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Background and Objectives: Recent studies suggest that the binary categorization of first-generation antipsychotics (FGAs) as being primarily responsible for extrapyramidal symptoms (EPSs) and second-generation antipsychotics (SGAs) for cardiometabolic abnormalities is an oversimplification. SGAs also demonstrate antagonistic affinity for D2 receptors, indicating their potential to induce EPSs. This study utilized the Korea Adverse Event Reporting System (KAERS) database to explore adverse drug event (ADE) signals related to both FGAs and SGAs. Materials and Methods: Relevant ADE reports from January 2013 to December 2022 were extracted from the KAERS database and analyzed using disproportionality analysis, employing the proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC) with its 95% lower confidence interval (LCI) indices. Results: Of the initial dataset of 2,890,702 ADE reports, those with insufficient data and duplicates were removed, resulting in a final dataset of 5249 reports for analysis. Aripiprazole, an SGA, showed signals for movement disorders, including EPSs (PRR 4.7, ROR 4.8, IC 2.2), tremors (PRR 5.3, ROR 5.4, IC 2.4), and akathisia (PRR 18.6, ROR 19.3, IC 3.5). Notably, for quetiapine, cardiovascular signals were detected, including increased blood pressure (PRR 2.1, ROR 2.3, IC 0.5), and tachyarrhythmia (PRR 13.9, ROR 14.1, IC 1.8), along with peripheral edema (PRR 2.5, ROR 2.5, IC 0.2). Metabolic abnormalities, such as weight gain and increased appetite, were identified for four SGAs: aripiprazole, olanzapine, quetiapine, and risperidone. Safety signals related to movement disorders were not detectable for FGAs, likely due to the limited number of ADE reports available for analysis. Conclusions: Our study findings support that the distribution of ADEs between FGAs and SGAs is not strictly binary. Aripiprazole, despite being an SGA, showed signals for extrapyramidal movement disorders. Four SGAs (aripiprazole, olanzapine, quetiapine, and risperidone) were linked to metabolic side effects, while quetiapine was associated with cardiovascular safety signals.

Introduction: Given the increasing rates of antipsychotic use in multiple psychiatric conditions, greater attention to the assessment, monitoring and documentation of their side effects is warranted. While a significant degree of attention has been provided to metabolic side effect monitoring, comparatively little is known about how clinicians screen for, document and monitor the motor side effects of antipsychotics (ie, parkinsonism, akathisia, dystonia and dyskinesias, collectively 'extrapyramidal side effects', EPS). This review aims to systematically assess the literature for insights into current trends in EPS monitoring practices within various mental health settings globally., Methods and Analysis: An electronic search will be performed using the OVID Medline, PubMed, Embase, CINAHL and APA PsycINFO databases for studies published in the last quarter century (1998 to present day). Two independent reviewers will conduct the initial title and abstract screenings, using predetermined criteria for inclusion and exclusion. A third reviewer will resolve disagreements if consensus cannot be reached. If selected for inclusion, full-text data extraction will then be conducted using a pilot-tested data extraction form. Quality assessment will be conducted for all included studies using a modified version of the Quality Improvement Minimum Quality Criteria Set. A narrative synthesis and summary of the data will be provided. All stages of the review process will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines., Ethics and Dissemination: Ethical approval is not required. Findings will be peer reviewed, published and shared verbally, electronically and in print with interested clinicians and will also be presented as posters or talks at relevant medical conferences and meetings., Prospero Registration Number: CRD42023482372., Competing Interests: Competing interests: MS has received honoraria/has been a consultant for AbbVie, Angelini, Lundbeck, Otsuka., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Extrapyramidal syndromes (EPS) represent neurological side effects of antipsychotic medications, characterized by motor disturbances. While previous studies have indicated the neuroprotective effects of vitamin D and A against EPS, the underlying mechanisms of this protection remain unclear., Methods: Twenty-four adult mice were categorized into four groups: positive and negative control groups, one receiving a dopamine antagonist, and the other receiving both a dopamine antagonist and vitamins D and A. Sections of the corticobasal loop, specifically the motor cortex (M1) and basal nuclei (CPu), were prepared for Immunohistochemistry (IHC) and stained with Glial Fibrillary Acidic Protein (GFAP) to visualize reactive astrocytes. ELISA assays for TNF-α, IL-6, IL-4, IL-13, and dopamine levels were performed on homogenized brain sections., Results: The EPS group exhibited a significant increase in TNF-α and IL-6 levels in M1 and CPu. Treatment with dopamine agonists and vitamin D&A resulted in significant reductions in IL-6 levels. Only the Vitamin D&A group showed a significant decline in TNF-α. The EPS group recorded significant decreases in IL-4 and IL-13, with IL-13 significantly elevated in the dopamine agonist and Vitamin D&A groups. IL-4 was notably increased in the Vitamin D&A groups. Dopamine concentration significantly declined in the EPS group, with improvements observed in the groups treated with dopamine agonists, and vitamin D&A. Reactive astrocytes were significantly expressed in the M1 and CPu of the EPS group but poorly expressed in other groups., Conclusions: EPS is linked to astrocyte activation, an upsurge in pro-inflammatory cytokines, a decline in anti-inflammatory cytokines, and dopamine in the corticobasal loop. Administration of vitamin D3 and A was found to suppres pro-inflammatory cytokines and repress anti-inflammatory cytokines associated with astrocyte activation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: The Drug-Induced Extrapyramidal Symptom Scale (DIEPSS) is a multidimensional rating scale for the assessment of drug-induced extrapyramidal symptoms (EPS), developed in 1994. It is suitable for evaluating EPS considering the degree of influence EPS has on daily activities and the subjective distress that it causes., Method: This study to evaluate the interrater and test-retest reliability of the DIEPSS Slovenian version conducted at the University Medical Center Maribor in Slovenia in November 2018., Results: Six raters performed the interrater assessment of 135 DIEPSS video clips with recordings of patients with EPS. A second assessment was then performed by 2 raters to evaluate the test-retest reliability, which was high (interclass correlation coefficients from 0.743 to 0.936)., Conclusions: The results for the Slovenian language version of the DIEPSS show high interrater and test-retest reliability, with high concordance rates for all evaluated items (interclass correlation coefficient > 0.8)., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Drug-induced extrapyramidal syndrome (EPS) remains a major problem in clinical psychiatry. This study aimed to examine the factor structure of drug-induced extrapyramidal symptoms observed in patients with schizophrenia and assessed using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS)., Methods: The participants were 1478 patients with a diagnosis of schizophrenia whose EPS was assessed using the DIEPSS in India, Indonesia, Japan, Malaysia, and Taiwan in the 2016 REAP AP-4 study. The records of the participants were randomly divided into two subgroups: the first for exploratory factor analysis of the eight DIEPSS items, and the second for confirmatory factor analysis., Results: The factor analysis identified three factors: F1 (gait and bradykinesia), F2 (muscle rigidity and tremor), and F3 (sialorrhea, akathisia, dystonia, and dyskinesia)., Conclusion: The results suggest that the eight individual items of the DIEPSS could be composed of three different mechanisms: acute parkinsonism observed during action (F1), acute parkinsonism observed at rest (F2), and central dopaminergic mechanisms with pathophysiology other than acute parkinsonism (F3)., (© 2022 John Wiley & Sons Ltd.)

Background: Antipsychotic-associated extrapyramidal syndromes (EPS) are a common side effect that may result in discontinuation of treatment. Although some clinical features of individuals who develop specific EPSs are well defined, no specific laboratory parameter has been identified to predict the risk of developing EPS., Methods: Three hundred and ninety hospitalizations of patients under antipsychotic medication were evaluated. Machine learning techniques were applied to laboratory parameters routinely collected at admission., Results: Random forests classifier gave the most promising results to show the importance of parameters in developing EPS. Albumin has the maximum importance in the model with 4.28% followed by folate with 4.09%. The mean albumin levels of EPS and non-EPS group was 4,06 ± 0,40 and 4,24 ± 0,37 (p = 0,027) and folate level was 6,42 ± 3,44 and 7,95 ± 4,16 (p = 0,05) respectively. Both parameters showed lower levels in EPS group., Conclusions: Our results suggest that relatively low albumin and folate levels may be associated with developing EPS. Further research is needed to determine cut-off levels for these candidate markers to predict EPS., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Primary negative symptoms of schizophrenia are usually resistant to monotherapy with antipsychotics. The present study sought to assess the efficacy and tolerability of Palmitoylethanolamide (PEA) adjunctive therapy in treatment of negative symptoms in patients with stable schizophrenia., Methods: This 8-week (trial timepoints: baseline, week 4, week 8), double-blind, placebo-controlled clinical trial randomized patients with schizophrenia in a 1:1 ratio to compare the efficacy and safety of 600 mg twice a day of PEA and matched placebo alongside a stable dose of risperidone. Outcome measures were the positive and the negative syndrome scale (PANSS), the extrapyramidal symptom rating scale (ESRS), and the Hamilton depression rating scale (HDRS). The primary outcome was change in the negative subscale score during the trial period between the groups. Safety of interventions were controlled and addressed during the trial., Results: A total of 50 participants completed the trial (25 in each group). Baseline characteristics of the groups were comparable (p>0.05). There was significant effect from time-treatment interaction on negative symptoms (p = 0.012) suggesting greater symptom improvement in the PEA group. In contrast, the longitudinal changes in positive symptoms and depressive symptoms were similar between groups (p values>0.05). Safety assessments showed no significant difference regarding extrapyramidal symptoms, measured by ESRS, and also frequency of other complications between PEA and placebo groups (p values>0.05)., Conclusions: Adjunctive therapy with PEA and risperidone alleviates schizophrenia-related primary negative symptoms in a safe manner., Competing Interests: Conflict of interest The authors of this manuscript declare that they have no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Extrapyramidal symptoms (EPSs) are adverse effects of antipsychotics. Different risks of EPSs have been attributed to the 3 classes of antipsychotics. This study aimed to assess EPS in a clinical sample of schizophrenia patients who are on LAI and compare the severity of EPSs among the following 3 antipsychotic groups: (1) partial agonist, (2) second-generation antipsychotics, and (3) first-generation antipsychotics., Methods: Ninety-two patients were recruited from the Schizophrenia Program Injection Clinic. Using the Extrapyramidal Symptom Rating Scale (ESRS), severity of EPS was assessed and information regarding factors associated with risk of EPS, including coprescriptions, comorbidities, and demographics, was obtained from medical charts. Group differences in ESRS scores and subscores were analyzed using 1-way analyses of variances., Results: Among the 3 groups, there was no significant difference in total ESRS scores and subscores. Risperidone was associated with higher ESRS scores when compared with paliperidone, aripiprazole, and flupenthixol. Doses above maximum were commonly used in the paliperidone group, and there was no significant difference in total ESRS scores between the low, average, or above-maximum doses of paliperidone., Conclusions: Our results demonstrated a comparative risk of EPS across all 3 antipsychotic classes. Risperidone was associated with more EPS compared with other medications. A higher threshold for the "maximum dose" of paliperidone could be considered and higher doses used with the same cautions as low-average doses., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Evaluate the long-term improvement and safety of aripiprazole in treating irritability in Asian children and adolescents (6-17 years) with autistic disorder. Methods: A 52-week, open-label, flexibly dosed (2-15 mg/day) study on the improvement and safety of aripiprazole in patients with autistic disorder who had completed an antecedent 12-week open-label study. The evaluation of efficacy was conducted using the Aberrant Behavior Checklist (ABC), Clinical Global Impression (CGI) scale, Child Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), Vineland Adaptive Behavior Scale (VABS), and the Parenting Stress Index-Short Form (PSI-SF). Safety and tolerability measurements included adverse events, vital signs, electrocardiography, laboratory tests, body weight, and extrapyramidal symptoms (EPSs). Results: During the 52-week treatment, all effectiveness variables, including ABC, CGI, CY-BOCS, VABS, and PSI-SF scores, showed improvement. Regarding safety, the proportion of patients who experienced any treatment-emergent adverse events (TEAEs) was 58.62% (34/58 subjects, 75 cases). The most common TEAE was nasopharyngitis reported in 20.69% (15/58 subjects, 15 cases) and the other TEAE with an incidence of ≥10% was weight increases in 18.97% (11/58 subjects, 11 cases). Of them, 27.59% (16/58 subjects, 28 cases) experienced adverse drug reactions (ADRs). The most common ADR was weight increase reported in 15.52% (9/58 subjects, nine cases). The incidence of serious adverse events (SAEs) was 5.17% (3/58 subjects, three cases), which were epiphysiolysis, seizure, and a suicide attempt, but these were not ADRs. There were no clinically significant changes found in the evaluation of EPSs. Conclusions: Aripiprazole showed improvement for behavioral problems and adaptive functioning and was well tolerated in patients with autistic disorder until nearly a year after drug use. The Clinical Trial Registration number: NCT02069977.

Background and Hypothesis: There is a substantial gap in life expectancy between patients with severe mental illness (SMI) and the general population and it is important to understand which factors contribute to this difference. Research suggests an association between tardive dyskinesia (TD) and mortality; however, results are inconclusive. In addition, studies investigating associations between parkinsonism or akathisia and mortality are rare. We hypothesized that TD would be a risk factor for mortality in patients with SMI., Study Design: We studied a cohort of 157 patients diagnosed predominantly with schizophrenia on the former Netherlands Antilles. TD, parkinsonism, and akathisia were assessed with rating scales on eight occasions over a period of 18 years. Twenty-four years after baseline, survival status and if applicable date of death were determined. Associations between movement disorders and survival were analyzed using Cox regression. Sex, age, antipsychotics, antidepressants and benzodiazepines at each measurement occasion were tested as covariates., Study Results: Parkinsonism was a significant risk factor with an HR of 1.02 per point on the motor subscale of the Unified Parkinson's Disease Rating Scale (range 0-56). TD and akathisia were not significantly associated with mortality., Conclusions: Parkinsonism may be an important risk factor for mortality in SMI patients. This finding calls for more follow-up and intervention studies to confirm this finding and to explore whether treatment or prevention of parkinsonism can reduce excess mortality., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Risperidone is commonly used to treat different psychiatric disorders worldwide. Knowledge on dose-concentration relationships of risperidone treatment in children and adolescents with schizophrenia or other psychotic disorders is, however, scarce and no age-specific therapeutic ranges have been established yet. Multicenter data of a therapeutic drug monitoring service were analyzed to evaluate the relationship between risperidone dose and serum concentration of the active moiety (risperidone (RIS) plus its main metabolite 9-hydroxyrisperidone (9-OH-RIS)) in children and adolescents with psychotic disorders. Patient characteristics, doses, serum concentrations and therapeutic outcomes were assessed by standardized measures. The study also aimed to evaluate whether the therapeutic reference range for adults (20-60 ng/ml) is applicable for minors. In the 64 patients (aged 11-18 years) included, a positive correlation between daily dose and the active moiety (RIS am ) concentration was found (r s  = 0.49, p = 0.001) with variation in dose explaining 24% (r s 2  = 0.240) of the variability in serum concentrations. While the RIS am concentration showed no difference, RIS as well 9-OH-RIS concentrations and the parent to metabolite ratio varied significantly in patients with co-medication of a CYP2D6 inhibitor. Patients with extrapyramidal symptoms (EPS) had on average higher RISam concentrations than patients without (p = 0.05). Considering EPS, the upper threshold of the therapeutic range of RIS am was determined to be 33 ng/ml. A rough estimation method also indicated a possibly decreased lower limit of the preliminary therapeutic range in minors compared to adults. These preliminary data may contribute to the definition of a therapeutic window in children and adolescents with schizophrenic disorders treated with risperidone. TDM is recommended in this vulnerable population to prevent concentration-related adverse drug reactions., (© 2022. The Author(s).)

What Is Known and Objective: Delirium is more common and life-threatening among the elderly. Currently, no other medications, including antipsychotics, have been approved for delirium. The number of practice guidelines recommends antipsychotics to be the first option among selected patients. This study aimed to identify the type of drug-related problems (DRPs) concerning antipsychotics use among elderly patients with delirium., Methods: A retrospective observational study was conducted by collecting data from 2013 to 2016 in Maharaj Nakorn Chiang Mai Hospital, Thailand. Inpatients who were 60 years and over, diagnosed with delirium by ICD-10 diseases coding F05.X and treated with antipsychotics for delirium were included. A modified version of the American Society of Hospital Pharmacists classification criteria (mASHP-delirium) was used., Results and Discussion: A total of 379 patients were enrolled. Mean daily dose of haloperidol (oral) was 1.06 ± 1.33 mg, haloperidol (intramuscular) 2.71 ± 1.88 mg, haloperidol (intravenous; IV) 3.42 ± 1.97 mg, risperidone was 0.71 ± 0.52 mg, and quetiapine was 19.26 ± 15.63 mg. Among all, 427 events were classified as DRPs. The most common DRPs included inappropriate duration, dose, route of administration or dosage form accounting for the 416 events (97.4%), followed by actual adverse drug reactions (extrapyramidal symptoms; EPS), 6 events (1.4%) and potential drug-drug interactions for 5 events (1.2%). Of those 416 events, 200 events (48.1%) antipsychotics were continued after discharge and continued for more than 10 days. Dosage exceeding initial dose or maximum daily dose accounted for 179 events (43.0%). Other DRPs such as inappropriate route haloperidol IV and receiving the extended-release dosage form of quetiapine involve 26 (6.3%) and 11 (2.6%) events, respectively., What Is New and Conclusion: To the best of our knowledge, this is the first study using mASHP-delirium to identify DRPs of antipsychotics in treating delirium among elderly patients. Several DRPs were found that might lead to severe adverse drug reactions, particularly EPS and QTc interval prolongation. However, all DRPs could be prevented by developing antipsychotic setting protocols and specialty consulting systems to communicate among healthcare providers caring for vulnerable groups of patients. In addition, a prospective pharmacist intervention is required., (© 2021 John Wiley & Sons Ltd.)

First generation antipsychotics (FGAs) are more likely to induce extrapyramidal side-effects (EPS) than second generation antipsychotics (SGAs), and EPS have been shown associated to cognitive deficits in schizophrenia. So far, no study has explored the relationships between EPS and social cognition (SC) in people with schizophrenia. Therefore, we assessed the prevalence of EPS in a large sample of drug-treated community-dwelling persons with schizophrenia and explored their relationships with patients' neurocognitive and SC abilities. 875 patients underwent EPS, psychopathological, neurocognitive and SC assessments by means of standardized measures. Relationships between EPS, psychopathology and neurocognitive and SC measures were investigated by correlation tests. Moreover, a partial correlation network was computed by means of a network analysis. 256 patients were treated with FGAs alone or in combination with SGA and 619 with SGAs. EPS were significantly more frequent in FGA-treated group than in the SGA-treated one. Patients with EPS disclosed a more severe psychopathology and were more impaired in neurocognitive and SC measures compared to those without EPS. Disorganization, expressive deficit, and duration of illness were significantly associated to both neurocognitive and SC measures while EPS were associated to neurocognitive measures only. The network analysis showed that parkinsonism was the sole EPS directly connected to both psychopathological and neurocognitive indices whereas no direct connection emerged between EPS and SC measures. Present findings confirm that EPS are still present in the era of SGAs and contribute, together with other clinical variables, to the neurocognitive but not to the SC impairment of patients with schizophrenia., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Persons of African ancestry are thought to carry a higher risk for extrapyramidal syndromes (EPS) in schizophrenia., Aim: We investigated the phenomenon of spontaneous and treatment-emergent EPS in a sample comprising Xhosa (South Africa) and Yoruba (Nigeria) Africans with first-episode schizophrenia and first exposure to antipsychotics., Methods: The Extrapyramidal Symptom Rating Scale (ESRS) and a variety of validated tools were used for the assessment of participants before, and two-weekly after treatment with low dose flupenthixol decanoate. Participants were followed up for 12 months. Association of EPS with clinical characteristics was investigated using Pearson's correlation and linear regression analyses., Results: Of 88 participants at baseline, 16 (18.1%) had at least one definite EPS prior to antipsychotic exposure and 34 (38.6%) had treatment-emergent EPS. While spontaneous Parkinsonism was associated with negative symptoms ( r  = 0.2, p  = 0.043; β  = 0.6, p  = 0.043), treatment-emergent EPS demonstrated non-significant correlations with clinical characteristics. Apart from dyskinesia, the frequency of treatment-emergent EPS decreased over 12 months observation., Conclusion: These findings support the hypothesis suggesting that spontaneously occurring Parkinsonism in schizophrenia may be the motor spectrum of negative symptomatology. Future studies of this relationship may lead to early identification of patients who may be more sensitive to EPS.

Objective: Many patients with bipolar disorder are treated exclusively in primary care settings, and the use of atypical antipsychotics as primary treatment for bipolar depression is increasing. Extrapyramidal symptoms (EPS) are common side effects of antipsychotic medications, and clinicians should actively monitor for these symptoms when prescribing antipsychotic medications. Accurate diagnosis of EPS is especially important as the symptoms can be highly distressing, and in some cases, life threatening. Our aim is to familiarize primary care providers and other clinicians prescribing antipsychotic medications with EPS and to aid in its rapid diagnosis and treatment., Method: We describe a case of lurasidone induced dystonia with prominent laryngospasm and oculogyric crisis which was missed for many years in the primary care setting, largely due to misdiagnosis of symptoms as being related to anxiety and panic attacks., Results: In addition to summarizing this illustrative case, we present the most common forms of EPS and summarize the primary therapies for each type of EPS., Conclusions: With increased management of bipolar disorder in the primary care setting and increased use of atypical antipsychotics as the primary therapy for bipolar disorder, it is essential that all practitioners are prepared to actively monitor for EPS, followed by its rapid diagnosis and treatment.

Context: Investigate whether 123 I-ioflupane SPECT (DaT SPECT) has the potential as a marker of basal ganglia damage in acute methanol poisoning., Methods: Prospective, single-centre, cohort study of patients with confirmed methanol poisoning was conducted. DaT SPECT was performed twice with semi-quantification using DaTQUANT TM and MRI-based volumetry was calculated. Specific binding ratios (SBR) of striatum, caudate nucleus, and putamen were correlated with laboratory parameters of outcome, volumetric data, and retinal nerve fibres layer (RNFL) thickness measurements., Results: Forty-two patients (mean age 46.3 ± 4.2 years; 8 females), including 15 with MRI-detected putamen lesions (group I) and 27 patients with intact putamen (group II), underwent DaT SPECT. Volumetry was calculated in 35 of the patients assessed. SBR values for the left putamen correlated with putamen volume ( r  = 0.665; p  < 0.001). Decreased bilateral SBR values were determined for the striatum and the putamen, but not for the nucleus caudate, in group I ( p  < 0.05). Significant correlation was observed between the SBR of the posterior putamen and arterial blood pH ( r  = 0.574; p  < 0.001) and other toxicological parameters of severity of poisoning/outcome including serum lactate, glucose, and creatinine concentrations ( p  < 0.05). The SBR of the posterior putamen positively correlated with the global RNFL thickness ( p  < 0.05). ROC analysis demonstrated a significant discriminatory ability of SBR of the posterior putamen with AUC = 0.753 (95%CI 0.604-0.902; p  = 0.007). The multivariate regression model demonstrated that arterial blood pH, age, and gender were the most significant factors associated with SBR of the posterior putamen., Conclusion: DaT SPECT demonstrates significant potential for the diagnosis of methanol-induced basal ganglia damage.

Background: Network analysis provides a new viewpoint that explicates intertwined and interrelated symptoms into dynamic causal architectures of symptom clusters. This is a process called 'symptomics' and is concurrently applied to various areas of symptomatology., Aims: Using the data from Research on Asian Psychotropic Prescription Patterns for Antipsychotics (REAP-AP), we aimed to estimate a network model of extrapyramidal syndrome in patients with schizophrenia., Methods: Using data from REAP-AP, extrapyramidal symptoms of 1046 Asian patients with schizophrenia were evaluated using the nine items of the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The estimated network of the ordered-categorical DIEPSS items consisted of nodes (symptoms) and edges (interconnections). A community detection algorithm was also used to identify distinctive symptom clusters, and correlation stability coefficients were used to evaluate the centrality stability., Results: An interpretable level of node strength centrality was ensured with a correlation coefficient. An estimated network of extrapyramidal syndrome showed that 26 (72.2%) of all possible 35 edges were estimated to be greater than zero. Dyskinesia was most centrally situated within the estimated network. In addition, earlier antipsychotic-induced extrapyramidal symptoms were divided into three distinctive clusters - extrapyramidal syndrome without parkinsonism, postural instability and gait difficulty-dominant parkinsonism, and tremor-dominant parkinsonism., Conclusions: Our findings showed that dyskinesia is the most central domain in an estimated network structure of extrapyramidal syndrome in Asian patients with schizophrenia. These findings are consistent with the speculation that acute dystonia, akathisia, and parkinsonism could be the risk factors of tardive dyskinesia.

Objectives: Extrapyramidal symptoms (EPS) induced by pharmacologic agents can cause patient discomfort and lead to emergency department visits. Analyzing these cases at a pediatric emergency department may help to elucidate the characteristic features of extrapyramidal syndrome in children., Methods: This retrospective study was conducted at Chang Gung Memorial Hospital in Taiwan. Pediatric patients with drug-induced extrapyramidal syndrome seeking treatment at our emergency department from January 2001 to December 2010 were enrolled. The patients' clinical features, drug history, demographic data, and treatment data were collected and analyzed., Results: One hundred nineteen patients (61 females, 58 males) were enrolled. Ninety-six patients could provide their drug history; all of whom took dopamine antagonists and 90% of whom took dopamine antagonists as antiemetic agents, with only 9 patients taking them for antipsychotic purposes. Metoclopramide syrup overdose was the main cause of extrapyramidal syndrome in patients under 2 years old. The average emergency room stay of the patients who could provide their drug history was shorter than that of those who could not., Conclusions: It is not uncommon for patients with drug-induced EPS to present to a pediatric emergency room owing to the use of dopamine antagonists as antiemetic agents. Clinical symptoms with a clear drug history are helpful for the diagnosis and management. Emphasizing the correct usage of liquid medications will reduce the risk of EPS.

Purpose of Review: Pediatric migraine is a common, chronic, and disabling neurological disorder in children and adolescents. Outpatient management is not always effective, and intravenous migraine management may be necessary for headache treatment in the pediatric emergency department. Most current treatment is based on retrospective evidence and there is a lack of well-designed randomized double-blinded controlled pediatric studies. Intravenous drug treatment agents including intravenous fluids, prochlorperazine, diphenhydramine, metoclopramide, dexamethasone, magnesium, valproate and propofol, and dihydroergotamine are reviewed in this paper., Recent Findings: Nineteen studies were reviewed including one prospective randomized double-blind; one single-blinded randomized; one prospective; and one open-label, randomized clinical trial. Most studies were retrospective and the quality of the studies was limited. No definite conclusions can be drawn from the studies, but appropriate prospective trials between major pediatric headache institutions will move pediatric intravenous migraine management forward.

Introduction: We explore the transcription factors involved in the molecular mechanism of antipsychotic (AP)-induced acute extrapyramidalsymptoms (EPS) in order to identify new candidate genes for pharmacogenetic studies., Methods: Protein-protein interaction (PPI) networks previously created from three pharmacogenomic models (in vitro, animal, and peripheral blood inhumans) were used to, by means of several bioinformatic tools; identify key transcription factors (TFs) that regulate each network. Once the TFs wereidentified, SNPs disrupting the binding sites (TFBS) of these TFs in the genes of each network were selected for genotyping. Finally, SNP-basedassociations with EPS were analyzed in a sample of 356 psychiatric patients receiving AP., Results: Our analysis identified 33 TFs expressed in the striatum, and 125 SNPs disrupting TFBS in 50 genes of our initial networks. Two SNPs (rs938112,rs2987902) in two genes (LSMAP and ABL1) were significantly associated with AP induced EPS (p < 0.001). These SNPs disrupt TFBS regulated byPOU2F1., Conclusion: Our results highlight the possible role of the disruption of TFBS by SNPs in the pharmacological response to AP.

Midazolam is commonly used for sedation during procedures because of its relative safety and predictability. Still, some rare undesirable medication reactions have been described. We report a case in which midazolam given before a peripheral nerve block caused acute onset dyskinetic extrapyramidal symptoms. These symptoms ultimately resolved following reversal of the midazolam with flumazenil. Given the widespread and multidisciplinary use of midazolam, practitioners should be aware of the potential for rare adverse reactions and be prepared to manage these scenarios.

An irreversible extrapyramidal syndrome occurs in man after intravenous abuse of "homemade" methcathinone (ephedrone, Mcat) that is contaminated with manganese (Mn) and is accompanied by altered basal ganglia function. Both Mcat and Mn can cause alterations in nigrostriatal function but it remains unknown whether the effects of the 'homemade' drug seen in man are due to Mcat or to Mn or to a combination of both. To determine how toxicity occurs, we have investigated the effects of 4-week intraperitoneal administration of Mn (30 mg/kg t.i.d) and Mcat (100 mg/kg t.i.d.) given alone, on the nigrostriatal function in male C57BL6 mice. The effects were compared to those of the 'homemade' mixture which contained about 7 mg/kg of Mn and 100 mg/kg of Mcat. Motor function, nigral dopaminergic cell number and markers of pre- and postsynaptic dopaminergic neuronal integrity including SPECT analysis were assessed. All three treatments had similar effects on motor behavior and neuronal markers. All decreased motor activity and induced tyrosine hydroxylase positive cell loss in the substantia nigra. All reduced 123 I-epidepride binding to D2 receptors in the striatum. Vesicular monoamine transporter 2 (VMAT2) binding was not altered by any drug treatment. However, Mcat treatment alone decreased levels of the dopamine transporter (DAT) and Mn alone reduced GAD immunoreactivity in the striatum. These data suggest that both Mcat and Mn alone could contribute to the neuronal damage caused by the 'homemade' mixture but that both produce additional changes that contribute to the extrapyramidal syndrome seen in man.

Objectives: Extrapyramidal symptoms (EPS) are a common adverse effect of antipsychotics. However, there are case reports describing EPS following treatment with antidepressants. It is not fully understood how antidepressants cause EPS, but a serotonergic input to dopaminergic pathways is a probable mechanism of action. Methods: Data from a multicenter drug-surveillance programme (AMSP, 'drug safety in psychiatry') which systemically documents severe drug reactions during psychiatric inpatient admissions, were reviewed to assess for EPS associated with antidepressant treatment. We identified 15 such cases, which were studied to detect similarities and to characterise risk factors. Results: We report on 15 patients with EPS following antidepressant-therapy between 1994 and 2016. EPS frequently occurred with selective serotonin reuptake inhibitor (SSRI) treatment alone (7/15 cases) or concomitant SSRI treatment (6/15 cases). EPS were most frequent with escitalopram-treatment (5 cases). The most common EPS was atypical dyskinesia (6/15 cases) followed by akathisia (4/15 cases). The mean age of onset for EPS was 54.93 years (SD 17.9). EPS occurred at any dosage and equally often in men and women. Conclusions: Our results highlight the possibility of EPS as an important, although uncommon, adverse effect of antidepressants. Clinicians should beware of this adverse effect and monitor early warning signs carefully.

Neurological soft signs (NSS) have garnered increasing attention in psychiatric research on motor abnormalities in schizophrenia spectrum disorders (SSD). However, it remains unclear whether the assessment of NSS severity could have been confounded by current antipsychotic dosage. In this study, we recruited 105 patients with SSD that underwent a comprehensive motor assessment evaluating NSS and extrapyramidal motor symptoms (EPMS) by means of standardized instruments. Current antipsychotic dosage equivalence estimates were determined by the classical mean dose method (doses equivalent to 1 mg/d olanzapine). We used multiple regression analyses to describe the relationship between NSS, EPMS and antipsychotic medication. In line with our expectations, current antipsychotic dosage had no significant effects on NSS total score (p = 0.27), abnormal involuntary movements (p = 0.17), akathisia (p = 0.32) and parkinsonism (p = 0.26). Further, NSS total score had a significant effect on akathisia (p = 0.003) and parkinsonism (p = 0.0001, Bonferroni corr.), but only marginal effect on abnormal involuntary movements (p = 0.08). Our results support the notion that NSS are not significantly modulated by current antipsychotic dosage in SSD. The associations between NSS, akathisia and parkinsonism, as revealed by this study, support the genuine rather than medication-dependent origin of particular motor abnormalities in SSD., Competing Interests: Declaration of Competing Interest The Authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2019. Published by Elsevier B.V.)

Background: The Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) is a multidimensional rating scale designed for the fast, easy and reliable assessment of extrapyramidal symptoms (EPSs) induced by antipsychotics. Aim: The aim of this study was to validate the level of inter-rater and test-retest reliability of the Norwegian translation of this scale. Methods: A total of 125 video clips showing a variety of or no signs of EPSs were used in the present study. The participants recorded were Japanese psychiatric patients receiving first- and/or second-generation antipsychotics. A total of 103 patients (47 males and 56 females), diagnosed with schizophrenia ( n  = 68) or mood disorders ( n  = 35) appeared in the video clips. Their mean age was 48.7 ± 16.3 years (range 18-80) at the time of video recording. Inter-rater agreement was assessed with five raters and test-retest reliability with three. Results: Inter-rater reliability analyses showed interclass correlation coefficients (ICCs) ranging from 0.74 to 0.93 for each individual item. Test-retest reliability analysed independently for each rater ranged from 0.71 to 0.96. Conclusions: Inter-rater and test-retest agreement exhibited satisfactory ICC levels above 0.70. The Norwegian version of the DIEPSS is a reliable instrument for the assessment of drug-induced EPSs.

Purpose/background: Dopamine receptor blocking agents (DRBAs), also known as antipsychotics, are medications widely used to treat a growing number of mental health diagnoses. However, their utility is limited by the potential to cause serious adverse movement reactions. Akathisia, dystonia, parkinsonism, and tardive dyskinesia (collectively known as extrapyramidal symptoms or EPSs) are associated with reduced social and occupational functioning, negative patient attitudes toward treatment, and nonadherence to pharmacotherapy. Neuroleptic malignant syndrome is a life-threatening reaction that can result from DRBA use and cause musculoskeletal dysfunction. The aim of this study is to profile patients who have developed DRBA-related movement adverse effects and identify risk factors significantly associated with each subtype of EPSs or other movement disorders (OMDs) such as neuroleptic malignant syndrome., Methods/procedures: A report of all potential DRBA-related EPSs or OMDs occurrences within a large community hospital network was generated using International Classification of Diseases, Ninth Revision (ICD-9) and 10th Revision (ICD-10) billing codes. Each patient encounter was manually reviewed to confirm that a documented case of DRBA-related EPSs or OMDs had indeed occurred and subsequently determine the likely causative agent(s)., Findings/results: The resultant cohort of 148 patients experiencing unique DRBA-related EPS or OMD events was analyzed. The average patient was female, middle-aged, and overweight. The most common DRBAs precipitating EPSs or OMDs were haloperidol and quetiapine. In the population studied, age was significantly associated with the subtype of EPSs experienced such that those patients with akathisia and dystonia tended to be younger, whereas those with tardive dyskinesia tended to be older. Body mass index (BMI) category was also negatively correlated with the incidence of dystonia. In addition, it was observed that exposure to specific DRBAs, classes, and routes of administration significantly affected the risk of developing different subtypes of EPSs or OMDs in the study population., Implications/conclusions: To our knowledge, this is the first study to describe an association between age and BMI with the risk of akathisia and dystonia, respectively, in patients taking DRBAs. Other trends observed with age and BMI in patients developing DRBA-related EPSs support previously reported findings. Expanding the knowledge base of individual characteristics associated with the risk of developing different subtypes of EPSs or OMDs can help providers and patients anticipate and attempt to mitigate these reactions, and may ultimately improve adherence to DRBA therapy.

The association between smoking and psychopathology and extrapyramidal side effects (EPSE) in schizophrenia has been controversial. This systematic review and meta-analysis compared psychopathology and EPSE between smoking and non-smoking schizophrenia patients. The PubMed, EMBASE, PsycINFO, Cochrane Library, and Web of Science databases were independently and systematically searched by two researchers to identify relevant articles. Standardized mean differences (SMDs) and their 95% confidence intervals (CI) were calculated with random effect models. Subgroup and meta-regression analyses were performed to explore sources of heterogeneity. The systematic review and meta-analysis included 29 studies that compared psychotic, depressive and anxiety symptoms and EPSE between smoking (n = 3591) and non-smoking schizophrenia patients (n = 2980). Smoking patients had significantly more severe positive symptoms (24 studies; SMD = 0.33, 95% CI: 0.16 to 0.50, P < 0.001), but less severe EPSE (7 studies; SMD = -0.20, 95% CI: -0.38 to -0.02, P = 0. 03). No significant group differences in negative, depressive and anxiety symptoms were found. In conclusion, this systematic review and meta-analysis found that smoking schizophrenia patients had more severe positive symptoms but less severe EPSE than non-smoking patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To describe clinical consequences of risperidone medication errors in children of less than 13 years and to estimate a clinically relevant toxic dose., Methods: All cases of risperidone medication errors managed by French Poison Centres from 2001 to 2012 were analyzed. Inclusion criteria were a delay of at least 2 hours between ingestion and request to the FPC in asymptomatic children, an ingested dose above two-fold the maximal daily dose for children above 5 years or any symptomatic patient at the time of first contact., Results: One hundred and sixty cases met our criteria. Median age was 8 years (range 0.9-12) and 28.1% were aged 5 years or less. Causes of the error were an incorrect dose in treated children (84.2%) or a dose given to a wrong child (15.8%). The median ingested dose was 0.1 mg/kg or 3.3-fold the maximum recommended dose. Overall, 59 children had no symptoms, 95 experienced minor symptoms and six moderate symptoms. Somnolence/sedation was the most common (73.3%). Of the 17 children who developed extrapyramidal disorders, all had minor or moderate symptoms and only five required a symptomatic treatment., Conclusions: Risperidone medication errors in children cause minimal effects. Somnolence and mild to moderate extrapyramidal reactions were the main features of toxicity, and significant cardiac or other neurological features were not observed. No case with severe toxicity was noted. At home surveillance can be proposed for children exposed to a dose ≤0.15 mg/kg.

Objectives: To assess baseline imbalances in placebo-controlled trials of atypical antipsychotics in dementia, and their association with neuropsychiatric symptoms (NPS), extrapyramidal symptoms (EPS), and mortality., Method: We searched for trials in multiple sources. Two reviewers extracted baseline characteristics and outcomes per treatment group. We calculated direction, range, pooled mean, and heterogeneity in the baseline differences, and used meta-regression for the relationship with the outcomes., Results: We identified 23 trials. Baseline type of dementia, cognitive impairment and NPS were poorly reported. The drug group had a higher mean age than the placebo group in nine trials and lower mean age in three trials (p = 0.073). The difference in percentage men between the drug and placebo group ranged from -9.7% to 4.4%. There were no statistically significant pooled baseline differences, but heterogeneity was present for age. Higher mean age at baseline in the drug versus placebo group was significantly associated with greater reduction in NPS, and higher percentage of non-White persons with lower risk of EPS. Imbalances were not significantly associated with risk of mortality., Conclusion: Randomized trials of atypical antipsychotics in dementia showed baseline imbalances that were associated with higher efficacy and lower risk of EPS for atypical antipsychotics versus placebo., (© 2018 The Authors International Journal of Methods in Psychiatric Research Published by John Wiley & Sons Ltd.)

We propose the use of the term tardive dyskinesia to refer to the original description of repetitive and complex oral-buccal-lingual (OBL) movements and the analogous repetitive movements of the limbs, trunk, or pelvis. The term tardive syndrome is an umbrella term to be used to refer to the spectrum of all persistent hyperkinetic, hypokinetic, and sensory phenomenologies resulting from chronic dopamine receptor blocking agent (DRBA) exposure. TD is a type of TS. The term tardive dystonia (TDyst) should be used when dystonia is the main feature of TS. Retrocollis and oromandibular dystonia appear to be the most common form of Tdyst. Tardive akathisia refers to the inability to remain still with an urge to move, giving the appearance of restlessness. In tardive tourettism, the patient has complex motor and phonic tics associated with premonitory urge and relief of tension after performing the tic behavior, thus resembling Tourette's syndrome. Tardive tremor is composed of mainly postural and kinetic tremors. It differs from the resting tremor seen in drug-induced parkinsonism. Tardive pain occurs in association with chronic use of DRBAs and involves the mouth, tongue, and genital region with no physical findings. In tardive parkinsonism, the patient has persistent parkinsonism even after discontinuation of the DRBA although this diagnosis is in question and may represent DRBA-uncovered idiopathic Parkinson's disease or coincident development of Parkinson's disease while taking DRBAs., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Paliperidone is FDA-approved for schizophrenia aged 12-17. However, the pharmacologic portfolio, extrapolation from adult studies, and the long track record of the parent drug, risperidone in child/adolescent psychiatric (CAP) population might expand its therapeutic potential., Methods: EMBASE, Ovid MEDLINE, PubMed, Scopus, Web of Science, and Cochrane Database of Systemic Reviews were searched for all relevant studies of using paliperidone in child psychiatry up to date of February 2019., Results: Sound evidence base supports its use in early-onset schizophrenia, juvenile bipolar, and autism spectrum disorder. A modicum of evidence supports its use in Tourette syndrome and as adjuventia in attention-deficit/hyperactivity disorder (ADHD)., Conclusion: Paliperidone has some dynamic and kinetic superiority to the parent drug risperidone. Nonetheless, larger rigorous studies would define the real place of the atypical antipsychotic paliperidone in child and adolescent psychiatry. Until then, risperidone with its long track record in CAP population would remain a first option though., (© 2019 S. Karger AG, Basel.)

Background: Although haloperidol is the most widely used drug in the treatment of delirium, evidence on the relevance of atypical antipsychotics (AAPs) is growing., Objective: To review the literature on the efficacy and tolerability of AAPs in the treatment of delirium., Methods: A systematic search of the literature published before April 2018 was performed on PubMed using the following search strings: "Delirium" and "Atypical antipsychotics", "Novel antipsychotics", "New antipsychotics", "Quetiapine", "Olanzapine", "Aripiprazole", "Risperidone", "Paliperidone", "Clozapine", "Asenapine", "Iloperidone", "Amisulpiride", "Ziprasidone", "Zotepine", "Sertindole", "Lurasidone" or "Perospirone"., Results: Twelve randomized controlled trials (RCTs) and 22 open trials were considered. Despite an overall lack of large-scale RCTs, there is some evidence supporting the efficacy of olanzapine and quetiapine in placebo controlled trials. In a recent and large RCT in elderly patients, risperidone and/or haloperidol were associated with a significantly worse outcome than placebo. While preliminary, the current comparative studies suggest that haloperidol and the AAPs olanzapine, quetiapine and risperidone are similarly effective, although treatment with AAPs is associated with a reduced incidence of extrapyramidal symptoms. Ziprasidone was not shown to be effective. No RCTs are available for other AAPs., Conclusions: Although the current evidence of the efficacy and tolerability of AAPs in the treatment of delirium is limited and the heterogeneity of the data precluded a meta-analysis, olanzapine and quetiapine seem to be adequate alternatives to haloperidol, especially in patients who are vulnerable for extrapyramidal symptoms, who require sedation or who have a history of haloperidol intolerance. Evidently, larger-scale RCTs are urgently required., (Copyright © 2018. Published by Elsevier Inc.)

Objective: Antipsychotic use in older patients is associated with many adverse effects, including tardive dyskinesia and extrapyramidal symptoms, which, in turn, increase the risk of falling. Antipsychotics are also associated with metabolic syndrome and cognitive impairment in older patients. Integrated care pathways (ICPs) are designed to manage specific conditions using standardized assessments and measurement-based interventions. This study aims to compare the use of recommended tools to monitor for adverse effects associated with antipsychotics in older patients managed within an ICP and those managed under usual care conditions-i.e., treatment as usual (TAU)., Methods: We reviewed and compared the health records of 100 older patients enrolled in an ICP for late-life schizophrenia with those of 100 older patients treated with antipsychotics under TAU conditions., Results: Monitoring rates were significantly higher in the ICP group than in the TAU group for all assessments: extrapyramidal symptoms (94% versus 5%), metabolic disturbances (91% versus 25%), fall risk (82% versus 35%), and cognitive impairment (72% versus 28%). Rates of antipsychotic polypharmacy were also six times higher in the TAU group., Conclusion: Older patients with schizophrenia treated with antipsychotics within an ICP experience higher rates of monitoring and less psychotropic polypharmacy than older patients treated with antipsychotics under TAU conditions. These findings suggest that an ICP can improve the quality of antipsychotic pharmacotherapy in older patients and thus possibly its effectiveness. This needs to be confirmed by a randomized controlled trial., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Extrapyramidal symptoms (EPS) are the major constraint in the use of antipsychotic agents. It is usually forewarned whenever therapy with these agents is considered. In this case, we present a child diagnosed with relapsed Wilm's tumour, who developed EPS just after a short duration of initiation of risperidone prescribed as an appetite stimulant. The patient became symptom free after management and risperidone was discontinued. Although risperidone has been approved to treat different indications in adolescents and children, scarce scientific evidence and our case report, are suggestive of further studies to establish safety of risperidone use in preschool children.

Purpose: To conduct an overview to summarize the efficacy and safety of aripiprazole for the treatment of schizophrenia., Methods: A literature search was performed in PubMed, the Cochrane Library, LILACS, and the Centre for Reviews and Dissemination, for articles published until March 31, 2017. We included systematic reviews with meta-analyses of randomized controlled trials assessing the efficacy, and/or the safety of aripiprazole, for patients with schizophrenia. Two authors independently performed the study selection, data extraction, and quality assessment. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach and the Risk of Bias in Systematic Review (ROBIS) tool were used to appraise the quality of evidence and the risk of bias in the reviews, respectively., Results: Fourteen studies fulfilled the inclusion criteria. Aripiprazole showed efficacy similar to that of both typical and atypical antipsychotic drugs (except olanzapine and amisulpride). Aripiprazole caused significantly lower weight gain and alterations in glucose and cholesterol levels, as compared to clozapine, risperidone, and olanzapine. In addition, aripiprazole caused significantly fewer general extrapyramidal side effects, less use of antiparkinsonian drugs, and akathisia, compared with typical antipsychotic drugs and risperidone. The overall quality of evidence in the reviews ranged from "very low" to "moderate," principally because of the risk of bias of original trials, inconsistency, and imprecision in the outcomes. According to the ROBIS tool, there are four reviews with "high" risk of bias and five with "unclear" risk of bias., Conclusions: Aripiprazole exhibited efficacy similar to that of other antipsychotic drugs and a better safety profile than that of typical (i.e., less some extrapyramidal side effects) and atypical (i.e., less metabolic changes) antipsychotic drugs.

Background: Antidepressants are one of the most prescribed classes of medications. A number of case reports have linked these drugs to extrapyramidal symptoms (EPSs), but no large epidemiologic study to date has examined this association. We sought to quantify the association of EPSs with different antidepressants by undertaking a large pharmacoepidemiologic study., Methods: A nested case-control study was conducted using a large health claims database in the United States from June 2006 to December 2015. Subjects with a diagnosis of primary Parkinson disease and those who received prescriptions of levodopa, ropinirole, pramipexole, domperidone, metoclopramide, entacapone, benztropine, selegiline, rasagiline, diphenhydramine, trihexyphenidyl, typical and atypical antipsychotics, and tricyclic antidepressants were excluded. Cases were followed to the first billing code for an extrapyramidal event or last date of enrollment in the cohort. For each case, 10 control subjects were matched by follow-up time, calendar time, and age through density-based sampling. Rate ratios were computed using conditional logistic regression adjusting for other covariates., Results: We identified 3,838 subjects with EPSs compared with 38,380 age-matched control subjects. Rate ratios with respect to EPSs were as follows: duloxetine, 5.68 (95% confidence interval [CI], 4.29-7.53); mirtazapine, 3.78 (95% CI, 1.71-8.32); citalopram, 3.47 (95% CI, 2.68-4.50); escitalopram, 3.23 (95% CI, 2.44-4.26); paroxetine, 3.07 (95% CI, 2.15-4.40); sertraline, 2.57 (95% CI, 2.02-3.28); venlafaxine, 2.37 (95% CI, 1.71-3.29); bupropion, 2.31 (95% CI, 1.67-3.21); and fluoxetine, 2.03 (95% CI, 1.48-2.78)., Conclusions: This observational study demonstrates a harmful association between the incidence of Parkinson disease or associated EPSs and use of the antidepressants duloxetine, mirtazapine, citalopram, escitalopram, paroxetine, sertraline, venlafaxine, bupropion, and fluoxetine.

Antipsychotic drugs are the mainstay of psychotic disorders. The 'typical' antipsychotic agents are commonly employed for the positive symptoms of schizophrenia, though at an expense of extrapyramidal side effects (EPS). In the present study, we employed haloperidol (HP)-induced catalepsy model in mice to evaluate the role of adenosine receptor antagonist and cyclooxygenase (COX) enzyme inhibitor in the amelioration of EPS. HP produced a full blown catalepsy, akinesia and a significant impairment in locomotion and antioxidant status. Pre-treatment with COX inhibitor; naproxen (NPx) and adenosine receptor antagonist; caffeine (CAF), showed a significant impact on HP-induced cataleptic symptoms. Adenosine exerts pivotal control on dopaminergic receptors and is also involved in receptor internalization and recycling. On the other hand, prostaglandins (PGs) are implicated as neuro-inflammatory molecules released due to microglial activation in both Parkinson's disease (PD) and antipsychotics-induced EPS. The involvement of these neuroeffector molecules has led to the possibility of use of CAF and COX inhibitors as therapeutic approaches to reduce the EPS burden of antipsychotic drugs. Both these pathways seem to be interlinked to each other, where adenosine modulates the formation of PGs through transcriptional modulation of COXs. We observed an additive effect with combined treatment of NPx and CAF against HP-induced movement disorder. These effects lead us to propose that neuromodulatory pathways of dopaminergic circuitry need to be explored for further understanding and utilizing the full therapeutic potential of antipsychotic agents.

Objectives: To describe a cohort of young users of risperidone and quetiapine in the province of Manitoba (Canada) and assess the risk for movement disorders in the two treatments., Methods: This was a population-based study conducted on all residents of the province of 19 years of age and younger who received prescriptions for risperidone or quetiapine between April 1, 1996, and March 31, 2011. Incident rates of antipsychotic use were reported. The risk for movement disorders in patients treated with quetiapine compared with those treated with risperidone was assessed by time-to-event analysis using Cox proportional hazards models., Results: Between April 1, 1996, and March 31, 2011, 23,888 youth (age ≤19 years) were prescribed an antipsychotic agent. Among them, 8756 were identified as new incident users. After applying exclusion criteria, 2594 individuals comprised the cohort of users of risperidone and quetiapine. The use of quetiapine was associated with a lower risk of extrapyramidal symptoms (EPSs) adverse events. The unadjusted and adjusted hazard ratios (95% confidence interval [CI]) for quetiapine versus risperidone were 0.83 (0.56-1.25) and 0.53 (0.34-0.83), respectively., Conclusion: EPS diagnoses have been detected in children treated with quetiapine; however, the risk of movement disorders appears to be higher with treatment with risperidone. Clinicians should always take into consideration the risk-benefit before treating children with antipsychotic medications and should be vigilant of the onset of drug-induced adverse events.

Cariprazine, a potent dopamine D3 and D2 receptor partial agonist antipsychotic with preferential binding to D3 receptors, is Food and Drug Administration approved for treating schizophrenia and manic or mixed episodes of bipolar I disorder. A post-hoc safety/tolerability analysis of data from the four acute trials in the cariprazine schizophrenia clinical development program (NCT00404573; NCT00694707; NCT01104766; NCT01104779) was carried out using the overall safety population (all patients who received ≥1 dose of study drug) and modal daily dose subgroups (1.5-3, 4.5-6, and 9-12 mg/day). These exploratory findings were summarized using descriptive statistics. Cariprazine was generally well tolerated. The incidence of treatment-emergent adverse events versus placebo was similar for cariprazine 1.5-3 mg/day and higher for cariprazine 4.5-6 and 9-12 mg/day; a dose-response relationship was observed for akathisia, extrapyramidal symptoms, and diastolic blood pressure. The mean changes in metabolic parameters were generally similar in cariprazine-treated and placebo-treated patients. There was no prolactin level increase or QTc value greater than 500 ms; small increases in mean body weight (∼1to2 kg) versus placebo were observed. Within the Food and Drug Administration-approved dose range (1.5-6 mg/day), cariprazine was generally safe and well tolerated in patients with schizophrenia.

Our previous study demonstrated that there have been changes in the patterns of prescription antipsychotic use in China over the period from 2002 to 2012. The aim of this study was to evaluate whether time trends were present for the prescription of anticholinergic medications (ACMs) during the observation period. A total of 14,013 patients with schizophrenia treated in 45 psychiatric hospitals/centers nationwide were surveyed in 2002, 2006 and 2012. Basic socio-demographic and clinical characteristics and the prescription of psychotropic drugs were recorded using a standardized protocol and data collection procedure. The frequency of ACM prescription was 25.9% in the whole sample (29.5%, 21.6%, and 27.4% in 2002, 2006 and 2012, respectively). In addition, different temporal trends were observed across age groups. Multiple logistic regression analysis of the entire sample showed that ACM prescriptions were predicted by females, outpatients, patients receiving high doses of antipsychotic medication, select study years, benzodiazepine users, patients displaying extrapyramidal side effects, as well as antipsychotic prescription patterns. Although there was more widespread use of second-generation antipsychotics over the past decade, the frequency of ACM use only slightly decreased. How to use ACM appropriately is still a therapeutic issue that needs to foster evidence-based prescription practice., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Atypical antipsychotic drugs (APDs) have been hypothesized to show reduced extrapyramidal side effects (EPS) due to their rapid dissociation from the dopamine D 2 receptor. However, support for this hypothesis is limited to a relatively small number of observations made across several decades and under different experimental conditions. Here we show that association rates, but not dissociation rates, correlate with EPS. We measured the kinetic binding properties of a series of typical and atypical APDs in a novel time-resolved fluorescence resonance energy transfer assay, and correlated these properties with their EPS and prolactin-elevating liabilities at therapeutic doses. EPS are robustly predicted by a rebinding model that considers the microenvironment of postsynaptic D 2 receptors and integrates association and dissociation rates to calculate the net rate of reversal of receptor blockade. Thus, optimizing binding kinetics at the D 2 receptor may result in APDs with improved therapeutic profile.Atypical antipsychotics show reduced extrapyramidal side effects compared to first generation drugs. Here the authors use time-resolved FRET to measure binding kinetics, and show that side effects correlate with drug association rates to the D 2 receptor, while dissociation rates correlate with prolactin elevation.

Purpose/background: Antipsychotics are efficacious for tics and are increasingly prescribed to children with behavioral disorders. Antipsychotics have important adverse effects, and systematic monitoring of drug safety is infrequently performed. The objectives of this study were to determine the feasibility of antipsychotic safety monitoring in children with Tourette Syndrome using a defined protocol and to evaluate the risk of adverse effects with chronic use., Methods/procedures: A prospective longitudinal study of children prescribed antipsychotics was performed. Children were monitored for extrapyramidal, metabolic, and hormonal adverse effects using the Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotic Medications guidelines. This included the measurement of height, weight, waist circumference, the Extrapyramidal Symptom Rating Scale, and laboratory tests of lipids, glucose, insulin, and prolactin at prespecified time points., Findings/results: Fifty-seven children who started on risperidone or aripiprazole were monitored for a mean of 10 months 3 days. Significant increases in body mass index (BMI) and waist circumference percentiles occurred with time. There was a significant time by drug interaction, with children on aripiprazole having smaller changes in BMI initially, followed by a faster rate of increase than with risperidone. There was a significant difference between Extrapyramidal Symptom Rating Scale scores on versus before starting antipsychotics and significant increases in insulin and prolactin. Change from a healthy to overweight or obese BMI percentile occurred in 26%. Extrapyramidal symptoms occurred in 35%. Medication was discontinued because of metabolic effects in 19%, and extrapyramidal symptoms in 7%., Implications/conclusions: Monitoring of antipsychotic safety in children is feasible and recommended to inform treatment decisions.