Assessment of weight gain in adult patients living with HIV receiving first-line dolutegravir-based or efavirenz-based ART regimens in routine care clinics in Tshwane district, South Africa: An observational study.

INTRODUCTION: Although dolutegravir (DTG) is deemed stable, safe, cost-effective, and clinically beneficial, it also carries the risk of side effects, including observed weight gain among patients on DTG-based antiretroviral therapy (ART) regimens. We compared weight changes among adults (≥18 years) initiating tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD) or tenofovir disoproxil fumarate, emtricitabine, and efavirenz (TEE) regimens and those switching from TEE to TLD (TEE-to-TLD switchers) in three large primary care facilities in South Africa METHODS: We conducted a retrospective longitudinal record review using patient medical records, extracting relevant demographic and clinical data from October 2018 to June 2021 from randomly selected adults who initiated TLD or TEE (initiators) and adult TEE-to-TLD switchers. We assessed weight, body mass index (BMI), and percentage weight changes for both groups and fitted linear regression and generalized linear models to determine factors associated with weight and BMI change and percentage weight change ≥10%, respectively, among treatment initiators. We fitted linear mixed-effect models among TEE-to-TLD switchers to consider repeated measures. RESULTS: Of 860 initiators, 450 (52.3%) initiated on TEE and 410 (47.7%) on TLD, with median follow-up of 1.4 years and 1.0 year, respectively. At initiation, 43.3% on TEE and 40.8% on TLD were overweight or obese. TLD initiators had an adjusted higher mean weight gain of 1.6 kg (p < 0.001) and mean BMI gain of 0.51 kg/m2 (p < 0.001) than TEE initiators. Independent risk factors for higher mean weight and BMI included age ≥50 years, male, on ART for >12 months, initial BMI of <18.5 kg/m2, and CD4 counts <200 cells/µL. Of 298 TEE-to-TLD switchers, 36.6% were overweight or obese at TEE initiation. Comparing before and after TLD switch, TEE-to-TLD switchers had an adjusted mean weight of 1.2 kg less while on TLD (p = 0.026). Being overweight and CD4 counts >350 cells/µL were independent risk factors for lower weight gain after TLD switch. CONCLUSIONS: We report more weight gain among TLD than among TEE initiators, although to a lesser extent than previously reported. TEE-to-TLD switchers experienced less weight gain after TLD switch; return to health before receiving TLD may be a contributory factor. The current findings are reassuring for those switching to a DTG-based regimen.

Assessment of the Effects of Dietary Vitamin D Levels on Olanzapine-Induced Metabolic Side Effects: Focus on the Endocannabinoidome-Gut Microbiome Axis.

Vitamin D deficiency is associated with poor mental health and dysmetabolism. Several metabolic abnormalities are associated with psychotic diseases, which can be compounded by atypical antipsychotics that induce weight gain and insulin resistance. These side-effects may be affected by vitamin D levels. The gut microbiota and endocannabinoidome (eCBome) are significant regulators of both metabolism and mental health, but their role in the development of atypical antipsychotic drug metabolic side-effects and their interaction with vitamin D status is unknown. We studied the effects of different combinations of vitamin D levels and atypical antipsychotic drug (olanzapine) exposure on whole-body metabolism and the eCBome-gut microbiota axis in female C57BL/6J mice under a high fat/high sucrose (HFHS) diet in an attempt to identify a link between the latter and the different metabolic outputs induced by the treatments. Olanzapine exerted a protective effect against diet-induced obesity and insulin resistance, largely independent of dietary vitamin D status. These changes were concomitant with olanzapine-mediated decreases in Trpv1 expression and increases in the levels of its agonists, including various N-acylethanolamines and 2-monoacylglycerols, which are consistent with the observed improvement in adiposity and metabolic status. Furthermore, while global gut bacteria community architecture was not altered by olanzapine, we identified changes in the relative abundances of various commensal bacterial families. Taken together, changes of eCBome and gut microbiota families under our experimental conditions might contribute to olanzapine and vitamin D-mediated inhibition of weight gain in mice on a HFHS diet.

Phytohemagglutinin ameliorates HFD-induced obesity by increasing energy expenditure.

Despite all modern advances in medicine, there are few reports of effective and safe drugs to treat obesity. Our objective was to screen anti-obesity natural compounds, and to verify whether they can reduce the body weight gain and investigate their molecular mechanisms. By using drug-screening methods, Phytohemagglutinin (PHA) was found to be the most anti-obesity candidate natural compound. Six-week-old C57BL/6J mice were fed with a high-fat diet (HFD) and intraperitoneally injected with 0.25 mg/kg PHA everyday for 8 weeks. The body weight, glucose homeostasis, oxygen consumption and physical activity were assessed. We also measured the heat intensity, body temperature and the gene expression of key regulators of energy expenditure. Prevention study results showed PHA treatment not only reduced the body weight gain but also maintained glucose homeostasis in HFD-fed mice. Further study indicated energy expenditure and uncoupling protein 1 (UCP-1) expression of brown adipose tissue (BAT) and white adipose tissue (WAT) in HFD-fed mice were significantly improved by PHA. In the therapeutic study, a similar effect was observed. PHA inhibited lipid droplet formation and upregulated mitochondrial-related gene expression during adipogenesis in vitro. UCP-1 KO mice displayed no differences in body weight, glucose homeostasis and core body temperature between PHA and control groups. Our results suggest that PHA prevent and treat obesity by increasing energy expenditure through upregulation of BAT thermogenesis.

Nicotinamide Protects Against Diet-Induced Body Weight Gain, Increases Energy Expenditure, and Induces White Adipose Tissue Beiging.

SCOPE: Interventions that boost NAD+ availability are of potential therapeutic interest for obesity treatment. The potential of nicotinamide (NAM), the amide form of vitamin B3 and a physiological precursor of nicotinamide adenine dinucleotide (NAD)+ , in preventing weight gain has not previously been studied in vivo. Other NAD+ precursors have been shown to decrease weight gain; however, their impact on adipose tissue is not addressed. METHODS AND RESULTS: Two doses of NAM (high dose: 1% and low dose: 0.25%) are given by drinking water to C57BL/6J male mice, starting at the same time as the high-fat diet feeding. NAM supplementation protects against diet-induced obesity by augmenting global body energy expenditure in C57BL/6J male mice. The manipulation markedly alters adipose morphology and metabolism, particularly in inguinal (i) white adipose tissue (iWAT). An increased number of brown and beige adipocyte clusters, protein abundance of uncoupling protein 1 (UCP1), mitochondrial activity, adipose NAD+ , and phosphorylated AMP-activated protein kinase (P-AMPK) levels are observed in the iWAT of treated mice. Notably, a significant improvement in hepatic steatosis, inflammation, and glucose tolerance is also observed in NAM high-dose treated mice. CONCLUSION: NAM influences whole-body energy expenditure by driving changes in the adipose phenotype. Thus, NAM is an attractive potential treatment for preventing obesity and associated complications.

Current and emerging long-acting antipsychotics for the treatment of schizophrenia.

Introduction: In this review, the authors discuss the role of long-acting injectable antipsychotics (LAIs) for schizophrenia, focusing on the effectiveness and new perspectives introduced by such treatment strategy. Despite their promising pharmacokinetic features and their potential advantages in medication adherence, clinical outcomes, and medical costs, LAIs are not habitually presented as an option for patients, especially in the early phase of schizophrenia.Areas covered: This review explores the panorama of available LAIs for the treatment of schizophrenia, first-episode of psychosis, approved indications, medical costs, medication adherence, side effects, effectiveness and differences between first-generation (FGA)-LAIs and second-generation (SGA)-LAIs.Expert Opinion: LAIs differ in terms of specific indications, approved injection sites, needle size, injection volume, injection interval as well as potential drug-drug interactions, and commonly reported adverse reactions. The approved indications have expanded beyond schizophrenia to include bipolar and schizoaffective disorder. SGA-LAIs are often preferred to FGA-LAIs. FGA-LAIs although are less chosen in new patients due to the induction of cognitive and extrapyramidal side effects, even if, on the other hand, many SGA-LAIs are burden by hyperprolactinemia and weight gain. After a review of the available evidence, insight is provided into the potential and current therapeutic opportunities offered by LAI antipsychotic formulations.

Second-Generation Antipsychotic Drugs for Patients with Schizophrenia: Systematic Literature Review and Meta-analysis of Metabolic and Cardiovascular Side Effects.

BACKGROUND AND OBJECTIVES: Second-generation antipsychotics (SGAs) for schizophrenia show different risk profiles, whose evidence has been evaluated through comparative reviews on randomized controlled trials (RCTs) and observational studies. METHODS: We performed a systematic review and meta-analysis of weight gains, metabolic and cardiovascular side effects of SGAs, relying on both RCTs and observational studies, by comparing variations between the start of treatment and the end of follow-up. The systematic review refers to papers published from June 2009 to November 2020. PRISMA criteria were followed. No restrictions on heterogeneity level have been considered for meta-analysis. A test for the summary effect measure and heterogeneity (I2 metric) was used. RESULTS: Seventy-nine papers were selected from 3076 studies (61% RCTs, 39% observational studies). Olanzapine and risperidone reported the greatest weight gain and olanzapine the largest BMI increase. Paliperidone showed the highest increase in total cholesterol, but is the only drug reporting an increase in the HDL cholesterol. Quetiapine XR showed the highest decrease in fasting glucose. Lurasidone showed the lowest increase in body weight and a reduction in BMI and was also the only treatment reporting a decrease in total cholesterol and triglycerides. The highest increase in systolic and diastolic blood pressure was reported by quetiapine XR. CONCLUSIONS: Despite some limitations (differences in the mean dosages per patient and other side effects not included) this paper provides the first complete meta-analysis on SGAs in variations on metabolic risk profile between start of treatment and end of follow-up, with useful results for clinical practice and possibly for future economic evaluation studies.

Safety assessment of desaminotyrosine: Acute, subchronic oral toxicity, and its effects on intestinal microbiota in rats.

In this work, the acute and subchronic toxicities of desaminotyrosine (DAT) by oral administration in SD rats and its effects on the intestinal microflora were investigated. The acute toxicity test showed that DAT is a low-toxic substance with a LD50 of 3129 mg/kg. The subchronic toxicity test showed that DAT has no toxicity at a low dose (125 mg/kg/day). However, DAT exhibited obvious toxicities to food intake, liver, kidney, and lung at higher dose (250 mg/kg/day and 500 mg/kg/day). DAT inhibited the food intake of rats in a dose-dependent manner. Serum biochemical analysis showed that DAT can increase the serum glucose level of rats. Fecal microbiota analysis showed that DAT treatment can significantly change the intestinal microflora of rats, the dose of 125 mg/kg/day has the most significant effect on the diversity of intestinal microbiota. In daily application, the side effects caused by DAT might be gastrointestinal irritation, weight loss, liver or kidney injury, and blood sugar elevation. Based on our study, the no-observed-adverse-effect level (NOAEL) of DAT is 125 mg/kg BW/day for rats.

Evaluation of tree lucerne (Chamaecytisus palmensis) dried leaves as a substitution for concentrate mixture on biological performance and socioeconomic of Washera sheep fed on desho grass hay.

BACKGROUND: The experiment was conducted to evaluate the effect of tree lucerne dried leaves (TLDL) as a substituting supplement for noug seed cake, and wheat bran concentrate mixtures (CM) on feed intake, digestibility, growth, carcass characteristics and economic benefits using Washera sheep fed desho grass hay as a basal diet. METHODS: Twenty-five male Washera sheep with an initial body weight of 16 ± 4.01 kg (mean ± SD) were used for both growth and digestibility trials which lasted for 90 and 10 days, respectively The experiment was conducted using a randomized complete block design having five blocks with five treatments (T1 = 0% TLDL + 100% CM; T2 = 25% TLDL + 75% CM; T3 = 50% TLDL + 50% CM; T4 = 75% TLDL + 25% CM and T5 = 100% TLDL + 0% CM). RESULTS: Significant (p < .05) differences were observed among treatments in total dry matter (DM), nutrients and metabolizable energy (ME) intake; as the level of TLDL increases total DM and nutrient intake decreased (p < .05) except neutral detergent fibre intake (NDFI) and acid detergent fibre intake (ADFI). Digestibility of DM, organic matter (OM) and crude protein (CP) were significantly reduced (p < .001) among the treatments increasing the substitution level of TLDL for local concentrate mixture, but non-significant for fibre fractions digestibility. Similarly, body weight, average daily gain and feed conversion efficiency were significantly different (p < .01) and highest in T1 than other treatments, whereas lowest values of the same parameters were observed for T5. Non-significant difference among treatments was observed in almost all of the carcass characteristics except for rib-eye area that showed significant difference among treatment and was highest in T1 and T2 (low level of TLDL inclusion). The economic analysis showed that supplementation TLDL was economically feasible in which the net return of the treatments were 31.66 (T1), 30.68 (T2) and 30.34 (T3), 27.88 (T4) and 26.32 (T5) USD (United States Dollar). CONCLUSIONS: It was concluded that TLDL could be used as alternative feed source by replacing concentrate mixture up to 75% (T4) which enhanced nutrient intake, digestibility and growth performance of Washera sheep. Finally, TLDL supplementation is recommended as replacement of CM up to 75% for its biological and economic feasibility.

Celastrol alleviates metabolic disturbance in high-fat diet-induced obese mice through increasing energy expenditure by ameliorating metabolic inflammation.

Celastrol, a natural triterpene, has been shown to treat obesity and its related metabolic disorders. In this study, we first assessed the relationship between the antiobesity effects of celastrol and its antiinflammatory activities. Our results showed that celastrol can reduce weight gain, ameliorate glucose intolerance, insulin resistance, and dyslipidemia without affecting food intake in high-fat diet-induced obese mice. A CLAMS was used to clarify the improvement of metabolic profiles was attribute to increased adipose thermogenesis after celastrol treatment. Further studies found that celastrol decreased the infiltration of macrophage as well as its inflammatory products (IL-1ß, IL-18, MCP-1α, and TNF-α) in liver and adipose tissues, which also displayed an obvious inhibition of TLR3/NLRP3 inflammasome molecules. This study demonstrated that celastrol could be a potential drug for treating metabolic disorders, the underlying mechanism is related to ameliorating metabolic inflammation, thus increasing body energy expenditure.

Safety assessment of propyl-propane-thiosulfonate (PTSO): 90-days oral subchronic toxicity study in rats.

Propyl-propane-thiosulfonate (PTSO) is one of the main organosulfur compounds present in Allium essentials oil. Different applications in the food sector have been proposed for PTSO, such as food and feed additive and as active packaging. However, the authorization of its use depends on its toxicity profile. Thus, as a part of its safety assessment, in this work a repeated dose 90-day oral toxicity study has been conducted for the first time in rats following the OECD guideline 408. PTSO was administered to groups of 10 male and 10 female rats at dose levels of 0, 14, 28, and 55 mg/kg/day. No clinical signs or mortality and no changes in body weight, food consumption and feed conversion efficiency were detected through the study. Moreover, no treatment-related changes in hematological and biochemical parameters were observed, for either sex or dose groups. The histopathology study performed revealed no differences in organ weights, and no morphological and histopathological changes were observed. Based on these results, the no-observed-adverse-effect level (NOAEL) of PTSO was judged to be ≥ 55 mg/kg/day for both sexes.

Assessment of Body Weight Changes in Patients with Inflammatory Bowel Diseases Initiating Biologic Therapy: A Prospective Cohort Study.

BACKGROUND: Prior studies have inconsistently suggested that biologic therapy may be associated with weight gain in inflammatory bowel disease patients (IBD). Our aim was to compare weight gain across different biologic therapy classes with distinct mechanisms of action. METHODS: This prospective cohort study recruited patients with moderate to severe IBD initiating outpatient biologic therapy with anti-TNF (infliximab, adalimumab), vedolizumab, or ustekinumab. Weight measurements were performed at weeks 0, 14, 30, and 54. Changes in weight between baseline and each of the follow-up visits were modeled as a continuous variable, and multivariate regression assessed the independent effect of therapeutic class on this outcome. RESULTS: Our study enrolled 269 patients (163 CD, 106 UC) initiating biologic therapy [99 anti-TNF (37%), 122 vedolizumab (45%), 48 ustekinumab (18%)]. From baseline, the weight significantly increased at week 14 with a mean of 0.36 kg (± 3.8 kg, p = 0.004) and continued to increase compared to baseline with 0.96 kg (± 3.9 kg, p < 0.001) and 1.29 kg (± 4.2 kg, p < 0.001) at week 30 and 54, respectively. On univariate and multivariable analysis, no significant differences between any of the biologic therapies for weight gain were seen at any time point (weight gain anti-TNF: 0.31 kg, 1.06 kg, 1.33 kg; VDZ: 0.30 kg, 0.83 kg, 1.10 kg; UST: 0.63 kg, 1.21 kg, 2.31 kg at wk 14, wk 30, and wk 54, respectively). None of the disease activity parameters showed any statistical association with weight gain. CONCLUSION: There was no difference in weight gain among the different biologic therapeutic classes.

An assessment of weight change associated with the initiation of a protease or integrase strand transfer inhibitor in patients with human immunodeficiency virus.

OBJECTIVE: Evidence suggests that integrase strand transfer inhibitors (INSTIs) are associated with greater weight gain than other antiretrovirals. This real-world study compares weight/body mass index (BMI) change between insured US patients with human immunodeficiency virus (HIV-1) initiating a protease inhibitor (PI) or INSTI. METHODS: A retrospective longitudinal study was conducted using Decision Resources Group's Real World Data Repository (7/17/2017-6/1/2019). Adult patients with HIV-1 who initiated a new PI or INSTI on or after 7/17/2018 (index date) and had ≥12 months of continuous pre-index clinical activity were included. Baseline characteristics were balanced using inverse probability of treatment weighting. The proportion of patients with ≥5% weight/BMI increases and mean weight/BMI change from pre- to post-index were compared using odds ratios (ORs) and mean differences (MDs). RESULTS: 20,367 patients (9993 PI, 10,374 INSTI) were included (mean age = 50 years; ∼30% females). Pre- and post-index weight and BMI measurements were available in 429 and 430 PI patients, and 397 and 383 INSTI patients, respectively (mean time between index and post-index measurements: ∼7 months). The PI cohort was 39%/49% less likely to experience ≥5% weight/BMI increase than the INSTI cohort, respectively (OR [≥5% weight gain] = 0.61; p = .014; OR [≥5% BMI gain] = 0.51; p < .001). Mean weight/BMI gain was significantly lower in the PI cohort than the INSTI cohort (weight MD = -1.90 kg [-4.19 lbs], BMI MD = -0.61kg/m2; both p < .001). CONCLUSIONS: Relative to INSTI, patients initiating a new PI were less likely to experience ≥5% weight/BMI gain post-index. Additionally, mean weight/BMI gain was lower in the PI than in the INSTI cohort.

Sesamol Increases Ucp1 Expression in White Adipose Tissues and Stimulates Energy Expenditure in High-Fat Diet-Fed Obese Mice.

Sesamol found in sesame oil has been shown to ameliorate obesity by regulating lipid metabolism. However, its effects on energy expenditure and the underlying molecular mechanism have not been clearly elucidated. In this study, we show that sesamol increased the uncoupling protein 1 (Ucp1) expression in adipocytes. The administration of sesamol in high-fat diet (HFD)-fed mice prevented weight gain and improved metabolic derangements. The three-week sesamol treatment of HFD-fed mice, when the body weights were not different between the sesamol and control groups, increased energy expenditure, suggesting that an induced energy expenditure is a primary contributing factor for sesamol's anti-obese effects. Consistently, sesamol induced the expression of energy-dissipating thermogenic genes, including Ucp1, in white adipose tissues. The microarray analysis showed that sesamol dramatically increased the Nrf2 target genes such as Hmox1 and Atf3 in adipocytes. Moreover, 76% (60/79 genes) of the sesamol-induced genes were also regulated by tert-butylhydroquinone (tBHQ), a known Nrf2 activator. We further verified that sesamol directly activated the Nrf2-mediated transcription. In addition, the Hmox1 and Ucp1 induction by sesamol was compromised in Nrf2-deleted cells, indicating the necessity of Nrf2 in the sesamol-mediated Ucp1 induction. Together, these findings demonstrate the effects of sesamol in inducing Ucp1 and in increasing energy expenditure, further highlighting the use of the Nrf2 activation in stimulating thermogenic adipocytes and in increasing energy expenditure in obesity and its related metabolic diseases.

Toward isolating reward changes in diet-induced obesity: A demand analysis.

Although hormonal and metabolic factors are well known to influence obesity, recent evidence suggests that obesity may be influenced also by changes in reward sensitivity akin to that seen in other 'reward pathologies', like substance use disorders. The current study sought to isolate changes in reward that may occur after the onset of diet-induced obesity by characterizing the economic demand for caloric (sucrose) and non-caloric (saccharin) reinforcers in a preclinical model of diet-induced obesity (DIO). We utilized economic demand analysis to measure baseline demand intensity (Q0) and demand elasticity (α) for sucrose and saccharin reinforcers in rats. After baseline measures were collected, rats were assigned randomly to a high-fat (HF) diet or low-fat (LF) control diet. After 8-weeks of diet exposure, HF rats were divided into obesity-resistant (OR) or obesity-prone (OP) groups based on weight after the 8-week HF diet exposure. Post-DIO demand data for each reinforcer were reassessed. At baseline, rats had higher demand intensity and lower elasticity for sucrose compared to saccharin. After 8-weeks of the high-fat diet, OP rats had significantly greater weight gain and lower demand elasticity for sucrose and saccharin and higher demand intensity for saccharin. The changes in sucrose and saccharin elasticity suggest that DIO-induced changes in food-related behavior are associated with changes in reward processes. The changes in demand intensity for saccharin suggest that demand intensity, as a measure of 'set point', is not directly linked to metabolic processes. The current study shows that microeconomic theory and demand analysis is able to isolate independent aspects of diet-induced reward changes related to caloric and non-caloric reinforcers.

Changes in feed consumption and water intake among broiler chickens subjected to melatonin treatment during the hot-dry season.

The experiment was conducted to evaluate changes in feed consumption and water intake among broiler chickens subjected to melatonin treatment during the hot-dry season. A total of 300 broiler chicks were selected and assigned into three groups, by simple random sampling, comprising 100 chicks each: group I was exposed to natural photoperiod of about 12-h light and 12-h darkness cycle (12D/12L), without melatonin supplementation; group II was kept under 24-h continuous lighting (CL), without melatonin supplementation; and group III was raised under 24-h CL and administered daily with melatonin orally at 0.5 mg/kg (CL + MEL). Live weight (LW), feed consumption, and water intake for each group were obtained at weekly intervals over a period of 8 weeks. On day 42 of age, the LW of 2420 ± 50 g/bird was obtained in group III administered with melatonin (CL + MEL), while LW values recorded in the 12D/12L and CL groups not administered with melatonin were 1470.00 ± 30.00 and 1907.00 ± 38.00 g/bird, respectively. The mean weight gain in CL + MEL (345.00 ± 21.01 g) was significantly (P < 0.05) higher than those of the 12D/12L (244.99 ± 18.67 g) and CL (307.48 ± 18.14 g) groups. Feed consumptions were significantly (P < 0.05) different in all the groups. Group II, raised on CL without melatonin supplementation, had the highest feed consumption value of 25.14 ± 0.51 g/bird from day 14, and attained the peak value of 206.77 ± 7.82 g/bird at day 56. The highest overall amount of water intake was recorded in the melatonin-treated group. In conclusion, melatonin administration to broiler chickens enhanced water intake but decreased feed consumption with increase in LW during the hot-dry season.

Physical health assistance in early recovery of psychosis: Study protocol for a randomized controlled trial.

AIM: Young people with psychotic disorders have poorer physical health compared to their healthy peers, a state compounded by the metabolic side-effects of antipsychotic medications. To address this, Orygen Youth Health has introduced physical health services including exercise physiologists and dieticians. These services are typically coordinated by the case manager and doctor. It is not yet known whether a treating team member dedicated to physical health will improve engagement, adherence and outcomes with these services. Hence, the protocol is presented here for a trial to evaluate the effect of including a physical health nurse in the care of young people with first-episode psychosis. METHODS: This will be a single-blind randomized controlled trial that includes 15- to 24-year-olds with first-episode psychosis who have just commenced (within 30 days) antipsychotic medication. The primary outcome will be the event of clinically significant weight gain (≥7% body weight). Participants will be assigned either a physical health nurse in their treating team (in addition to the case manager and doctor) for a 12-week period, or treatment as usual (case manager and doctor). Research assessments will be conducted at baseline, 12 and 26 weeks. Activity trackers worn by participants for the study's duration will measure sleep and physical activity. CONCLUSION: The present study will determine whether a physical health nurse will facilitate participants in attending and engaging in physical health interventions and whether this will be associated with physical health improvements or the prevention of worsening physical health.

Bayesian Meta-analysis of Multiple Continuous Treatments with Individual Participant-Level Data: An Application to Antipsychotic Drugs.

Modeling dose-response relationships of drugs is essential to understanding their safety effects on patients under realistic circumstances. While intention-to-treat analyses of clinical trials provide the effect of assignment to a particular drug and dose, they do not capture observed exposure after factoring in nonadherence and dropout. We develop a Bayesian method to flexibly model the dose-response relationships of binary outcomes with continuous treatment, permitting multiple evidence sources, treatment effect heterogeneity, and nonlinear dose-response curves. In an application, we examine the risk of excessive weight gain for patients with schizophrenia treated with the second-generation antipsychotics paliperidone, risperidone, or olanzapine in 14 clinical trials. We define exposure as total cumulative dose (daily dose × duration) and convert to units equivalent to 100 mg of olanzapine (OLZ doses). Averaging over the sample population of 5891 subjects, the median dose ranged from 0 (placebo randomized participants) to 6.4 OLZ doses (paliperidone randomized participants). We found paliperidone to be least likely to cause excessive weight gain across a range of doses. Compared with 0 OLZ doses, at 5.0 OLZ doses, olanzapine subjects had a 15.6% (95% credible interval: 6.7, 27.1) excess risk of weight gain; corresponding estimates for paliperidone and risperidone were 3.2% (1.5, 5.2) and 14.9% (0.0, 38.7), respectively. Moreover, compared with nonblack participants, black participants had a 6.8% (1.0, 12.4) greater risk of excessive weight gain at 10.0 OLZ doses of paliperidone. Nevertheless, our findings suggest that paliperidone is safer in terms of weight gain risk than risperidone or olanzapine for all participants at low to moderate cumulative OLZ doses.

Real-life assessment of aripiprazole monthly (Abilify Maintena) in schizophrenia: a Canadian naturalistic non-interventional prospective cohort study.

BACKGROUND: With previously established efficacy of aripiprazole once-monthly injectable formulation (AOM) in pre-registration randomized controlled trials, the current study was designed to evaluate its effectiveness in patients treated for schizophrenia in regular clinical settings in Canada. METHODS: Following their clinicians' decision to prescribe AOM, 193 patients with a diagnosis of schizophrenia, were recruited from 17 Canadian community or hospital-based settings. The primary outcome of global functioning was assessed with the Global Assessment of Functioning Scale (GAF) at 3-month intervals for 1 year. Secondary outcomes (social and occupational functioning and illness severity) and adverse drug reactions (ADR) were also assessed. RESULTS: A majority of the 169 evaluable patients were within the first 5 years of diagnosis (early phase). A linear mixed model analysis showed a significant main effect of time (Type III test p < 0.001) after adjusting for baseline GAF score, with a change in mean GAF scores from 49 at baseline to 61 at 12 months. No differences between early vs late phase were observed. Results on secondary outcome measures of function (Social and Occupational Functioning Scale) and illness severity (Clinical Global Impression-Severity Scale and Brief Psychiatric Rating Scale) were similar. Serious ADRs were observed in 29 (14.6%) patients and akathisia in 18 (9.1%) patients. At month-12, significant (≥7%) weight gain was observed in 25.7% (n = 27/105) of patients. CONCLUSIONS: Treatment with AOM is effective in improving symptoms and functioning in schizophrenia patients treated in regular clinical settings. Akathisia was infrequent while one quarter of patients gained clinically significant weight. TRIAL REGISTRATION: Unique identifier: NCT02131415 . First posted: 06 May 2014.

Bile acid supplementation decreases body mass gain in C57BL/6J but not 129S6/SvEvTac mice without increasing energy expenditure.

Supplementation of cholate to a high fat diet can protect mice from diet-induced, increased body mass gain. It has been hypothesized that uncoupling protein 1 dependent, non-shivering thermogenesis in brown adipocytes provides the mechanism of increased energy expenditure to counteract excessive energy intake. We scrutinized this conjecture in wildtype mice and mice genetically devoid of a functional uncoupling protein 1 gene (C57BL/6J) as well as mice of the 129S6/SvEvTac strain that, in comparison, display an extraordinary capacity to recruit ectopic brown adipocytes. Protection from diet-induced, increased body mass gain by cholate supplementation was absent in 129S6/SvEvTac mice, a consequence of much lower bile acid absorption and spillover in this strain. Conversely, Ucp1-KO mice did not differ from C57BL/6J wildtype controls in any parameter assessed. Daily energy expenditure and resting metabolic rate of C57BL/6J mice remained unaffected by cholate supplementation. We conclude that protection of mice from diet-induced, increased body mass gain by cholate supplementation depends on the specific genetic background of C57BL/6J mice, does not involve increased energy expenditure and is independent of uncoupling protein 1 dependent non-shivering thermogenesis.

Voluntary Corn Oil Ingestion Increases Energy Expenditure and Interscapular UCP1 Expression Through the Sympathetic Nerve in C57BL/6 Mice.

SCOPE: Previously, it has been found that corn oil ingestion activates both the gustatory system and brain reward system, stimulating motivation for eating. In the present study, the effect of voluntary corn oil ingestion on body weight gain and energy metabolism in mice is investigated. METHODS AND RESULTS: Voluntary corn oil ingestion with normal chow feeding does not lead to higher body weight than that of only the chow-fed control group. Mice that ingested corn oil have a higher total caloric intake and energy expenditure than did mice in the control group. Further, voluntary corn oil ingestion significantly upregulates Ucp1 mRNA and protein in interscapular brown adipose tissue (IBAT). Finally, the sympathetic nerve connected to IBAT was surgically transacted, then the body weight is measured for 8 weeks. IBAT sympathetic nerve transection surgery does not affect the body weight gain and food intake; however, when mice ingested corn oil, it induces significant body weight gain without changing the total caloric intake. IBAT sympathetic nerve transection surgery significantly suppresses UCP1 upregulation by corn oil ingestion. CONCLUSION: The present data suggest that corn oil ingestion activates IBAT through the sympathetic nerve, upregulating UCP1 expression and increasing energy expenditure.