Effect of aripiprazole on neural tube development in early chick embryos.

INTRODUCTION: Aripiprazole (ARI) is a recently developed antipsychotic medication that belongs to the second generation of antipsychotics. The literature has contradictory information regarding ARI, which has been classified as pregnant use category C by the FDA. METHODS: 125 pathogen-free fertilized eggs were incubated for 28 h and divided into five groups of 25 eggs each (including the control group), and 18 eggs with intact integrity were selected from each group. After the experimental groups were divided, ARI was administered subblastodermally with a Hamilton micro-injector at 4 different doses (1 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg). At the 48th hour of incubation, all eggs were hatched and embryos were removed from the embryonic membranes. And then morphologic (position of the neural tube (open or closed), crown-rump length, number of somites, embryological development status), histopathologic (apoptosis (caspase 3), cell proliferation (PCNA), in situ recognition of DNA breaks (tunnel)), genetic (BRE gene expression) analyzes were performed. RESULTS: According to the results of the morphological analysis, when the frequency of neural tube patency was evaluated among the experimental groups, a statistically significant difference was determined between the control group and all groups (p < 0.001). In addition, the mean crown-rump length and somite number of the embryos decreased in a dose-dependent manner compared to the control group. It was determined that mRNA levels of the BRE gene decreased in embryos exposed to ARI compared to the control group (p < 0.001). CONCLUSION: Morphologically, histopathologically, and genetically, aripiprazole exposure delayed neurogenesis and development in early chick embryos. These findings suggest its use in pregnant women may be teratogenic. We note that these results are preliminary for pregnant women, but they should be expanded and studied with additional and other samples.

Mechanisms of adverse mammary effect induced by olanzapine and therapeutic interventions in rat model.

BACKGROUND: Olanzapine antagonizes dopamine receptors and is prescribed to treat multiple psychiatric conditions. The main side effect of concern for olanzapine is weight gain and metabolic syndrome. Olanzapine induces hyperprolactinemia, however its effect on the mammary gland is poorly documented. METHODS: Rats received olanzapine by gavage or in drinking water at 1, 3, and 6 mg/kg/day for 5-40 days or 100 days, with and without coadministration of bromocriptine or aripiprazole and using once daily or continuous administration strategies. Histomorphology of the mammary gland, concentrations of prolactin, estradiol, progesterone, and olanzapine in serum, mammary gland and adipose tissue, and mRNA and protein expressions of prolactin receptors were analyzed. RESULTS: In adult and prepubescent female rats and male rats, olanzapine induced significant development of mammary glands in dose- and time-dependent manners, with histopathological hyperplasia of mammary ducts and alveoli with lumen dilation and secretion, marked increase of mammary prolactin receptor expression, a marker of breast tissue, and with mild increase of circulating prolactin. This side effect can be reversed after medication withdrawal, but long-term olanzapine treatment for 100 days implicated tumorigenic potentials indicated by usual ductal epithelial hyperplasia. Olanzapine induced mammary development was prevented with the coaddition of the dopamine agonist bromocriptine or partial agonist aripiprazole, or by continuous administration of medication instead of a once daily regimen. CONCLUSIONS: These results shed light on the previously overlooked effect of olanzapine on mammary development and present experimental evidence to support current clinical management strategies of antipsychotic induced side effects in the breast.

CYP-catalysed cycling of clozapine and clozapine-N-oxide promotes the generation of reactive oxygen species in vitro.

Clozapine is an effective atypical antipsychotic indicated for treatment-resistant schizophrenia, but is under-prescribed due to the risk of severe adverse drug reactions such as myocarditis.A mechanistic understanding of clozapine cardiotoxicity remains elusive.This study aimed to investigate the contribution of selected CYP isoforms to cycling between clozapine and its major circulating metabolites, N-desmethylclozapine and clozapine-N-oxide, with the potential for reactive species production.CYP supersome™-based in vitro techniques were utilised to quantify specific enzyme activity associated with clozapine, clozapine-N-oxide and N-desmethylclozapine metabolism.The formation of reactive species within each incubation were quantified, and known intermediates detected.CYP3A4 predominately catalysed clozapine-N-oxide formation from clozapine and was associated with concentration-dependent reactive species production, whereas isoforms favouring the N-desmethylclozapine pathway (CYP2C19 and CYP1A2) did not produce reactive species.Extrahepatic isoforms CYP2J2 and CYP1B1 were also associated with the formation of clozapine-N-oxide and N-desmethylclozapine but did not favour one metabolic pathway over another.Unique to this investigation is that various CYP isoforms catalyse clozapine-N-oxide reduction to clozapine.This process was associated with the concentration-dependent formation of reactive species with CYP3A4, CYP1B1 and CYP1A1 that did not correlate with known reactive intermediates, implicating metabolite cycling and reactive oxygen species in the mechanism of clozapine-induced toxicity.

Second-generation antipsychotic quetiapine blocks voltage-dependent potassium channels in coronary arterial smooth muscle cells.

Voltage-dependent K+ (Kv) channels play an important role in restoring the membrane potential to its resting state, thereby maintaining vascular tone. In this study, native smooth muscle cells from rabbit coronary arteries were used to investigate the inhibitory effect of quetiapine, an atypical antipsychotic agent, on Kv channels. Quetiapine showed a concentration-dependent inhibition of Kv channels, with an IC50 of 47.98 ± 9.46 µM. Although quetiapine (50 µM) did not alter the steady-state activation curve, it caused a negative shift in the steady-state inactivation curve. The application of 1 and 2 Hz train steps in the presence of quetiapine significantly increased the inhibition of Kv current. Moreover, the recovery time constants from inactivation were prolonged in the presence of quetiapine, suggesting that its inhibitory action on Kv channels is use (state)-dependent. The inhibitory effects of quetiapine were not significantly affected by pretreatment with Kv1.5, Kv2.1, and Kv7 subtype inhibitors. Based on these findings, we conclude that quetiapine inhibits Kv channels in both a concentration- and use (state)-dependent manner. Given the physiological significance of Kv channels, caution is advised in the use of quetiapine as an antipsychotic due to its potential side effects on cardiovascular Kv channels.

Role of prolactin in the protective effect of amisulpride against 1,2-Diacetylbenzene's neurotoxicity.

Exposure to organic solvents is associated with various health problems, including neurodegenerative diseases. Among these solvents, 1,2-diethylbenzene is notable for its ability to produce a toxic metabolite, 1,2-Diacetylbenzene (DAB), which can cause memory impairment. Prolactin (PRL) is theorized to protect the central nervous system. Certain antipsychotic drugs, known for increasing PRL secretion, have shown to improve cognitive performance in psychotic Alzheimer's patients. Among these, amisulpride stands out for its high efficacy, limited side effects, and high selectivity for dopamine D2 receptors. In our study, we explored the potential of amisulpride to inhibit DAB-induced neurotoxicity via PRL activation. Our results show that amisulpride enhances the PRL/JAK/STAT, PI3K/AKT, and BDNF/ERK/CREB pathways, playing critical roles in PRL's neuroprotection pathways and memory formation. Additionally, amisulpride inhibited DAB-triggered NLRP3 inflammasome activation and apoptosis. Collectively, these findings suggest that amisulpride may be a promising therapeutic intervention for DAB-induced neurotoxicity, partly through activating the PRL pathway.

B-GOS alleviates olanzapine-induced lipid disturbances in mice by enriching Akkermansia and upregulation of PGRMC1-Wnt signaling.

Although olanzapine (OLZ) remains one of the most efficacious antipsychotic medications for the treatment of schizophrenia, there are significant tolerability issues related to its metabolic profile such as weight gain and dyslipidemia. Our previous studies have demonstrated that progesterone receptor membrane component 1 (PGRMC1) plays a key role in antipsychotic-induced metabolic side effects. Prebiotics showed positive effects on lipid metabolism, however, limited studies focused on their therapeutic potential and mechanisms in treating antipsychotic-induced lipid metabolic disorders. Herein, our study aims to explore the effects of the prebiotic B-GOS on lipid disturbances induced by OLZ and elucidate its underlying mechanisms via PGRMC1 pathway. In an 8-week study, long-term intraperitoneal administration of OLZ at a dosage of 8 mg/kg/day in mice induced lipid disturbances as manifested by significantly increased lipid indexes in plasma and liver. B-GOS effectively alleviated the OLZ-induced abnormal lipid metabolism by enhancing the diversity of the gut microbiota, with a 100-fold increase in Akkermansia abundance and a 10-fold decrease in Faecalibaculum abundance. Followed by the B-GOS related changes of gut microbiota, OLZ-induced substantial hepatic inhibition of PGRMC1, and associated protein factors of Wnt signaling pathway (Wnt3a, ß-catenin, and PPAR-γ) were reversed without affecting plasma levels of short-chain fatty acids. Taken together, prebiotics like B-GOS enriching Akkermansia offer a promising novel approach to alleviate antipsychotic-induced lipid disturbances by modulating the PGRMC1-Wnt signaling pathway.

Allyl isothiocyanate, a TRPA1 agonist, protects against olanzapine-induced hypothalamic and hepatic metabolic aberrations in female mice.

Olanzapine, a widely prescribed atypical antipsychotic, poses a great risk to the patient's health by fabricating a plethora of severe metabolic and cardiovascular adverse effects eventually reducing life expectancy and patient compliance. Its heterogenous receptor binding profile has made it difficult to point out a specific cause or treatment for the related side effects. Growing body of evidence suggest that transient receptor potential (TRP) channel subfamily Ankyrin 1 (TRPA1) has pivotal role in pathogenesis of type 2 diabetes and obesity. With this background, we aimed to investigate the role of pharmacological manipulations of TRPA1 channels in antipsychotic (olanzapine)-induced metabolic alterations in female mice using allyl isothiocyanate (AITC) and HC-030031 (TRPA1 agonist and antagonist, respectively). It was found that after 6 weeks of treatment, AITC prevented olanzapine-induced alterations in body weight and adiposity; serum, and liver inflammatory markers; glucose and lipid metabolism; and hypothalamic appetite regulation, nutrient sensing, inflammatory and TRPA1 channel signaling regulating genes. Furthermore, several of these effects were absent in the presence of HC-030031 (TRPA1 antagonist) indicating protective role of TRPA1 agonism in attenuating olanzapine-induced metabolic alterations. Supplementary in-depth studies are required to study TRPA1 channel effect on other aspects of olanzapine-induced metabolic alterations.

Antipsychotic drug-induced behavioral abnormalities in common carp: The potential involvement of the gut microbiota-brain axis.

The effects of antipsychotic drugs on aquatic organisms have received widespread attention owing to their widespread use and continued release in aquatic environments. The toxicological effects of antipsychotics on aquatic organisms, particularly fish, are unexplored, and the underlying mechanisms remain unelucidated. This study aimed to use common carp to explore the effects of antipsychotics (olanzapine [OLA] and risperidone [RIS]) on behavior and the potential mechanisms driving these effects. The fish were exposed to OLA (0.1 and 10 µg/L) and RIS (0.03 and 3 µg/L) for 60 days. Behavioral tests and neurological indicators showed that exposure to antipsychotics could cause behavioral abnormalities and neurotoxicity in common carp. Further, 16 S rRNA sequencing revealed gut microbiota alteration and decreased relative abundance of some strains related to SCFA production after OLA and RIS exposure. Subsequently, a pseudo-sterile common carp model was successfully constructed, and transplantation of the gut microbiota from antipsychotic-exposed fish caused behavioral abnormalities and neurotoxicity in pseudo-sterile fish. Further, SCFA supplementation demonstrated that SCFAs ameliorated the behavioral abnormalities and neurological damage caused by antipsychotic exposure. To our knowledge, the present study is the first to investigate the effects of antipsychotics on various complex behaviors (swimming performance and social behavior) in common carp, highlighting the potential health risks associated with antipsychotic drug-induced neurotoxicity in fish. Although these results do not fully elucidate the mechanisms underlying the effects of antipsychotic drugs on fish behavior, they serve as a valuable initial investigation and form the basis for future research.

The impact of piperazine and antipsychotic co-exposures and CB1 blockade on the effects elicited by AMB-FUBINACA, a synthetic cannabinoid, in mice.

BACKGROUND & PURPOSE: The constant emergence and broad toxicological effects of synthetic cannabinoids create a discernible public health threat. The synthetic cannabinoid AMB-FUBINACA (AMB-FUB) is a potent agonist at the CB1 receptor and has been associated with numerous fatalities. Synthetic cannabinoids are commonly abused alongside other drugs and medications, including a "party pill" drug, para-fluorophenylpiperazine (pFPP), and the antipsychotic risperidone. This research aimed to investigate the mechanisms underpinning AMB-FUB toxicity and the impact of clinically relevant co-exposures in vivo. EXPERIMENTAL APPROACH: Male and female C57Bl/6 mice received a single dose of AMB-FUB (3 or 6 mg kg-1), pFPP (10 or 20 mg kg-1) or vehicle intraperitoneally. Mice were co-exposed to AMB-FUB (3 mg kg-1) and pFPP (10 mg kg-1) or risperidone (0.5 mg kg-1) to investigate these drug combinations. To study receptor-dependency and potential rescue of AMB-FUB toxicity, rimonabant (3 mg kg-1) was administered both pre- and post-AMB-FUB. Adverse effects caused by drug administration, including hypothermia and convulsions, were recorded. KEY RESULTS: AMB-FUB induced CB1-dependent hypothermia and convulsions in mice. The combination of AMB-FUB and pFPP significantly potentiated hypothermia, as did risperidone pre-treatment. Interestingly, risperidone provided significant protection from AMB-FUB-induced convulsions in female mice. Pre- and post-treatment with rimonabant was able to significantly attenuate both hypothermia and convulsions in mice administered AMB-FUB. CONCLUSION & IMPLICATIONS: Factors such as dose, CB1 signalling, and substance co-exposure significantly contribute to the toxicity of AMB-FUBINACA. Mechanistic understanding of synthetic cannabinoid toxicity and fatality can help inform overdose treatment strategies and identify vulnerable populations of synthetic cannabinoid users.

Prenatal aripiprazole induces alterations of rat placenta: a histological, immunohistochemical and ultrastructural study.

Antipsychotic drugs (APDs) are used to treat many psychiatric illnesses as schizophrenia. Typical antipsychotic drugs (TAPDs) are being used; however, they have many side effects. Atypical antipsychotic drugs (AAPDs) are newer medications with known fewer side effects. Aripiprazole (ARI) is an AAPD, recommended by healthcare providers, even during pregnancy. It can cross the placental barrier and enter fetal circulation, so it might be possible that ARI can adversely impair normal placental development and growth, if it is given prenatally. ARI was applied orally to pregnant female rats in two doses (3& 6 mg/kg body weight). On gestation day 20, the mothers were sacrificed, and the placentas were removed and processed for general histological and electron microscopic evaluations. Immunohistochemistry was done using anti-PCNA (proliferating cell nuclear antigen), anti-Bax (for apoptosis) and anti-vascular endothelial growth factor alpha (VEGFA). Morphological evaluation revealed degenerative changes in the placenta as dark nuclei, vacuolization, and cyst formation. Ultra-structurally, there was degeneration of cellular components including organelles and nuclei. These changes were found in different cells of the basal and labyrinth zones and were dose dependent. Immunohistochemistry revealed upregulation of Bax and VEGFA and downregulation of PCNA. Prenatal administration of the AAPD, ARI to pregnant female rats resulted in histological changes in the placenta. Additionally, there was a decrease in cellular proliferation and increase in apoptosis, and vascular impairment. This indicates placental atrophy and dysgenesis and might suggest possible teratogenic effects to ARI, which needs further evaluation.

Bilateral ocular deposit of chlorpromazine / Depósito ocular bilateral de clorpromazina

ABSTRACT Chlorpromazine is a medication widely used in psychiatry for the treatment of psychoses, especially schizophrenia. Since 1964, published articles have been correlating this medication with the appearance of ocular alterations. In this paper, we report the case of a 65-year-old patient with ocular effects due to long-term therapy with chlorpromazine. Biomicroscopy of both eyes presented diffuse granular brown deposits, most prominent at the deep stroma and corneal endothelium level. Also showed anterior subcapsular brown deposits with a stellate pattern in the lens. The total amount exceeds 2.000g (significant for the ocular alterations described) considering the patient's daily dosage of chlorpromazine of 300mg for ten years. After performing complete ophthalmic evaluation and discarding other causes for the ocular deposits, we diagnosed a secondary corneal deposit and cataract due to the use of chlorpromazine. This case reinforces the importance of periodic follow-up with an ophthalmologist for chlorpromazine users to trace ocular changes, heeding the exposure time and its dosage.

RESUMO A clorpromazina é uma medicação muito empregada na psiquiatria para tratamento de psicoses, especialmente em casos de esquizofrenia. Desde 1964 existem artigos publicados que correlacionam o uso dessa medicação com o aparecimento de alterações oculares. Neste trabalho, relatamos o caso de um paciente de 65 anos com efeitos oculares devido à terapia de longo prazo com clorpromazina. A biomicroscopia de ambos os olhos apresentou depósitos granulares difusos e de cor marrom, mais proeminente ao nível do estroma profundo e do endotélio da córnea, além de depósitos castanhos subcapsulares anteriores centrais em um padrão estrelado no cristalino. Considerando a dose diária de clorpromazina de 300mg por 10 anos usada pelo paciente, a quantidade total ultrapassa 2.000g (dose considerada significativa para as alterações oculares descritas). Após avaliação oftalmológica completa e descartado outras causas desses depósitos oculares, foram diagnosticados depósito corneano e catarata secundários ao uso de clorpromazina. O caso apresentado reforça a importância do acompanhamento oftalmolÓgico periÓdico de usuários de clorpromazina para o rastreio de alteraçÕes oculares, atentando-se ao tempo de exposição à droga e à posologia da mesma.

Síndrome Neuroléptico Maligno / Malignant neuroleptic syndrome

El síndrome neuroléptico maligno constituye una complicación infrecuente asociada con el uso de neruolépticos. El cuadro establecido tiene toma de conciencia, rigidez generalizada, disautonomías asociadas con rabdomiólisis con creatinin fosfoquinasa elevada. Se presenta un paciente del sexo masculino de 31 años de edad, con antecedentes de cuadros delirantes alucinatorios a los 7 años, a los 21 y el actual. Los primeros síntomas comenzaron 2 meses antes de su ingreso, con alucinaciones auditivas. Comienza tratamiento con haloperidol; al no mejorar el cuadro psicótico y estar muy agresivo deciden asociarle clorpromazina. Un mes después presenta fiebre y manifestaciones respiratorias. Días después empeora la fiebre, aparece la rigidez axial y la sialorrea. Es trasladado a cuidados intensivos con el diagnóstico de síndrome neuroléptico maligno, comienza tratamiento específico, no obstante fallece a los 3 días. Se concluye que el síndrome neuroléptico maligno es una complicación neurológica infrecuente pero muy grave, con una elevada mortalidad en los casos no tratados de manera precoz

Emprego da levomepromazina no bloqueio da arritmia induzida pela adrenalina em cäes anestesiados pelo sevoflurano / The use of levomepromazine to blokade the arrhythmia induced by the epinephrine in dogs anesthetized with sevoflurane

Este experimento objetivou estudar o possível efeito antiarritmogênico da levomepromazina em cäes anestesiados pelo sevoflurano e submetidos a doses crescentes de adrenalina. Para tal, foram empregados 21 animais adultos, machos e fêmeas, sem raça definida e considerados sadios. Os cäes foram separados em dois grupos, sendo um de 11 (G1) e outro de 10 (G2) animais. O G1 recebeu, por via intravenosa, soluçäo salina a 0,9 por cento, na dose de 0,2ml/kg (placebo), seguida 15 minutos após, pela aplicaçäo de tiopental, pela mesma via, na dose suficiente para abolir o reflexo laringotraqueal. Procedeu-se à intubaçäo orotraqueal e iniciou-se a administraçäo de sevoflurano a 2,5V por cento, em circuito anestésico semi-fechado. Decorridos 20 minutos da induçäo anestésica, iniciou-se a administraçäo contínua, por via intravenosa, com emprego de bomba de infusäo, de soluçäo de adrenalina a 2 por cento, em doses crescentes de 1, 2, 3, 4 e 5µg/kg/min (M1 a M5, respectivamente), com incremento da dose a intervalos de 10 minutos. Para o G2, empregou-se a mesma metodologia substituindo-se o placebo por levomepromazina, na dose de 1mg/kg. Foi tomado o traçado eletrocardiográfico, na derivaçäo D2, a partir da induçäo da anestesia. Para efeito estatístico, foi considerado o número total de batimentos cardíacos de origem näo sinusal, coincidentes com cada dose de adrenalina. Os dados numéricos foram submetidos à Análise de Perfil, quando foi possível constatar que as médias do G1 foram crescentes de M1 a M3, diminuindo a partir deste último, até M5. No G2, foi encontrada arritmia ventricular sustentada apenas em M5. Os achados permitiram concluir que a levomepromazina minimiza a arritmia ventricular sustentada, induzida pela adrenalina em cäes anestesiados pelo sevoflurano.

Síndrome neuroléptico maligno consecutivo a psicotrópicos y antidepresivos / Malignant neuroleptic syndrome due to psychotropic and antidepressant drugs

Se han estudiado, tres casos clínicos de intoxicación por consumo de neurolépticos que cumplen los criterios diagnósticos del síndrome neurolépticos malignos. Dos de ellos, estuvieron relacionados a la ingesta excesiva de tranilcipromina y trifluoperazina; el tercero, a la asociación de haloperidol y levopromazina. De los tres casos, dos de ellos fallecieron y uno de ellos se puedo efectuar la necropsia; el paciente que sobrevivió presentó síntomas iniciales de síndrome neuroléptico maligno, obteniéndose respuesta favorable al tratamiento. Se revisa el espectro de los síndromes neurolépticos malignos, el diagnóstico diferencial y el esquema de tratamiento

Drogas psicotrópicas e coraçäo / Psychotropic drugs and the heart

A moderna Psicofarmacoterapia teve início na década de 1960 e revolucionou o tratamento das doenças mentais. De modo sucessivo e, principalmente no início, empírico, antidepressivos como o diazepam, além do lítio e da carbamazepina foram sendo lançados. Muitas dessas drogas, como os antidepressivos tricíclicos, provocam, mesmo em doses terapêuticas, importantes açöes cardiológicas; eles também interagem, farmacoldinâmica ou farmacocineticamente, com medicamentos usados em Cardiologia. Neste artigo, säo abordados os principais efeitos cardiológicos diretos ou indiretos dos psicofármacos usados na terapêutica psiquiátrica.