Metabolic disturbances associated with antipsychotic drug treatment in patients with schizophrenia:State-of-the-art and future perspectives

Metabolic disturbances and obesity are major cardiovascular risk factors in patients with schizophrenia,resulting in a higher mortality rate and shorter life expectancy compared with those in the general population.Although schizophrenia and metabolic disturbances may share certain genetic or pathobiological risks,antipsychotics,particularly those of second generation,may further increase the risk of weight gain and metabolic disturbances in patients with schizophrenia.This review included articles on weight gain and metabolic disturbances related to antipsychotics and their mechanisms,monitoring guidelines,and interventions.Nearly all antipsychotics are associated with weight gain,but the degree of the weight gain varies considerably.Although certain neurotransmitter receptorbinding affinities and hormones are correlated with weight gain and specific metabolic abnormalities,the precise mechanisms underlying antipsychoticinduced weight gain and metabolic disturbances remain unclear.Emerging evidence indicates the role of genetic polymorphisms associated with antipsychotic-induced weight gain and antipsychotic-induced metabolic disturbances.Although many guidelines for screening and monitoring antipsychotic-induced metabolic disturbances have been developed,they are not routinely implemented in clinical care.Numerous studies have also investigated strategies for managing antipsychotic-induced metabolic disturbances.Thus,patients and their caregivers must be educated and motivated to pursue a healthier life through smoking cessation and dietary and physical activity programs.If lifestyle intervention fails,switching to another antipsychotic drug with a lower metabolic risk or adding adjunctive medication to mitigate weight gain should be considered.Antipsychotic medications are essential for schizophrenia treatment,hence clinicians should monitor and manage the resulting weight gain and metabolic disturbances.

Obesity, the Obesity Epidemic, and Metabolic Dysfunction: The Conundrum Presented by the Disconnect between Evolution and Modern Societies

Currently, there is an obesity epidemic in the developed world, with both adults and children being affected. The consequences of this epidemic on health and health outcomes have impact at multiple levels, and it is increasing. The basis for this epidemic, which appears to have emerged with significance ~40 - 50 years ago, is unknown but is believed by many to have much of its basis in poor diets and inactivity/sedentary behaviour. Analysis of the human genome has revealed >100 loci which exhibit risk for development of obesity. Why there are so many loci, and how they benefited humans evolutionarily are unknown. In spite of these limitations, there are urgent needs for effective short-term interventions to assist those with obesity, as well as longer-term needs to effectively prevent development of obesity. For the former, personalized exercise programs, use of prebiotics, optimal nutrition and surgical interventions can be effective for some individuals but more interventions that address cause are also needed. For longer term solutions more detailed genetic and epigenetic understanding of risk will be required. An attractive speculation is that the genomic risk factors for obesity (>100 identified) have been retained evolutionarily to address acute metabolic needs and current conditions have converted such risks to a chronic state, making reversal more difficult and with more consequences, including possible epigenetic modifications of risk genes. Other contributing factors to chronic obesity could also relate to chemical disruptors in the environment over the past 50+ years which may impact metabolic regulation via the established risk genomic risk factors or new variants. Therefore, to effectively control this high impact epidemic of obesity likely requires a more detailed genetic and epigenetic analysis of families with obesity and analysis of isolated populations, as well as a more thorough investigation of chemicals capable of being metabolic disruptors in this regard. Thus, the long-term solution(s) to the obesity epidemic will require a concerted multidisciplinary approach that may be more complex than just becoming more active and avoiding sedentary behavior.

Alterations in gut microbiota are related to metabolite profiles in spinal cord injury

Studies have shown that gut microbiota metabolites can enter the central nervous system via the blood-spinal cord barrier and cause neuroinflammation, thus constituting secondary injury after spinal cord injury. To investigate the correlation between gut microbiota and metabolites and the possible mechanism underlying the effects of gut microbiota on secondary injury after spinal cord injury, in this study, we established mouse models of T8–T10 traumatic spinal cord injury. We used 16 S rRNA gene amplicon sequencing and metabolomics to reveal the changes in gut microbiota and metabolites in fecal samples from the mouse model. Results showed a severe gut microbiota disturbance after spinal cord injury, which included marked increases in pro-inflammatory bacteria, such as Shigella, Bacteroides, Rikenella, Staphylococcus, and Mucispirillum and decreases in anti-inflammatory bacteria, such as Lactobacillus, Allobaculum, and Sutterella. Meanwhile, we identified 27 metabolites that decreased and 320 metabolites that increased in the injured spinal cord. Combined with pathway enrichment analysis, five markedly differential amino acids(L-leucine, L-methionine, L-phenylalanine, L-isoleucine and L-valine) were screened out, which play a pivotal role in activating oxidative stress and inflammatory responses following spinal cord injury. Integrated correlation analysis indicated that the alteration of gut microbiota was related to the differences in amino acids, which suggests that disturbances in gut microbiota might participate in the secondary injury through the accumulation of partial metabolites that activate oxidative stress and inflammatory responses. Findings from this study provide a new theoretical basis for improving the secondary injury after spinal cord injury through fecal microbial transplantation.

Cluster analysis reveals a homogeneous subgroup of PCOS women with metabolic disturbance associated with adverse reproductive outcomes

Background:Polycystic ovarian syndrome(PCOS)is a heterogeneous and complex reproductive endocrinological disease that could lead to infertility.There were many attempts to classify PCOS but it remains unclear whether there is a specific subgroup of PCOS that is associated with the best or worst reproductive outcomes of assisted reproductive techniques(ART).Methods:Infertile PCOS patients who underwent their first cycle of in vitro fertilization(IVF)in West China Second University Hospital,Sichuan University from January 2019 to December 2021 were included.Basic clinical and laboratory information of each individual were extracted.Unsupervised cluster analysis was performed.Controlled ovarian stimulation parameters and reproductive outcomes were collected and compared between the different clusters of PCOS.Results:Our analysis clustered women with PCOS into"reproductive","metabolic",and"balanced"clusters based on nine traits.Reproductive group was characterized by high levels of testosterone(T),sex hormone-binding globulin(SHBG),follicular stimulation hormone(FSH),luteinizing hormone(LH),and anti-Müllerian hormone(AMH).Metabolic group was characterized by high levels of body mass index(BMI),fasting insulin,and fasting glucose.Balanced group was characterized by low levels of the aforementioned reproductive and metabolic parameters,except for SHBG.Compared with PCOS patients in reproductive and balanced clusters,those in metabolic cluster had lower rates of good quality day 3 embryo and blastocyst formation.Moreover,PCOS patients in the reproductive cluster had greater fresh embryo transfer(ET)cancelation rate and clinical pregnancy rate after fresh ET than metabolic cluster(odds ratio[OR]=3.37,95%confidence interval[CI]:1.77-6.44,and OR=6.19,95%CI:1.58-24.24,respectively).And compared with PCOS of metabolic cluster,PCOS of balanced cluster also had higher chance for fresh ET cancelation(OR=2.83,95%CI:1.26-6.35).Conclusion:Our study suggested that PCOS patients in metabolic cluster may be associated with adverse reproductive outcomes and might need individualized treatment and careful monitoring before and during ART.

Effects of bixin in high-fat diet-fed-induced fatty liver in C57BL/6J mice

Objective:To evaluate the anti-obesity activity of bixin(BIX) on C57BL/6J mice which were fed a high-fat diet(HFD) and to determine the mechanism of this effect.Methods:C57BL/6J mice were separately fed a high-calorie diet or a normal diet for 8weeks,then they were treated with BIX for another 13 weeks.After administration for 13 weeks,the animals were sacrificed.Body adiposity,serum lipid level,and insulin resistance were evaluated.In addition,a histological assay of pancreas and liver,an evaluation of the inhibitory properties on pancreatic lipase,and a-amylase were conducted.Results:Administration of BIX significantly decreased the body weight gain,adipocyte size,fat pad weights,hepatic lipid levels in HFD-induced obese mice.In addition,reduced liver weight exhibited decreased serum leptin levels,malic enzyme,glucose-6-phosphate dehydrogenase,hepatic fatty acid synthase,aspartate aminotransferase,alanine aminotransferase and hepatic phosphatidate phosphohydrolase activity.However,superoxide dismutase,catalase,glutathione peroxidase,and glutathione levels were increased in hepatic tissue.BIX also decreased lipid and carbohydrates absorption due to inhibition of pancreatic lipase and a-amylase.Long term supplementation of BIX significantly decreased hyperlipidemia,insulin resistance and glucose level.Decreased levels of hepatic steatosis and the islets of Langerhans appeared less shrunken in HFD-fed mice.Conclusions:The antiobesity effect of BIX appears to be associated at least in part,to its inhibitory effect on lipids and carbohydrate digestion enzymes such as pancreatic lipase,a-glucosidase,and a-amylase.The results suggested that BIX also act as an antioxidant and may treat visceral obesity normalizing glucose levels,improving insulin resistance and increasing energy expenditure.Therefore,achiote which has a main component,the carotenoid BIX,could be a viable food for the treatment of obesity and diabetes.

Study on Prevention and Treatment of Diabetes in Middle and Aged Women with Kidney Deficiency and Bone Metabolic Disturbance

Objective: To study the therapeutic effect of Chinese herbal medicine (CHM) for supplementing Qi, activating blood circulation and tonifying Kidney on prevention and treatment of diabetes in middle and aged women with Kidney Deficiency and bone metabolic disturbance. Methods: Clinical observation was taken in 52 patients, who were divided into two groups, the control group (treated with hypoglycemic agent alone) and the treated group (treated with hypoglycemic agent and CHM). Results: Before treatment, patients in both groups showed obviously higher blood alkaline phosphatase, β2-microglobulin (β2-MG) level, urinary β2-MG, calcium and phosphorus level, but lower serum estradiol level than those in normal subjects. After 3 months' treatment, no apparent change in serum estradiol level was observed, but other parameters were all lowered obviously in the two groups, with the changes revealed more obviously in the treated group. The symptoms of Kidney Deficiency, such as lumbodorsal pain, fatigue, palpitation and vertigo, were improved after treatment, which was also more obviously in the treated group. Conclusion: CHM for supplementing Qi, activating blood circulation and tonifying Kidney was effective in improving Kidney Deficiency and mineral substance loss in bones in middle and aged diabetic women patients. The CHM and western drugs acted synergistically.

Metabolic profile differences in ACTH-dependent and ACTH-independent Cushing syndrome

Background:The most common etiologies of Cushing’’s syndrome(CS)are adrenocorticotropic hormone(ACTH)-producing pituitary adenoma(pitCS)and primary adrenal gland disease(adrCS),both of which burden patients with metabolic disturbance.The aim of this study was to compare the metabolic features of pitCS and adrCS patients.Methods:A retrospective review including 114 patients(64 adrCS and 50 pitCS)diagnosed with CS in 2009-2019 was performed.Metabolic factors were then compared between pitCS and adrCS groups.Results:Regarding sex,females suffered both adrCs(92.2%)and pitCS(88.0%)more frequently than males.Regarding age,patients with pitCS were diagnosed at a younger age(35.40±11.94 vs.39.65±11.37 years,p=0.056)than those with adrCS,although the difference was not statistically significant.Moreover,pitCS patients had much higher ACTH levels and more serious occurrences of hypercortisolemia at all time points(8 AM,4 PM,12 AM)than that in adrCS patients.Conversely,indexes,including body weight,BMI,blood pressure,serum total cholesterol,low density lipoprotein cholesterol(LDL-C),high density lipoprotein cholesterol(HDL-C),triglycerides,fasting plasma glucose,and uric acid,showed no differences between adrCS and pitCS patients.Furthermore,diabetes prevalence was higher in pitCS patients than in adrCS patients;however,there were no significant differences in hypertension or dyslipidemia prevalence between the two.Conclusions:Although adrCS and pitCS had different pathogenetic mechanisms,different severities of hypercortisolemia,and different diabetes prevalences,both etiologies had similar metabolic characteristics.

The association of olanzapine-induced metabolic disturbance related measures with TCF7L2 gene expression

Objective To investigate the relationship between olanzapine induced metabolic disturbance related measures and TCF7L2 gene expression.Methods Thirty adult C57BL/61 mice,in accordance with the random number table,were divided into 3 groups that were