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      Effects of Metformin on Spatial and Verbal Memory in Children with ASD and Overweight Associated with Atypical Antipsychotic Use

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          Abstract

          Objectives: Studies in humans and rodents suggest that metformin, a medicine typically used to treat type 2 diabetes, may have beneficial effects on memory. We sought to determine whether metformin improved spatial or verbal memory in children with autism spectrum disorder (ASD) and overweight associated with atypical antipsychotic use.

          Methods: We studied the effects of metformin (Riomet ®) concentrate on spatial and verbal memory in 51 youth with ASD, ages 6 through 17 years, who were taking atypical antipsychotic medications, had gained significant weight, and were enrolled in a trial of metformin for weight management. Phase 1 was a 16-week, randomized, double-blind, placebo-controlled, parallel-group comparison of metformin (500–850 mg given twice a day) versus placebo. During Phase 2, all participants took open-label metformin from week 17 through week 32. We assessed spatial and verbal memory using the Neuropsychological Assessment 2nd Edition (NEPSY–II) and a modified children's verbal learning task.

          Results: No measures differed between participants randomized to metformin versus placebo, at either 16 or 32 weeks, after adjustment for multiple comparisons. Sixteen-week change in memory for spatial location on the NEPSY–II was nominally better among participants randomized to placebo. However, patterns of treatment response across all measures revealed no systematic differences in performance, suggesting that metformin had no effect on spatial or verbal memory in these children.

          Conclusions: Although further study is needed to support these null effects, the overall impression is that metformin does not affect memory in overweight youth with ASD who were taking atypical antipsychotic medications.

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          Most cited references14

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          Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation.

          Although endogenous recruitment of adult neural stem cells has been proposed as a therapeutic strategy, clinical approaches for achieving this are lacking. Here, we show that metformin, a widely used drug, promotes neurogenesis and enhances spatial memory formation. Specifically, we show that an atypical PKC-CBP pathway is essential for the normal genesis of neurons from neural precursors and that metformin activates this pathway to promote rodent and human neurogenesis in culture. Metformin also enhances neurogenesis in the adult mouse brain in a CBP-dependent fashion, and in so doing enhances spatial reversal learning in the water maze. Thus, metformin, by activating an aPKC-CBP pathway, recruits neural stem cells and enhances neural function, thereby providing a candidate pharmacological approach for nervous system therapy. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription.

            Epidemiological, clinical and experimental evidence suggests a link between type 2 diabetes and Alzheimer's disease (AD). Insulin modulates metabolism of beta-amyloid precursor protein (APP) in neurons, decreasing the intracellular accumulation of beta-amyloid (Abeta) peptides, which are pivotal in AD pathogenesis. The present study investigates whether the widely prescribed insulin-sensitizing drug, metformin (Glucophage(R)), affects APP metabolism and Abeta generation in various cell models. We demonstrate that metformin, at doses that lead to activation of the AMP-activated protein kinase (AMPK), significantly increases the generation of both intracellular and extracellular Abeta species. Furthermore, the effect of metformin on Abeta generation is mediated by transcriptional up-regulation of beta-secretase (BACE1), which results in an elevated protein level and increased enzymatic activity. Unlike insulin, metformin exerts no effect on Abeta degradation. In addition, we found that glucose deprivation and various tyrphostins, known inhibitors of insulin-like growth factors/insulin receptor tyrosine kinases, do not modulate the effect of metformin on Abeta. Finally, inhibition of AMP-activated protein kinase (AMPK) by the pharmacological inhibitor Compound C largely suppresses metformin's effect on Abeta generation and BACE1 transcription, suggesting an AMPK-dependent mechanism. Although insulin and metformin display opposing effects on Abeta generation, in combined use, metformin enhances insulin's effect in reducing Abeta levels. Our findings suggest a potentially harmful consequence of this widely prescribed antidiabetic drug when used as a monotherapy in elderly diabetic patients.
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              Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin.

              To determine incidence of dementia in type 2 diabetic (T2DM) patients, and whether there are adverse or favorable effects of oral agents (OA) in DM, we obtained a representative cohort of 800,000 from Taiwan’s National Health Insurance database. Those who, as of on January 1, 2000, were 50 years or older and dementia free (n = 127,209) were followed until December 31, 2007, in relation to absence (n = 101,816) or presence (n = 25,393) of T2DM, and whether any OA was used. Dementia was ascertained by ICD9-CM or A-code. Dementia incidence densities (DID) and fully adjusted Cox proportional hazard models were used to estimate association between dementia, DM, and OA. Notably, DID (per 10,000 person-years)was markedly increased with DM (without medication), compared to DM free subjects (119 versus 46). Using non-DM as reference, the adjusted hazard ratios (HRs) (95% confidence interval) for DM without and with OA were 2.41 (2.17–2.66) and 1.62 (1.49–1.77), respectively. For T2DM, compared with no medication, sulfonylureas alone reduced the HR from 1 to 0.85 (0.71–1.01), metformin alone to 0.76 (0.58–0.98), while with combined oral therapy the HR was 0.65 (0.56–0.74). Adjustments included cerebrovascular diseases so that non-stroke related dementias were found to be decreased in DM with sulfonylurea and metformin therapy. T2DM increases the risk of dementia more than 2-fold. On the other hand, sulfonylureas may decrease the risk of dementia, as does metformin; together, these 2 OAs decrease the risk of dementia in T2DM patients by 35% over 8 years.
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                Author and article information

                Journal
                J Child Adolesc Psychopharmacol
                J Child Adolesc Psychopharmacol
                cap
                Journal of Child and Adolescent Psychopharmacology
                Mary Ann Liebert, Inc. (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
                1044-5463
                1557-8992
                01 May 2018
                01 May 2018
                01 May 2018
                : 28
                : 4
                : 266-273
                Affiliations
                [ 1 ]Nisonger Center, Ohio State University , Columbus, Ohio.
                [ 2 ]Columbia University and New York Psychiatric Institute, New York, New York.
                [ 3 ]Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania.
                [ 4 ]Vanderbilt University , Nashville, Tennessee.
                [ 5 ]Biostatistics Center, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
                [ 6 ]Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, University of Toronto, Toronto, Canada.
                Author notes
                Address correspondence to: Michael G. Aman, PhD, Nisonger Center, Ohio State University McCampbell Hall, 1581 Dodd Drive, Columbus, OH 43210, E-mail: aman.1@ 123456osu.edu
                Article
                10.1089/cap.2017.0072
                10.1089/cap.2017.0072
                5952346
                29620914
                0996a87d-76e0-4e04-a423-bd8daa1af580
                © Michael G. Aman et al. 2018; Published by Mary Ann Liebert, Inc.

                This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are cited.

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                Page count
                Figures: 2, Tables: 2, References: 26, Pages: 8
                Categories
                Original Articles

                metformin,autism spectrum disorder,overweight,atypical antipsychotic,memory

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