title: Relationship between levels of insulin or triglycerides and serum concentrations of the atypical antipsychotics clozapine and olanzapine in patients on treatment with therapeutic doses.
abstract: BACKGROUND
  Recent results suggest that treatment with the atypical antipsychotics clozapine and olanzapine is associated with increased insulin and lipid levels.
  
  
  OBJECTIVE
  The aim of the present study was to investigate potential relationships between insulin or other hormones related to glucose-insulin homeostasis or lipids and steady-state serum concentrations of clozapine or olanzapine in patients on therapeutic doses.
  
  
  METHODS
  Thirty-four patients, diagnosed with schizophrenia or related psychoses according to the DSM-IV criteria and treated with clozapine ( n=18) or olanzapine ( n=16), were studied. Median treatment time with the antipsychotics was 5.3 years (range 0.5-16.3 years). Fasting blood samples for insulin, C-peptide, insulin-like growth factor I, insulin-like growth factor binding protein-1, leptin, glucose and lipids were analyzed and investigated in relation to the patients' drug serum concentrations.
  
  
  RESULTS
  Hyperinsulinemia was found in 30-60% of the patients, hyperglycemia in 10-30%, hyperlipidemia in 40-60% and hyperleptinemia in 10-20%. Moreover, levels of insulin, C-peptide and triglycerides correlated positively to the clozapine serum concentration and to the ratio of olanzapine to N-desmethylolanzapine concentrations. In contrast, levels of C-peptide, leptin and blood glucose were inversely correlated to the serum concentration of the metabolite N-desmethylolanzapine.
  
  
  CONCLUSIONS
  Metabolic abnormalities (i.e. hyperinsulinemia, hyperlipidemia and hyperleptinemia) and insulin resistance were associated with both clozapine and olanzapine treatments. Levels of insulin and triglycerides increased by increasing clozapine serum concentration and by increasing ratio of olanzapine to N-desmethylolanzapine; the last due to the metabolite N-desmethylolanzapine probably having an inverse effect to the main compound olanzapine. Thus, the metabolic abnormalities induced by these two drugs are clozapine-concentration dependent in clozapine-treated patients, and ratio of olanzapine to N-desmethylolanzapine-concentration dependent in olanzapine-treated patients.
authors.affiliation: Department of Molecular Medicine, Sollentuna Psychiatric Polyclinic, Karolinska Institute, Stockholm, Sweden. Kristina.Melkersson@cns.ki.se
authors.forename: K I
authors.initials: KI
authors.lastname: Melkersson
authors.forename: M-L
authors.initials: ML
authors.lastname: Dahl
mesh_terms: D000328:Adult; D001569:Benzodiazepines / Q000097:blood* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002096:C-Peptide / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000097:blood* / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004305:Dose-Response Relationship, Drug; D005260:Female; D006728:Hormones / Q000097:blood; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D011863:Radioimmunoassay; D012559:Schizophrenia / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D012907:Smoking; D013223:Statistics as Topic; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D006728:Hormones; D007328:Insulin; D008055:Lipids; D014280:Triglycerides; D001569:Benzodiazepines; D003024:Clozapine; D000077152:Olanzapine