|
1
|
Khouma A, Moeini MM, Plamondon J, Richard D, Caron A, Michael NJ. Histaminergic regulation of food intake. Front Endocrinol (Lausanne) 2023; 14:1202089. [PMID: 37448468 PMCID: PMC10338010 DOI: 10.3389/fendo.2023.1202089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 06/06/2023] [Indexed: 07/15/2023] Open
Abstract
Histamine is a biogenic amine that acts as a neuromodulator within the brain. In the hypothalamus, histaminergic signaling contributes to the regulation of numerous physiological and homeostatic processes, including the regulation of energy balance. Histaminergic neurons project extensively throughout the hypothalamus and two histamine receptors (H1R, H3R) are strongly expressed in key hypothalamic nuclei known to regulate energy homeostasis, including the paraventricular (PVH), ventromedial (VMH), dorsomedial (DMH), and arcuate (ARC) nuclei. The activation of different histamine receptors is associated with differential effects on neuronal activity, mediated by their different G protein-coupling. Consequently, activation of H1R has opposing effects on food intake to that of H3R: H1R activation suppresses food intake, while H3R activation mediates an orexigenic response. The central histaminergic system has been implicated in atypical antipsychotic-induced weight gain and has been proposed as a potential therapeutic target for the treatment of obesity. It has also been demonstrated to interact with other major regulators of energy homeostasis, including the central melanocortin system and the adipose-derived hormone leptin. However, the exact mechanisms by which the histaminergic system contributes to the modification of these satiety signals remain underexplored. The present review focuses on recent advances in our understanding of the central histaminergic system's role in regulating feeding and highlights unanswered questions remaining in our knowledge of the functionality of this system.
Collapse
Affiliation(s)
- Axelle Khouma
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec, QC, Canada
| | - Moein Minbashi Moeini
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec, QC, Canada
| | - Julie Plamondon
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, QC, Canada
| | - Denis Richard
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, QC, Canada
- Faculté de Medicine, Université Laval, Québec, QC, Canada
| | - Alexandre Caron
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec, QC, Canada
- Montreal Diabetes Research Center, Montreal, QC, Canada
| | - Natalie Jane Michael
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec, QC, Canada
| |
Collapse
|
|
2
|
Dynamic Changes in Plasma Metabolic Profiles Reveal a Potential Metabolite Panel for Interpretation of Fatal Intoxication by Chlorpromazine or Olanzapine in Mice. Metabolites 2022; 12:metabo12121184. [PMID: 36557223 PMCID: PMC9782175 DOI: 10.3390/metabo12121184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/11/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
Diagnosing the cause of fatal intoxication by antipsychotic agents is an important task in forensic practice. In the 2020 Annual Report of the American Association of Poison Control Centers, among 40 deaths caused by antipsychotics, 21 cases were diagnosed as "probably responsible", thereby indicating that more objective diagnostic tools are needed. We used liquid chromatography-mass spectrometry-based integrated metabolomics analysis to measure changes in metabolic profiles in the plasma of mice that died from fatal intoxication due to chlorpromazine (CPZ) or olanzapine (OLA). These results were used to construct a stable discriminative classification model (DCM) comprising L-acetylcarnitine, succinic acid, and propionylcarnitine between fatal intoxication caused by CPZ/OLA and cervical dislocation (control). Performance evaluation of the classification model in mice that suffered fatal intoxication showed relative specificity for different pharmacodynamic drugs and relative sensitivity in different life states (normal, intoxication, fatal intoxication). A stable level of L-acetylcarnitine and variable levels of succinic acid and propionylcarnitine between fatal-intoxication and intoxication groups revealed procedural perturbations in metabolic pathways related to fatal intoxication by CPZ/OLA. Additional stability studies revealed that decomposition of succinic acid in fatal-intoxication samples (especially in the OLA group) could weaken the prediction performance of the binary-classification model; however, levels of these three potential metabolites measured within 6 days in fresh samples kept at 4 °C revealed a good performance of our model. Our findings suggest that metabolomics analysis can be used to explore metabolic alterations during fatal intoxication due to use of antipsychotic agents and provide evidence for the cause of death.
Collapse
|
|
3
|
Long-term effects of adolescent exposure to olanzapine in C57BL/6 J mice and the impact of dietary fish oil supplementation. Psychopharmacology (Berl) 2022; 239:3117-3131. [PMID: 35896725 DOI: 10.1007/s00213-022-06193-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 07/13/2022] [Indexed: 11/27/2022]
Abstract
RATIONALE Second-generation antipsychotic (SGA) medications can produce abnormal weight gain and metabolic dysfunction in children, but little is known about the post-treatment consequences of adolescent SGA exposure. OBJECTIVES The objective of this study was to determine the long-term, post-treatment effects of adolescent olanzapine exposure on weight and metabolic function and whether dietary fish oil (FO) modulated any observed effects of olanzapine. METHODS Male and female mice were fed a high-fat, high-sugar (HF-HS) diet or an HF-HS diet supplemented with fish oil (HF-HS-FO) and were treated with olanzapine or vehicle for 29 days beginning on postnatal day 37. RESULTS In male mice, adolescent olanzapine treatment suppressed weight gain during and after treatment and improved metabolic function in adulthood; dietary fish oil reduced weight gain, increased expression of fatty acid oxidation genes, and decreased expression of genes associated with fatty acid synthesis and inflammation. In contrast, few effects were observed in female mice. CONCLUSIONS The current results suggest that adolescent olanzapine exposure can produce long-term alterations in weight and metabolic function in male mice and that dietary fish oil can reduce adverse effects of lifelong consumption of an HF-HS diet. Because expected adverse effects of adolescent olanzapine treatment were not observed, the potential beneficial effects of dietary fish oil for SGA-induced weight gain and metabolic dysfunction could not be evaluated.
Collapse
|
|
4
|
Yang Y, Shen M, Li L, Long Y, Wang L, Lang B, Wu R. Olanzapine Promotes the Occurrence of Metabolic Disorders in Conditional TCF7L2-Knockout Mice. Front Cell Dev Biol 2022; 10:890472. [PMID: 35874808 PMCID: PMC9298277 DOI: 10.3389/fcell.2022.890472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 05/16/2022] [Indexed: 11/29/2022] Open
Abstract
Objectives: Schizophrenia (SCZ) patients display higher incidence of metabolic syndrome (MetS) and comorbidity of type II diabetes. Both atypical antipsychotics and genetic variants are believed to predispose the patients with the risk, but their interplay remains largely unknown. TCF7L2 is one of the most common genes strongly associated with glucose homeostasis which also participates in the pathogenesis of schizophrenia. In this study, we aimed to explore the regulatory roles of TCF7L2 in atypical antipsychotics-induced MetS. Methods: Mice with pancreatic β-cell–specific Tcf7l2 deletion (CKO) were generated. The CKO mice and control littermates were subjected to olanzapine (4 mg/kg/day) or saline gavage for 6 weeks. Metabolic indices, β cell mass, and the expressing levels of TCF7L2 and GLP-1R in the pancreatic tissue were closely monitored. Results: Tcf7l2 CKO mice displayed a spectrum of core features of MetS, which included remarkably increased rate of weight gain, higher fasting insulin, higher values of blood lipids (cholesterol, triglyceride, and low-density lipoprotein), impaired glucose tolerance, and hypertrophy of adipocytes. Notably, these effects could be further exacerbated by olanzapine. In addition, Tcf7l2 CKO mice with the olanzapine group showed significantly decreased expressions of GLP-1R protein and a trend of reduced pancreatic β-cell mass. RT-qPCR revealed that the CKO mice presented a significantly less transcription of Sp5, an important element of the Wnt signaling pathway. Conclusion: Our study illustrates that mice with pancreatic β-cell–targeted Tcf7l2 deletion were more vulnerable to suffer metabolic abnormalities after olanzapine administration. This impairment may be mediated by the reduced expression of GLP-1R.
Collapse
Affiliation(s)
- Ye Yang
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Manjun Shen
- Shenzhen Nanshan Center for Chronic Disease Control, Department of Psychiatry, Shenzhen, China
| | - Li Li
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yujun Long
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Lu Wang
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Bing Lang
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Bing Lang, ; Renrong Wu,
| | - Renrong Wu
- National Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Bing Lang, ; Renrong Wu,
| |
Collapse
|
|
5
|
Abolghasemi A, Manca C, Iannotti FA, Shen M, Leblanc N, Lacroix S, Martin C, Flamand N, Di Marzo V, Silvestri C. Assessment of the Effects of Dietary Vitamin D Levels on Olanzapine-Induced Metabolic Side Effects: Focus on the Endocannabinoidome-Gut Microbiome Axis. Int J Mol Sci 2021; 22:12361. [PMID: 34830242 PMCID: PMC8620071 DOI: 10.3390/ijms222212361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/02/2021] [Accepted: 11/02/2021] [Indexed: 12/19/2022] Open
Abstract
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.
Collapse
Affiliation(s)
- Armita Abolghasemi
- Centre de Recherche, l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC G1V 4G5, Canada; (A.A.); (C.M.); (M.S.); (N.L.); (S.L.); (C.M.); (N.F.); (V.D.M.)
- Département de Médecine, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
- Joint International Unit between the National Research Council (CNR) of Italy and Université Laval on Chemical and Biomolecular Research on the Microbiome and Its Impact on Metabolic Health and Nutrition (UMI-MicroMeNu), Université Laval, Québec, QC G1V 0A6, Canada
| | - Claudia Manca
- Centre de Recherche, l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC G1V 4G5, Canada; (A.A.); (C.M.); (M.S.); (N.L.); (S.L.); (C.M.); (N.F.); (V.D.M.)
- Département de Médecine, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
- Joint International Unit between the National Research Council (CNR) of Italy and Université Laval on Chemical and Biomolecular Research on the Microbiome and Its Impact on Metabolic Health and Nutrition (UMI-MicroMeNu), Université Laval, Québec, QC G1V 0A6, Canada
| | - Fabio A. Iannotti
- Joint International Unit between the National Research Council (CNR) of Italy and Université Laval on Chemical and Biomolecular Research on the Microbiome and Its Impact on Metabolic Health and Nutrition (UMI-MicroMeNu), Institute of Biomolecular Chemistry, National Council of Research (Consiglio Nazionale delle Ricerche), 80087 Pozzuoli, Italy;
| | - Melissa Shen
- Centre de Recherche, l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC G1V 4G5, Canada; (A.A.); (C.M.); (M.S.); (N.L.); (S.L.); (C.M.); (N.F.); (V.D.M.)
- Département de Médecine, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
| | - Nadine Leblanc
- Centre de Recherche, l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC G1V 4G5, Canada; (A.A.); (C.M.); (M.S.); (N.L.); (S.L.); (C.M.); (N.F.); (V.D.M.)
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, QC G1V 0A6, Canada
| | - Sébastien Lacroix
- Centre de Recherche, l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC G1V 4G5, Canada; (A.A.); (C.M.); (M.S.); (N.L.); (S.L.); (C.M.); (N.F.); (V.D.M.)
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, QC G1V 0A6, Canada
| | - Cyril Martin
- Centre de Recherche, l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC G1V 4G5, Canada; (A.A.); (C.M.); (M.S.); (N.L.); (S.L.); (C.M.); (N.F.); (V.D.M.)
| | - Nicolas Flamand
- Centre de Recherche, l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC G1V 4G5, Canada; (A.A.); (C.M.); (M.S.); (N.L.); (S.L.); (C.M.); (N.F.); (V.D.M.)
- Département de Médecine, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
| | - Vincenzo Di Marzo
- Centre de Recherche, l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC G1V 4G5, Canada; (A.A.); (C.M.); (M.S.); (N.L.); (S.L.); (C.M.); (N.F.); (V.D.M.)
- Département de Médecine, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
- Joint International Unit between the National Research Council (CNR) of Italy and Université Laval on Chemical and Biomolecular Research on the Microbiome and Its Impact on Metabolic Health and Nutrition (UMI-MicroMeNu), Université Laval, Québec, QC G1V 0A6, Canada
- Joint International Unit between the National Research Council (CNR) of Italy and Université Laval on Chemical and Biomolecular Research on the Microbiome and Its Impact on Metabolic Health and Nutrition (UMI-MicroMeNu), Institute of Biomolecular Chemistry, National Council of Research (Consiglio Nazionale delle Ricerche), 80087 Pozzuoli, Italy;
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, QC G1V 0A6, Canada
- École de Nutrition, Faculté des Sciences de L’agriculture et de L’alimentation (FSAA), Université Laval, Québec, QC G1V 0A6, Canada
- Centre Nutrition, Santé et Société (NUTRISS), Université Laval, Québec, QC G1V 0A6, Canada
| | - Cristoforo Silvestri
- Centre de Recherche, l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC G1V 4G5, Canada; (A.A.); (C.M.); (M.S.); (N.L.); (S.L.); (C.M.); (N.F.); (V.D.M.)
- Département de Médecine, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
- Joint International Unit between the National Research Council (CNR) of Italy and Université Laval on Chemical and Biomolecular Research on the Microbiome and Its Impact on Metabolic Health and Nutrition (UMI-MicroMeNu), Université Laval, Québec, QC G1V 0A6, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, QC G1V 0A6, Canada
- Centre Nutrition, Santé et Société (NUTRISS), Université Laval, Québec, QC G1V 0A6, Canada
| |
Collapse
|
|
6
|
Abd-Elrazek A, Elnawawy T. The Effect of Minor Doses of Olanzapine-Solid Lipid Nanoparticles on an Animal Model of Schizophrenia (Neurochemical and Behavioral Study) and the Side Effect. DRUG DELIVERY LETTERS 2019; 9:308-320. [DOI: 10.2174/2210303109666190619103230] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 04/03/2019] [Accepted: 05/08/2019] [Indexed: 09/02/2023]
Abstract
Background and Objective:Olanzapine (OLZ) is an atypical psychotic agent; the poor bioavailability of olanzapine is the most important issue in its treatment. The present work was carried out to evaluate the oral form of olanzapine solid lipid nanoparticles (OLZ-SLN) to overcome its poor bioavailability and compare between the effect of different doses of OLZ and OLZ-SLN on ketamineinduced schizophrenic-like symptoms. The study was extended to evaluate the adverse effects of subchronic administration of these doses of OLZ and its SLN.Methods:OLZ-SLN was prepared by hot homogenization, particle size, zeta potential and in vitro release and entrapping efficiency studies were performed. In order to assess the effective dose in the treatment of schizophrenia, the effect of different doses of OLZ and OLZ-SLN on open field was assessed and passive avoidance tests were carried out. The test was performed to examine the effects of excitatory and inhibitory amino acids, as well as dopamine and serotonin levels in the brain regions.Results and Conclusion:The new oral formula showed high stability and sustained release. The administration of low and high dose of OLZ-SLN equivalent to (1/10 and 1/20 from the therapeutic dose before ketamine attenuated the behavioral abnormalities by blocking the effect of ketamine-induced increase in glutamate, dopamine and serotonin levels and enhanced apoptosis were studied in the brain areas. In addition, the sub-chronic treatment with OLZ-SLN showed no adverse effect while the treatment with OLZ free form did.
Collapse
Affiliation(s)
- Areeg Abd-Elrazek
- Department of Physiology, National Organization for Drug Control and Research (NODCAR), Giza, Egypt
| | - Tayseer Elnawawy
- Department of Pharmaceutics, National Organization for Drug Control and Research (NODCAR), Giza, Egypt
| |
Collapse
|
|
7
|
Townsend LK, Peppler WT, Bush ND, Wright DC. Obesity exacerbates the acute metabolic side effects of olanzapine. Psychoneuroendocrinology 2018; 88:121-128. [PMID: 29241148 DOI: 10.1016/j.psyneuen.2017.12.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 11/13/2017] [Accepted: 12/08/2017] [Indexed: 01/08/2023]
Abstract
Olanzapine is a second-generation antipsychotic used in the management of schizophrenia and various off-label conditions. The acute metabolic responses of olanzapine recapitulate many of the side effects associated with obesity. Obesity rates are high in the schizophrenic population, but it is unknown whether pre-existing obesity-associated metabolic dysfunction augments the acute side effects of olanzapine. To address this question, we compared the responses to olanzapine in lean and high-fat diet-induced (HFD) obese mice. Four weeks of HFD (60%kcal from fat) led to obese, hyperglycemic, and insulin resistant mice. Olanzapine-induced hyperglycemia and systemic insulin resistance were exacerbated in HFD-induced obese mice. Olanzapine also profoundly inhibited insulin signalling in skeletal muscle and liver, which appears to be exacerbated by obesity. The greater olanzapine-induced hyperglycemia may also result from increased hepatic glucose output in obese mice as pyruvate challenge led to significantly higher blood glucose concentrations, with associated increases in hepatic content of gluconeogenic enzymes. Olanzapine also suppressed RER while acutely increasing oxygen consumption in obese mice. A single olanzapine treatment reduced physical activity for up to 24h, regardless of obesity. Considering obesity is very common in the schizophrenic population, these data suggest that previous research may be under-estimating the severity of olanzapine's acute side effects.
Collapse
Affiliation(s)
- Logan K Townsend
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph ON, Canada
| | - Willem T Peppler
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph ON, Canada
| | - Natasha D Bush
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph ON, Canada
| | - David C Wright
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph ON, Canada.
| |
Collapse
|
|
8
|
Delis F, Rosko L, Shroff A, Leonard KE, Thanos PK. Oral haloperidol or olanzapine intake produces distinct and region-specific increase in cannabinoid receptor levels that is prevented by high fat diet. Prog Neuropsychopharmacol Biol Psychiatry 2017; 79:268-280. [PMID: 28619471 DOI: 10.1016/j.pnpbp.2017.06.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 06/02/2017] [Accepted: 06/12/2017] [Indexed: 10/19/2022]
Abstract
Clinical studies show higher levels of cannabinoid CB1 receptors (CB1R) in the brain of schizophrenic patients while preclinical studies report a significant functional interaction between dopamine D2 receptors and CB1Rs as well as an upregulation of CB1Rs after antipsychotic treatment. These findings prompted us to study the effects of chronic oral intake of a first and a second generation antipsychotic, haloperidol and olanzapine, on the levels and distribution of CB1Rs in the rat brain. Rats consumed either regular chow or high-fat food and drank water, haloperidol drinking solution (1.5mg/kg), or olanzapine drinking solution (10mg/kg) for four weeks. Motor and cognitive functions were tested at the end of treatment week 3 and upon drug discontinuation. Two days after drug discontinuation, rats were euthanized and brains were processed for in vitro receptor autoradiography. In chow-fed animals, haloperidol and olanzapine increased CB1R levels in the basal ganglia and the hippocampus, in a similar, but not identical pattern. In addition, olanzapine had unique effects in CB1R upregulation in higher order cognitive areas, in the secondary somatosensory cortex, in the visual and auditory cortices and the geniculate nuclei, as well as in the hypothalamus. High fat food consumption prevented antipsychotic-induced increase in CB1R levels in all regions examined, with one exception, the globus pallidus, in which they were higher in haloperidol-treated rats. The results point towards the hypothesis that increased CB1R levels could be a confounding effect of antipsychotic medication in schizophrenia that is circumveneted by high fat feeding.
Collapse
Affiliation(s)
- Foteini Delis
- Department of Pharmacology, Medical School, University of Ioannina, 45110, Ioannina, Greece
| | - Lauren Rosko
- Georgetown University Medical Center, Georgetown University, Washington, DC, 20007, USA
| | - Aditya Shroff
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Research Institute on Addictions, University at Buffalo, Buffalo, NY, 14203, USA
| | - Kenneth E Leonard
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Research Institute on Addictions, University at Buffalo, Buffalo, NY, 14203, USA
| | - Panayotis K Thanos
- Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Research Institute on Addictions, University at Buffalo, Buffalo, NY, 14203, USA.
| |
Collapse
|
|
9
|
Courty E, Gobalakichenane P, Garcia M, Muscat A, Kazakian C, Ledent T, Moldes M, Blondeau B, Mitanchez D, Buyse M, Fève B. Antenatal antipsychotic exposure induces multigenerational and gender-specific programming of adiposity and glucose tolerance in adult mouse offspring. DIABETES & METABOLISM 2017; 44:281-291. [PMID: 28729164 DOI: 10.1016/j.diabet.2017.06.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 05/17/2017] [Accepted: 06/14/2017] [Indexed: 12/22/2022]
Abstract
Second-generation antipsychotics (SGAs) are well known for their metabolic side effects in humans, including obesity and diabetes. These compounds are maintained during pregnancy to prevent the relapse of psychoses, but they readily diffuse across the placenta to the fetus, as documented with the widely-prescribed drug olanzapine (OLZ). However, observational studies have provided conflicting results on the potential impact of SGAs on fetal growth and body weight, and their effects on metabolic regulation in the offspring. For this reason, our study has tested whether antenatal exposure of CD1 mice to OLZ influenced metabolic outcomes in the offspring of the first (F1) and second (F2) generations. In F1 mice, OLZ antenatal treatment caused a decrease in neonatal body weight in both genders, an effect that persisted throughout life only in male animals. Interestingly, F1 female mice also displayed altered glucose homoeostasis. F2 mice, generated by mating normal males with F1 female mice exposed to OLZ during antenatal life, exhibited higher neonatal body weights which persisted only in F2 female animals. This was associated with expansion of fat mass and a concordant pattern of adipose tissue gene expression. Moreover, male and female F2 mice were glucose-intolerant. Thus, our study has demonstrated that antenatal OLZ exposure induces multigenerational and gender-specific programming of glucose tolerance in the offspring mice as adults, and points to the need for careful monitoring of children exposed to SGAs during pregnancy.
Collapse
Affiliation(s)
- E Courty
- Inserm, Saint-Antoine Research Center, Saint-Antoine Hospital, Sorbonne University, Pierre-and-Marie-Curie University Paris 06, 75012 Paris, France; Hospitalo-Universitary Institute, ICAN, 75013 Paris, France
| | - P Gobalakichenane
- Inserm, Saint-Antoine Research Center, Saint-Antoine Hospital, Sorbonne University, Pierre-and-Marie-Curie University Paris 06, 75012 Paris, France; Hospitalo-Universitary Institute, ICAN, 75013 Paris, France; Department of Neonatology, Armand-Trousseau Hospital, 75012 Paris, France
| | - M Garcia
- Inserm, Saint-Antoine Research Center, Saint-Antoine Hospital, Sorbonne University, Pierre-and-Marie-Curie University Paris 06, 75012 Paris, France; Hospitalo-Universitary Institute, ICAN, 75013 Paris, France
| | - A Muscat
- Inserm, Saint-Antoine Research Center, Saint-Antoine Hospital, Sorbonne University, Pierre-and-Marie-Curie University Paris 06, 75012 Paris, France; Hospitalo-Universitary Institute, ICAN, 75013 Paris, France
| | - C Kazakian
- Inserm, Saint-Antoine Research Center, Saint-Antoine Hospital, Sorbonne University, Pierre-and-Marie-Curie University Paris 06, 75012 Paris, France; Hospitalo-Universitary Institute, ICAN, 75013 Paris, France
| | - T Ledent
- Inserm, Saint-Antoine Research Center, Saint-Antoine Hospital, Sorbonne University, Pierre-and-Marie-Curie University Paris 06, 75012 Paris, France
| | - M Moldes
- Inserm, Saint-Antoine Research Center, Saint-Antoine Hospital, Sorbonne University, Pierre-and-Marie-Curie University Paris 06, 75012 Paris, France; Hospitalo-Universitary Institute, ICAN, 75013 Paris, France
| | - B Blondeau
- Inserm, Saint-Antoine Research Center, Saint-Antoine Hospital, Sorbonne University, Pierre-and-Marie-Curie University Paris 06, 75012 Paris, France; Hospitalo-Universitary Institute, ICAN, 75013 Paris, France
| | - D Mitanchez
- Inserm, Saint-Antoine Research Center, Saint-Antoine Hospital, Sorbonne University, Pierre-and-Marie-Curie University Paris 06, 75012 Paris, France; Hospitalo-Universitary Institute, ICAN, 75013 Paris, France; Department of Neonatology, Armand-Trousseau Hospital, 75012 Paris, France
| | - M Buyse
- Inserm, Saint-Antoine Research Center, Saint-Antoine Hospital, Sorbonne University, Pierre-and-Marie-Curie University Paris 06, 75012 Paris, France; Hospitalo-Universitary Institute, ICAN, 75013 Paris, France; Paris-Sud University, EA 4123, 92296 Châtenay-Malabry, France; Department of Pharmacy, Saint-Antoine Hospital, AP-HP, 75012 Paris, France
| | - B Fève
- Inserm, Saint-Antoine Research Center, Saint-Antoine Hospital, Sorbonne University, Pierre-and-Marie-Curie University Paris 06, 75012 Paris, France; Hospitalo-Universitary Institute, ICAN, 75013 Paris, France; Department of Endocrinology, Saint-Antoine Hospital, AP-HP, 75012 Paris, France.
| |
Collapse
|
|
10
|
Lazzari P, Serra V, Marcello S, Pira M, Mastinu A. Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats. Eur Neuropsychopharmacol 2017; 27:667-678. [PMID: 28377074 DOI: 10.1016/j.euroneuro.2017.03.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Revised: 03/05/2017] [Accepted: 03/23/2017] [Indexed: 12/24/2022]
Abstract
Weight gain is an important side effect of most atypical antipsychotic drugs such as olanzapine. Moreover, although many animal models with metabolic side effects have been well defined, the interaction with other pathways has to be considered. The endocannabinoid system and the CB1 receptor (CB1R) are among the most promising central and peripheral targets involved in weight and energy balance. In this study we developed a rat model based 15-days treatment with olanzapine that shows weight gain and an alteration of the blood parameters involved in the regulation of energy balance and glucose metabolism. Consequently, we analysed whether, and by which mechanism, a co-treatment with the novel CB1R neutral antagonist NESS06SM, could attenuate the adverse metabolic effects of olanzapine compared to the reference CB1R inverse agonist rimonabant. Our results showed alterations of the cannabinoid markers in the nucleus accumbens and of orexigenic/anorexigenic markers in the hypothalamus of female rats treated with olanzapine. These molecular modifications could explain the excessive food intake and the resulting weight gain. Moreover, we confirmed that a co-treatment with CB1R antagonist/inverse agonist compounds decreased food intake and weight increment and restored all blood parameters, without altering the positive effects of olanzapine on behaviour. Furthermore, rimonabant and NESS06SM restored the metabolic enzymes in the liver and fat tissue altered by olanzapine. Therefore, CB1 receptor antagonist/inverse agonist compounds could be good candidate agents for the treatment of weight gain induced by olanzapine.
Collapse
Affiliation(s)
- P Lazzari
- Kemotech Srl, Edificio 3, Località Piscinamanna, 09010 Pula, CA, Italy
| | - V Serra
- Institute of Translational Pharmacology, UOS of Cagliari, National Research Council, Scientific and Technological Park of Sardinia - Polaris, Pula, CA, Italy
| | - S Marcello
- Institute of Translational Pharmacology, UOS of Cagliari, National Research Council, Scientific and Technological Park of Sardinia - Polaris, Pula, CA, Italy
| | - M Pira
- Kemotech Srl, Edificio 3, Località Piscinamanna, 09010 Pula, CA, Italy
| | - A Mastinu
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; Institute of Translational Pharmacology, UOS of Cagliari, National Research Council, Scientific and Technological Park of Sardinia - Polaris, Pula, CA, Italy.
| |
Collapse
|
|
11
|
Atypical antipsychotics and effects on feeding: from mice to men. Psychopharmacology (Berl) 2016; 233:2629-53. [PMID: 27251130 DOI: 10.1007/s00213-016-4324-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 05/15/2016] [Indexed: 12/22/2022]
Abstract
RATIONALE So-called atypical antipsychotics (AAPs) are associated with varying levels of weight gain and associated metabolic disturbances, which in patients with serious mental illness (SMI) have been linked to non-compliance and poor functional outcomes. Mechanisms underlying AAP-induced metabolic abnormalities are only partially understood. Antipsychotic-induced weight gain may occur as a result of increases in food intake and/or changes in feeding. OBJECTIVE In this review, we examine the available human and preclinical literature addressing AAP-related changes in feeding behavior, to determine whether changes in appetite and perturbations in regulation of food intake could be contributing factors to antipsychotic-induced weight gain. RESULTS In general, human studies point to disruption by AAPs of feeding behaviors and food consumption. In rodents, increases in cumulative food intake are mainly observed in females; however, changes in feeding microstructure or motivational aspects of food intake appear to occur independent of sex. CONCLUSIONS The findings from this review indicate that the varying levels of AAP-related weight gain reflect changes in both appetite and feeding behaviors, which differ by type of AAP. However, inconsistencies exist among the studies (both human and rodent) that may reflect considerable differences in study design and methodology. Future studies examining underlying mechanisms of antipsychotic-induced weight gain are recommended in order to develop strategies addressing the serious metabolic side effect of AAPs.
Collapse
|
|
12
|
Manu P, Dima L, Shulman M, Vancampfort D, De Hert M, Correll CU. Weight gain and obesity in schizophrenia: epidemiology, pathobiology, and management. Acta Psychiatr Scand 2015; 132:97-108. [PMID: 26016380 DOI: 10.1111/acps.12445] [Citation(s) in RCA: 196] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/27/2015] [Indexed: 01/17/2023]
Abstract
OBJECTIVE To review recent advances in the epidemiology, pathobiology, and management of weight gain and obesity in patients with schizophrenia and to evaluate the extent to which they should influence guidelines for clinical practice. METHOD A Medline literature search was performed to identify clinical and experimental studies published in 2005-2014 decade. RESULTS Weight gain and obesity increase the risk of adult-onset diabetes mellitus and cardiovascular disorders, non-adherence with pharmacological interventions, quality of life, and psychiatric readmissions. The etiology includes adverse effects of antipsychotics, pretreatment/premorbid genetic vulnerabilities, psychosocial and socioeconomic risk factors, and unhealthy lifestyle. Patients with schizophrenia have higher intake of calories in the form of high-density food and lower energy expenditure. The inverse relationship between baseline body mass index and antipsychotic-induced weight gain is probably due to previous antipsychotic exposure. In experimental models, the second-generation antipsychotic olanzapine increased the orexigenic stimulation of hypothalamic structures responsible for energy homeostasis. CONCLUSION The management of weight gain and obesity in patients with schizophrenia centers on behavioural interventions using caloric intake reduction, dietary restructuring, and moderate-intensity physical activity. The decision to switch antipsychotics to lower-liability medications should be individualized, and metformin may be considered for adjunctive therapy, given its favorable risk-benefit profile.
Collapse
Affiliation(s)
- P Manu
- The Zucker Hillside Hospital, New York, NY, USA.,Albert Einstein College of Medicine, New York, NY, USA.,Hofstra North Shore - LIJ School of Medicine, Hempstead, NY, USA
| | - L Dima
- Faculty of Medicine, Transilvania University, Brasov, Romania
| | - M Shulman
- The Zucker Hillside Hospital, New York, NY, USA
| | - D Vancampfort
- KU Leuven Department of Rehabilitation Sciences, Leuven, Belgium
| | - M De Hert
- University Psychiatric Centre KU Leuven, Kortenberg, Belgium
| | - C U Correll
- The Zucker Hillside Hospital, New York, NY, USA.,Albert Einstein College of Medicine, New York, NY, USA.,Hofstra North Shore - LIJ School of Medicine, Hempstead, NY, USA
| |
Collapse
|
|
13
|
Ballon JS, Pajvani U, Freyberg Z, Leibel RL, Lieberman JA. Molecular pathophysiology of metabolic effects of antipsychotic medications. Trends Endocrinol Metab 2014; 25:593-600. [PMID: 25190097 DOI: 10.1016/j.tem.2014.07.004] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 07/21/2014] [Accepted: 07/23/2014] [Indexed: 11/23/2022]
Abstract
Antipsychotic medications are associated with major metabolic changes that contribute to medical morbidity and a significantly shortened life span. The mechanisms for these changes provide us with a broader understanding of central nervous and peripheral organ-mediated metabolic regulation. This paper reviews an extensive literature regarding putative mechanisms for effects of antipsychotic medications on weight regulation and glucose homeostasis as well as potential inherent metabolic risks of schizophrenia itself. We present a model suggesting that peripheral antipsychotic targets play a critical role in drug-induced weight gain and diabetes. We propose that a better understanding of these mechanisms will be crucial to developing improved treatments for serious mental illnesses as well as providing potentially novel therapeutic targets of metabolic disorders including diabetes.
Collapse
Affiliation(s)
- Jacob S Ballon
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Division of Experimental Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA
| | - Utpal Pajvani
- Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Naomi Berrie Diabetes Institute, New York, NY 10032, USA
| | - Zachary Freyberg
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA
| | - Rudolph L Leibel
- Naomi Berrie Diabetes Institute, New York, NY 10032, USA; Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Jeffrey A Lieberman
- Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Division of Experimental Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA.
| |
Collapse
|
|
14
|
Phosphorylation of hypothalamic AMPK on serine(485/491) related to sustained weight loss by alpha-lipoic acid in mice treated with olanzapine. Psychopharmacology (Berl) 2014; 231:4059-69. [PMID: 24733236 DOI: 10.1007/s00213-014-3540-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Accepted: 03/14/2014] [Indexed: 12/17/2022]
Abstract
RATIONALE Alpha-lipoic acid (ALA) was shown to suppress atypical antipsychotic drug (AAPD)-induced weight gain. However, its mode of action has remained unidentified. OBJECTIVE We aimed to identify mechanisms underlying anti-obesity effects of ALA in mice treated with olanzapine. METHODS We compared body weight and food intake among vehicle-, olanzapine-, and olanzapine plus ALA-treated mice, and measured hypothalamic AMP-activated protein kinase (AMPK) activity by detecting levels of Thr(172) and Ser(485/491) phosphorylation, which indicate activation and inhibition of AMPK, respectively. RESULTS Body weights were increased by olanzapine in parallel with increased levels of Thr(172) phosphorylation of hypothalamic AMPK. Initially increased rate of weight gain was diminished as Thr(172) phosphorylation levels were decreased to control levels after 10 days of olanzapine treatment. ALA successfully not only prevented olanzapine-induced weight gain but also induced additional weight loss even relative to control levels throughout the treatment period. During the initial stage, ALA's action was indicated by both suppression of olanzapine-induced Thr(172) phosphorylation and an increase in Ser(485/491) phosphorylation levels. However, in the later stage when no more increases in Thr(172) phosphorylation and weight gain by olanzapine were observed, ALA's action was only indicated by increased levels of Ser(485/491) phosphorylation. CONCLUSIONS Our data suggest that anti-obesity effects of ALA may be related to modulation of both Ser(485/491) phosphorylation and Thr(172) phosphorylation of hypothalamic AMPK, while olanzapine-induced weight gain may be only associated with increase in Thr(172) phosphorylation. This might be an important mechanistic clue for the future development of anti-obesity drugs beyond control of AAPD-induced weight gain.
Collapse
|
|
15
|
Volpato AM, Zugno AI, Quevedo J. Recent evidence and potential mechanisms underlying weight gain and insulin resistance due to atypical antipsychotics. BRAZILIAN JOURNAL OF PSYCHIATRY 2014; 35:295-304. [PMID: 24142093 DOI: 10.1590/1516-4446-2012-1052] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 12/20/2012] [Indexed: 12/26/2022]
Abstract
OBJECTIVE Atypical antipsychotics (AAPs) promote obesity and insulin resistance. In this regard, the main objective of this study was to present potential mechanisms and evidence concerning side effects of atypical antipsychotics in humans and rodents. METHOD A systematic review of the literature was performed using the MEDLINE database. We checked the references of selected articles, review articles, and books on the subject. RESULTS This review provides consistent results concerning the side effects of olanzapine (OL) and clozapine (CLZ), whereas we found conflicting results related to other AAPs. Most studies involving humans describe the effects on body weight, adiposity, lipid profile, and blood glucose levels. However, it seems difficult to identify an animal model replicating the wide range of changes observed in humans. Animal lineage, route of administration, dose, and duration of treatment should be carefully chosen for the replication of the findings in humans. CONCLUSIONS Patients undergoing treatment with AAPs are at higher risk of developing adverse metabolic changes. This increased risk must be taken into account when making decisions about treatment. The influence of AAPs on multiple systems is certainly the cause of such effects. Specifically, muscarinic and histaminergic pathways seem to play important roles.
Collapse
Affiliation(s)
- Ana Maria Volpato
- Universidade do Extremo Sul Catarinense, Laboratory of Neurosciences, CriciúmaSC, Brazil
| | | | | |
Collapse
|
|
16
|
Li X, Johnson MS, Smith DL, Li Y, Kesterson RA, Allison DB, Nagy TR. Effects of risperidone on energy balance in female C57BL/6J mice. Obesity (Silver Spring) 2013; 21:1850-7. [PMID: 23408466 PMCID: PMC3657586 DOI: 10.1002/oby.20350] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2012] [Accepted: 12/12/2012] [Indexed: 11/08/2022]
Abstract
OBJECTIVE To investigate the effect of risperidone on energy expenditure and weight gain in female C57BL/6J mice. DESIGN AND METHODS Body weight and composition, food intake, energy expenditure, and activity were determined weekly. mRNA expression of uncoupling protein 1 in brown adipose tissue, orexin, and brain-derived neurotrophic factor in the hypothalamus were quantified using real-time PCR. RESULTS Risperidone tended to induce a greater body weight gain (P = 0.052) and significantly higher food intake (P = 0.038) relative to the placebo-treated group. Risperidone-treated mice had a higher resting energy expenditure (P = 0.001) and total energy expenditure (TEE) (P = 0.005) than the placebo group. There were no effects of treatment, time, and treatment by time on non-resting (or activity-related) energy expenditure between groups. Risperidone-treated mice showed a significantly lesser locomotor activity than placebo-treated mice over 3 weeks (P < 0.001). Risperidone induced a higher UCP1 mRNA (P = 0.003) and a lower orexin mRNA (P = 0.001) than placebo. CONCLUSION Risperidone-induced weight gain is associated with hyperphagia and a reduction in locomotor activity in C57BL/6J mice. Additionally, higher total and resting energy expenditure were accompanied by higher levels of UCP1 mRNA in BAT. The increased TEE could not offset the total intake of energy through risperidone-induced hyperphagia, therefore resulting in weight gain in female C57BL/6J mice.
Collapse
Affiliation(s)
- Xingsheng Li
- Department of Nutrition Sciences, University of Alabama at Birmingham
| | - Maria S. Johnson
- Department of Nutrition Sciences, University of Alabama at Birmingham
| | - Daniel L. Smith
- Department of Nutrition Sciences, University of Alabama at Birmingham
| | - Yan Li
- Department of Nutrition Sciences, University of Alabama at Birmingham
| | | | - David B. Allison
- Department of Nutrition Sciences, University of Alabama at Birmingham
- Department of Biostatistics, University of Alabama at Birmingham
| | - Tim R. Nagy
- Department of Nutrition Sciences, University of Alabama at Birmingham
| |
Collapse
|
|
17
|
Park S, Yi KK, Kim MS, Hong JP. Effects of ziprasidone and olanzapine on body composition and metabolic parameters: an open-label comparative pilot study. Behav Brain Funct 2013; 9:27. [PMID: 23866300 PMCID: PMC3729530 DOI: 10.1186/1744-9081-9-27] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 06/28/2013] [Indexed: 12/27/2022] Open
Abstract
Background In contrast to olanzapine, ziprasidone has been reported to cause minimal or no weight gain. This study aimed to compare the effects of ziprasidone and olanzapine on weight, body composition, appetite, resting energy expenditure, substrate oxidation, and metabolic parameters in adults with schizophrenia or other psychotic disorders. Methods Twenty adults with schizophrenia or other psychotic disorders were randomized 1:1 to ziprasidone 20–160 mg/day or olanzapine 5–20 mg/day for 12 weeks. The mean doses during the 12-week study period were 109(range: 65–140) mg/day for ziprasidone and 11.6(range: 8.2–15.5) mg/day for olanzapine. Body weight, appetite, body composition, resting energy expenditure, and metabolic parameters were measured before and after drug treatment. Outcome measurements before and after medication were compared, and ziprasidone- and olanzapine-treated patients were compared. Results After 12 weeks, olanzapine-treated patients showed significant weight gain, particularly fat gain, with increased low density lipoprotein-cholesterol and decreased high density lipoprotein-cholesterol concentrations. In contrast, ziprasidone-treated patients showed no significant weight gain with increased high density lipoprotein-cholesterol concentration. Conclusions Ziprasidone was associated with a lower propensity for weight gain and central fat deposition than olanzapine. Studies in larger patient samples are required to confirm these results.
Collapse
|
|
18
|
Zugno AI, Barcelos M, Oliveira LD, Canever L, Luca RDD, Fraga DB, Matos MP, Rezin GT, Scaini G, Búrigo M, Streck EL, Quevedo J. Energy metabolism, leptin, and biochemical parameters are altered in rats subjected to the chronic administration of olanzapine. BRAZILIAN JOURNAL OF PSYCHIATRY 2012; 34:168-75. [DOI: 10.1590/s1516-44462012000200009] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2011] [Accepted: 08/06/2011] [Indexed: 01/07/2023]
|
|
19
|
Park S, Kim MS, Namkoong C, Park MH, Hong JP. The effect of ziprasidone on body weight and energy expenditure in female rats. Metabolism 2012; 61:787-93. [PMID: 22209671 DOI: 10.1016/j.metabol.2011.10.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Revised: 10/19/2011] [Accepted: 10/19/2011] [Indexed: 11/17/2022]
Abstract
Ziprasidone, a novel antipsychotic agent with a unique receptor-binding profile, has been reported to have lower propensity for weight gain compared with other atypical antipsychotics. Here, we examined the effects of ziprasidone on resting energy expenditure, physical activity, thermogenesis, food intake, and weight gain in female Sprague-Dawley rats. Ziprasidone (20 mg/kg) or vehicle was administered once daily for 7 weeks; and body weight, food intake, resting energy expenditure, locomotor activity, colonic temperature on cold exposure, and abdominal fat were measured. Compared with control animals, ziprasidone-treated rats gained significantly less weight (P = .031), had a lower level of physical activity (P = .016), showed a higher resting energy expenditure (P < .001), and displayed a greater capacity for thermogenesis when subjected to cold (P < .001). In addition, ziprasidone-treated rats had a lower level of abdominal fat than did controls, although the difference was not significant. Ziprasidone had no effect on food intake. Our results indicate that, in female Sprague-Dawley rats, a 7-week treatment regimen of ziprasidone induces a significant decrease in weight gain by increasing resting energy expenditure without decreasing food intake and even with a lower level of physical activity. Further studies are needed to elucidate the precise mechanism of lower propensity of weight gain of ziprasidone.
Collapse
Affiliation(s)
- Subin Park
- Department of Psychiatry, Asan Medical Center, Ulsan University College of Medicine, Seoul, South Korea
| | | | | | | | | |
Collapse
|
|
20
|
Sejima E, Yamauchi A, Nishioku T, Koga M, Nakagama K, Dohgu S, Futagami K, Kataoka Y. A role for hypothalamic AMP-activated protein kinase in the mediation of hyperphagia and weight gain induced by chronic treatment with olanzapine in female rats. Cell Mol Neurobiol 2011; 31:985-9. [PMID: 21681559 PMCID: PMC11498405 DOI: 10.1007/s10571-011-9663-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2010] [Accepted: 02/12/2011] [Indexed: 10/18/2022]
Abstract
Olanzapine is known to be advantageous with respect to outcome and drug compliance in patients with schizophrenia. However, olanzapine has adverse effects, including a higher incidence of weight gain and metabolic disturbances, when compared with those of other antipsychotic agents. The mechanisms underlying these adverse events remain obscure. Female rats were orally administered olanzapine (2 mg/kg) or vehicle once a day for 2 weeks to ascertain if hypothalamic AMP-activated protein kinase (AMPK) mediates olanzapine-induced weight gain and hyperphagia. Body weight and food intake in each rat were evaluated every day and every two days, respectively. After the termination of drug treatment, we measured the protein levels of AMPK and phosphorylated AMPK in the hypothalamus using western blot analyses. Olanzapine significantly increased body weight and food intake. The phosphorylation levels of AMPK were significantly elevated by olanzapine. These results suggest that activation of hypothalamic AMPK may mediate hyperphagia and weight gain induced by chronic treatment with olanzapine.
Collapse
Affiliation(s)
- Ei Sejima
- Department of Pharmaceutical Care and Health Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan
- Department of Pharmacy, Fukuoka University Hospital, 7-45-1, Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan
| | - Atsushi Yamauchi
- Department of Pharmaceutical Care and Health Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan
| | - Tsuyoshi Nishioku
- Department of Pharmaceutical Care and Health Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan
| | - Mitsuhisa Koga
- Department of Pharmaceutical Care and Health Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan
| | - Kengo Nakagama
- Department of Pharmaceutical Care and Health Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan
| | - Shinya Dohgu
- Department of Pharmaceutical Care and Health Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan
| | - Kojiro Futagami
- Department of Pharmacy, Fukuoka University Hospital, 7-45-1, Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan
| | - Yasufumi Kataoka
- Department of Pharmaceutical Care and Health Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan
- BBB Laboratory, PharmaCo-Cell Co. Ltd, Nagasaki, 852-8523 Japan
| |
Collapse
|
|
21
|
Teff KL, Kim SF. Atypical antipsychotics and the neural regulation of food intake and peripheral metabolism. Physiol Behav 2011; 104:590-8. [PMID: 21664918 PMCID: PMC3139777 DOI: 10.1016/j.physbeh.2011.05.033] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Revised: 05/26/2011] [Accepted: 05/31/2011] [Indexed: 12/18/2022]
Abstract
The atypical antipsychotics (AAPs) are associated with weight gain and an increased incidence of metabolic disease including type 2 diabetes mellitus. Epidemiological, cross-sectional and prospective studies suggest that two of the AAPs, olanzapine and clozapine, cause the most dramatic weight gain and metabolic impairments including increased fasting glucose, insulin and triglycerides. Relative to the other AAPs, both olanzapine and clozapine exhibit a particularly high antagonistic affinity for histamine and muscarinic receptors which have been hypothesized as mediators of the reported increase in weight and glucose abnormalities. In this article, we review the current evidence for the AAP associated weight gain and abnormal glucose metabolism. We postulate that the effects of the AAPs on food intake and peripheral metabolism are initially independently regulated but with increasing body adiposity, the early AAP-induced impairments in peripheral metabolism will be exacerbated, thereby establishing a vicious cycle such that the effects of the AAP are magnified by the known pathophysiological consequences of obesity. Furthermore, we examine how inhibition of the histaminergic pathway may mediate increases in food intake and the potential role of the vagus nerve in the reported peripheral metabolic effects.
Collapse
Affiliation(s)
- Karen L Teff
- Monell Chemical Senses Center, 3500 Market Street, Philadelphia, PA 19104, USA.
| | | |
Collapse
|
|
22
|
Fernø J, Varela L, Skrede S, Vázquez MJ, Nogueiras R, Diéguez C, Vidal-Puig A, Steen VM, López M. Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation. PLoS One 2011; 6:e20571. [PMID: 21695181 PMCID: PMC3113797 DOI: 10.1371/journal.pone.0020571] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Accepted: 05/04/2011] [Indexed: 11/25/2022] Open
Abstract
The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance.
Collapse
Affiliation(s)
- Johan Fernø
- Dr. Einar Martens' Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
- * E-mail: (JF); (ML)
| | - Luis Varela
- Department of Physiology, School of Medicine, University of Santiago de Compostela-Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
| | - Silje Skrede
- Dr. Einar Martens' Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
| | - María Jesús Vázquez
- Department of Physiology, School of Medicine, University of Santiago de Compostela-Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
| | - Rubén Nogueiras
- Department of Physiology, School of Medicine, University of Santiago de Compostela-Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
| | - Carlos Diéguez
- Department of Physiology, School of Medicine, University of Santiago de Compostela-Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
| | - Antonio Vidal-Puig
- Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Vidar M. Steen
- Dr. Einar Martens' Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
| | - Miguel López
- Department of Physiology, School of Medicine, University of Santiago de Compostela-Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
- * E-mail: (JF); (ML)
| |
Collapse
|
|
23
|
Scotti MAL, Lee G, Stevenson SA, Ostromecki AM, Wied TJ, Kula DJ, Gessay GM, Gammie SC. Behavioral and pharmacological assessment of a potential new mouse model for mania. Physiol Behav 2011; 103:376-83. [PMID: 21397618 PMCID: PMC3081909 DOI: 10.1016/j.physbeh.2011.03.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2011] [Revised: 03/02/2011] [Accepted: 03/04/2011] [Indexed: 10/18/2022]
Abstract
Bipolar disorder (BPD) is a devastating long-term disease for which a significant symptom is mania. Rodent models for mania include psychostimulant-induced hyperactivity and single gene alterations, such as in the Clock or DAT genes, but there is still a pressing need for additional models. Recently, our lab isolated a line of mice, termed Madison (MSN), that exhibit behavioral characteristics that may be analogous to symptoms of mania. In this study we quantified possible traits for mania and tested the response to common anti-BPD drugs in altering the behavioral profiles observed in this strain. Relative to other mouse lines, MSN mice showed significant elevations of in-cage hyperactivity levels, significant decreases in daytime sleep, and significant increases in time swimming in the forced swim test. In terms of sexual behavior, the MSN mice showed significantly higher number of mounts and a trend toward higher time mounting. In separate studies, olanzapine and lithium (or respective controls) were administered to MSN mice for at least 2weeks and response to treatments was evaluated. Olanzapine (1mg/kg/day) significantly decreased in-cage hyperactivity and significantly increased time sleeping. Lithium (0.2-0.4% in food) significantly decreased in-cage hyperactivity. Given the behavioral phenotypes and the response to anti-BPD treatments, we propose that MSN mice may provide a possible new model for understanding the neural and genetic basis of phenotypes related to mania and for developing pharmaceutical treatments.
Collapse
Affiliation(s)
- Melissa-Ann L. Scotti
- Department of Psychiatry, University of Illinois at Chicago, Chicago, IL
- Department of Psychology, Northern Illinois University, DeKalb, IL
| | - Grace Lee
- Department of Neuroscience, Tufts University, Medford, MA
| | - Sharon A. Stevenson
- Department of Zoology, Neuroscience Training Program, University of Wisconsin, Madison, WI
| | | | - Tyler J. Wied
- Department of Zoology, Neuroscience Training Program, University of Wisconsin, Madison, WI
| | - Daniel J. Kula
- Department of Zoology, Neuroscience Training Program, University of Wisconsin, Madison, WI
| | - Griffin M. Gessay
- Department of Zoology, Neuroscience Training Program, University of Wisconsin, Madison, WI
| | - Stephen C. Gammie
- Department of Zoology, Neuroscience Training Program, University of Wisconsin, Madison, WI
| |
Collapse
|
|
24
|
Oh KJ, Park J, Lee SY, Hwang I, Kim JB, Park TS, Lee HJ, Koo SH. Atypical antipsychotic drugs perturb AMPK-dependent regulation of hepatic lipid metabolism. Am J Physiol Endocrinol Metab 2011; 300:E624-32. [PMID: 21224484 DOI: 10.1152/ajpendo.00502.2010] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Dysregulation of lipid metabolism is a key feature of metabolic disorder related to side effects of antipsychotic drugs. Here, we investigated the molecular mechanism by which second-generation atypical antipsychotic drugs (AAPDs) affect hepatic lipid metabolism in liver. AAPDs augmented hepatic lipid accumulation by activating expression of sterol regulatory element-binding protein (SREBP) transcription factors, with subsequent induction of downstream target genes involved in lipid and cholesterol synthesis in hepatocytes. We confirmed the direct involvement of SREBPs on AAPD-induced expression of lipogenic and cholesterogenic genes by utilization of adenovirus for dominant negative SREBP (Ad-SREBP-DN). Interestingly, AAPDs significantly decreased phosphorylation of AMPKα and expression of fatty acid oxidation genes. Treatment of constitutive active AMPK restored AAPD-mediated dysregulation of genes involved in both lipid synthesis and fatty acid oxidation. Moreover, AAPDs decreased transcriptional activity of PPARα, a critical transcriptional regulator for controlling hepatic fatty acid oxidation, via an AMPK-dependent manner. Close investigations revealed that mutations at the known p38 MAPK phosphorylation sites (S6/12/21A), but not mutations at the putative AMPKα phosphorylation sites (S167/373/453A), block AAPD-dependent reduction of PPARα transcriptional activity, suggesting that p38 MAPK might be also involved in the regulatory pathway as a downstream effector of AAPDs/AMPK. Taken together, these data suggest that AAPD-stimulated hepatic dysregulation of lipid metabolism could result from the inhibition of AMPK activity, and pharmaceutical means to potentiate AMPK activity would contribute to restore hepatic lipid homeostasis that occurs during AAPD treatment.
Collapse
Affiliation(s)
- Kyoung-Jin Oh
- Dept. of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, South Korea
| | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Coccurello R, Moles A. A murine model of atypical antipsychotic-induced weight gain and metabolic dysregulation. ACTA ACUST UNITED AC 2010; Chapter 9:Unit9.33. [PMID: 20578036 DOI: 10.1002/0471142301.ns0933s52] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
In comparison with conventional, first-generation antipsychotics (e.g., haloperidol), the administration of atypical antipsychotics (AAPs) has been associated with a higher risk of metabolic derangements, including body weight increase, dysregulation of glucose homeostasis, fat accumulation, and even liability to develop type II diabetes. Since this is a serious clinical problem that may be further exacerbated in overweight schizophrenics, establishing animal models of AAP-induced adverse effects may contribute to clarifying the mechanisms underlying these effects. Here we present three basic protocols by which this problem has been modeled. The three protocols differ in many aspects (routes of administration, extent of the chronic treatment, diets, and dosage regimen), and the pros and cons of each procedure are systematically detailed throughout. It should be noted that several factors (e.g., species, sex, duration, and class of AAPs) could restrict the feasibility of these models, as well as their correspondence to the clinical condition.
Collapse
Affiliation(s)
- Roberto Coccurello
- Institute of Neuroscience, National Research Council (C.N.R.), Rome, Italy
| | | |
Collapse
|
|
26
|
Tan W, Fan H, Yu PH. Induction of subcutaneous adipose proliferation by olanzapine in rodents. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:1098-103. [PMID: 20541579 DOI: 10.1016/j.pnpbp.2010.06.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2010] [Revised: 06/03/2010] [Accepted: 06/04/2010] [Indexed: 12/19/2022]
Abstract
Weight gain induced by atypical antipsychotics causes a serious health concern in the treatment of schizophrenic patients. In the present study chronic treatment of female Wistar rats with olanzapine caused weight gain, but limited effect on food intake. A dramatic drug-induced morphological change of the subcutaneous adipose tissue was observed, i.e. development of a pinkish coloration with the appearance of a "fish egg"-like texture. Histological examination revealed a massive increase in the proliferation of undifferentiated adipocytes. Such proliferation was detected as early as the third day after olanzapine treatment. The changes progressed in a time- and dose-dependent manner. The proliferation of adipose tissue was detected in rats treated with olanzapine independent of increases in weight gain. Protein profiles of the adipose tissue were also altered by olanzapine. These results suggest that olanzapine-induced weight gain may be not solely due to an effect on behavioural satiety. The potential involvement of adipose neuronal input and proliferation are discussed.
Collapse
Affiliation(s)
- W Tan
- Department of Pharmacology and Neuropsychiatry Research Unit University, of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E4.
| | | | | |
Collapse
|
|
27
|
Protection from olanzapine-induced metabolic toxicity in mice by acetaminophen and tetrahydroindenoindole. Int J Obes (Lond) 2010; 34:970-9. [PMID: 20065957 DOI: 10.1038/ijo.2009.291] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
OBJECTIVE In mice and in humans, treatment with the second-generation antipsychotic drug olanzapine (OLZ) produces excessive weight gain, adiposity and secondary metabolic complications, including loss of glucose and insulin homeostasis. In mice consuming a high-fat (HF) diet, a similar phenotype develops, which is inhibited by the analgesic acetaminophen (APAP) and by the antioxidant tetrahydroindenoindole (THII). Therefore, we examined the ability of APAP and THII to prevent metabolic changes in mice receiving OLZ. DESIGN AND MEASUREMENT C57BL/6J mice received either a normal diet or a HF diet, and were administered daily dosages of OLZ (3 mg kg(-1) body weight), alone or with APAP (30 mg kg(-1) body weight) or THII (4.5 mg kg(-1) body weight), for 10 weeks. Parameters of body composition and metabolism, including glucose and insulin homeostasis and oxidative stress, were examined. RESULTS OLZ treatment doubled the HF diet-induced increases in body weight and percent body fat. These increases were partially prevented by both APAP and THII, although food consumption was constant in all groups. The THII protection was associated with an increase in whole body and mitochondrial respiration. OLZ also exacerbated, and both APAP and THII prevented, HF diet-induced loss of glucose tolerance and insulin resistance. As increased body fat promotes insulin resistance by a pathway involving oxidative stress, we evaluated production of reactive oxygen and lipid peroxidation in white adipose tissue (WAT). HF diet caused an increase in lipid peroxidation, NADPH-dependent O(2) uptake and H(2)O(2) production, which were further exacerbated by OLZ. APAP, THII and the NADPH oxidase inhibitor, diphenyleneiodonium chloride, each abolished oxidative stress in WAT. CONCLUSIONS We conclude that both APAP and THII intervene in the development of obesity and metabolic complications associated with OLZ treatment.
Collapse
|
|
28
|
30 days of continuous olanzapine infusion determines energy imbalance, glucose intolerance, insulin resistance, and dyslipidemia in mice. J Clin Psychopharmacol 2009; 29:576-83. [PMID: 19910724 DOI: 10.1097/jcp.0b013e3181bfe13e] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The aim of this study was to model in mice the association between metabolic syndrome and the administration of atypical antipsychotic (AAP). Two dosages (4 and 8 mg/kg per day) of olanzapine (OL) were infused in 36 female mice for 30 days by osmotic mini-pumps. This study was also designed to further extend the implications raised in other experiments by our model of AAP-induced metabolic dysregulation. Through the use of the osmotic mini-pumps, this model is aimed to circumvent the shorter (than in humans) half-life of AAPs in rodents and to chronically administer OL by a reliable and less disturbing method. Indirect calorimetry was used to evaluate metabolic rate (MR) and respiratory exchange ratio together with weight and caloric intake. Serum insulin, leptin, and glucose tolerance (oral glucose tolerance test) were assessed. Pancreatic beta cells insulin levels, periuterine and liver fat content were also analyzed. Olanzapine-infused mice exhibited a reduction of overall MR (kilojoule per hour) and resting MR and respiratory exchange ratio, with periuterine fat significantly enlarged. All metabolic alterations were detected at the highest dose, with major effects found on weight gain and hyperphagia. Impaired glucose metabolism, associated with hyperinsulinemia and hyperleptinemia were found. Insulin resistance was evidenced by the raise of HOMA-IR index. Increased insulin and lipid storage were detected at pancreatic and hepatic levels respectively. These findings illustrate the development of a cluster of risk factors (metabolic syndrome) and, for the first time, a decrease of energy expenditure (MR) due to chronic OL infusion.
Collapse
|
|
29
|
Cope MB, Li X, Jumbo-Lucioni P, DiCostanzo CA, Jamison WG, Kesterson RA, Allison DB, Nagy TR. Risperidone alters food intake, core body temperature, and locomotor activity in mice. Physiol Behav 2008; 96:457-63. [PMID: 19084548 DOI: 10.1016/j.physbeh.2008.11.011] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2008] [Revised: 11/06/2008] [Accepted: 11/21/2008] [Indexed: 11/17/2022]
Abstract
Risperidone induces significant weight gain in female mice; however, the underlying mechanisms related to this effect are unknown. We investigated the effects of risperidone on locomotor activity, core body temperature, and uncoupling protein (UCP) and hypothalamic orexin mRNA expression. Female C57BL/6J mice were acclimated to individual housing and randomly assigned to either risperidone (4 mg/kg BW day) or placebo (PLA). Activity and body temperature were measured over 48-hour periods twice a week for 3 weeks. Food intake and body weights were measured weekly. UCP1 (BAT), UCP3 (gastrocnemius), and orexin (hypothalamus) mRNA expressions were measured using RT-PCR. Risperidone-treated mice consumed more food (p=0.050) and gained more weight (p=0.0001) than PLA-treated mice after 3 weeks. During the initial 2 days of treatment, there was an acute effect of treatment on activity (p=0.046), but not body temperature (p=0.290). During 3 weeks of treatment, average core body temperatures were higher in risperidone-treated mice compared to controls during the light phase (p=0.0001), and tended to be higher during the dark phase (p=0.057). Risperidone-treated mice exhibited lower activity levels than controls during the dark phase (p=0.006); there were no differences in activity during the light phase (p=0.47). UCP1 (p<0.01) and UCP3 (p<0.05) mRNA expressions were greater in risperidone-treated mice compared to controls, whereas, orexin mRNA expression was lower in risperidone-treated mice (p<0.01). These results suggest that risperidone-induced weight gain in mice is a consequence of increased energy intake and reduced activity, while the elevation in body temperature may be a result of thermogenic effect of food intake and elevated UCP1, UCP3, and a reduced hypothalamic orexin expression.
Collapse
Affiliation(s)
- Mark B Cope
- Department of Nutrition Sciences, University of Alabama at Birmingham, United States
| | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Coregulation of genes in the mouse brain following treatment with clozapine, haloperidol, or olanzapine implicates altered potassium channel subunit expression in the mechanism of antipsychotic drug action. Psychiatr Genet 2008; 18:226-39. [PMID: 18797397 DOI: 10.1097/ypg.0b013e3283053019] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Antipsychotic drugs are the most effective treatment for the psychotic symptoms of schizophrenia, yet their mechanism of action remains largely unknown. OBJECTIVES Earlier studies have shown gene expression changes in rodent brains after treatment with antipsychotic drugs. We aimed to further characterize these changes using whole-genome transcript profiling to explore coregulation of genes after multiple antipsychotic drug treatment studies. METHODS This study involved transcript profile analysis after 7-day treatment of inbred C57BL/6 mice with conventional (haloperidol) or atypical (clozapine or olanzapine) antipsychotic drugs. Microarray analysis was undertaken using whole-brain mRNA on Affymetrix 430v2 arrays, with quantitative reverse transcriptase-PCR used to confirm gene expression changes. Western blotting was also used to explore translation of gene dysregulation to protein changes and to explore anatomical specificity of such changes. MAIN RESULTS Thirteen genes showed verified regulation by multiple antipsychotic drugs - three genes significantly upregulated and 10 genes significantly downregulated by treatment. These genes encode proteins that function in various biological processes including neurogenesis, cell adhesion, and four genes are involved in voltage-gated ion channels: neural precursor cell developmentally downregulated gene 4 (Nedd4), Kv channel interacting protein 3 (KChip3), potassium voltage-gated channel, shaker-related subfamily, alpha1 (Kcna1) encoding Kv1.1 protein and beta1 (Kcnab1) encoding Kvbeta1 protein. The translation of these gene expression changes to protein dysregulation for Kv1.1, KCHIP3, and NEDD4 was confirmed by western blot, with regional protein analyses undertaken for Kv1.1 and KCHIP3. CONCLUSION These results suggest that transcriptional regulation of ion channels, crucial for neurotransmission, may play a role in mediating antipsychotic drug effects.
Collapse
|
|
31
|
Wallingford NM, Sinnayah P, Bymaster FP, Gadde KM, Krishnan RK, McKinney AA, Landbloom RP, Tollefson GD, Cowley MA. Zonisamide prevents olanzapine-associated hyperphagia, weight gain, and elevated blood glucose in rats. Neuropsychopharmacology 2008; 33:2922-33. [PMID: 18322467 DOI: 10.1038/npp.2008.9] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Olanzapine (OLZ), one of the second-generation atypical antipsychotics (SGAs), has shown relative advantages in patient adherence and outcomes. However, OLZ has also been associated with a higher incidence of weight gain than most other SGAs. Excessive weight gain may in turn contribute to long-term health concerns for some individuals. Zonisamide (ZNS), a medication approved in the United States as an adjunct in the management of epilepsy, has a diverse pharmacological profile, including sodium channel blockade, monoamine enhancement, and inhibition of carbonic anhydrase. ZNS has also been reported to cause weight loss in both humans and rodents. We hypothesized that this profile might be beneficial when co-administered with OLZ. To test this hypothesis, we evaluated the effects of OLZ on body weight, as well as the pathways known to regulate feeding behavior and arousal in the Sprague-Dawley rat. As indicated via c-Fos expression, we found an OLZ-induced activation in the nucleus accumbens and orexin neurons in the lateral hypothalamus. An OLZ-associated development of hyperphagia, weight gain and elevated blood glucose in the rat was also found. These outcomes were attenuated and reversed in the presence of concomitant ZNS. These results suggest the hypothesis that ZNS may effectively treat or prevent weight gain or metabolic changes associated with the SGAs. Future studies of this combination in patients through appropriately designed human clinical studies are encouraged.
Collapse
Affiliation(s)
- Nicholas M Wallingford
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Baptista T, ElFakih Y, Uzcátegui E, Sandia I, Tálamo E, Araujo de Baptista E, Beaulieu S. Pharmacological management of atypical antipsychotic-induced weight gain. CNS Drugs 2008; 22:477-95. [PMID: 18484791 DOI: 10.2165/00023210-200822060-00003] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Excessive bodyweight gain was reported during the 1950s as an adverse effect of typical antipsychotic drug treatment, but the magnitude of bodyweight gain was found to be higher with the atypical antipsychotic drugs that were introduced after 1990. Clozapine and olanzapine produce the greatest bodyweight gain, ziprasidone and aripiprazole have a neutral influence, and quetiapine and risperidone cause an intermediate effect. In the CATIE study, the percentage of patients with bodyweight gain of >7% compared with baseline differed significantly between the antipsychotic drugs, i.e. 30%, 16%, 14%, 12% and 7% for olanzapine, quetiapine, risperidone, perphenazine (a typical antipsychotic) and ziprasidone, respectively (p<0.001). Appetite stimulation is probably a key cause of bodyweight gain, but genetic polymorphisms modify the bodyweight response during treatment with atypical antipsychotics. In addition to nutritional advice, programmed physical activity, cognitive-behavioural training and atypical antipsychotic switching, pharmacological adjunctive treatments have been assessed to counteract excessive bodyweight gain. In some clinical trials, nizatidine, amantadine, reboxetine, topiramate, sibutramine and metformin proved effective in preventing or reversing atypical antipsychotic-induced bodyweight gain; however, the results are inconclusive since few randomized, placebo-controlled clinical trials have been conducted. Indeed, most studies were short-term trials without adequate statistical power and, in the case of metformin, nizatidine and sibutramine, the results are contradictory. The tolerability profile of these agents is adequate. More studies are needed before formal recommendations on the use of these drugs can be made. Meanwhile, clinicians are advised to use any of these adjunctive treatments according to their individual pharmacological and tolerability profiles, and the patient's personal and family history of bodyweight gain and metabolic dysfunction.
Collapse
Affiliation(s)
- Trino Baptista
- Department of Physiology, Los Andes University Medical School, Mérida, Venezuela.
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Coccurello R, Caprioli A, Conti R, Ghirardi O, Borsini F, Carminati P, Moles A. Olanzapine (LY170053, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] benzodiazepine), but not the novel atypical antipsychotic ST2472 (9-piperazin-1-ylpyrrolo[2,1-b][1,3]benzothiazepine), chronic administration induces weight gain, hyperphagia, and metabolic dysregulation in mice. J Pharmacol Exp Ther 2008; 326:905-11. [PMID: 18567835 DOI: 10.1124/jpet.108.137240] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
A mouse model of atypical antipsychotic-associated adverse effects was used to compare the liability to induce weight gain, food intake, and metabolic alterations after chronic olanzapine (OL; LY170053, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3-b][1,5] benzodiazepine) and ST2472 (ST; 9-piperazin-1-ylpyrrolo[2,1-b][1,3]benzothiazepine) administration. By adding two equipotent doses (3 and 6 mg/kg) of either OL or ST to a high-sweet, high-fat (HS-HF) diet, mice were allowed to self-administer drugs up to 50 days. Body weight and food intake were evaluated daily. Locomotor activity was recorded over 48 h at two different time points. Dyslipidemia was measured by central visceral obesity. Blood serum levels of insulin (IN), glucose (Glu), triglycerides (TGs), nonesterified fatty acids (NEFAs), cholesterol (Ch), and ketone (Ke) bodies were quantified. OL treatment at 3 mg/kg enhanced body weight, whereas at the highest dose, the increase became evident only during the last 10 days of treatment. OL (3 mg/kg) increased HS-HF intake over time, whereas the highest dose reduced intake during the second 10 and final 10 days of administration. Both compounds induced nocturnal hypomotility at the highest dose. In contrast to ST, 3 mg/kg OL elevated serum levels of IN, Glu, TG, NEFA, Ch, and Ke, whereas 6 mg/kg OL elevated those of Glu, TG, and Ch. In contrast, ST did not affect weight gain, food intake, and metabolic markers. Given the similarities between OL-induced obesogenic effects and medical reports, this study further supports the view that ST may represent a new class of agents characterized by a low propensity to induce side effects with promising clinical safety.
Collapse
Affiliation(s)
- Roberto Coccurello
- Institute of Neuroscience, National Research Council, Via del Fosso di Fiorano, 64-00143 Rome, Italy
| | | | | | | | | | | | | |
Collapse
|
|
34
|
Mohammad MK, Al-Masri IM, Taha MO, Al-Ghussein MAS, Alkhatib HS, Najjar S, Bustanji Y. Olanzapine inhibits glycogen synthase kinase-3beta: an investigation by docking simulation and experimental validation. Eur J Pharmacol 2008; 584:185-191. [PMID: 18295757 DOI: 10.1016/j.ejphar.2008.01.019] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2007] [Revised: 12/21/2007] [Accepted: 01/15/2008] [Indexed: 11/20/2022]
Abstract
Olanzapine was investigated as an inhibitor of glycogen synthase kinase-3beta (GSK-3beta) in an attempt to evaluate its effect on blood glucose level. The investigation included simulated docking experiments to fit olanzapine within the binding pocket of GSK-3beta followed by in vitro enzyme inhibition assay as well as in vivo subchronic animal treatment. Olanzapine was found to readily fit within the binding pocket of GSK-3beta in a low energy orientation characterized with optimal attractive interactions bridging the tricyclic thienobenzodiazepine nitrogen and sulfur atoms of olanzapine and the residue of VAL-135 of GSK-3beta. In vivo experiments showed a significant decrease in fasting blood glucose level in Balb/c mice at 1.0, 2.0 and 3.0 mg/kg dose levels (P<0.05) and 6 fold increase in liver glycogen level at the 3 mg/kg dose level (P<0.001). Moreover; olanzapine was found to potently inhibit recombinant GSK-3beta in vitro (IC(50) value=91.0 nM). Our findings strongly suggest that olanzapine has significant GSK-3beta inhibition activity that could justify some of its pharmacological effects and glucose metabolic disturbances.
Collapse
Affiliation(s)
- Mohammad K Mohammad
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Amman 11942, Jordan.
| | | | | | | | | | | | | |
Collapse
|
|
35
|
Cooper GD, Harrold JA, Halford JCG, Goudie AJ. Chronic clozapine treatment in female rats does not induce weight gain or metabolic abnormalities but enhances adiposity: implications for animal models of antipsychotic-induced weight gain. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:428-36. [PMID: 17933447 DOI: 10.1016/j.pnpbp.2007.09.012] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2007] [Revised: 08/09/2007] [Accepted: 09/18/2007] [Indexed: 10/22/2022]
Abstract
The ability of clozapine to induce weight gain in female rats was investigated in three studies with progressively lowered doses of clozapine. In an initial preliminary high dose study, clozapine at 6 and 12 mg/kg (i.p., b.i.d.) was found to induce weight loss. In a subsequent intermediate dose study, we obtained no evidence for clozapine-induced weight gain despite using identical procedures and doses of clozapine (1-4 mg/kg, i.p., b.i.d.) with which we have observed olanzapine-induced weight gain, hyperphagia, enhanced adiposity and metabolic changes [Cooper G, Pickavance L, Wilding J, Halford J, Goudie A (2005). A parametric analysis of olanzapine-induced weight gain in female rats. Psychopharmacology; 181: 80-89.]. Instead, clozapine induced weight loss without alteration in food intake and muscle mass or changes in levels of glucose, insulin, leptin and prolactin. However, these intermediate doses of clozapine enhanced visceral adiposity and elevated levels of adiponectin. In a final study, low doses of clozapine (0.25-0.5 mg/kg, i.p, b.i.d.) induced weight loss. These data demonstrate that clozapine-induced weight gain can be much more difficult to observe in female rats than olanzapine-induced weight gain. Moreover, these findings contrast with clinical findings with clozapine, which induces substantial weight gain in humans. Clozapine-induced enhanced adiposity appears to be easier to observe in rats than weight gain. These findings, along with other preclinical studies, suggest that enhanced adiposity can be observed in the absence of antipsychotic-induced weight gain and hyperphagia, possibly reflecting a direct drug effect on adipocyte function independent of drug-induced hyperphagia [e.g. Minet-Ringuet J, Even P, Valet P, Carpene C, Visentin V, Prevot D, Daviaud D, Quignard-Boulange A, Tome D, de Beaurepaire R (2007). Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment. Molecular Psychiatry; 12: 562-571.]. These and other findings which show that the results of studies of antipsychotic treatment in animals do not always mimic clinical findings have important implications for the use of animal models of antipsychotic-induced weight gain. With regard to weight gain the results obtained appear to depend critically on the experimental procedures used and the specific drugs studied. Thus such models are not without limitations. However, they do consistently demonstrate the ability of various antipsychotics to enhance adiposity.
Collapse
Affiliation(s)
- G D Cooper
- School of Psychology, University of Liverpool, Liverpool, UK
| | | | | | | |
Collapse
|
|
36
|
Cope MB, Jumbo-Lucioni P, Walton RG, Kesterson RA, Allison DB, Nagy TR. No effect of dietary fat on short-term weight gain in mice treated with atypical antipsychotic drugs. Int J Obes (Lond) 2007; 31:1014-22. [PMID: 17224931 DOI: 10.1038/sj.ijo.0803533] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
RATIONALE Atypical antipsychotic drugs (AAD) induce significant weight gain in female C57BL/6J mice. The effect of dietary fat on weight gain and serum lipids in this model is unknown. OBJECTIVES Test the hypothesis that the obesigenic effects of these drugs are greater in the presence of a high-fat diet. METHODS Female C57BL/6J mice were treated with atypical antipsychotics for 3 weeks and fed either a low-fat or high-fat diet (4.6 vs 15.6% fat by wt). Food intake (FI), body weight (BW), body composition, and serum lipids were measured during treatment with optimized doses of olanzapine, quetiapine, and risperidone. Energy intake (EI) and feed efficiency (FE) were calculated. Group differences in change were analyzed via repeated measures analysis of variance (ANOVA). Serum lipid concentrations, EI and FE were compared using two-way ANOVA. RESULTS AAD-treated mice gained significantly more weight than controls after 3 weeks (P<0.001). Treatment and diet had significant effects on FI and EI over time (P<0.001). AAD-treated mice had significantly higher FE than controls (P<0.05); however, there was no significant drug by diet interaction (P=0.65). Risperidone low-fat mice gained significantly more absolute fat mass than placebo low-fat mice (P<0.05). All treatment groups, except quetiapine low-fat and olanzapine high-fat, gained significantly more absolute lean mass than placebo controls (P<0.05). Cholesterol levels were significantly lower in quetiapine and risperidone than placebo (P<0.05). Risperidone low-fat mice had significantly higher triglyceride levels than placebo and risperidone high-fat mice (P<0.05). CONCLUSIONS A high-fat diet does not increase AAD-induced BW gain in female mice during a 3-week treatment period.
Collapse
Affiliation(s)
- M B Cope
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-3360, USA
| | | | | | | | | | | |
Collapse
|