0 %), rigor (73.0 %), stupor (54.0 %), and agitation (49.0 %). Eleven variables with statistically significant discriminatory power remained after statistical analysis: diaphoresis (odds ratio (OR) 10.011), rigor (OR 9.550), fever (OR 7.317), tremor (OR 4.064), laboratory evidence of muscle injury (OR 3.542), leukocytosis (OR 3.081), negativism (OR 0.262), posturing (OR 0.241), waxy flexibility (OR 0.223), stupor (OR 0.158), and stereotypy (OR 0.122)., Conclusions: Catatonia and neuroleptic malignant syndrome can be distinguished, at least on a descriptive level. There is a strong syndromal overlap. Our findings might be influenced by the fact that they are based on case reports, which reflect the respective authors' clinical opinion of the patient's condition.

Question Under Study: The frequency of severe adverse drug reactions (ADRs) from psychotropic drugs was investigated in hospitalised psychiatric patients in relation to their age. Specifically, the incidence of ADRs in patients up to 60 years was compared to that of patients older than 60 years., Methods: Prescription rates of psychotropic drugs and reports of severe ADRs were collected in psychiatric hospitals in Switzerland between 2001 and 2010. The data stem from the drug surveillance programme AMSP., Results: A total of 699 patients exhibited severe ADRs: 517 out of 28,282 patients up to 60 years (1.8%); 182 out of 11,446 elderly patients (1.6%, ns). Logistic regression analyses showed a significantly negative relationship between the incidence of ADRs and patients' age in general and in particular for weight gain, extrapyramidal motor system (EPMS) symptoms, increased liver enzymes and galactorrhoea. A significantly negative relationship was observed for age and the dosages of olanzapine, quetiapine, risperidone, valproic acid and lamotrigine. When comparing age groups, frequency of ADRs was lower in general for antipsychotic drugs and anticonvulsants, in particular for valproic acid in the elderly. Weight gain was found to be lower in the elderly for antipsychotic drugs, in particular for olanzapine. For the group of mood-stabilising anticonvulsants (carbamazepine, lamotrigine and valproic acid) the elderly exhibited a lower incidence of reported allergic skin reactions., Conclusion: The results suggest that for psychiatric inpatients the incidence of common severe ADRs (e.g., weight gain or EPMS symptoms) arising from psychotropic medication decreases with the age of patients.

Purpose: The etiology, pathophysiology, clinical presentation, and management of drug-induced hyperthermia (DIH) syndromes are reviewed., Summary: DIH syndromes are a rare and often overlooked cause of body temperature elevation and can be fatal if not recognized promptly and managed appropriately. There are five major DIH syndromes: (1) neuroleptic malignant syndrome, (2) serotonin syndrome, (3) anticholinergic poisoning, (4) sympathomimetic poisoning, and (5) malignant hyperthermia. The differential diagnosis of DIH syndromes can be challenging because symptoms are generally nonspecific, ranging from blood pressure changes and excessive sweating to altered mental status, muscle rigidity, convulsions, and metabolic acidosis. Evidence from the professional literature (per a MEDLINE search for articles published through November 2011) indicates that few currently available treatment options can reduce the duration of hyperthermia; therefore, prompt identification of the provoking agent based on the patient's medication history, the clinical presentation, and the timing of symptom onset is essential to determine the appropriate treatment and mitigate potentially life-threatening sequelae. For all DIH syndromes, appropriate management includes the immediate discontinuation of the suspected offending agent(s) and supportive care (external cooling, volume resuscitation as needed); in some cases, pharmacologic therapy (e.g., a benzodiazepine, bromocriptine, dantrolene) may be appropriate, with the selection of a specific agent primarily determined by the medication history and suspected DIH syndrome., Conclusion: DIH is a hypermetabolic state caused by medications and other agents that alter neurotransmitter levels. The treatment of DIH syndromes includes supportive care and pharmacotherapy as appropriate.

Objective: To describe patients with neuroleptic malignant syndrome (NMS), to establish occurrence of NMS, to investigate risk factors of NMS, and to investigate mortality associated with NMS., Method: We conducted a longitudinal register linkage case-control study of NMS., Result: In health care registers covering the period from 1996 to 2007, we identified, among 224 372 patients with organic, psychotic, affective, or neurotic diagnosis, 83 patients with NMS, equivalent to an occurrence of 0.04%. Treatment with second-generation antipsychotics (SGAs) in the 3 months preceding admission increased the NMS risk (OR 4.66; 95% CI 1.96 to 11.10) and also first-generation antipsychotics (FGAs) of high potency (OR 23.41; 95% CI 5.29 to 103.61) and mid potency (OR 4.81; 95% CI 1.96 to 11.79), and depot antipsychotics (OR 4.53; 95% CI 1.60 to 12.80). Benzodiazepines (BDZs) also increased the risk of NMS (OR 3.43; 95% CI 1.68 to 12.80). NMS was associated with an increased mortality (HR 1.88; 95% CI 1.19 to 2.98) in patients, compared with sex-, age-, and diagnosis-matched control subjects, but no significant difference in mortality between patients and control subjects was observed after the initial 30 days (P = 0.27)., Conclusions: The occurrence of NMS is low, and the prediction of NMS is difficult. Previous treatment with FGAs, SGAs, and BDZs was identified as a risk factor for developing NMS. NMS increased mortality within 30 days after NMS.

Neuroleptic Malignant Syndrome (NMS), a potentially fatal complication of neuroleptic therapy is described. It is found to be associated with a variety of medical and psychiatric conditions. Various risk factors and non specific investigations pathognomic to various medical conditions has been proposed. The mortality and morbidity associated with NMS can be decreased with early recognition, early discontinuation of the neuroleptics and aggressive treatment.

Objective: To analyze clinical characteristics, time lag between diagnosis and treatment, and outcome of patients treated for catatonia, with the intention to improve daily clinical care., Method: A retrospective case study., Results: Between 1991 and 2009, a total of 34 patients were clinically diagnosed to have benign catatonia (n=13), malignant catatonia (n=11) and neuroleptic malignant syndrome (n=10). A total of 63 additional psychiatric diagnoses were present, and half of the patients had comorbid medical and neurological disorders. The mean time lags between first catatonic symptoms and first treatment and between first catatonic symptoms and second treatment were 15±36 and 58±92 days, respectively. Of the 34 patients, 26 (76%) improved, with complete remission in 20 (58%); mortality rate was 9% (n=3)., Conclusions: Retrospective evaluation of 34 catatonic patients revealed a great variety of psychiatric diagnoses and somatic comorbidity. Although treatment was effective in 76%, time lag between the first symptoms and effective treatment was remarkably long. Based on our retrospective critical evaluation, a clinical protocol has been developed to improve daily care for these complex and very ill patients., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Purpose: Neuroleptic malignant syndrome (NMS) is a rare and life threatening condition usually defined as a complication of treatment with antipsychotics characterized by severe rigidity, tremor, fever, altered mental status, autonomic dysfunction, and elevated serum creatine phosphokinase and white blood cell count. The literature on this topic is rather extensive, but many aspects related to the syndrome are thought to be controversial. The aim of this paper, written with the clinician in mind, is to summarize some of the most prominent controversies that may have importance in usual clinical practice., Methods: The literature was searched for reviews, reports on the series of cases, individual case reports of NMS, and other clinically and theoretically important information., Results: There are controversies associated with virtually all important aspects of NMS. At the moment, it is not clear if this drug reaction is idiosyncratic or not, what diagnostic criteria are the most appropriate for usual clinical practice, and it seems that the estimated incidence is not in accordance with the number of treated patients. There are rather different approaches to the pathophysiological mechanisms, differential diagnosis, and treatment., Conclusions: Some of the controversies related to NMS have an influence on our understanding of the condition and may have importance in clinical practice. There is a need for further research that should elucidate these controversies., ((c) 2010 John Wiley & Sons, Ltd.)

Purpose: A case study is presented to discuss the importance of accurate assessment of a patient in the emergency department (ED) who develops neuroleptic malignant syndrome (NMS)., Conclusions: There has been a significant increase in the number of patients with psychiatric emergencies seeking treatment in the ED. The most frequently used medication for treating these patients is a high-potency typical antipsychotic (neuroleptic). Although NMS is a rare condition, it is a potentially fatal complication of neuroleptic medications., Practice Implications: Early identification of this potentially life-threatening syndrome will lead to prompt treatment and improve the care of this vulnerable population.

Aim: The aim of the present study was to evaluate demographics, clinical features, psychiatric diagnoses and prognosis of neuroleptic malignant syndrome (NMS) reported in Turkey, and to assess their association with mortality., Methods: Data on all reported cases of NMS in the Turkish Psychiatric Index between 1985 and 2005 were collected. The type, dosage and administration period of neuroleptics, the clinical and laboratory findings; and prognosis were compared in terms of mortality., Results: Thirty-six patients with a mean age of 33.67 +/- 16.98 years were identified. Fifteen (41.7%) were diagnosed as having schizophrenia or other psychotic disorders and the same number were diagnosed as having affective disorder. Remaining five (13.9%) were diagnosed with other psychiatric disorders and 1 (2.7%) had no psychiatric diagnosis. Twenty-two (61.1%) of the NMS cases were associated with high potency typical neuroleptics. Association between an atypical antipsychotic and NMS has been reported in one case. NMS appeared within 7 days after initiation of the antipsychotic medication in the majority of samples (n = 19, 52.8%). Several combinations of rescue treatments were used in the majority of cases (n = 19, 52.8%), although bromocriptine (n = 22, 61.1%) was the most frequently preferred rescue treatment for NMS. Benzodiazepines were significantly better than the other treatment options in preventing mortality. Five out of the 36 patients (13.9%) with NMS had died. Age was the only significant independent factor that was associated with mortality., Conclusions: Benzodiazepines may be included in the treatment of NMS. The mortality rate due to NMS in Turkey was lower than the previously reported rates from other developing countries.

Objective: Neuroleptic malignant syndrome (NMS) is a severe iatrogenic complication of treatment with antipsychotic medication. The purpose of this report is to examine the published cases of NMS in children and adolescents receiving atypical antipsychotic medication and review early warning symptoms, risk factors, and treatment in this population., Method: An extensive review of the literature from 1990 to 2008 was conducted via computerized searches (PubMed and Ovid) to identify case reports. Descriptive statistics were employed to describe our findings., Results: There were 23 episodes in 20 subjects, with ages ranging from 11 to 18 years. Increased creatine phosphokinase (CPK) was the most common finding (100%), followed by fever (78%), tachycardia (74%), rigidity (70%), and altered mental status (61%). The number of NMS symptoms ranged from 1 to 11 (mean 4.7 +/- 2.4) and positive laboratory findings ranged from 1 to 4 (2.2 +/- 1). The duration of NMS (mean 6.1 +/- 6.4 days) was one third of the duration associated with typical antipsychotics. Patients treated with bromocriptine had a shorter duration of illness, whereas the same was not true for those receiving dantrolene. In all cases, the NMS symptoms eventually resolved and there were no reported deaths or permanent sequelae., Conclusions: NMS is a serious condition. Symptom presentation related to atypical agents differs from that seen with older antipsychotic medications.

Catatonia is the psychiatric syndrome of disturbed motor functions amid disturbances in mood and thought first described in 1874. It was quickly found in 10% to 38% of psychiatric populations. After it was tied to schizophrenia as a type in the psychiatric classification, its recognition became increasingly limited and by the 1980s questions were asked as to where the catatonics had gone. The decline is largely owing to the change in venue for psychiatric practice from asylum to office, the rejection of physical examination, and the dependence on item rating scales for diagnosis. In the 1970s, broad surveys again showed that catatonia was as common as before among patients with mania and depression, and as a toxic response to neuroleptic drugs. The latter recognition, that the neuroleptic malignant syndrome is the same syndrome as malignant catatonia, and is effectively treated as such, sparked a renewed interest. Clinicians developed rating scales to identify the catatonia syndrome and applied the immediate relief afforded by a barbiturate or a benzodiazepine as a diagnostic test, the lorazepam test. Effective treatments were described as high doses of benzodiazepines and electroconvulsive therapy (ECT). Surveys using catatonia rating scales showed catatonia to have many faces. Catatonia is presently limited to a type of schizophrenia in the psychiatric classification. Its recognition as a disorder of its own, such as delirium and dementia, should now be recognized. This experience reinforced the utility of the medical model for diagnosis. An application for melancholia is described.

Introduction: Current data regarding risk factors of neuroleptic malignant syndrome (NMS) are limited. This study aims to examine factors associated with increased risk of NMS in patients with bipolar disorder., Methods: A retrospective, population-based, case-control study was performed using a medical claims database covering January 1998 to December 2002. Fifty cases with a diagnosis of NMS were identified and matched with 800 controls. Conditional logistic regression analysis was used to estimate crude and adjusted odds ratios (ORs) of risk of NMS., Results: Antipsychotic use was associated with an increased risk of NMS after controlling for other pharmacologic and clinical factors (OR = 2.36, 95% CI = 1.08-5.19). Other factors associated with an increased risk of NMS included being male (OR = 2.07, 95% CI = 1.07-4.02), confusion (OR = 2.91, 95% CI = 1.17-7.28), dehydration (OR = 3.99, 95% CI = 1.50-10.57), delirium (OR = 4.93, 95% CI = 2.07-11.72), and extrapyramidal symptoms (OR = 3.50, 95% CI = 1.10-11.09)., Conclusions: Given the widespread use of antipsychotics for the treatment of bipolar disorder, clinicians should be vigilant of the potential pharmacologic and clinical factors associated with increased risk of NMS in patients with bipolar disorder.

Antipsychotic drugs are widely and increasingly prescribed for neurobehavioral disorders in elderly patients. However, the efficacy of these drugs has not been consistently demonstrated in geriatric populations and there are continuing concerns regarding adverse effects. Among the latter are severe neurological disorders, including neuroleptic malignant syndrome. Although the incidence and mortality of neuroleptic malignant syndrome may have declined with heightened awareness of this disorder and the development of newer drugs, neuroleptic malignant syndrome still occurs in association with the use of antipsychotics. To enhance patient safety and clinical vigilance among practitioners, the authors present a clinical overview of neuroleptic malignant syndrome.

Neuroleptic malignant syndrome (NMS) is a rare, life-threatening but potentially treatable condition. This study was performed to investigate the clinical spectrum, antecedent events and outcome of NMS patients admitted in the Neurology department of a large teaching hospital of North India. Fourteen cases of NMS were taken after a thorough search during a three-year period (May 2000 to April 2003). The Incidence of NMS was 1.40/ 1000 patients treated with neuroleptics and mortality rate was 14.28%. Amongst the neuroleptics Haloperidol (parenteral) was implicated as a most common drug for NMS in 57% of patients. An association with coexisting precipitating illness was clearly recorded in 71.4% patients. All the recorded patients of NMS received 500-700 mg CPZ equivalent/day of neuroleptics. NMS as an indiosyncratic phenomenon was noticed in 28% patients. 85.7% responded to dopaminergic drugs along with supportive treatment and showed partial or complete recovery within 7-14 days. In those with partial recovery residual deficits included Parkinsonian features, depression and diaphoresis in a small percentage of patients.

Objective: The aim of this study was to examine published reports for sources of excessive variance in neuroleptic malignant syndrome (NMS) incidence estimates., Data Sources: An unrestricted computerized MEDLINE search was conducted with a comprehensive search logic and supplemented by secondary references and a manual search of an extensive personal library., Study Selection: Studies were analyzed if they presented original data and provided at least 2 of the following: number of NMS cases, number of patients at risk, or ratio of cases to patients at risk. Twenty-six of the 28 candidate studies met these minimal criteria., Data Extraction: Variables included incidence, year of study publication, mean year of NMS occurrence, patient population at risk, study design, diagnostic criteria, and country of origin., Data Synthesis: Standard error, which reflects study size, accounted for 90.8% of the variance (beta = .953, P < .001) in this international series of 26 NMS incidence estimates. Incidence was significantly lower in 7 studies the time end points of which were set in advance of case identification (chi(2) = 71.08, P < .001). No other variable was significantly related to incidence., Conclusions: Neuroleptic malignant syndrome incidence estimates to date are non-trivially biased such that larger study size (patients at risk) is strongly related to lower observed incidence. Future studies can minimize the contribution of this and other sources of experimental error by incorporating several very feasible recommendations.

Objective of this paper is to review drug-induced movement disorders (D-IMD) treated patients on Department of Neurology in University Hospital Osijek. We reviewed patients treated during 10 years period (from 1992 to 2002). Analysed group consisted of 14 patients. Reasons for hospitalisation were swallowing problems in 6 patients, neuroleptic malignant syndrome (NMS) in 3 patients, stroke in 2 patients, bolus choking in 2 patients, and speech disturbance in 1 patient. Working diagnosis for most of our patients was neurological disease, yet only later D-IMD diagnosis was established excluding primary neurological disease, or as associated disease to basic neurological disorder. Nine patients have diagnosed as Parkinson syndrome, 3 patients as NMS, and 4 as orolingual dyskinesia, either autonomously, or in combination with Parkinson syndrome. D-IMD was most frequently caused by neuroleptics. Thus the small number of patients hospitalised regarding this syndrome on Department of Neurology.

The authors review the literature on persistent sequelae of neuroleptic malignant syndrome (NMS). They highlight the clinical presentations, assessment, and management of persistent sequelae and stress the need to take preventive steps to minimize their occurrence. The authors conducted a Medline and PubMed search for papers on residual sequelae of NMS. They cross-referenced the available papers and "operationalized" the diagnostic criteria for persistent neuropsychiatric sequelae. A total of 31 cases of neuropsychiatric sequelae of NMS were identified. With reduction in mortality from NMS, persistent sequelae of NMS have assumed clinical importance. Long-term sequelae persist for weeks to months after amelioration of an acute episode. Individuals with a preexisting CNS insult are more predisposed to develop persistent sequelae. A high index of awareness for persistent sequelae is warranted because antipsychotics are widely used for psychiatric disorders besides schizophrenia. Awareness of such outcomes and the use of evidence-based strategies to minimize risk factors will help clinicians in reducing the persistent sequelae of NMS.

The development of a rating scale for neuroleptic malignant syndrome (NMS) is described. The clinical and laboratory features of NMS were categorised into six domains after a thorough literature review and examination of patients. The reliability of this scale was established on 25 NMS patients and 50 control subjects based on chart reviews. A factor analysis supported a six-factor solution. The validity of the scale was indicated by the relationship of the severity rating to duration of illness and outcome. The inter-rater reliability of the scale was established prospectively in 10 subjects. The scale offers a measure of severity of NMS in the clinical setting so as to support the clinical diagnosis, monitor patients and determine their progress. The scale may be applicable not only to NMS or suspected NMS but also to NMS-like syndromes such as lethal catatonia.

A recurrent neural network, modified to handle highly incomplete training data is described. Unsupervised pattern recognition is demonstrated in the WHO database of adverse drug reactions. Comparison is made to a well established method, AutoClass, and the performances of both methods is investigated on simulated data. The neural network method performs comparably to AutoClass in simulated data, and better than AutoClass in real world data. With its better scaling properties, the neural network is a promising tool for unsupervised pattern recognition in huge databases of incomplete observations.

Background: Severe sensitivity to neuroleptic agents is a major clinical problem in dementia with Lewy bodies (DLB), but has not been determined in Parkinson's disease (PD) and PD with dementia (PDD)., Method: Severe neuroleptic sensitivity reactions (NSRs) were evaluated according to an operationalized definition blind to clinical and neuropathologic diagnoses in prospectively studied patients exposed to neuroleptics from 2 centers. The study was conducted from June 1995 to May 2003., Results: Ninety-four patients were included (15 with DLB, 36 with PDD, 26 with PD, 17 with Alzheimer's disease, all diagnosed with various operational criteria). Severe NSR only occurred in patients with Lewy body disease: DLB (8 [53%]), PDD (14 [39%]), and PD (7 [27%]), but did not occur in Alzheimer's disease (p = .006). Severe NSR was not associated with other clinical or demographic features. In DLB, severe NSR was not associated with neuropathologic indices (Consortium to Establish a Registry for Alzheimer's Disease staging, Braak staging, or cortical distribution of Lewy bodies)., Conclusions: An operationalized evaluation of severe NSR blind to diagnosis confirmed the high prevalence in DLB and identified high frequencies in Parkinson's disease and PDD with important implications for clinical practice.

Objective: To assess acute akinesia in patients with Parkinson disease (PD) ("acute akinesia" defined as a sudden deterioration in motor performance that persists for > or =48 hours despite treatment)., Methods: The study population was a cohort of 675 patients followed regularly for 12 years in the authors' outpatient clinic. All patients were studied when acute akinesia led to hospitalization. Unified Parkinson's Disease Rating Scale (UPDRS) scores were rated during the akinetic state and compared with ratings obtained 1.6 +/- 0.9 months before the onset or after recovery., Results: Twenty-six patients developed acute akinesia; in 17 of the 26 patients, new akinetic symptoms first manifested at the onset of an infectious disease or after surgery and appeared unrelated to changes in treatment or altered levodopa kinetics. In nine patients, acute akinesia developed concurrently with gastrointestinal diseases or drug manipulations showed features of neuroleptic malignant syndrome. Acute akinesia severe enough to increase the UPDRS Motor Subscale score by 31.4 +/- 12.8 appeared within 2 to 3 days and persisted for 11.2 +/- 6.2 days despite attempts to increase the dopaminergic drug dose or administer continuous subcutaneous apomorphine infusion. Symptomatic recovery began 4 to 26 days after the onset of acute akinesia and appeared incomplete in 10 patients. Four patients of 26 died despite treatment. Levodopa kinetics were normal in all patients without gastrointestinal disease and in one patient with gastric stasis., Conclusions: Acute akinesia is a life-threatening complication of Parkinson disease (PD). It is unlike the "wearing-off" phenomenon that occurs when dopaminergic drug levels decline and responds to dopaminergic rescue drugs. Acute akinesia may be a clinical entity distinct from the previously described PD motor fluctuations.

Background: Neuroleptic Malignant Syndrome (NMS) is an uncommon but potentially fatal complication of antipsychotic and neuroleptic drug treatment., Objectives: This study estimated the frequency, clinical presentation, and outcome of NMS in a referral center for neurological, neurosurgical and psychiatric disorders in Mexico., Methods: The authors conducted a thorough search of psychiatry, neurology, neurosurgery and intensive care unit records for cases of NMS during the 10-year period between 1990 and 1999. They examined the clinical features, course and treatment of the NMS episodes, and performed a follow-up survey for residual symptoms and clinical outcome. The mean time to follow-up assessment was 36 months., Results: A total of eight of 4831 neuroleptic-treated patients had an episode of NMS (incidence 0.165%). Seven of the eight patients were treated with haloperidol. Other neuroleptics agents associated with NMS were depot pipotiazine palmitate and levomepromazine maleate. One patient received lithium concomitantly. No fatal outcome was found. Only one patient developed persistent clinical sequelae, consisting of extrapyramidal and cerebellar symptoms, three years after the NMS episode., Conclusions: The slightly low frequency of NMS found in this study compared with studies conducted in other countries may be attributable to the advent and use of newer atypical antipsychotics in Mexico, the rigorous demands for NMS diagnostic criteria and the lack of familiarity with the diagnosis between physicians.