RESUMEN
This study aims to investigate the potential correlation between the use of olanzapine, a psychopharmacological intervention commonly prescribed in Anorexia Nervosa treatment, and the occurrence of Refeeding Syndrome. Despite the acknowledged nutritional and biochemical impacts of olanzapine, the literature lacks information regarding its specific association with Refeeding Syndrome onset in individuals with Anorexia Nervosa. This is a naturalistic, retrospective, observational study, reporting the occurrence of Refeeding Syndrome in children and adolescents with Anorexia Nervosa, treated or untreated with olanzapine. Dosages and serum levels of olanzapine were assessed for potential associations with the occurrence of Refeeding Syndrome and specific variations in Refeeding Syndrome-related electrolytes. Overall, 113 patients were enrolled, including 46 (41%) who developed a Refeeding Syndrome. Mild (87%), moderate (6.5%), and severe (6.5%) Refeeding Syndrome was described, at a current average intake of 1378 ± 289 kcal/day (39 ± 7.7 kcal/kg/die), frequently associated with nasogastric tube (39%) or parenteral (2.2%) nutrition. Individuals receiving olanzapine experienced a more positive phosphorus balance than those who did not (F(1,110) = 4.835, p = 0.030), but no difference in the occurrence of Refeeding Syndrome was documented. The mean prescribed doses and serum concentrations of olanzapine were comparable between Refeeding Syndrome and no-Refeeding Syndrome patients. Conclusion: The present paper describes the occurrence of Refeeding Syndrome and its association with olanzapine prescriptions in children and adolescents with Anorexia Nervosa. Olanzapine was associated with a more positive phosphorus balance, but not with a different occurrence of Refeeding Syndrome. Further, longitudinal studies are required. What is Known: ⢠Refeeding Syndrome (RS) is a critical complication during refeeding in malnourished patients, marked by electrolyte (phosphorus, magnesium, potassium) imbalances. ⢠Olanzapine, an atypical antipsychotic with nutritional and biochemical impacts, is used in Anorexia Nervosa (AN) treatment, however data concerning its association with RS are lacking. What is New: ⢠The study observed RS in 46/113 (41%) young patients with AN. ⢠Olanzapine-treated individuals showed a higher improvement in serum phosphate levels than untreated ones, although no impact on the occurrence of Refeeding Syndrome was observed.
Asunto(s)
Anorexia Nerviosa , Hipofosfatemia , Síndrome de Realimentación , Niño , Humanos , Adolescente , Estudios Retrospectivos , Olanzapina/efectos adversos , Anorexia Nerviosa/complicaciones , Anorexia Nerviosa/tratamiento farmacológico , Síndrome de Realimentación/etiología , Hipofosfatemia/inducido químicamente , Fósforo , Equilibrio HidroelectrolíticoRESUMEN
Olanzapine is a second-generation antipsychotic that disrupts metabolism and is associated with an increased risk of type 2 diabetes. The hypothalamus is a key region in the control of whole-body metabolic homeostasis. The objective of the current study was to determine how acute peripheral olanzapine administration affects transcription and serine/threonine kinase activity in the hypothalamus. Hypothalamus samples from rats were collected following the pancreatic euglycemic clamp, thereby allowing us to study endpoints under steady state conditions for plasma glucose and insulin. Olanzapine stimulated pathways associated with inflammation, but diminished pathways associated with the capacity to combat endoplasmic reticulum stress and G protein-coupled receptor activity. These pathways represent potential targets to reduce the incidence of type 2 diabetes in patients taking antipsychotics.
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Antipsicóticos , Diabetes Mellitus Tipo 2 , Humanos , Ratas , Animales , Olanzapina/farmacología , Olanzapina/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Benzodiazepinas/farmacología , Benzodiazepinas/metabolismo , Antipsicóticos/farmacología , Antipsicóticos/metabolismo , Hipotálamo/metabolismo , Perfilación de la Expresión GénicaRESUMEN
The main cause of second-generation antipsychotic (SGA)-induced obesity is considered due to the antagonism of serotonin 2c receptors (5-HT2cR) and activation of ghrelin receptor type 1a (GHSR1a) signalling. It is reported that 5-HT2cR interacted with GHSR1a, however it is unknown whether one of the SGA olanzapine alters the 5-HT2cR/GHSR1a interaction, affecting orexigenic neuropeptide signalling in the hypothalamus. We found that olanzapine treatment increased average energy intake and body weight gain in mice; olanzapine treatment also increased orexigenic neuropeptide (NPY) and GHSR1a signaling molecules, pAMPK, UCP2, FOXO1 and pCREB levels in the hypothalamus. By using confocal fluorescence resonance energy transfer (FRET) technology, we found that 5-HT2cR interacted/dimerised with the GHSR1a in the hypothalamic neurons. As 5-HT2cR antagonist, both olanzapine and S242084 decreased the interaction between 5-HT2cR and GHSR1a and activated GHSR1a signaling. The 5-HT2cR agonist lorcaserin counteracted olanzapine-induced attenuation of interaction between 5-HT2cR and GHSR1a and inhibited activation of GHSR1a signalling and NPY production. These findings suggest that 5-HT2cR antagonistic effect of olanzapine in inhibition of the interaction of 5-HT2cR and GHSR1a, activation GHSR1a downstream signaling and increasing hypothalamic NPY, which may be the important neuronal molecular mechanism underlying olanzapine-induced obesity and target for prevention metabolic side effects of antipsychotic management in psychiatric disorders.
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Antipsicóticos , Neuropéptidos , Animales , Ratones , Antipsicóticos/efectos adversos , Hipotálamo/metabolismo , Neuronas/metabolismo , Neuropéptidos/metabolismo , Obesidad/inducido químicamente , Obesidad/metabolismo , Olanzapina/efectos adversosRESUMEN
Advances have been made in recent years in using opioid receptor antagonists as an adjunct therapy to psychotropic medication to reduce debilitating weight gain and metabolic adverse effects associated with in particular second generation antipsychotics. However, it is unknown whether second generation antipsychotics produce a change in opioid receptor expression in the brain. The present study investigated early changes in opioid receptor expression in the female rat hypothalamus, a master controller of hunger and metabolic regulation, after acute treatment with olanzapine, a commonly used second generation antipsychotic. Using quantitative spatial in situ hybridization and receptor autoradiography, expression levels of the three opioid receptors; kappa, mu and delta, were determined at mRNA and protein level, respectively, in the five hypothalamic areas: paraventricular nucleus, arcuate nucleus, ventromedial nucleus, dorsomedial nucleus and lateral hypothalamus. After 48 h of olanzapine treatment at clinically relevant plasma concentration weight gain and food intake changes, and increased plasma glucose were observed in female rats. Olanzapine treatment also led to a significant increase in mu opioid receptor availability in the arcuate nucleus, which contains both satiety and hunger controlling neurons. No other areas showed any opioid receptor expressional changes with olanzapine treatment on neither at mRNA nor protein level. Technical difficulties made it impossible to analyze mRNA levels in the lateral hypothalamus and overall binding of delta opioid receptors. Thus, the present study provided insights in to how olanzapine at clinically relevant plasma levels already at an early stage modulated the opioid system in the hypothalamus.
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Antipsicóticos , Receptores Opioides mu , Ratas , Femenino , Animales , Olanzapina/farmacología , Olanzapina/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Antipsicóticos/farmacología , Hipotálamo/metabolismo , Receptores Opioides/metabolismo , Conducta Alimentaria , Aumento de Peso , ARN MensajeroRESUMEN
Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B-KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B-KO male mice were fed an OLA-supplemented diet or treated via i.p. Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.
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Hígado Graso , Transducción de Señal , Masculino , Animales , Ratones , Olanzapina/metabolismo , Transducción de Señal/fisiología , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Proteínas Quinasas Activadas por AMP/metabolismo , Hígado/metabolismo , Hígado Graso/tratamiento farmacológico , Hígado Graso/genética , Hígado Graso/prevención & control , Ratones Noqueados , Inflamación/metabolismo , Ácido Graso Sintasas/metabolismo , Aumento de Peso , Hipotálamo/metabolismo , Ratones Endogámicos C57BLRESUMEN
Psychosis is a state of mind that makes it difficult to determine what is real and what is not. Psychosis can have serious negative effects. Like many psychiatric phenomena, psychosis has a variety of causes, such as schizophrenia, bipolar disorder, and psychotic depression. Antipsychotic medications, psychotherapy, and social support are the most common treatments. Antipsychotic drugs reduce the symptoms of psychosis by changing brain chemistry. Based on the mechanism of action, antipsychotics have two groups, typical and atypical. Most people who take antipsychotics experience side effects. People taking typical antipsychotics tend to have higher rates of extrapyramidal side effects, but some atypical drugs, especially olanzapine, are associated with the risk of significant weight gain, diabetes, and metabolic syndrome, which, in turn, increases the risk of atherosclerotic cardiovascular disease and premature death. Physical exercise, diet regimen, psychoeducation, monotherapy, or switching to an alternative antipsychotic are strategies to correct metabolic aberrates in atypical antipsychotic users. In light of several successful studies on the use of medicinal plants to control metabolic syndrome, this article briefly reviews the studies on some herbal medications for the management of metabolic disorders associated with atypical antipsychotics and discusses probable mechanisms. Therefore, we searched the Cochrane, Scopus, PubMed, and Google Scholar databases for works published before July, 2022, on the effect of herbal medications on antipsychotic-related metabolic abnormalities in animals or humans. We recommend that some herbal medicines may be efficient for regulating the metabolic changes related to atypical antipsychotics due to their multipotential action, and more efforts should be made to make herbal drug treatments more effective. We hope this review will be a reference for research on developing herbal therapeutics for metabolic alterations in antipsychotic customers.
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Antipsicóticos , Síndrome Metabólico , Esquizofrenia , Humanos , Animales , Antipsicóticos/efectos adversos , Síndrome Metabólico/inducido químicamente , Síndrome Metabólico/tratamiento farmacológico , Olanzapina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Aumento de PesoRESUMEN
Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia. While Agrp is expressed specifically in the arcuate nucleus of the hypothalamus and plays a critical role in appetite stimulation, Nr5a2 is expressed in both the CNS and periphery, but its role in food intake behaviors remains unknown. In this study, we investigated the role of hypothalamic Nr5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, olanzapine treatment resulted in a dose-dependent increase in gene expression of Nr5a2 and Agrp. In mice, the pharmacological inhibition of NR5A2 decreased olanzapine-induced hyperphagia and weight gain, while the knockdown of Nr5a2 in the arcuate nucleus partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation studies showed for the first time that NR5A2 directly binds to the Agrp promoter region. Lastly, the analysis of single-cell RNA seq data confirms that Nr5a2 and Agrp are co-expressed in a subset of neurons in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake. These findings can inform future clinical development of APs that do not activate hyperphagia and weight gain.
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Hiperfagia , Animales , Humanos , Ratones , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Proteína Relacionada con Agouti/farmacología , Antipsicóticos/efectos adversos , Ingestión de Alimentos , Hiperfagia/inducido químicamente , Hiperfagia/genética , Hiperfagia/metabolismo , Hipotálamo/metabolismo , Olanzapina/efectos adversos , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/farmacología , Receptores Citoplasmáticos y Nucleares/uso terapéutico , Aumento de PesoRESUMEN
Schizophrenia (SCZ) is a severe brain disorder characterized by an intriguing clinical panel that has begun to gain interest due to its particular phenotype. Having considered the role of gut microflora in psychiatry, the latest discoveries might offer further insight into the underlying mechanisms. Thus, we aimed to offer an updated overview of the therapeutic potential of microorganism-derived supplements alongside dedicated protocols that target the re-establishment of the host's eubiosis. Based on combinations of specific keywords, we performed searches in four databases (PubMed/Medline, ISI Web of Knowledge, Scopus, and ScienceDirect) for the established interval (2018-2022) and identified twenty two eligible cases, restricted only to human patients' experiences. Up until the writing of this manuscript, it has been revealed that the administration of specific lactic acid bacteria strains (Lactobacillus and Bifidobacterium), or those combined with vitamin D and selenium, maintain the integrity of the gut flora, preventing antagonistic effects including inflammation, antipsychotic-related body weight gain (olanzapine) and other metabolic dysfunctionalities. However, there are multiple antipsychotics that exert a potent effect upon gut flora, influencing a plethora of pathways and creating a dysbalance ratio between beneficial and opportunistic pathogens. Risperidone, amisulpride, and clozapine are just a few examples, but the current literature is unfortunately inconsistent and reported data is contradictory, which is why we support additional studies in this context. Moreover, we further argue the utility of studying how distinct controlled substances influence microbial communities, considering that ketamine is proved to alleviate depressive-like behavior as opposed to amphetamine and phencyclidine, which are known substances to trigger SCZ-like symptoms in experimental models. Probiotics may be regarded as the most consequential vehicle through which the gut flora can be successfully influenced, in adequate doses exerting a beneficial role as an alternative approach to alleviate SCZ symptoms.
Asunto(s)
Antipsicóticos , Clozapina , Microbioma Gastrointestinal , Probióticos , Esquizofrenia , Humanos , Esquizofrenia/tratamiento farmacológico , Antipsicóticos/uso terapéutico , Olanzapina , Clozapina/uso terapéutico , Probióticos/uso terapéutico , PrebióticosRESUMEN
BACKGROUND: Second-generation antipsychotics (SGAs) are a mainstay therapy for schizophrenia. SGA-treated patients present higher risk for weight gain, dyslipidemia and hyperglycemia. Herein, we evaluated the effects of olanzapine (OLA), widely prescribed SGA, in mice focusing on changes in body weight and energy balance. We further explored OLA effects in protein tyrosine phosphatase-1B deficient (PTP1B-KO) mice, a preclinical model of leptin hypersensitivity protected against obesity. METHODS: Wild-type (WT) and PTP1B-KO mice were fed an OLA-supplemented diet (5 mg/kg/day, 7 months) or treated with OLA via intraperitoneal (i.p.) injection or by oral gavage (10 mg/kg/day, 8 weeks). Readouts of the crosstalk between hypothalamus and brown or subcutaneous white adipose tissue (BAT and iWAT, respectively) were assessed. The effects of intrahypothalamic administration of OLA with adenoviruses expressing constitutive active AMPKα1 in mice were also analyzed. RESULTS: Both WT and PTP1B-KO mice receiving OLA-supplemented diet presented hyperphagia, but weight gain was enhanced only in WT mice. Unexpectedly, all mice receiving OLA via i.p. lost weight without changes in food intake, but with increased energy expenditure (EE). In these mice, reduced hypothalamic AMPK phosphorylation concurred with elevations in UCP-1 and temperature in BAT. These effects were also found by intrahypothalamic OLA injection and were abolished by constitutive activation of AMPK in the hypothalamus. Additionally, OLA i.p. treatment was associated with enhanced Tyrosine Hydroxylase (TH)-positive innervation and less sympathetic neuron-associated macrophages in iWAT. Both central and i.p. OLA injections increased UCP-1 and TH in iWAT, an effect also prevented by hypothalamic AMPK activation. By contrast, in mice fed an OLA-supplemented diet, BAT thermogenesis was only enhanced in those lacking PTP1B. Our results shed light for the first time that a threshold of OLA levels reaching the hypothalamus is required to activate the hypothalamus BAT/iWAT axis and, therefore, avoid weight gain. CONCLUSION: Our results have unraveled an unexpected metabolic rewiring controlled by hypothalamic AMPK that avoids weight gain in male mice treated i.p. with OLA by activating BAT thermogenesis and iWAT browning and a potential benefit of PTP1B inhibition against OLA-induced weight gain upon oral treatment.
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Proteínas Quinasas Activadas por AMP , Hipotálamo , Masculino , Ratones , Animales , Olanzapina/metabolismo , Olanzapina/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Fosforilación , Hipotálamo/metabolismo , Termogénesis/fisiología , Peso Corporal , Metabolismo Energético , Aumento de Peso , Tejido Adiposo Pardo/metabolismoRESUMEN
RATIONALE: Second-generation antipsychotic (SGA) medications can produce abnormal weight gain and metabolic dysfunction in children, but little is known about the post-treatment consequences of adolescent SGA exposure. OBJECTIVES: The objective of this study was to determine the long-term, post-treatment effects of adolescent olanzapine exposure on weight and metabolic function and whether dietary fish oil (FO) modulated any observed effects of olanzapine. METHODS: Male and female mice were fed a high-fat, high-sugar (HF-HS) diet or an HF-HS diet supplemented with fish oil (HF-HS-FO) and were treated with olanzapine or vehicle for 29 days beginning on postnatal day 37. RESULTS: In male mice, adolescent olanzapine treatment suppressed weight gain during and after treatment and improved metabolic function in adulthood; dietary fish oil reduced weight gain, increased expression of fatty acid oxidation genes, and decreased expression of genes associated with fatty acid synthesis and inflammation. In contrast, few effects were observed in female mice. CONCLUSIONS: The current results suggest that adolescent olanzapine exposure can produce long-term alterations in weight and metabolic function in male mice and that dietary fish oil can reduce adverse effects of lifelong consumption of an HF-HS diet. Because expected adverse effects of adolescent olanzapine treatment were not observed, the potential beneficial effects of dietary fish oil for SGA-induced weight gain and metabolic dysfunction could not be evaluated.
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Antipsicóticos , Animales , Antipsicóticos/farmacología , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Ácidos Grasos , Femenino , Aceites de Pescado/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Olanzapina , Azúcares , Aumento de PesoRESUMEN
Weight gain is the one of the most important factors which increases global burden of psychiatric disorder. Second-generation antipsychotics, olanzapine (Olz) and valproic acid (Vpa) in particular, are held responsible for weight gain. However, it is still uncertain how these drugs cause this. Thus, the rats selected for the experiment were randomly divided into 3 groups. The 1st group received only 0.5 ml saline solution intraperitoneally (n = 20, control group); the second group was given 200 mg / kg Vpa intraperitoneally (n = 20, Vpa group) and 2 mg / kg Olz was given intraperitoneally to the 3rd group (n = 20, Olz group) between 8 and 10 am for 30 days. We examined serum leptin, adiponectin, resistin, TNF-α, IL-6, ghrelin level and, the amount of ghrelin secreting cells in the stomach and growth hormone secretagogue receptor-1a (GHSR-1a, ghrelin receptor) expression in the hypothalamus. The hypothalamic GHS-1a receptor index was significantly higher in the Olz group compared with the control group and Vpa group (p = 0.036 and p = 0.016 respectively). Ghrelin immune positive cell index in stomach was statistically significantly lower in the Vpa group compared with the control and Olz groups (p = 0.028 and p = 0.013 respectively) There was no difference between the groups in terms of serum leptin, resistin, IL-6 and ghrelin levels. In the Vpa group, a statistically significant increase was found in serum adiponectin level compared with both the control group and the Olz group (p = 0009 and p = 0024 respectively) and, significant decrease was found in serum TNF-α level compared to Olz group (p = 0007). In conclusion, we found that the main cause of weight gain in Olz use was the increase in the number of hypothalamic ghrelin receptors. Investigating the mechanism by which Olz increases the number of ghrelin receptors may help to develop effective treatment strategies in preventing obesity in psychiatric patients.
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Ghrelina , Receptores de Ghrelina , Adiponectina/metabolismo , Animales , Ghrelina/metabolismo , Ghrelina/farmacología , Hipotálamo/metabolismo , Interleucina-6/metabolismo , Leptina/metabolismo , Olanzapina/farmacología , Ratas , Receptores de Ghrelina/metabolismo , Resistina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ácido Valproico/farmacología , Aumento de PesoRESUMEN
Antipsychotics have been widely accepted as a treatment of choice for psychiatric illnesses such as schizophrenia. While atypical antipsychotics such as aripiprazole are not associated with obesity and diabetes, olanzapine is still widely used based on the anticipation that it is more effective in treating severe schizophrenia than aripiprazole, despite its metabolic side effects. To address metabolic problems, metformin is widely prescribed. Hypothalamic proopiomelanocortin (POMC) neurons have been identified as the main regulator of metabolism and energy expenditure. Although the relation between POMC neurons and metabolic disorders is well established, little is known about the effects of olanzapine and metformin on hypothalamic POMC neurons. In the present study, we investigated the effect of olanzapine and metformin on the hypothalamic POMC neurons in female mice. Olanzapine administration for 5 days significantly decreased Pomc mRNA expression, POMC neuron numbers, POMC projections, and induced leptin resistance before the onset of obesity. It was also observed that coadministration of metformin with olanzapine not only increased POMC neuron numbers and projections but also improved the leptin response of POMC neurons in the olanzapine-treated female mice. These findings suggest that olanzapine-induced hypothalamic POMC neuron abnormality and leptin resistance, which can be ameliorated by metformin administration, are the possible causes of subsequent hyperphagia. [BMB Reports 2022; 55(6): 293-298].
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Antipsicóticos , Metformina , Animales , Antipsicóticos/metabolismo , Antipsicóticos/farmacología , Aripiprazol/metabolismo , Aripiprazol/farmacología , Femenino , Hipotálamo/metabolismo , Leptina/metabolismo , Metformina/metabolismo , Metformina/farmacología , Ratones , Neuronas/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Olanzapina/metabolismo , Olanzapina/farmacología , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Proopiomelanocortina/farmacologíaRESUMEN
Children are prescribed second-generation antipsychotic (SGA) medications, such as olanzapine (OLZ) for FDA-approved and "off-label" indications. The long-term impact of early-life SGA medication exposure is unclear. Olanzapine and other SGA medications are known to cause excessive weight gain in young and adult patients, suggesting the possibility of long-term complications associated with the use of these drugs, such as obesity, diabetes, and heart disease. Further, the weight gain effects of OLZ have previously been shown to depend on the presence of gut bacteria and treatment with OLZ, which shifts gut bacteria toward an "obesogenic" profile. The purpose of the current study was to evaluate changes in gut bacteria in adult mice following early life treatment with OLZ and being fed either a high-fat diet or a high-fat diet supplemented with fish oil, which has previously been shown to counteract gut dysbiosis, weight gain, and inflammation produced by a high-fat diet. Female and male C57Bl/6J mice were fed a high fat diet without (HF) or with the supplementation of fish oil (HF-FO) and treated with OLZ from postnatal day (PND) 37-65 resulting in four groups of mice: mice fed a HF diet and treated with OLZ (HF-OLZ), mice fed a HF diet and treated with vehicle (HF), mice fed a HF-FO diet and treated with OLZ (HF-FO-OLZ), and mice fed a HF-FO diet and treated with vehicle (HF-FO). Following euthanasia at approximately 164 days of age, we determined changes in gut bacteria populations and serum LPS binding protein, an established marker of gut inflammation and dysbiosis. Our results showed that male HF-FO and HF-FO-OLZ mice had lower body weights, at sacrifice, compared to the HF group, with a comparable body weight across groups in female mice. HF-FO and HF-FO-OLZ male groups also exhibited lower serum LPS binding protein levels compared to the HF group, with no differences across groups in female mice. Gut microbiota profiles were also different among the four groups; the Bacteroidetes-to-Firmicutes (B/F) ratio had the lowest value of 0.51 in the HF group compared to 0.6 in HF-OLZ, 0.9 in HF-FO, and 1.1 in HF-FO-OLZ, with no differences in female mice. In conclusion, FO reduced dietary obesity and its associated inflammation and increased the B/F ratio in male mice but did not benefit the female mice. Although the weight lowering effects of OLZ were unexpected, FO effects persisted in the presence of olanzapine, demonstrating its potential protective effects in male subjects using antipsychotic drugs.
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Aceites de Pescado/administración & dosificación , Microbioma Gastrointestinal/efectos de los fármacos , Obesidad/terapia , Olanzapina/efectos adversos , Caracteres Sexuales , Animales , Peso Corporal , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/etiología , Aumento de Peso/efectos de los fármacosRESUMEN
Cyperus rotundus L. is used to treat multiple clinical conditions like inflammation, diarrhea, pyrosis, and metabolic disorders including diabetes and obesity. The present study aimed to predict the interaction of reported bioactives from Cyperus rotundus against obesity via network pharmacology and to evaluate the efficacy of hydroalcoholic extract of Cyperus rotundus against the olanzapine-induced weight gain and metabolic disturbances in experimental animals. Reported phytochemicals of Cyperus rotundus were retrieved from the open-source database(s) and published literature and their targets were predicted using SwissTargetPrediction, enriched in STRING, and bioactives-proteins-pathways network was constructed using Cytoscape. Further, the hydroalcoholic extract of Cyperus rotundus (100, 200, and 400 mg/kg/day, p.o.) was co-administered with olanzapine (2 mg/kg, i.p.) for 21 days in Sprague Dawley rats. During treatment, body weight and food intake were recorded; after the successful completion of 21 days of treatment, animals were fasted to perform oral glucose and insulin tolerance tests. Further, the animals were euthanized; blood and abdominal fat were collected for lipid profiling and histopathological examination respectively. Herein, network pharmacology predicted neuroactive ligand-receptor interaction as a primarily modulated pathway and protein tyrosine phosphatase 1b as a majorly triggered protein via the combined action of bioactives. Further, Cyperus rotundus significantly reversed weight gain, cumulative food intake, ameliorated the lipid and glucose metabolism, and promoted energy expenditure.
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Cyperus , Animales , Olanzapina , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-Dawley , Aumento de PesoRESUMEN
Introduction: Olanzapine (OLZ) is one of the second-generation antipsychotics drugs (APDs) used to treat several psychiatric illnesses. Olanzapine treatment is often associated with many metabolic side effects in a dose dependent manner such as obesity, dyslipidemia and insulin resistance, induction of type II diabetes and acute pancreatitis in some patients. Methods: Hyperbaric Oxygen therapy (HBOT) was investigated as a tool to mitigate olanzapine metabolic side effects in rats. Thirty-six female Sprague Dawley (SD) rats were divided into 4 groups; rats on olanzapine treatment either exposed to hyperbaric oxygen therapy (HBOOLZ) or left without exposure (OLZ) then non-treated rats that either exposed to hyperbaric oxygen therapy or left without exposure (control). Rats received Hyperbaric Oxygen therapy for 35 days at 2.4 atmospheres absolute (ATA) for 2.5 h daily followed by intraperitoneal injection of olanzapine at 10 mg/kg or placebo. Results: Rats on either hyperbaric oxygen therapy or olanzapine had a significant loss in body weight. Olanzapine treatment showed a decrease in serum insulin level, triglyceride, highdensity lipoprotein (HDL) cholesterol, and lipase level but an increase in fasting blood sugar (FBS), insulin resistance index (HOMA-IR) and amylase, while rats' exposure to hyperbaric oxygen therapy reversed these effects. The Pancreatic Langerhans islets were up-regulated in both hyperbaric oxygen therapy and olanzapine treatments but the combination (HBOOLZ) doubled these islets number. Discussion: This study advocated that hyperbaric oxygen therapy can be an alternative approach to control or reverse many metabolic disorders (MDs) associatedwith olanzapine treatment. In addition, it seems that hyperbaric oxygen therapy positively affect the pancreatic Langerhans cells activity and architecture.
Asunto(s)
Diabetes Mellitus Tipo 2 , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Oxigenoterapia Hiperbárica , Resistencia a la Insulina , Islotes Pancreáticos , Pancreatitis , Animales , Femenino , Ratas , Enfermedad Aguda , Proliferación Celular , Olanzapina/efectos adversos , Ratas Sprague-DawleyRESUMEN
Secondary metabolic disturbances in patients with schizophrenia or bipolar disorder may be attributed to olanzapine. It is important to prevent mild metabolic disorders progressing to metabolic syndrome. This study aims to investigate the effects of berberine on intestinal flora in patients with mild metabolic disorders induced by olanzapine. A total of 132 patients with schizophrenia, bipolar disorder, or schizoaffective psychosis that had been treated with olanzapine for at least 9 months were randomly assigned ([Formula: see text] = 66 each) to receive berberine or placebo tablets for 12 weeks. Metabolic assessments and intestinal flora were quantified at baseline and after 4, 8, and 12 weeks of treatment. Incidence rates of adverse reactions were recorded. FPG, FPI, HOMA-IR, HbA1, TG, BMI, and WC were significantly lower in patients who received berberine compared to placebo after 12 weeks of treatment ([Formula: see text]< 0.05). The abundance of firmicutes and coliform were significantly lower and the abundance of bacteroides significantly higher in patients who received berberine compared to placebo after 12 weeks of treatment ([Formula: see text]< 0.05). In patients who received berberine, the abundance of firmicutes was significantly decreased, and the abundance of bacteroides was significantly increased, and in patients who received placebo, the abundance of firmicutes was significantly increased post-treatment, compared to baseline (both [Formula: see text]< 0.05). In conclusions, berberine may regulate intestinal flora and metabolism in patients with schizophrenia or bipolar disorder and mild metabolic disturbances induced by olanzapine.
Asunto(s)
Antipsicóticos , Berberina , Microbioma Gastrointestinal , Enfermedades Metabólicas , Antipsicóticos/efectos adversos , Benzodiazepinas/efectos adversos , Humanos , Olanzapina/efectos adversosRESUMEN
Type 2 diabetes and obesity are major problems worldwide and dietary polyphenols have shown efficacy to ameliorate signs of these diseases. Anthocyanins from berries display potent antioxidants and protect against weight gain and insulin resistance in different models of diet-induced metabolic syndrome. Olanzapine is known to induce an accelerated form of metabolic syndrome. Due to the aforementioned, we evaluated whether delphinidin-3,5-O-diglucoside (DG) and delphinidin-3-O-sambubioside-5-O-glucoside (DS), two potent antidiabetic anthocyanins isolated from Aristotelia chilensis fruit, could prevent olanzapine-induced steatosis and insulin resistance in liver and skeletal muscle cells, respectively. HepG2 liver cells and L6 skeletal muscle cells were co-incubated with DG 50 µg/mL or DS 50 µg/mL plus olanzapine 50 µg/mL. Lipid accumulation was determined in HepG2 cells while the expression of p-Akt as a key regulator of the insulin-activated signaling pathways, mitochondrial function, and glucose uptake was assessed in L6 cells. DS and DG prevented olanzapine-induced lipid accumulation in liver cells. However, insulin signaling impairment induced by olanzapine in L6 cells was not rescued by DS and DG. Thus, anthocyanins modulate lipid metabolism, which is a relevant factor in hepatic tissue, but do not significantly influence skeletal muscle, where a potent antioxidant effect of olanzapine was found.
Asunto(s)
Antocianinas/farmacología , Elaeocarpaceae/metabolismo , Glucósidos/farmacología , Antocianinas/química , Antocianinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hígado Graso/metabolismo , Glucósidos/química , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Hipoglucemiantes/farmacología , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos , Lípidos/farmacología , Hígado/efectos de los fármacos , Hígado/patología , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Olanzapina , Extractos Vegetales/farmacología , Polifenoles/farmacologíaRESUMEN
AIM: Contradiction overwhelms chemerin link to feeding behavior. Neither the chemerin central role on appetite regulation nor its relation to hypothalamic histamine and AMPK is verified. MAIN METHODS: Food intake, body weight and hypothalamic biochemical changes were assessed after a single intra-cerebroventricular or intraperitoneal injection (ip) (1 µg/kg or 16 µg/kg, respectively) or chronic ip administration (8 µg/kg/day) of chemerin for 14 or 28 days. Hypothalamic neurobiochemical changes in chemerin/histamine/AMPK induced by either 8-week high fat diet (HFD) or food restriction were also investigated. To confirm chemerin-histamine crosstalk, these neurobiochemical changes were assessed under settings of H1-receptor agonism and/or antagonism by betahistine and/or olanzapine, respectively for 3 weeks. KEY FINDINGS: Chemerin-injected rats exhibited anorexigenic behavior in both acute and chronic studies that was associated with a decreased AMPK activity in the arcuate nucleus (ARC). However, with long-term administration, chemerin anorexigenic effect gradually ceased. Contrarily to food restriction, 8-week HFD increased ARC expression of chemerin and its receptor CMKLR1, reducing food intake via an interplay of H1-receptors and AMPK activity. Blockage of H1-receptors by olanzapine disrupted chemerin signaling pathway with an increased AMPK activity, augmenting food intake. These changes were reversed to normal by betahistine coadministration. SIGNIFICANCE: Chemerin is an anorexigenic adipokine, whose dysregulation is implicated in diet, and olanzapine-induced obesity through a histamine/AMPK axis in the ARC. Hypothalamic chemerin/CMKLR1 expression is a dynamic time-dependent response to changes in body weight and/or food intake. Targeting chemerin as a novel therapeutic approach against antipsychotic- or diet-induced obesity is worth to be further delineated.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Quimiocinas/metabolismo , Dieta , Histamina/metabolismo , Hipotálamo/metabolismo , Obesidad/inducido químicamente , Obesidad/metabolismo , Olanzapina/efectos adversos , Animales , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/metabolismo , Betahistina/administración & dosificación , Peso Corporal/efectos de los fármacos , Restricción Calórica , Quimiocinas/administración & dosificación , Dieta Alta en Grasa , Conducta Alimentaria/efectos de los fármacos , Femenino , Antagonistas de los Receptores Histamínicos H1/farmacología , Inyecciones Intraperitoneales , Ratas Wistar , Receptores de Quimiocina/metabolismo , Receptores Histamínicos H1/metabolismoRESUMEN
The use and availability of cannabis for recreational and medical purposes has become more widespread with increased legalization. Adverse health outcomes of this increased use include cannabinoid hyperemesis syndrome (CHS), which is underrecognized in medical settings. Cessation of substance use is the recommendation of choice for the complete resolution of CHS. However, interventions that provide rapid relief may be necessary in treatment-refractory cases. Little evidence is available to guide care in these cases. Here we report 4 cases of treatment-refractory CHS, all of which remitted after treatment with olanzapine. Olanzapine is known to block multiple neurotransmitter receptors involved in nausea and vomiting in chemotherapy-induced nausea and vomiting. Outcomes of the cases reported here suggest that off-label use of olanzapine may be effective in the symptomatic treatment of refractory CHS and may be the preferred treatment in cases in which comorbid psychotic symptoms or agitation are present.