Glucose Metabolism in Relation to Schizophrenia and Antipsychotic Drug Treatment

Dwyer, Donard S.; Bradley, Ronald J.; Kablinger, Anita S.; Freeman, Arthur J

doi:10.3109/10401230109148955

Cited by 59 publications

(37 citation statements)

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“…Data indicate that clozapine is associated with the greatest weight gain, followed by olanzapine, and then by risperidone and quetiapine having intermediate effects, and ziprasidone and aripiprazole conferring the lowest risk for weight gain (Newcomer, 2005a, b;Harvey and Bowie, 2005;Dwyer et al, 2001). Obesity can increase the risk of overt diabetes in high-risk individuals, and provides at least a partial explanation for higher rates of diabetes in SGAs-treated patients.…”

Section: Introductionmentioning

confidence: 99%

“…Obesity can increase the risk of overt diabetes in high-risk individuals, and provides at least a partial explanation for higher rates of diabetes in SGAs-treated patients. SGAs are also known to exacerbate insulin resistance (Newcomer, 2005b;Dwyer et al, 2001;Bergman and Ader, 2005) without commensurate increments in insulin secretion , and these events are accompanied by a predictable worsening of glucose tolerance. Although progressive obesity can reduce insulin sensitivity, it is not clear whether the ability of SGAs to induce insulin resistance is entirely explained by weight gain or whether there is a component of the insulin resistance that is independent of the obesity.…”

Section: Introductionmentioning

confidence: 99%

“…As early as the mid1960s, associations between diabetes and conventional neuroleptic drugs were reported, but evidence has accumulated that the risk is significantly greater for some of the SGAs. Thus, the exacerbation of obesity, diabetes, and cardiovascular disease risk in SGA-treated patients is increasingly being recognized as a critical issue in the overall care of the schizophrenic patient (Ananth and Kolli, 2005;Dwyer et al, 2001;Ananth et al, 2002;Casey, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Atypical Antipsychotic Drugs Directly Impair Insulin Action in Adipocytes: Effects on Glucose Transport, Lipogenesis, and Antilipolysis

Vestri

Maianu

Moellering

et al. 2006

Neuropsychopharmacol

140

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Treatment with second-generation antipsychotics (SGAs) has been associated with weight gain and the development of diabetes mellitus, although the mechanisms are unknown. We tested the hypothesis that SGAs exert direct cellular effects on insulin action and substrate metabolism in adipocytes. We utilized two cultured cell models including 3T3-L1 adipocytes and primary cultured rat adipocytes, and tested for effects of SGAs risperidone (RISP), clozapine (CLZ), olanzapine (OLZ), and quetiapine (QUE), together with conventional antipsychotic drugs butyrophenone (BUTY), and trifluoperazine (TFP), over a wide concentration range from 1 to 500 mM. The effects of antipsychotic drugs on basal and insulin-stimulated rates of glucose transport were studied at 3 h, 15 h, and 3 days. Both CLZ and OLZ (but not RISP) at doses as low as 5 mM were able to significantly decrease the maximal insulin-stimulated glucose transport rate by B40% in 3T3-L1 cells, whereas CLZ and RISP reduced insulin-stimulated glucose transport rates in primary cultured rat adipocytes by B50-70%. Conventional drugs (BUTY and TFP) did not affect glucose transport rates. Regarding intracellular glucose metabolism, both SGAs (OLZ, QUE, RISP) and conventional drugs (BUTY and TFP) increased basal and/or insulin-stimulated glucose oxidation rates, whereas rates of lipogenesis were increased by CLZ, OLZ, QUE, and BUTY. Finally, rates of lipolysis in response to isoproterenol were reduced by the SGAs (CLZ, OLZ, QUE, RISP), but not by BUTY or TFP. These experiments demonstrate that antipsychotic drugs can differentially affect insulin action and metabolism through direct cellular effects in adipocytes. However, only SGAs were able to impair the insulin-responsive glucose transport system and to impair lipolysis in adipocytes. Thus, SGAs directly induce insulin resistance and alter lipogenesis and lipolysis in favor of progressive lipid accumulation and adipocyte enlargement. These effects of SGAs on adipocytes could explain, in part, the association of SGAs with weight gain and diabetes. Neuropsychopharmacology (2007) 32, 765-772.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Atypical Antipsychotic Drugs Directly Impair Insulin Action in Adipocytes: Effects on Glucose Transport, Lipogenesis, and Antilipolysis

Vestri

Maianu

Moellering

et al. 2006

Neuropsychopharmacol

140

View full text Add to dashboard Cite

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“…As antipsychotics induce numerous changes in metabolism both in vitro (Ferno et al 2005;Minet-Ringuet et al 2007;Vallejo-Illarramendi et al 2005) and in vivo (Bettinger et al 2000;Dwyer et al 2001;Newcomer 2004;Newcomer and Haupt 2006;Newcomer et al 2002), we hypothesized that increased lactate concentrations observed in postmortem brains of patients with schizophrenia are the result of treatment with antipsychotics and not a primary feature of the disease. Moreover, we hypothesized that increased lactic acid concentrations would be associated with decreased pH and perhaps decreased gene expression, and thus constitute an important confound in postmortem gene expression studies.…”

Section: Introductionmentioning

confidence: 99%

Increased lactate levels and reduced pH in postmortem brains of schizophrenics: Medication confounds

Halim

Lipska

Hyde

et al. 2008

Journal of Neuroscience Methods

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A number of postmortem studies have found decreased pH in brains of patients with schizophrenia. Insofar as lower pH has been associated with decreased mRNA expression in postmortem human brain, decreased pH in schizophrenia may represent an important potential confound in comparisons between patients and controls. We hypothesized that decreased pH may be related to increased concentration of lactic acid. However, in contrast to the previous notion that an increase in lactic acid represents evidence for primary metabolic abnormalities in schizophrenia, we hypothesized that this increase is secondary to prior antipsychotic treatment. We have tested this by first demonstrating that lactate levels in the cerebellum of patients with schizophrenia (n=35) are increased relative to control subjects (n=42) by 28%, p=0.001. Second, we have shown that there is an excellent correlation between lactate levels in the cerebellum and pH, and that this correlation is particularly strong in patients (r=− 0.78, p=3e-6). Third, we have shown in rats that chronic haloperidol (0.8 mg/kg/day) and clozapine (5 mg/kg/day) increase lactic acid concentration in the frontal cortex relative to vehicle (by 31% and 22% respectively, p<0.01). These data suggest that lactate increases in postmortem human brain of patients with schizophrenia are associated with decreased pH and that these changes are possibly related to antipsychotic treatment rather than a primary metabolic abnormality in the prefrontal cortex of patients with schizophrenia.

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“…Changes in brain metabolism are also implicated in neuropsychiatric disorders, such as schizophrenia, which affect some of the human-specific cognitive abilities (8,9). Furthermore, direct measurements of 21 metabolites in the prefrontal cortex of adult human controls compared with human schizophrenia patients, chimpanzees, and rhesus macaques, carried out using proton NMR spectroscopy have shown significant overlap between human-specific evolutionary changes and metabolic differences between controls and schizophrenia patients (10).…”

mentioning

confidence: 99%

Rapid metabolic evolution in human prefrontal cortex

Giavalisco

Liu

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Human evolution is characterized by the rapid expansion of brain size and drastic increase in cognitive capabilities. It has long been suggested that these changes were accompanied by modifications of brain metabolism. Indeed, human-specific changes on gene expression or amino acid sequence were reported for a number of metabolic genes, but actual metabolite measurements in humans and apes have remained scarce. Here, we investigate concentrations of more than 100 metabolites in the prefrontal and cerebellar cortex in 49 humans, 11 chimpanzees, and 45 rhesus macaques of different ages using gas chromatography-mass spectrometry (GC-MS). We show that the brain metabolome undergoes substantial changes, both ontogenetically and evolutionarily: 88% of detected metabolites show significant concentration changes with age, whereas 77% of these metabolic changes differ significantly among species. Although overall metabolic divergence reflects phylogenetic relationships among species, we found a fourfold acceleration of metabolic changes in prefrontal cortex compared with cerebellum in the human lineage. These human-specific metabolic changes are paralleled by changes in expression patterns of the corresponding enzymes, and affect pathways involved in synaptic transmission, memory, and learning.H uman evolution is characterized by rapid expansion of brain size and increase in cognitive capabilities, leading to the emergence of unique and complex cognitive skills. These changes have long been associated with changes in brain metabolism, in particular with respect to increased energy demand (1). Large brains are metabolically costly. Thus, humans allocate approximately 20% of their total energy to the brain, compared with 11-13% for apes and 2-8% for other mammalian species (2). This increased metabolic demand has been associated with elevated expression of genes involved in neuronal functions and energy metabolism (3, 4). These changes may have been evolutionary advantageous, as indicated by signatures of positive selection reported for the amino acid changes, which occur in the mitochondrial electron-transport chain proteins, in anthropoid primates and humans, as well as elevated expression of the energy metabolism pathways in the human brain (5, 6). On the histological level, human brains show the largest density of glia cells relative to neurons in the prefrontal cortex, which provides an indirect indication of increased neuronal metabolic demand (7).Changes in brain metabolism are also implicated in neuropsychiatric disorders, such as schizophrenia, which affect some of the human-specific cognitive abilities (8, 9). Furthermore, direct measurements of 21 metabolites in the prefrontal cortex of adult human controls compared with human schizophrenia patients, chimpanzees, and rhesus macaques, carried out using proton NMR spectroscopy have shown significant overlap between human-specific evolutionary changes and metabolic differences between controls and schizophrenia patients (10). Notably, this study has identified not ...

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Glucose Metabolism in Relation to Schizophrenia and Antipsychotic Drug Treatment

Cited by 59 publications

References 0 publications

Atypical Antipsychotic Drugs Directly Impair Insulin Action in Adipocytes: Effects on Glucose Transport, Lipogenesis, and Antilipolysis

Atypical Antipsychotic Drugs Directly Impair Insulin Action in Adipocytes: Effects on Glucose Transport, Lipogenesis, and Antilipolysis

Increased lactate levels and reduced pH in postmortem brains of schizophrenics: Medication confounds

Rapid metabolic evolution in human prefrontal cortex

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