Hyperglycemia and type 2 diabetes mellitus are more common in schizophrenia than in the general population. Type 2 diabetes mellitus is characterized by disturbances in insulin action on skeletal muscle, liver and adipose tissue. Diabetes causes increased morbidity and mortality due to acute (e.g., diabetic ketoacidosis) and long-tenn (e.g., cardiovascular disease) complications. The combination of hyperglycemia, dyslipidemia and abdominal adiposity is even more strongly associated with increased cardiovascular morbidity and mortality. The association of type 2 diabetes and hyperglycemia with schizophrenia was first noted prior to the introduction of antipsychotic medications, suggesting that these patients may be at increased risk. Since then, however, additional glucoregulatory abnormalities (e.g., new Onset diabetes), dyslipidemia, and increased weight and adiposity have all been associated with antipsychotic medications. Concern about antipsychotic effects on glucose, lipids and adiposity has increased recently, focusing on the widely-used newer medications, clozapine and olanzapine. Increased abdominal adiposity can secondarily decrease insulin sensitivity and antipsychotics can increase adiposity. However, medication effects on glucose control and insulin action may also occur independent of differences in adiposity. This project aims to a) evaluate the effects of selected antipsychotic medications on insulin action in skeletal muscle (glucose disposal), liver (glucose production) and adipose tissue (whole-body lipolysis), b) evaluate the effects of selected antipsychotic medications on abdominal adipose tissue mass, total body fat and total fat-free mass, and c) explore the longitudinal effects of treatment with selected ant:ipsychotics on glucose tolerance, lipid profiles, abdominal adipose tissue mass, total body fat and total fat-free mass. These hypotheses will be evaluated by measuring 1) whole-body glucose and lipid kinetics with the use of gold-standard stable isotopetracer methodology, 2) body composition using dual energy x-ray absorptiometry and magnetic resonance imaging, and 3) longitudinal changes in glucose tolerance and lipid profiles.
The aims will be addressed in non-diabetic schizophrenia patients chronically treated with risperidone, olanzapine, clozapine, or haloperidol, and untreated healthy controls. Re-evaluations will also be performed in patients treated with olanzapine and risperidone (from groups above), crossed over to treatment with the other agent for 6 months. Relevant data is critically needed to target basic research, identify long-term cardiovascular consequences, and plan therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063985-02
Application #
6529247
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Cuerdon, Timothy
Project Start
2001-09-20
Project End
2006-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
2
Fiscal Year
2002
Total Cost
$638,378
Indirect Cost
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Amiel, Jonathan M; Mangurian, Christina V; Ganguli, Rohan et al. (2008) Addressing cardiometabolic risk during treatment with antipsychotic medications. Curr Opin Psychiatry 21:613-8
Morrato, Elaine H; Newcomer, John W; Allen, Richard R et al. (2008) Prevalence of baseline serum glucose and lipid testing in users of second-generation antipsychotic drugs: a retrospective, population-based study of Medicaid claims data. J Clin Psychiatry 69:316-22
Haupt, Dan W; Fahnestock, Peter A; Flavin, Karen A et al. (2007) Adiposity and insulin sensitivity derived from intravenous glucose tolerance tests in antipsychotic-treated patients. Neuropsychopharmacology 32:2561-9
Newcomer, John W; Hennekens, Charles H (2007) Severe mental illness and risk of cardiovascular disease. JAMA 298:1794-6
Newcomer, John W (2005) Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 19 Suppl 1:1-93
Haupt, Dan W; Luber, Angela; Maeda, Justin et al. (2005) Plasma leptin and adiposity during antipsychotic treatment of schizophrenia. Neuropsychopharmacology 30:184-91
Newcomer, John W; Nasrallah, Henry A; Loebel, Antony D (2004) The Atypical Antipsychotic Therapy and Metabolic Issues National Survey: practice patterns and knowledge of psychiatrists. J Clin Psychopharmacol 24:S1-6
Haupt, Dan W; Newcomer, John W (2002) Abnormalities in glucose regulation associated with mental illness and treatment. J Psychosom Res 53:925-33
Newcomer, John W; Haupt, Dan W; Fucetola, Robert et al. (2002) Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch Gen Psychiatry 59:337-45
Haupt, D W; Newcomer, J W (2001) Hyperglycemia and antipsychotic medications. J Clin Psychiatry 62 Suppl 27:15-26; discussion 40-1