Search

Objective Schizophrenia is associated with profound cognitive and psychosocial impairments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used for diabetes and obesity treatment, and animal studies have indicated cognitive-enhancing effects. In this investigator-initiated, double-blind, randomized, placebo-controlled trial, we tested non-metabolic effects of exenatide once-weekly (Bydureon™) in obese, antipsychotic-treated patients with schizohrenia spectrum disorder. Method Before and after 3 months of exenatide (N = 20) or placebo (N = 20) treatment, patients were assessed with the following: Brief Assessment of Cognition in Schizophrenia (BACS), Rey–Osterreith complex figure test (REY), Short-Form Health Survey (SF-36), Personal and Social Performance Scale (PSP) and the Positive and Negative Syndrome Scale (PANSS). We used BACS composite score as the main outcome measure. Results Repeated measures analysis of variance on BACS composite score showed significant effect of ‘Time’ (P < 0.001), no effect of ‘Group’ (P = 0.64) and no ‘Time*Group’ interaction (P = 0.77). For REY, SF-36, PSP and PANSS, only significant ‘Time’ effects were found. Conclusion The non-significant results of this first clinical trial exploring non-metabolic effects of a long-acting GLP-1RA in patients with schizophrenia could reflect a general problem of translating cognitive-enhancing effects of GLP-1RAs from animals to humans or be explained by factors specifically related to schizophrenia spectrum patients with obesity such as antipsychotic treatment.

To evaluate if glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce antipsychotic-associated body weight gain in patients with schizophrenia, when compared to controls.We systematically searched PubMed/EMBASE/PsycINFO/Cochrane using the search terms '(antipsychotic and GLP-1RA)'. Individual participant data from studies randomizing patients to GLP-1RA or control were meta-analysed. The primary outcome was difference in body weight between GLP-1RA and control; secondary outcomes included cardio-metabolic variables and adverse drug reactions (ADRs). Multiple linear regression was conducted including sex, age, psychosis severity, metabolic variable, ADRs, and GLP-1RA agent.Three studies (exenatide once-weekly = 2; liraglutide once-daily = 1) provided participant-level data (n = 164, age = 40.0 ± 11.1 years, body weight = 105.8 ± 20.8 kg). After 16.2 ± 4.0 weeks of treatment, body weight loss was 3.71 kg (95% CI = 2.44-4.99 kg) greater for GLP-1RA versus control (p0.001), number-needed-to-treat ≥5% body weight loss = 3.8 (95% CI = 2.6-7.2). Waist circumference, body mass index, HbA1c, fasting glucose and visceral adiposity were each significantly lower with GLP-1RA. Sex, age, psychosis severity, nausea, any ADR, and GLP-1RA agent did not significantly impact outcomes. Body weight loss with GLP-1RAs was greater for clozapine/olanzapine-treated patients (n = 141) than other antipsychotics (n = 27) (4.70 kg, 95% CI = 3.13-6.27 vs. 1.5 kg, 95% CI = -1.47-4.47) (p0.001). Nausea was more common with GLP-1RAs than control (53.6% vs. 27.5%, p = 0.002, number-needed-to-harm = 3.8).GLP-1RAs are effective and tolerable for antipsychotic-associated body weight gain, particularly clozapine/olanzapine-treated patients. With few included patients, further studies are required before making routine use recommendations for GLP-1RAs.

BACKGROUND: Low bone mineral density (BMD) may constitute an underestimated comorbidity in schizophrenia patients undergoing long-term antipsychotic treatment. Glucagon-like peptide 1 (GLP-1) receptor agonists are antidiabetic drugs, which may also affect bone turnover. The current study comprises planned secondary analyses of the ‘TAO study’: Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist. The TAO study was an investigator-initiated, double-blind, randomized, placebo-controlled trial, investigating the effects of three months treatment with the GLP-1 receptor agonist exenatide 2 mg once-weekly in chronic obese, antipsychotic-treated patients with schizophrenia spectrum disorder. METHODS: First, we compared baseline bone turnover markers (BTMs) of 45 chronic, obese, antipsychotic-treated patients with the Danish Health2006 study cohort as reference population, and we calculated bone mineral density (BMD) T- and Z-scores. Second, investigated effects of three months of GLP-1 receptor agonist exenatide 2 mg once-weekly (n=23), or placebo (n=22) on BTMs and BMD in these patients. Data were initially analyzed without covariates by two-way repeated measures ANOVA. All analyses were repeated with mean prolactin level as a covariate to evaluate the potential effect of prolactin. RESULTS: In women (n=24), all baseline BTM measurements of procollagen type I N-terminal propeptide (PINP) and C-terminal cross-linking telopeptide of type I collagen (CTX) were within reference values. In men (n=21), 5% displayed lower PINP and 14% displayed lower CTX. One patient displayed BMD Z-score

Aims Schizophrenia is associated with cardiovascular co-morbidity and a reduced life-expectancy of up to 20 years. Antipsychotics are dopamine D2 receptor antagonists and the standard of medical care in schizophrenia, but the drugs are associated with severe metabolic side effects like obesity and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are registered for treatment of both obesity and type 2 diabetes. We investigated metabolic effects of the GLP-1RA, exenatide once-weekly, in non-diabetic, antipsychotic-treated, obese patients with schizophrenia. Material and Methods Antipsychotic-treated, obese, non-diabetic, schizophrenia spectrum patients were randomized to double-blinded adjunctive treatment with once-weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for three months. The primary outcome was body weight loss after treatment and repeated measures analysis of variance was used as statistical analysis. Results Between March 2013 and June 2015, 40 patients completed the trial. At baseline, the mean body weight was 118.3 ± 16.0 kg in the exenatide group and 111.7 ± 18.0 kg in the placebo group, with no group differences (P = 0.23). The exenatide and placebo groups experienced significant (P = 0.004), however, similar (P = 0.98) weight losses of 2.24 ± 3.3 kg and 2.23 ± 4.4 kg, respectively, after three months of treatment. Conclusions Treatment with exenatide once-weekly did not promote weight loss in obese, antipsychotic-treated patients with schizophrenia compared to placebo. Our results could suggest that the body weight-lowering effect of GLP-1RAs involves dopaminergic signaling, but blockade of other receptor systems may also play a role. Nevertheless, anti-obesity regimens effective in the general population may not be readily implemented in antipsychotic-treated patients with schizophrenia ClinicalTrials.gov identifier: NCT01794429

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are registered for treatment of both obesity and type 2 diabetes, and we investigated metabolic and cognitive effects of the GLP-1RA, exenatide once weekly, in nondiabetic, antipsychotic-treated, obese patients with schizophrenia.

Background Antipsychotic-induced weight gain constitutes a major unresolved clinical problem which may ultimately be associated with reducing life expectancy by 25 years. Overweight is associated with brain deterioration, cognitive decline and poor quality of life, factors which are already compromised in normal weight patients with schizophrenia. Here we outline the current strategies against antipsychotic-induced weight gain, and we describe peripheral and cerebral effects of the gut hormone glucagon-like peptide-1 (GLP-1). Moreover, we account for similarities in brain changes between schizophrenia and overweight patients. Discussion Current interventions against antipsychotic-induced weight gain do not facilitate a substantial and lasting weight loss. GLP-1 analogs used in the treatment of type 2 diabetes are associated with significant and sustained weight loss in overweight patients. Potential effects of treating schizophrenia patients with antipsychotic-induced weight gain with GLP-1 analogs are discussed. Conclusions We propose that adjunctive treatment with GLP-1 analogs may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in schizophrenia patients with antipsychotic-induced weight gain. Clinical research to support this idea is highly warranted.

Questions Do vascular plant species richness and β-diversity differ between managed and structurally complex unmanaged stands? To what extent do species richness and β-diversity relate to forest structural attributes and heterogeneity?. Location Five National Parks in central and southern Italy. Methods We sampled vascular plant species composition and forest structural attributes in eight unmanaged temperate mesic forest stands dominated or co-dominated by beech, and in eight comparison stands managed as high forests with similar environmental features. We compared plant species richness, composition and β-diversity, across pairs of stands (unmanaged vs. managed) using Generalized Linear Mixed (effect) Models (GLMMs). β-diversity was quantified both at the scale of each pair of stands using plot-to-plot dissimilarity matrices (species turnover), and across the whole dataset, considering the distance in the multivariate species space of individual plots from the centroid of the plots within the same stand (compositional heterogeneity). We modelled the relationship between species diversity (richness and β-diversity) and forest structural heterogeneity and individual structural variables using GLMMs and Multiple Regression on Distance Matrices. Results Species composition differed significantly between managed and unmanaged stands, but not richness and β-diversity. We found weak evidence that plant species richness increased with increasing levels of structural heterogeneity and canopy diversification. At the scale of individual stands, species turnover was explained by different variables in distinct stands, with variables related to deadwood quantity and quality being selected most often. Conversely, we did not find support to the hypothesis that compositional heterogeneity varies as a function of forest structural characteristics at the scale of the whole dataset. Conclusions Structurally complex unmanaged stands have a distinct herb-layer species composition from that of mature stands in similar environmental conditions; nevertheless, we did not find significantly higher levels of vascular plant species richness and β-diversity in unmanaged stands. β-diversity was related to patterns of deadwood accumulation, while for species richness the evidence that it increases with increasing levels of canopy diversification was weak. These results suggest that emulating natural disturbance, and favoring deadwood accumulation and canopy diversification may benefit some, but not all facets of plant species diversity in Apennine beech forests. This article is protected by copyright. All rights reserved.