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Patient response to antipsychotic drugs varies and may be related to clinical and genetic heterogeneity. This study aimed to determine the performance of clinical, genetic, and hybrid models to predict the response of first episode of psychosis (FEP). patients to the antipsychotic risperidone. We evaluated 141 antipsychotic-naïve FEP patients before and after 10 weeks of risperidone treatment. Patients who had a response rate equal to or higher than 50% on the Positive and Negative Syndrome Scale were considered responders (n = 72; 51%). Analyses were performed using a support vector machine (SVM), k-nearest neighbors (kNN), and random forests (RF). Clinical and genetic (with single-nucleotide variants [SNVs]) models were created separately. Hybrid models (clinical+genetic factors) with and without feature selection were created. Clinical models presented greater balanced accuracy 63.3% (confidence interval [CI] 0.46-0.69) with the SVM algorithm than the genetic models (balanced accuracy: 58.5% [CI 0.41-0.76] - kNN algorithm). The hybrid model, which included duration of untreated psychosis, Clinical Global Impression-Severity scale scores, age, cannabis use, and 406 SNVs, showed the best performance (balanced accuracy: 72.9% [CI 0.62-0.84] - RF algorithm). A hybrid model, including clinical and genetic predictors, can provide enhanced predictions of response to antipsychotic treatment.

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Although commonly used in clinical practice, scientific literature about clozapine prescription patterns in Colombia is scarce. A cross-sectional observational study was conducted in an outpatient clinic in Bogotá, Colombia. Between 2016 and 2018, clozapine was prescribed to 2603 patients, mainly for Schizophrenia Spectrum Disorders and Bipolar and Depressive Disorders, at a median dose of 100mg/day. After controlling for other variables, older age was the only variable that explained the use of doses lower than 100mg/day. Clozapine was not only used for Treatment-Resistant Schizophrenia, and further studies are needed to explain these differences.

Aunque se utiliza comúnmente en la práctica clínica, la literatura científica sobre los patrones de prescripción de clozapina en Colombia es escasa. Se realizó un estudio observacional transversal en el servicio ambulatorio de una clínica de referencia en Bogotá, Colombia. Entre 2016 y 2018, se recetó clozapina a 2603 pacientes, principalmente para esquizofrenia y trastornos relacionados, trastorno afectivo bipolar y trastornos depresivos, a una dosis media de 100 mg/día. Después de controlar otras variables, la edad avanzada fue la única variable que explicó el uso de dosis inferiores a 100 mg/día. La clozapina no se utilizó sólo para la esquizofrenia resistente al tratamiento, y se necesitan estudios adicionales para explicar estas diferencias.

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Cannabidiol (CBD) is a major phytocannabinoid in the Cannabis sativa plant. In contrast to Δ9-tetrahydrocannabinol (THC), CBD does not produce the typical psychotomimetic effects of the plant. In addition, CBD has attracted increased interest due to its potential therapeutic effects in various psychiatric disorders, including schizophrenia. Several studies have proposed that CBD has pharmacological properties similar to atypical antipsychotics. Despite accumulating evidence supporting the antipsychotic potential of CBD, the mechanisms of action in which this phytocannabinoid produces antipsychotic effects are still not fully elucidated. Here, we focused on the antipsychotic properties of CBD indicated by a series of preclinical and clinical studies and the evidence currently available about its possible mechanisms. Findings from preclinical studies suggest that CBD effects may depend on the animal model (pharmacological, neurodevelopmental, or genetic models for schizophrenia), dose, treatment schedule (acute vs. repeated) and route of administration (intraperitoneal vs local injection into specific brain regions). Clinical studies suggest a potential role for CBD in the treatment of psychotic disorders. However, future studies with more robust sample sizes are needed to confirm these positive findings. Overall, although more studies are needed, current evidence indicates that CBD may be a promising therapeutic option for the treatment of schizophrenia.

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Schizophrenia (SCZ) is a severe psychiatric disorder with unclear pathophysiology. Moreover, there is no specific biological marker to help clinicians to define a diagnosis, and medication is decided according to the psychiatrist's experience. In this scenario, microRNAs (miRNAs), which are small noncoding RNA molecules that regulate several genes, emerge as potential peripheral biomarkers to help not only the evaluation of the disease state but also the treatment response. Here, we systematically reviewed indexed literature and evaluated follow-up studies investigating the changes in miRNA expression due to antipsychotic treatment. We also assessed target genes and performed pathway enrichment analysis of miRNAs listed in this systematic review. A total of 11 studies were selected according to research criteria, and we observed that 28 miRNAs play a relevant role in schizophrenia pathogenesis or response to antipsychotic treatment, seven of those of extreme interest as possible biomarkers either for condition or treatment. Predicted targets of the miRNAs reviewed here were previously associated with schizophrenia in genome-wide studies, and pathway analysis showed enrichment for genes related to neural processes. With this review, we expect to highlight the importance of miRNAs in schizophrenia pathogenesis and its treatment and point out interesting miRNAs to future studies.

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Recent randomized controlled trials (RCTs) have shown a benefit of brexpiprazole in managing agitation in patients with Alzheimer's disease (AD). However, its efficacy and safety remain unclear. We systematically searched PubMed, Embase, and Cochrane Library for RCTs comparing brexpiprazole with placebo in patients with agitation and AD. Three studies comprising 1,048 patients were included. In patients with agitation and AD, brexpiprazole significantly improved the Cohen-Mansfield Agitation Inventory total score (CMAI) at any dose (MD -3.05; 95% CI -5.12, -0.98; p < 0.01; I2 = 19%) and at 2 mg (MD -4.36; 95% CI -7.02, -1.70; p < 0.01; I2 = 0%) over 12 weeks. Brexpiprazole at any dose and 2 mg also showed benefit in the Clinical Global Impression - Severity of illness (CGI-S) score as related to agitation over 12 weeks (MD -0.20; 95% CI -0.36, -0.05; p < 0.01; I2 = 35%). There is no significant difference between the groups in the incidence of at least one treatment-emergent adverse events (TEAEs; RR 1.14; 95% CI 0.95, 1.37; p = 0.16; I2 = 45%) and all-cause mortality (RR 1.99; 95% CI 0.37, 10.84; p = 0.42; I2 = 0%). Brexpiprazole at any dose significantly increased the Simpson-Angus Scale (SAS; MD 0.47; 95% CI 0.28, 0.66; p < 0.01). Our results suggest that brexpiprazole is more efficacious than placebo in the treatment of agitation in AD patients. Further studies are still necessary to confirm long-term effects of brexpiprazole.Prospero registry: CRD42023486694.

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OBJECTIVES: The primary objective was to describe the standardized body mass index (z-BMI) trajectory of children and adolescents admitted to a psychiatric reference center in Mexico City according to their diagnosis and medication use. The secondary objective was to compare z-BMI between antipsychotic users and non-users. METHODS: This is a retrospective cohort study. The psychiatric diagnosis, prescribed medications, serial heights, and weights were collected from the medical records. RESULTS: The median baseline z-BMI of the 129 analyzed cases was 0.88 (interquartile range [IQR]: 0-1.92), and the prevalence of excessive weight (obesity or overweight) was 46.8 %. At the end of follow-up (median 50.3 weeks), the median change in z-BMI was -0.09 (IQR: -0.68 to 0.42). New long-term users of antipsychotics (n=29) had an increase in their z-BMI, in contrast to never-users (median difference 0.73, p=0.01) and to previous users (median difference 0.92, p=0.047). The 59 subjects with excessive weight at admission had a median z-BMI change of -0.39 (IQR: -0.81 to -0.04). Among patients with excessive weight and depression, there was a greater decrease in z-BMI in sertraline users (n=13) compared with fluoxetine users (n=15) (median -0.65 vs. 0.21, p<0.001). CONCLUSIONS: New long-term users of antipsychotics showed a significant increase in their z-BMI. Patients with depressive disorders and obesity on sertraline therapy tended to show a decrease in their z-BMI.

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AIMS: To conduct a systematic review and meta-analysis with the aim of synthesizing existing data on the efficacy and safety of topiramate as an adjunctive treatment for reducing second-generation antipsychotic (SGA)-associated weight gain in children aged 4-18 years. METHODS: We conducted a comprehensive search of PubMed, Embase, PsychNet and Web of Science from time of their inception up to 12 February 2024, including randomized controlled trials that compared SGA treatment with and without topiramate co-administration in children. The primary outcomes were changes in body weight and body mass index (BMI). Heterogeneity was assessed using I2 statistics. RESULTS: This systematic review included five randomized trials, totalling 139 participants (43.9% female; mean [SD] age 11.9 [3.5] years). Four of these trials were included in the meta-analysis, comprising 116 subjects. We found that topiramate was significantly effective both in reducing SGA-associated weight gain, with a mean difference of -2.80 kg (95% confidence interval [CI] -5.28 to -0.31; p = 0.037, I2 = 86.7%) and a standardized mean difference (SMD) of -1.33 (95% CI -2.14 to -0.51; p = 0.014, I2 = 31.7%), and in reducing BMI change compared to placebo (SMD -1.90, 95% CI -3.09 to -0.70; p = 0.02, I2 = 0%). Sedation risk was lower with topiramate than with placebo (odds ratio 0.19, 95% CI 0.11-0.32; p < 0.01, I2 = 0%). No significant differences were found in dropouts, any other side effects, and metabolic parameters, such as triglycerides, total cholesterol, low-density lipoprotein, high-density lipoprotein, and glucose. None of the included studies reported assessments on cognitive side effects. CONCLUSION: This meta-analysis suggests that topiramate is an effective and safe option for mitigating SGA-associated weight gain in children.

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BACKGROUND: The antiemetic effectiveness of olanzapine, as a prophylactic off-label antiemetic drug, for Postoperative Nausea and Vomiting (PONV) is unknown. In this systematic review and meta-analysis, the authors evaluate the efficacy and side effects of olanzapine as a prophylactic antiemetic in adult patients who undergo general anesthesia and assess adverse effects. METHODS: A systematic search was done on electronic bibliographic databases in July 2023. Randomized controlled trials of olanzapine as a prophylactic antiemetic for PONV in adults who underwent general anesthesia were included. The authors excluded non-RCTs and retracted studies. The authors set no date of publication or language limits. The outcomes were the incidence of PONV within 24 h postoperatively and the safety of olanzapine. The risk of bias was assessed according to the tool suggested by the National Heart, Lung, and Blood Institute. RESULTS: Meta-analysis included 446 adult patients. Olanzapine reduced on average 38 % the incidence of PONV. The estimated risk ratio (95 % CI) of olanzapine versus control was 0.62 (0.42-0.90), p = 0.010, I2 = 67 %. In the subgroup meta-analysis, doses of olanzapine (10 mg) reduced on average 49 % of the incidence of PONV (RR = 0.51 [0.34-0.77], p = 0.001, I2 = 31 %). CONCLUSIONS: This systematic review with meta-analysis indicated that olanzapine as a prophylactic antiemetic alone or combined with other antiemetic agents reduced the incidence of postoperative nausea and vomiting. However, this conclusion must be presented with some degree of uncertainty due to the small number of studies included. There was a lack of any evidence to draw conclusions on side effects.

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INTRODUCTION: Clozapine, a second-generation antipsychotic (SGA), is considered the gold standard medication to treat patients with treatment-resistant schizophrenia (TRS). Despite its efficacy, clozapine is associated with adverse effects, notably neutropenia and agranulocytosis. Other hematological adverse effects are less common. Severe anemia is a rare adverse effect seldom reported in the literature and is typically associated with pure red cell aplasia (PRCA). Nevertheless, the benefits of clozapine in managing TRS make rechallenge a reasonable option. CASE REPORT: We present the case of a 35-year-old man with TRS, resistant to previous antipsychotics, who experienced severe anemia during clozapine treatment. An investigation for clozapine-induced anemia revealed PRCA on myelogram. After discontinuing clozapine, the patient's hemoglobin levels recovered. Subsequent treatments with olanzapine, zuclopenthixol, and aripiprazole proved ineffective, leading us to consider a clozapine rechallenge. The rechallenge, monitored for 58 days, resulted in improved psychiatric symptoms and stable hemoglobin levels. The patient remained stable during 6 months of follow-up, with no hematological changes. DISCUSSION: PRCA is a very rare adverse effect of clozapine. The cause of drug-induced PRCA is still unknown; for clozapine, there are no studies. Rechallenge after a severe and rare adverse effect is a complex decision. This case is the first to report a successful clozapine rechallenge following severe anemia without other blood dyscrasias, emphasizing the imperative need for close monitoring during the rechallenge process. Further study is warranted to understand the predictive factors for a successful outcome in clozapine rechallenges.

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RESUMEN Introducción: Las reacciones adversas a medicamentos (RAM) son manifestaciones clínicas o de laboratorio no deseadas que se relacionan con el consumo de medicamentos. Las RAM se asocian con un riesgo significativo de morbimortalidad e ingresos hospitalarios. Los antipsicóticos poseen una reducida ventana terapéutica y se han relacionado con la manifestación de una diversidad de RAM. Objetivo: Evaluar el patrón de las RAM debido a fármacos antipsicóticos, detectadas en pacientes atendidos en el Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz entre diciembre de 2021 y mayo de 2022. Métodos: Estudio observacional, descriptivo, prospectivo y transversal de una serie de casos. La gravedad, la severidad y la calidad de la información de la notificación de las RAM se definieron conforme a la NOM-220-SSA1-2016, instalación y operación de la farmacovigilancia, mientras que la causalidad se determinó mediante el algoritmo de Naranjo. Resultados: La incidencia de las RAM fue del 59% y se detectó una o más RAM en 52 de los 88 pacientes que estaban en tratamiento antipsicótico durante el periodo de estudio. El 45% de las RAM tuvo una causalidad probable y el 55%, posible; únicamente tres RAM se clasificaron como graves, debido a que prolongaron la estancia hospitalaria y pusieron en peligro la vida del paciente. Conclusiones: Las RAM de los sistemas gastrointestinal y endocrino fueron las más incidentes, y la hiperprolactinemia fue la más frecuente. La olanzapina y clozapina fueron los medicamentos que más RAM provocaron. Se recomienda fomentar la cultura de notificación y seguimiento de RAM causadas por fármacos antipsicóticos.

ABSTRACT Introduction: Adverse Drug Reactions (ADR) are unwanted clinical or laboratory manifestations that are related to drug use. ADR are common and are associated with significant risk of morbidity, mortality and hospital admissions. Antipsychotics have a reduced therapeutic window, and have been related to the manifestation of a variety of ADR. Objetive: To evaluate the pattern of ADRs due to antipsychotic drugs detected in patients treated at the Ramón de la Fuente Muñiz National Institute of Psychiatry between December 2021 and May 2022. Methods: Observational, descriptive, prospective and cross-sectional study of a series of cases. The seriousness, severity, and quality of the information in the notification of the ADR were defined in accordance with NOM-220-SSA1-2016, Installation and Operation of Pharmacovigilance, while causality was determined using the Naranjo algorithm. Results: The incidence of ADRs was 59%, with one or more ADR detected in 52 of the 88 patients who were receiving antipsychotic treatment during the study period. Forty-five percent of the ADR had probable causality and 55% possible; only three ADR were classified as serious as they prolonged the hospital stay and endangered the patient's life. Conclusions: The ADR of the gastrointestinal and endocrine systems were the most incidental, with hyperprolactinemia being the most frequent. Olanzapine and clozapine were the medications that caused the most ADR. It is recommended to promote the culture of notification and follow-up of ADR caused by antipsychotic drugs.

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ABSTRACT Neuroleptic malignant syndrome (NMS) is a neurologic emergency potentially fatal. This rare side effect is most commonly associated with first-generation antipsychotics and less frequently with atypical or second-generation antipsychotics. The diagnosis relies on both clinical and laboratory criteria, with other organic and psychiatric conditions being ruled out. CASE REPORT: A 39-year-old female patient, who is institutionalized and completely dependent, has a medical history of recurrent urinary infections and colonization by carbapenem-resistant Klebsiella pneumoniae. Her regular medication regimen included sertraline, valproic acid, quetiapine, risperidone, lorazepam, diazepam, haloperidol, baclofen, and fentanyl. The patient began experiencing dyspnea. Upon physical examination, she exhibited hypotension and a diminished vesicular murmur at the right base during pulmonary auscultation. Initially, after hospitalization, she developed high febrile peaks associated with hemodynamic instability, prompting the initiation of antibiotic treatment. Despite this, her fever persisted without an increase in blood inflammatory parameters, and she developed purulent sputum, necessitating antibiotherapy escalation. The seventh day of hospitalization showed no improvement in symptoms, suggesting NNMS as a differential diagnosis. All antipsychotic and sedative drugs, as well as antibiotherapy, were discontinued, after which the patient showed significant clinical improvement. CONCLUSION: Antipsychotic agents are commonly employed to manage behavioral changes linked to various disorders. However, their severe side effects necessitate a high degree of vigilance, the cessation of all medications, and the implementation of supportive care measures. A prompt and accurate diagnosis of NMS is crucial to alleviating the severe, prolonged morbidity and potential mortality associated with this syndrome.

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Abstract Background: The antiemetic effectiveness of olanzapine, as a prophylactic off-label antiemetic drug, for Postoperative Nausea and Vomiting (PONV) is unknown. In this systematic review and meta-analysis, the authors evaluate the efficacy and side effects of olanzapine as a prophylactic antiemetic in adult patients who undergo general anesthesia and assess adverse effects. Methods: A systematic search was done on electronic bibliographic databases in July 2023. Randomized controlled trials of olanzapine as a prophylactic antiemetic for PONV in adults who underwent general anesthesia were included. The authors excluded non-RCTs and retracted studies. The authors set no date of publication or language limits. The outcomes were the incidence of PONV within 24 h postoperatively and the safety of olanzapine. The risk of bias was assessed according to the tool suggested by the National Heart, Lung, and Blood Institute. Results: Meta-analysis included 446 adult patients. Olanzapine reduced on average 38 % the incidence of PONV. The estimated risk ratio (95 % CI) of olanzapine versus control was 0.62 (0.42-0.90), p = 0.010, I2 = 67 %. In the subgroup meta-analysis, doses of olanzapine (10 mg) reduced on average 49 % of the incidence of PONV (RR = 0.51 [0.34-0.77], p = 0.001, I2 = 31 %). Conclusion: This systematic review with meta-analysis indicated that olanzapine as a prophylactic antiemetic alone or combined with other antiemetic agents reduced the incidence of postoperative nausea and vomiting. However, this conclusion must be presented with some degree of uncertainty due to the small number of studies included. There was a lack of any evidence to draw conclusions on side effects.

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This document constitutes the third and last part of the Third Argentine Consensus on the Management of Bipolar Disorders carried out by the Argentine Association of Biological Psychiatry (AAPB). Continuing with the initial objective, this section of the Consensus on the Management of Bipolar Disorders is focused on the management of bipolar disorders in special populations. This section constitutes a comprehensive review and expert consideration of the scientific evidence on: a) the management of bipolar disorders in treatment-resistant patients; b) the management of bipolar disorder in childhood and adolescence; c) the management of bipolar disorders in women during their perinatal period and, d) the management of bipolar disorders in older adults.

Este documento constituye la tercera y última parte del Tercer Consenso Argentino sobre el Manejo de los Trastornos Bipolares llevada a cabo por la Asociación Argentina de Psiquiatría Biológica (AAPB). Siguiendo con el objetivo propuesto por el comité de expertos, en la actual versión del Consenso sobre el manejo de los trastornos bipolares, esta sección está enfocada al abordaje de los Trastornos Bipolares en situaciones especiales. Esto configura una revisión exhaustiva de la evidencia científica  sobre: a) el manejo de los trastornos bipolares en pacientes resistentes al tratamiento, b) el manejo de los trastornos bipolares en la mujer en el período perinatal, c) el manejo del trastorno bipolar en la etapa infantojuvenil y d) el manejo de los trastornos bipolares en los adultos mayores.

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It is known that inflammation worsen the course of schizophrenia and induce high clozapine serum levels. However, no study evaluated this change in function of clozapine daily dose in schizophrenia. We assessed the correlation between inflammation and severity symptoms in patients with schizophrenia that take and do not take clozapine. We also assessed the correlation between clozapine daily dose and inflammatory markers to patients who take this drug. Patients were recruited from Schizophrenia Ambulatory and Psychosocial Care Center of Clinical Hospital of Porto Alegre and from an association of relatives of patients with schizophrenia. Exam results, and other important clinical exam were assessed in patients record or patients were asked to show their exam in the case of outpatients. We included 104 patients, 90 clozapine users and 14 non-clozapine users. We calculate the systemic inflammatory markers [neutrophil-lymphocyte ratio (NLR), systemic immune inflammation index (SII), and the psychopathology severity by the Brief Psychiatric Rating Scaled anchored (BPRS-a)]. These variables were compared between clozapine users and non-clozapine users. It was used mean/median test according to data distributing, with study factor (SII, MLR, and PLR), the clinical outcome: severity of symptomatology (BPRS score), and clozapine daily dose as adjustment factor. Clozapine users exhibited a significantly higher neutrophil count (mean ± SD: 5.03 ± 2.07) compared to non-clozapine users (mean ± SD: 3.48 ± 1.27; p = 0.031). After controlling for comorbidity, other parameters also showed significant differences. These findings are consistent with previous studies that have demonstrated an inflammatory response following the administration of clozapine.

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The LQFM05 is a prototype drug designed for treatment of psychiatric disorders, such as schizophrenia, exhibiting anxiolytic- and antidepressant-like (12 or 24 µmol/kg) effects in classical behavioral tests. In order to evaluate its pharmacokinetic properties, a liquid chromatography method coupled to a quadrupole time of flight mass spectrometry system (LC-QTOF/MS) was developed and fully validated for LQFM05 analysis in rat plasma and tissue samples (brain, heart, liver, and kidneys). Liquid-liquid extraction, solid phase extraction and protein precipitation were assessed as clean-up procedures for biological samples and analyte enrichment. Plasma and tissue samples underwent protein precipitation as a preliminary step, using acetonitrile. Linearity was fully demonstrated for the dynamic range (10.0 to 900.0 ng/mL), with r2 values higher than 0.99 (RSDslope ≤ 2%, Fcal < Ftab, Ccal < Ctab). Biodistribution studies in rats revealed high brain tissue concentrations (12.4 µg/g), suggesting elevated drug affinity to the main therapeutic target tissue, showing a blood partition coefficient of 1.9. Kidneys also showed great exposure and tissue affinity, suggesting a potential extrahepatic clearance. Likewise, all examined tissues exhibited satisfactory LQFMF05 distribution. The mass fragmentation spectrum indicated the presence of its main metabolite, LQFM235, yielded by high hepatic hydroxylation route, an equally bioactive derivative. Lastly, the developed LC-QTOF/MS method was shown to be sensitive (LOQ = 10 ng/mL), precise and accurate for LQFM05 determination in tissue homogenates and plasma samples.

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Schizophrenia is a neurodevelopmental disorder characterized by a loss of dendritic spines in the medial prefrontal cortex (mPFC). Multiple subclinical and clinical studies have evidenced the ability of antipsychotics to improve neuroplasticity. In this study, it was evaluated the effect of the atypical antipsychotic aripiprazole (ARI) on the behavioral and mPFC neuronal disturbances of rats with neonatal ventral hippocampus lesion (nVHL), which is a heuristic developmental model relevant to the study of schizophrenia. ARI attenuated open field hyperlocomotion in the rats with nVHL. Also, ARI ameliorated structural neuroplasticity disturbances of the mPFC layer 3 pyramidal cells, but not in the layer 5 neurons. These effects can be associated with the ARI capability of increasing brain-derived neurotrophic factor (BDNF) levels. Moreover, in the animals with nVHL, ARI attenuated the immunoreactivity for some oxidative stress-related molecules such as the nitric oxide synthase 2 (NOS-2), 3-nitrotyrosine (3-NT), and cyclooxygenase 2 (COX-2), as well as the reactive astrogliosis in the mPFC. These results contribute to current knowledge about the neurotrophic, anti-inflammatory, and antioxidant properties of antipsychotics which may be contributing to their clinical effects and envision promising therapeutic targets for the treatment of schizophrenia.

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Introducción: Los antipsicóticos son medicamentos que pueden producir elevaciones transitorias de las enzimas hepáticas. La clozapina es un antipsicótico atípico usado en el tratamiento de la esquizofrenia refractaria a los antipsicóticos convencionales y existe evidencia que puede producir elevaciones de las transaminasas hepáticas, expresión de dafño hepático con patrón hepatocelular. Métodos: Reporte de caso y revisión no sistemática de la literatura relevante. Presentación del caso: Una mujer de 39 años con diagnóstico de esquizofrenia paranoide acudió a un servicio de urgencias de un hospital general por náuseas, vómitos e ictericia que apareció tras el inicio de clozapina. No hubo mejoría clínica de la paciente durante la hospitalización, que falleció a los 44 días de su ingreso. Revisión de la literatura: La clozapina puede elevar las cifras de función hepática de manera transitoria y asintomática. Hay criterios clínicos para recomendar la suspensión de este antipsicótico. Conclusiones: Este caso es el tercero en la literatura que registra un desenlace fatal tras un cuadro de hepatotoxicidad inducido por clozapina. © 2021 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España, S.L.U. Todos los derechos reservados.

Introduction: Antipsychotics are drugs that can produce transient elevations of hepatic enzymes. Clozapine is an atypical antipsychotic used in treatment-resistant schizophrenia and there is evidence that it can produce elevations of hepatic transaminases, expression of liver damage in a hepatocellular pattern. Methods: Case report and non-systematic review of the relevant literature. Case presentation: A 39-year-old woman with a diagnosis of paranoid schizophrenia attended the emergency department of a general hospital for nausea, vomiting and jaundice that appeared after the initiation of clozapine. There was no clinical improvement during hospitalization, and death occurred after 44 days. Literature review: Clozapine can increase the liver enzyme levels transiently and asymptomatically; however, there are clinical criteria that recommend the withdrawal of the antipsychotic. Conclusions: This is the third case reported in the literature of a fatal outcome of clozapine-induced hepatotoxicity.

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INTRODUCTION: Neuroleptic malignant syndrome (NMS) is uncommon, with an incidence of 0.01%-3.23%, and is associated with the use of drugs that intervene with dopamine, causing hyperthermia, muscular rigidity, confusion, autonomic instability and death. CASE REPORT: A 35-year-old man with a history of catatonia, refractory epilepsy and functional impairment, required frequent changes in his anticonvulsant and antipsychotic treatment, due to adverse effects. During 2019, in the month of July, clozapine was changed to amisulpride, in September he developed fever, muscle stiffness, stupor, diaphoresis and tachypnea over a two-week period; paraclinical tests showed elevated creatine phosphokinase (CPK) and leukocytosis, so NMS was considered. The antipsychotic was withdrawn and he was treated with bromocriptine and biperiden, with a good response. Ten days after discharge, he began treatment with olanzapine, which generated a similar episode to the one described in December, with subsequent management and resolution. DISCUSSION: The diagnosis is based on the use of drugs that alter dopamine levels, plus altered state of consciousness, fever, autonomic instability and paraclinical tests showing leukocytosis and elevated CPK. Differential diagnoses must be ruled out. Early diagnosis generally leads to total remission, although some patients will suffer complications, long-term sequelae or recurrences. The recurrence in this case derived from the early reintroduction of the neuroleptic after the first episode. Treatment should be individualised according to severity to avoid mortality. CONCLUSIONS: Atypical antipsychotics are rarely suspected of generating NMS. Moreover, the time to reintroduction after an episode must also be taken into account.

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Introducción: El síndrome neuroléptico maligno (SNM) es infrecuente, con una incidencia del 0,01 al 3,23%, y tiene relación con el consumo de fármacos que interfieren con la dopamina; genera hipertermia, rigidez muscular, confusión, inestabilidad autonómica y la muerte. Caso clínico: Un varón de 35 arios, con antecedentes de catatonía, epilepsia refractaria y deterioro funcional, en tratamiento anticonvulsivo y antipsicótico, requirió cambio frecuente por efectos adversos de este. En julio de 2019 se cambió la clozapina por amisulprida; en septiembre se inicia un cuadro de 2 semanas de fiebre, rigidez muscular, estupor, diaforesis y taquipnea; los paraclínicos mostraron aumento de la creatininasa (CK) y leucocitosis, por lo que se consideró SNM. Se retiró el antipsicótico y se trató con bromocriptina y biperideno, que obtuvieron buena respuesta. A los 10 días del egreso, se inició tratamiento con olanzapina, que generó en diciembre un cuadro clínico similar al descrito, con posterior tratamiento y resolución. Discusión: El diagnóstico se basa en la toma de fármacos que alteren la dopamina, más alteración del estado de conciencia, fiebre e inestabilidad autonómica, junto con paraclínicos como leucocitosis y elevación de la CK. Se debe descartar diagnósticos diferenciales. El diagnóstico temprano generalmente lleva a la remisión total; algunos tendrán complicaciones, secuelas a largo plazo o recidivas. La recurrencia en este caso derivó de la reintroducción temprana del neuroléptico después del primer episodio. El tratamiento se debe individualizar según la gravedad para evitar la muerte. Conclusiones: Rara vez se sospecha que los antipsicóticos atípicos generen SNM; a su vez se debe tener en cuenta el tiempo a la reintroducción después de un episodio.

Introduction: Neuroleptic malignant syndrome (NMS) is uncommon, with an incidence of 0.01% to 3.23%, and is associated with the use of drugs that intervene with dopamine, causing hyperthermia, muscular rigidity, confusion, autonomic instability and death. Case report: A 35-year-old man with a history of catatonia, refractory epilepsy and functional impairment, required frequent changes in his anticonvulsant and antipsychotic treatment, due to adverse effects. During 2019, in the month of July, clozapine was changed to amisul-pride, in September he developed fever, muscle stiffness, stupor, diaphoresis and tachypnea over a two-week period; paraclinical tests showed elevated creatine phosphokinase (CPK) and leukocytosis, so NMS was considered. The antipsychotic was withdrawn and he was treated with bromocriptine and biperiden, with a good response. Ten days after discharge, he began treatment with olanzapine, which generated a similar episode to the one described in December, with subsequent management and resolution. Discussion: The diagnosis is based on the use of drugs that alter dopamine levels, plus altered state of consciousness, fever, autonomic instability and paraclinical tests showing leukocy-tosis and elevated CPK. Differential diagnosis must be ruled out. Early diagnosis generally leads to total remission, although some patients will suffer complications, long-term sequelae or recurrences. The recurrence in this case derived from the early reintroduction of the neuroleptic after the first episode. Treatment should be individualised according to severity to avoid mortality. Conclusions: Atypical antipsychotics are rarely suspected of generating NMS. Moreover, the time to reintroduction after an episode must also be taken into account.

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The antipsychotic drug, olanzapine, is prescribed for postpartum psychosis. Possible adverse effects on fertility of offspring are unclear. We investigated the effects of administering olanzapine via lactation on testicular development and endocrine function of prepuberal male rats. Olanzapine was administered to mothers at 2.5, 5 or 10 mg/kg. We found in male offspring increased body weight, decreased gonadosomatic index, testicular weight and epididymal weight. The volume of seminiferous tubules, seminiferous epithelium, Leydig cells, intertubule tissue and lymphatic space was reduced in rat pups exposed to olanzapine. Tubule diameter and length, seminiferous epithelium height, Leydig cell size and nuclear diameter also were reduced. Testosterone levels were reduced in the groups exposed to olanzapine, while prolactin levels were increased. We observed histopathology in testes of animals whose mothers had been treated with 2.5 mg/kg olanzapine; more severe pathology was observed in offspring whose mothers were administered higher doses. Administration of olanzapine to mothers during lactation produced testicular and endocrine pathology in prepuberal rats in a dose-dependent manner.

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