Effects of quetiapine administration on sperm quality and testicular histology.

Quetiapine is one of the most commonly prescribed antipsychotics to treat schizophrenia in adults, in particular. In this study, quetiapine's effects were assessed on healthy sperm production in rats at repeated-pharmacological doses. Additionally, the effects of quetiapine on oxidative status and hormonal balance were also evaluated in rats. Quetiapine was administered to rats orally at 10, 20, and 40 mg/kg body weight doses for 28 days. At the end of this period, body and organ weights were measured, sperm concentration, motility, and morphology were determined, sperm damage was assessed, and histopathological analysis of testicular tissue was performed. Additionally, serum FSH, LH, and testosterone levels as male reproductive hormones were measured. Catalase, superoxide dismutase, glutathione, and malondialdehyde levels were determined for evaluating the oxidative status of testicular tissue. The findings obtained in this study showed that relative epididymis weights and sperm concentration decreased and abnormal sperm morphology increased in quetiapine-administered rats. Irregularity of typical architecture of the seminiferous tubules and germinal cell disorganization was observed in testicular sections of 20 and 40 mg/kg quetiapine-administered rats. Further, serum LH and testosterone levels decreased in 20 and 40 mg/kg quetiapine-administered rats. Additionally, decreased catalase and superoxide dismutase activities in testicular tissue of quetiapine-administered rats and increased malondialdehyde levels in testicular tissue of 40 mg/kg quetiapine-administered rats were measured. In conclusion, quetiapine treatment decreased sperm quality, altered hormone levels, and induced oxidative stress may be considered potential contributors to this adverse effect.

Quetiapine induces myocardial necroptotic cell death through bidirectional regulation of cannabinoid receptors.

Quetiapine is a common atypical antipsychotic used to treat mental disorders such as schizophrenia, bipolar disorder, and major depressive disorder. There has been increasing number of reports describing its cardiotoxicity. However, the molecular mechanisms underlying quetiapine-induced myocardial injury remain largely unknown. Herein, we reported a novel cell death type, quetiapine-induced necroptosis, which accounted for quetiapine cardiotoxicity in mice and proposed novel therapeutic strategies. Quetiapine-treated hearts showed inflammatory infiltration and evident fibrosis after 21-day continuous injection. The specific increases of protein levels of RIP3, MLKL and the phosphorylation of MLKL showed that quetiapine induced necroptotic cell death both in vivo and in vitro. Pharmacologic blockade of necroptosis using its specific inhibitor Necrostatin-1 attenuated quetiapine-induced myocardial injury in mice. In addition, quetiapine imbalanced the endocannabinoid system and caused opposing effects on two cannabinoid receptors (CB1R and CB2R). Specific antagonists of CB1R (AM 281, Rimonabant), but not its agonist ACEA significantly ameliorated the heart histopathology induced by chronic quetiapine exposure. By contrast, specific agonists of CB2R (JWH-133, AM 1241), but not its antagonist AM 630 exerted beneficial roles against quetiapine cardiotoxicity. The protective agents (AM 281, Rimonabant, AM 1241, and JWH-133) consistently inactivated the quetiapine-induced necroptosis signaling. Quetiapine bidirectionally regulates cannabinoid receptors and induces myocardial necroptosis, leading to cardiac toxic effects. Therefore, pharmacologic inhibition of CB1R or activation of CB2R represents promising therapeutic strategies against quetiapine-induced cardiotoxicity.

Risk of Major Malformations in Infants Following First-Trimester Exposure to Quetiapine.

OBJECTIVE: Second-generation antipsychotics are commonly prescribed to reproductive-age women for the treatment of a spectrum of psychiatric disorders. Quetiapine is the most commonly prescribed medication in this class, and therefore a better understanding of its reproductive safety profile is critical. The goal of this study was to determine the risk of major malformations among infants exposed to quetiapine during pregnancy compared with a group of infants whose mothers had a history of psychiatric morbidity but who did not use a second-generation antipsychotic during pregnancy. METHOD: The National Pregnancy Registry for Atypical Antipsychotics interviews pregnant women ages 18-45 during pregnancy and the postpartum period. Obstetric, labor, and delivery medical records and pediatric medical records from the first 6 months of life were screened for evidence of major malformations, followed by adjudication by a blinded dysmorphologist. Women with first-trimester exposure to quetiapine were compared with control subjects without exposure to second-generation antipsychotics. RESULTS: As of March 2017, 888 women had enrolled prospectively and 357 were eligible for analysis. Of these, 152 women with first-trimester exposure to quetiapine were compared with 205 control subjects without any second-generation antipsychotic exposure. For the 155 infants born to women in the exposed group (including three sets of twins), two major malformations were confirmed (1.3%), compared with three major malformations among the 210 infants born in the unexposed group (including five sets of twins) (1.4%). The unadjusted odds ratio for major malformations between infants with and without quetiapine exposure was 0.90 (95% CI=0.15, 5.46), which is consistent with the pooled estimate of the available controlled data on fetal exposure to quetiapine. CONCLUSIONS: These data regarding the safety of fetal exposure to quetiapine in a small sample of well-characterized participants are reassuring given that the confidence interval does not exceed a fivefold increased risk of major malformations relative to psychiatric control subjects. Future analyses based on ongoing data collection will produce more precise estimates.

Are vasopressors useful in toxin-induced cardiogenic shock?

OBJECTIVE: Overdoses with cardio-depressive medications can result in toxin-induced cardiogenic shock (TICS), a life-threatening condition characterized by severe hypotension and ineffective tissue perfusion. Vasopressors are often employed in the treatment of shock to increase heart rate and blood pressure. We sought to conduct a systematic review of the literature to evaluate the effectiveness of vasopressors in improving hemodynamic function and survival in the treatment of TICS. DATA SOURCES: We searched PubMed, EMBASE, TOXLINE, and International Pharmaceutical Abstracts. STUDY SELECTION: We included studies evaluating the use of vasopressors in humans or animals with TICS. We limited human study types to randomized controlled trials, clinical trials, observational studies, and case reports. DATA EXTRACTION: Our search yielded 913 citations and 144 of these met our inclusion criteria. 130 were human case reports and 14 were animal studies. DATA SYNTHESIS: Human case report data showed vasopressors were ineffective more often than they were partially or fully effective. In the majority of animal studies, vasopressor treatment failed to improve hemodynamic parameters and resulted in decreased survival. CONCLUSIONS: Human case reports and controlled animal experiments lead to different conclusions about vasopressors in TICS. Most animal studies indicate that vasopressors impair hemodynamic function and increase mortality. In contrast, human case reports suggest that vasopressors are often ineffective but not necessarily harmful.

An Acute Ocfentanil Fatality: A Case Report with Postmortem Concentrations.

A 24-year-old man known to consume illegal drugs was found dead in his apartment. A reclosable plastic zipper bag containing several hundred milligrams of a brown powder was found close to the dead body and the first assumption of the investigators was death due to heroin intoxication. Therefore, a legal autopsy was ordered. The following toxicological analysis revealed ocfentanil in urine and in the brown powder. Four different approaches for the determination of the ocfentanil concentrations in peripheral whole blood are described. Enrichment of ocfentanil from the powder was realized. With this reference, it was possible to determine the ocfentanil concentration in the seized powder to be 0.91%. Concentrations of ocfentanil were also determined in the sampled body fluids using the standard addition procedure. In peripheral blood 9.1 µg/L, in heart blood 27.9 µg/L and in urine 480 µg/L were measured. In addition, the antidepressant citalopram, the neuroleptic quetiapine and cannabinoids were found in urine and subsequently quantified in peripheral blood.

Experimental and in silico assessment of fate and effects of the antipsychotic drug quetiapine and its bio- and phototransformation products in aquatic environments.

The antipsychotic drug quetiapine (QUT) has been frequently detected in sewage treatment plants. However, information on the fate of QUT in aquatic environments and its behavior during UV treatment is limited. In this study, QUT is shown not to be readily biodegradable in the Closed Bottle Test and the Manometric Respirometry Test according to OECD guidelines. The main biotransformation product (BTP) formed in the tests, a carboxylic acid derivative, was identified by means of high-resolution mass spectrometry. This BTP is presumably a human metabolite and showed higher detection rates than QUT in a river sampling campaign conducted in northern Germany. UV elimination kinetics of QUT at different initial concentrations (226.5, 45.3, 11.3, and 2.3 µmol L-1) were faster at lower initial concentrations. All seven phototransformation products (PTPs) could be still identified at initial concentration of 11.3 µmol L-1. The photolytic mixture generated after 128 min of photolysis of QUT was not better biodegradable than QUT. Initial UV treatment of QUT led to the formation of several additional BTPs. Four of them were identified. The bacterial cytotoxicity and genotoxicity before and after phototransformation of QUT in a modified luminescent bacteria test (LBT) and the umu-test (ISO/FDIS 13829) showed cytotoxic effects in the LBT for QUT. Furthermore, PTPs had similar cytotoxic effects on luminescent bacteria. The umu-test did not reveal any genotoxic activity for QUT or PTPs. In conclusion, the release of QUT into sewage treatment plants and aquatic environments could result in the formation of a main BTP. Additional UV treatment of QUT would lead to the formation of additional BTPs. Moreover, treatment did not result in lower toxicity to tested organisms. In conclusion, UV treatment of QUT should be considered critically as a potential treatment for QUT in aquatic systems.

Severe proarrhythmic potential of risperidone compared to quetiapine in an experimental whole-heart model of proarrhythmia.

In several case reports, proarrhythmic effects of antipsychotic drugs have been reported. The aim of the present study was to investigate if application of risperidone or quetiapine has the potential to provoke polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In 24 isolated rabbit hearts, risperidone (5 and 10 µM, n = 12) or quetiapine (5 and 10 µM, n = 12) was infused after obtaining baseline data. Eight endocardial and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant QT prolongation after application of risperidone as compared with baseline (5 µM: +29 ms, 10 µM: +35 ms, p < 0.01) accompanied by an increase of action potential duration. Administration of risperidone also significantly increased spatial dispersion of repolarization (5 µM: +16 ms, 4 µM: +19 ms; p < 0.05) as well as temporal dispersion of repolarization. Lowering of potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations (EADs) in 8 of 12 hearts and polymorphic ventricular tachycardia resembling torsade de pointes in 6 of 12 hearts (10 µM, 49 episodes). The results were compared with hearts treated with quetiapine (5 and 10 µM). Quetiapine led to an increase in QT interval (5 µM: +10 ms; 10 µM: +28 ms; p < 0.05) and a similar increase of APD90. However, treatment with quetiapine did not result in significant alterations of spatial and temporal dispersion of repolarization. No ventricular arrhythmias were observed in this group. In the present study, quetiapine demonstrated a safe electrophysiologic profile despite significant QT prolongation. In contrast, risperidone led to a more marked prolongation of myocardial repolarization combined with a more marked increase of dispersion of repolarization.

Análisis segmentario del pelo para detectar la exposición crónica a drogas psicoactivas / Segmental hair testing to disclose chronic exposure to psychoactive drugs

Se presenta el caso de un niño sano de 4 años de edad que ingresa en la sala de hospitalización pediátrica por la sospecha de una intoxicación accidental debido a la ingesta de fármacos narcolépticos (metilfenidato, sertralina y quetiapina), que tomaba de forma pautada su hermano de 8 años de edad que padecía un síndrome de Asperger. La evaluación objetiva de la intoxicación se puede realizar con la determinación de los fármacos y sus metabolitos en matrices biológicas con una ventana de tiempo corta (sangre y orina) o larga (pelo). En el hospital se realizó un análisis de sangre y orina mediante inmunoanálisis (confirmado mediante espectrometría líquida-cromatografía de masas) y se identificó la presencia de sertralina y quetiapina y sus metabolitos. Con la sospecha de administración crónica de fármacos al niño, se procedió al análisis del pelo con cromatografía líquida de ultra-alto rendimiento-espectrometría de masas en tándem. El pelo se dividió en 6 segmentos consecutivos de 2 cm de longitud, de forma que permitieron estudiar la ingesta de los fármacos durante los últimos 12 meses. En los primeros 4 segmentos se encontró quetiapina con una concentración media de 1,00 ng/mg ± 0,94 ng/mg de pelo y en todos los segmentos se encontraron sertralina y su metabolito, desmetil-sertralina, con una concentración media de 2,65 ± 0,94 ng/mg y 1,50 ± 0,94 ng/mg de pelo, respectivamente. El análisis de pelo resultó negativo para metilfenidato y su metabolito (ácido ritalínico). La detección en matrices biológicas de fármacos psicoactivos demostró la intoxicación aguda y crónica por quetiapina y sertralina, administradas por la madre

This study presents the case of a 4-year-old healthy child admitted to the paediatric ward for suspected accidental intoxication due to ingestion of narcoleptic drugs (methylphenidate, sertraline and quetiapine), taken on a regular basis by his 8-year-old brother affected by Asperger syndrome. Intoxication can be objectively assessed by measurements of drugs and metabolites in biological matrices with short-term (blood and urine) or long-term (hair) detection windows. At the hospital, the child’s blood and urine were analysed by immunoassay (confirmed by liquid chromatography-mass spectrometry), and sertraline and quetiapine and their metabolites were identified. The suspicion that the mother administered drugs chronically prompted the analysis of six, consecutive 2-cm segments of the child’s hair, using ultra-high performance liquid chromatographytandem mass spectrometry, thereby accounting for ingestion over the previous 12 months. Quetiapine was found in the first four segments with a mean concentration of 1.00 ng/mg ± 0.94 ng/mg hair while sertraline and its metabolite, desmethyl-sertraline, were found in all segments with a mean concentration of 2.65 ± 0.94 ng/mg and 1.50 ± 0.94 ng/mg hair, respectively. Hair analyses were negative for methylphenidate and its metabolite (ritalinic acid). Biological matrices testing for psychoactive drugs disclosed both acute and chronic intoxication with quetiapine and sertraline administered by the mother

Prenatal exposure to a novel antipsychotic quetiapine: impact on neuro-architecture, apoptotic neurodegeneration in fetal hippocampus and cognitive impairment in young rats.

Reports on prenatal exposure to some of the first generation antipsychotic drugs like, haloperidol, their effects on fetal neurotoxicity and functional impairments in the offspring, are well documented. But studies on in utero exposure to second generation antipsychotics, especially quetiapine, and its effects on fetal neurotoxicity, apoptotic neurodegeneration, postnatal developmental delay and neurobehavioral consequences are lacking. Therefore, the present study was undertaken to evaluate the effect of prenatal administration to equivalent therapeutic doses of quetiapine on neuro-architectural abnormalities, neurohistopathological changes, apoptotic neurodegeneration in fetal hippocampus, and postnatal development and growth as well as its long-lasting imprint on cognitive impairment in young-adult offspring. Pregnant Wistar rats (n=24) were exposed to selected doses (55 mg, 80 mg and 100mg/kg) of quetiapine, equivalent to human therapeutic doses, from gestation day 6 to 21 orally with control subjects. Half of the pregnant subjects of each group were sacrificed at gestation day 21 for histopathological, confocal and electron microscopic studies and rest of the dams were allowed to deliver naturally. Their pups were reared postnatally up to 10 weeks of age for neurobehavioral observations. In quetiapine treated groups, there was significant alterations in total and differential thickness of three typical layers of hippocampus associated with neuronal cells deficit and enhanced apoptotic neurodegeneration in the CA1 area of fetal hippocampus. Prenatally drug treated rat offspring displayed post-natal developmental delay till postnatal day 70, and these young-adult rats displayed cognitive impairment in Morris water maze and passive avoidance regimes as long-lasting impact of the drug. Therefore, quetiapine should be used with cautions considering its developmental neurotoxicological and neurobehavioral potential in animal model, rat.