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Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder.

ABSTRACT: OBJECTIVE:The purpose of this study was to determine whether metformin promotes weight loss in overweight outpatients with chronic schizophrenia or schizoaffective disorder. METHOD:In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ?27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16. RESULTS:Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was -3.0 kg (95% CI=-4.0 to -2.0) for the metformin group and -1.0 kg (95% CI=-2.0 to 0.0) for the placebo group, with a between-group difference of -2.0 kg (95% CI=-3.4 to -0.6). Metformin also demonstrated a significant between-group advantage for BMI (-0.7; 95% CI=-1.1 to -0.2), triglyceride level (-20.2 mg/dL; 95% CI=-39.2 to -1.3), and hemoglobin A1c level (-0.07%; 95% CI=-0.14 to -0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation. CONCLUSIONS:Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia.

SUBMITTER: Jarskog LF

PROVIDER: S-EPMC3874085 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder.

Jarskog L Fredrik LF Hamer Robert M RM Catellier Diane J DJ Stewart Dawn D DD Lavange Lisa L Ray Neepa N Golden Lauren H LH Lieberman Jeffrey A JA Stroup T Scott TS

The American journal of psychiatry 20130901 9

<h4>Objective</h4>The purpose of this study was to determine whether metformin promotes weight loss in overweight outpatients with chronic schizophrenia or schizoaffective disorder.<h4>Method</h4>In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients cont ...[more]

PMID: 23846733

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Project description:Background To compare estimated 10-year and 30-year cardiovascular risk in primary care patients with and without serious mental illness (SMI; bipolar disorder, schizophrenia, or schizoaffective disorder). Methods and Results All patients aged 18 to 75 years with a primary care visit in January 2016 to September 2018 were included and were grouped into those with and without SMI using diagnosis codes. Ten-year cardiovascular risk was estimated using atherosclerotic cardiovascular disease scores for patients aged 40 to 75 years without cardiovascular disease; 30-year cardiovascular risk was estimated using Framingham risk scores for patients aged 18 to 59 years without cardiovascular disease. Demographic, vital sign, medication, diagnosis, and health insurance data were collected from the electronic health record by a clinical decision support system. Descriptive statistics examined unadjusted differences, while general linear models examined differences for continuous variables and logistic regression models for categorical variables. Models were then adjusted for age, sex, race, ethnicity, and insurance type. A total of 11 333 patients with SMI and 579 924 patients without SMI were included. After covariate adjustment, 10-year cardiovascular risk was significantly higher in patients with SMI (mean, 9.44%; 95% CI, 9.29%-9.60%) compared with patients without SMI (mean, 7.99%; 95% CI, 7.97-8.02). Similarly, 30-year cardiovascular risk was significantly higher in those with SMI (25% of patients with SMI in the highest-risk group compared with 11% of patients without SMI; P<0.001). The individual cardiovascular risk factors contributing most to increased risk for those with SMI were elevated body mass index and smoking. Among SMI subtypes, patients with bipolar disorder had the highest 10-year cardiovascular risk, while patients with schizoaffective disorder had the highest 30-year cardiovascular risk. Conclusions The significantly increased cardiovascular risk associated with SMI is evident even in young adults. This suggests the importance of addressing uncontrolled major cardiovascular risk factors in those with SMI at as early an age as possible. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02451670.

Project description:The coordinated dynamic interactions of large-scale brain circuits and networks have been associated with cognitive functions and behavior. Recent advances in network neuroscience have suggested that the anatomical organization of such networks puts fundamental constraints on the dynamical landscape of brain activity, i.e., the different states, or patterns of regional activation, and transition between states the brain can display. Specifically, it has been shown that densely connected, central regions control the transition between states that are "easily" reachable (in terms of expended energy), whereas weakly connected areas control transitions to states that are hard-to-reach. Changes in large-scale brain activity have been hypothesized to underlie many neurological and psychiatric disorders. Evidence has emerged that large-scale dysconnectivity might play a crucial role in the pathophysiology of schizophrenia, especially regarding cognitive symptoms. Therefore, an analysis of graph and control theoretic measures of large-scale brain connectivity in patients offers to give insight into the emergence of cognitive disturbances in the disorder. To investigate these potential differences between patients with schizophrenia (SCZ), patients with schizoaffective disorder (SCZaff) and matched healthy controls (HC), we used structural MRI data to assess the microstructural organization of white matter. We first calculate seven graph measures of integration, segregation, centrality and resilience and test for group differences. Second, we extend our analysis beyond these traditional measures and employ a simplified noise-free linear discrete-time and time-invariant network model to calculate two complementary measures of controllability. Average controllability, which identifies brain areas that can guide brain activity into different, easily reachable states with little input energy and modal controllability, which characterizes regions that can push the brain into difficult-to-reach states, i.e., states that require substantial input energy. We identified differences in standard network and controllability measures for both patient groups compared to HCs. We found a strong reduction of betweenness centrality for both patient groups and a strong reduction in average controllability for the SCZ group again in comparison to the HC group. Our findings of network level deficits might help to explain the many cognitive deficits associated with these disorders.

Project description:Schizophrenia is associated with alterations in working memory that reflect dysfunction of dorsolateral prefrontal cortex (DLPFC) circuitry. Working memory depends on the activity of excitatory pyramidal cells in DLPFC layer 3 and, to a lesser extent, in layer 5. Although many studies have profiled gene expression in DLPFC gray matter in schizophrenia, little is known about cell-type-specific transcript expression in these two populations of pyramidal cells. We hypothesized that interrogating gene expression, specifically in DLPFC layer 3 or 5 pyramidal cells, would reveal new and/or more robust schizophrenia-associated differences that would provide new insights into the nature of pyramidal cell dysfunction in the illness. We also sought to determine the impact of other variables, such as a diagnosis of schizoaffective disorder or medication use at the time of death, on the patterns of gene expression in pyramidal neurons. Individual pyramidal cells in DLPFC layers 3 or 5 were captured by laser microdissection from 36 subjects with schizophrenia or schizoaffective disorder and matched normal comparison subjects. The mRNA from cell collections was subjected to transcriptome profiling by microarray followed by quantitative PCR validation. Expression of genes involved in mitochondrial (MT) or ubiquitin-proteasome system (UPS) functions were markedly downregulated in the patient group (P-values for MT-related and UPS-related pathways were <10(-7) and <10(-5), respectively). MT-related gene alterations were more prominent in layer 3 pyramidal cells, whereas UPS-related gene alterations were more prominent in layer 5 pyramidal cells. Many of these alterations were not present, or found to a lesser degree, in samples of DLPFC gray matter from the same subjects, suggesting that they are pyramidal cell specific. Furthermore, these findings principally reflected alterations in the schizophrenia subjects were not present or present to a lesser degree in the schizoaffective disorder subjects (diagnosis of schizoaffective disorder was the most significant covariate, P<10(-6)) and were not attributable to factors frequently comorbid with schizophrenia. In summary, our findings reveal expression deficits in MT- and UPS-related genes specific to layer 3 and/or layer 5 pyramidal cells in the DLPFC of schizophrenia subjects. These cell type-specific transcriptome signatures are not characteristic of schizoaffective disorder, providing a potential molecular-cellular basis of differences in clinical phenotypes.

Project description:BACKGROUND:People with severe mental illness (SMI) are two to three times more likely to be overweight and obese than the general population and this is associated with significant morbidity and premature mortality. Although lifestyle interventions can support people with SMI to lose weight, some are unable to make the necessary lifestyle changes or, despite making the changes, continue to gain weight. OBJECTIVE:To assess the feasibility and acceptability of delivering a full-scale trial evaluating whether liraglutide 3.0?mg, a once-daily injectable therapy, may be an effective treatment of overweight and obesity in people with schizophrenia, schizoaffective disorder and first-episode psychosis. METHODS:Design: a single-centre, double-blind, randomised, placebo-controlled trial. SETTING:mental health facilities within Southern Health NHS Trust. PARTICIPANTS:60 adults with schizophrenia, schizoaffective or first-episode psychosis prescribed antipsychotic medication will be recruited. Participants will be overweight or obese, defined by their baseline BMI which will be: • BMI ? 30?kg/m2 or • BMI ? 27?kg/m2 to <?30?kg/m2 in the presence of at least one weight-related consequence. This is in concordance with the current EU licence for liraglutide (maximum dosage 3.0?mg). INTERVENTION:participants will be allocated in a 1:1 ratio using a computer-based randomisation programme to either once-daily subcutaneously administered liraglutide or placebo, titrated to 3.0?mg daily, for 6?months. All participants will receive standardised written information about healthy eating and exercise at their randomisation visit. OUTCOMES:the main aim of the study is to gather data on recruitment, consent, retention and adherence. Qualitative interviews with a purposive sub-sample of participants and healthcare workers will provide data on intervention feasibility and acceptability. Secondary clinical outcome measurements will be assessed at 3 and 6?months and will include: weight, fasting plasma glucose, lipid profile, HbA1c level; and the Brief Psychiatric Rating Scale. DISCUSSION:This study should provide evidence of the potential benefits of liraglutide (maximum dosage 3.0?mg daily) on body weight and metabolic variables in people with schizophrenia, schizoaffective disorder and first-episode psychosis. It will also address the feasibility and acceptability of the use of liraglutide in mental health settings. This will inform the design of a longer outcome study that will be needed to determine whether any weight loss can be maintained in the long term. TRIAL REGISTRATION:Universal Trial Number (UTN), ID: U1111-1203-0068. Registered on on 2/10/2017. European Clinical Trials Database (EudraCT), ID: 2017-004064-35. Registered on 3/10/2017.

Dataset Information

Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder.

Publications

Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder.

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