, Volume 170, Issue 2, pp 157–166

Relationship between levels of insulin or triglycerides and serum concentrations of the atypical antipsychotics clozapine and olanzapine in patients on treatment with therapeutic doses

Original Investigation



Recent results suggest that treatment with the atypical antipsychotics clozapine and olanzapine is associated with increased insulin and lipid levels.


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.


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.


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.


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.


Antipsychotic agents Clozapine Olanzapine Adverse effects Insulin Lipids 


  1. Allain CC, Poon LS, Chan CS, Richmond W, Fu PC (1974) Enzymatic determination of total serum cholesterol. Clin Chem 20:470–475Google Scholar
  2. Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al (1999) Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156:1686–1696PubMedGoogle Scholar
  3. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Press, WashingtonGoogle Scholar
  4. Bang P, Eriksson U, Sara V, Wivall I-L, Hall K (1991) Comparison of acid ethanol extraction and acid gel filtration prior to IGF-I and IGF-II radioimmunoassays: improvement of determinations in acid ethanol extracts by the use of truncated IGF-I as radioligand. Acta Endocrinol 124:620–629PubMedGoogle Scholar
  5. Baxter RC (1991) Insulin-like growth factor (IGF) binding proteins: the role of serum IGFBPs in regulating IGF availability. Acta Paediatr Scand 372:107–114Google Scholar
  6. Brismar K, Grill V, Efendic S, Hall K (1991) The insulin-like growth factor binding protein-1 in low and high insulin responders before and during dexamethasone treatment. Metabolism 40:728–732PubMedGoogle Scholar
  7. Brismar K, Hilding A, Lindgren B (1995) Regulation of IGFBP-1 in humans. Prog Growth Factor Res 6:449–456PubMedGoogle Scholar
  8. Budavari S, O'Neil MJ, Smith A, Heckelman PE, Kinneary JF (eds) (1996) The Merck Index. An encyclopedia of chemicals, drugs, and biologicals, 12th edn. Merck, Rahway, New Jersey, pp 411, 1170Google Scholar
  9. Catlow JT, Barton RD, Clemens M, Gillespie TA, Goodwin M, Swanson SP (1995) Analysis of olanzapine in human plasma utilizing reversed-phase high-performance liquid chromatography with electrochemical detection. J Chromatogr 668:85–90PubMedGoogle Scholar
  10. Conley RR, Tamminga CA, Bartko JJ, Richardson C, Peszke M, Lingle J, et al (1998) Olanzapine compared with chlorpromazine in treatment-resistant schizophrenia. Am J Psychiatry 155:914–920PubMedGoogle Scholar
  11. Cusin I, Sainsbury A, Doyle P, Rohner-Jeanrenaud F, Jeanrenaud B (1995) The ob gene and insulin. A relationship leading to clues to the understanding of obesity. Diabetes 44:1467–1470PubMedGoogle Scholar
  12. Fitton A, Heel RC (1990) Clozapine. A review of its pharmacological properties, and therapeutic use in schizophrenia. Drugs 40:722–747PubMedGoogle Scholar
  13. Fulton B, Goa KL (1997) Olanzapine. A review of its pharmacological properties and therapeutic efficacy in the management of schizophrenia and related psychoses. Drugs 53:281–298PubMedGoogle Scholar
  14. Gauch R, Michaelis W (1971)The metabolism of 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine (clozapine) in mice, dogs and human subjects. Farm Ed Prat 26:667–681Google Scholar
  15. Gaulin BD, Markowitz JS, Caley CF, Nesbitt LA, Dufresne RL (1999) Clozapine-associated elevation in serum triglycerides. Am J Psychiatry 156:1270–1272PubMedGoogle Scholar
  16. Ghaeli P, Dufresne RL (1996) Serum triglyceride levels in patients treated with clozapine. Am J Health Syst Pharm 53:2079–2081PubMedGoogle Scholar
  17. Girard J (1997) Is leptin the link between obesity and insulin resistance ? Diabetes Metab 23:16–24Google Scholar
  18. Hartman ML (1996) Physiological regulators of growth hormone secretion. In: Juul A, Jørgensen JOL (eds) Growth hormone in adults: Physiological and clinical aspects, 1st edn. Cambridge University Press, New York, pp 5–219Google Scholar
  19. Henderson DC, Cagliero E, Gray C, Nasrallah RA, Hayden DL, Schoenfeld DA, et al (2000) Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study. Am J Psychiatry 157:975–981PubMedGoogle Scholar
  20. Hickey MS, Israel RG, Gardiner SN, Considine RV, McCammon MR, Tyndall GL, et al (1996) Gender differences in serum leptin levels in humans. Biochem Mol Med 59:1–6CrossRefPubMedGoogle Scholar
  21. Hilding A, Hall K, Wivall-Helleryd I-L, Sääf M, Melin A-L, Thoren M (1999) Serum levels of insulin-like growth factor I in 152 patients with growth hormone deficiency, aged 19–82 years, in relation to those in healthy subjects. J Clin Endocrinol Metab 84:2013–2019PubMedGoogle Scholar
  22. Hägg S, Spigset O, Söderström TG (2000) Association of venous thromboembolism and clozapine. Lancet 355:1155–1156CrossRefPubMedGoogle Scholar
  23. Kassahun K, Mattiuz E, Nyhart E, Obermeyer B, Gillespie T, Murphy A, et al (1997) Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drug Metab Dispos 25:81–93PubMedGoogle Scholar
  24. Kilian JG, Kerr K, Lawrence C, Celermajer DS (1999) Myocarditis and cardiomyopathy associated with clozapine. Lancet 354:1841–1845PubMedGoogle Scholar
  25. Kissebah AH (1992) Insulin actions in vivo: insulin and lipoprotein metabolism. In: Alberti KG, DeFronzo H, Keen H, Zimmet P (eds) International textbook of diabetes mellitus. Wiley, Chichester, pp 439–457Google Scholar
  26. Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, et al (1996) Acute and chronic effect of insulin on leptin production in humans. Studies in vivo and in vitro. Diabetes 45:699–701PubMedGoogle Scholar
  27. Koro CE, Fedder DO, L´Italien GJ, Weiss SS, Magder LS, Kreyenbuhl J, et al (2002) Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case-control study. BMJ 325:243–245CrossRefPubMedGoogle Scholar
  28. Ma Z, Gingerich RL, Santiago JV, Klein S, Smith CH, Landt M (1996) Radioimmunoassay of leptin in human plasma. Clin Chem 42:942–946PubMedGoogle Scholar
  29. Madsbad S, Hartling SG, Faber OK (1997) C-peptide and proinsulin. In: Alberti KG, Zimmet P, DeFronzo RA, Keen H (eds) International textbook of diabetes mellitus, 2nd edn. Wiley, Chichester, pp 355–381Google Scholar
  30. Melkersson KI, Hulting A-L (2001) Insulin and leptin levels in patients with schizophrenia or related psychoses—a comparison between different antipsychotic agents. Psychopharmacology 154:205–212CrossRefPubMedGoogle Scholar
  31. Melkersson KI, Hulting AL, Brismar KE (1999) Different influences of classical antipsychotics and clozapine on glucose–insulin homeostasis in patients with schizophrenia or related psychoses. J Clin Psychiatry 60:783–791PubMedGoogle Scholar
  32. Melkersson KI, Hulting AL, Brismar KE (2000) Elevated levels of insulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses. J Clin Psychiatry 61:742–749PubMedGoogle Scholar
  33. Melkersson K, Khan A, Hilding A, Hulting A-L (2001) Different effects of antipsychotic drugs on insulin release in vitro. Eur Neuropsychopharmacol 11:327–332CrossRefPubMedGoogle Scholar
  34. Olefsky JM (1997) Insulin resistance. In: Porte D, Sherwin RS (eds) Diabetes mellitus, 5th edn. Appleton and Lange, Stamford, pp 513–552Google Scholar
  35. Osser DN, Najarian DM, Dufresne RL (1999) Olanzapine increases weight and serum triglyceride levels. J Clin Psychiatry 60:767–770PubMedGoogle Scholar
  36. Povoa G, Roovete A, Hall K (1984) Cross-reaction of serum somatomedin-binding protein in a radioimmunoassay developed for somatomedin-binding protein isolated from human amniotic fluid. Acta Endocrinol 107:563–570PubMedGoogle Scholar
  37. Powell DR, Lee PD, Suwanichkul A (1994) Similarities in the regulation of hIGFBP-1 and PEPCK gene expression. In: Baxter RC, Gluckman PD, Rosenfeld RG (eds) The insulin-like growth factors and their regulatory proteins. Elsevier, Amsterdam, pp 141–150Google Scholar
  38. Sernyak MJ, Leslie DL, Alarcon RD, Losonczy MF, Rosenheck R (2002) Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 159:561–566CrossRefPubMedGoogle Scholar
  39. Seufert J, Kieffer TJ, Leech CA, Holz GG, Moritz W, Ricordi C, et al (1999) Leptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus. J Clin Endocrinol Metab 84:670–676PubMedGoogle Scholar
  40. Skogh E, Reis M, Dahl M-L, Lundmark J, Bengtsson F (2002) Therapeutic drug monitoring data on olanzapine and its N-dimethyl metabolite in the naturalistic clinical setting. Ther Drug Monit 24:518–526CrossRefPubMedGoogle Scholar
  41. Spayd RW, Bruschi B, Burdick BA, Dappen GM, Eikenberry JN, Esders TW, et al (1978) Multilayer film elements for clinical analysis: applications to representative chemical determinations. Clin Chem 24:1343–1350PubMedGoogle Scholar
  42. Tanizawa Y, Okuya S, Ishihara H, Asano T, Yada T, Oka Y (1997) Direct stimulation of basal insulin secretion by physiological concentrations of leptin in pancreatic beta cells. Endocrinology 138:4513–4516PubMedGoogle Scholar
  43. Tollefson GD, Beasley CM, Tran PV, Street JS, Krueger JA, Tamura RN, et al (1997) Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 154:457–465PubMedGoogle Scholar
  44. Walker AM, Lanza LL, Arellano F, Rothman KJ (1997) Mortality in current and former users of clozapine. Epidemiology 8:671–677PubMedGoogle Scholar
  45. Woods SC, Kaiyala K, Porte D, Schwartz MW (1997) Food intake and energy balance. In: Porte D, Sherwin RS (eds) Diabetes mellitus, 5th edn. Appleton and Lange, Stamford, pp 175–192Google Scholar
  46. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  1. 1.Department of Molecular Medicine, Sollentuna Psychiatric PolyclinicKarolinska InstituteStockholmSweden
  2. 2.Department of Medical SciencesClinical Pharmacology, University HospitalUppsalaSweden

Personalised recommendations