Effect of Intravenous Lipid Emulsion on Clozapine Acute Toxicity in Rats

  • Yousefsani, Bahareh Sadat (Research Institute for Islamic and Complementary Medicine, Iran University of Medical Sciences) ;
  • Mohajeri, Seyed Ahmad (Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences) ;
  • Moshiri, Mohammad (Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences) ;
  • Jafarian, Amir Hossein (Cancer Molecular Pathology Research Center, Ghaem Hospital, Faculty of Medicine, Mashhad University of Medical Sciences) ;
  • Hosseinzadeh, Hossein (Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences)
  • Received : 2019.02.02
  • Accepted : 2019.05.31
  • Published : 2019.09.30


Objectives: Many studies have been reported the efficacy of intravenous lipid emulsion (ILE) as an antidote on acute lipophilic drug toxicity. Clozapine, highly lipophilic dibenzodiazepine neuroleptics, is an important medication in the schizophrenia therapy regimen. Acute intoxication with antipsychotics is one of the main reasons for the referral of poisoned patients to the hospital. We expected that ILE could be used for the therapy of acute clozapine intoxicated patients. Methods: We used two groups of consisting of six male rats. Both groups received a toxic dose of clozapine (40 mg/kg) intravenously, via the tail vein. After 15 minutes, they were treated with intravenous infusion of 18.6 mg/kg normal saline (NS group), or 18.6 mg/kg ILE 20% (ILE group). We evaluated blood pressure (BP) and heart rate by power lab apparatus through the tail artery, ataxia by a rat rotary circle, seizure scores and death in multiple times after starting clozapine administration. For biochemical and pathological evaluations the samples of tissue and blood were taken. Results: Our results demonstrated that ILE 20% could return hypotension-induced clozapine better than normal saline. Furthermore, ataxia and seizure have rectified more rapidly and deaths reduced. Clozapine administration causes pancreatitis and lung injury but fat emulsion did not show an optimal effect on tissue damages caused by clozapine toxicity. Conclusion: In conclusion, ILE can remove toxic signs of clozapine same as other lipophilic medicines, however, clinical uses of ILE for this intention requires more appraisement to determine the precise implication and safety.


  1. Aksel G, Guneysel O, Tasyurek T, Kozan E, Cevik SE. Intravenous Lipid Emulsion Therapy for Acute Synthetic Cannabinoid Intoxication: Clinical Experience in Four Cases. Case reports in emergency medicine. 2015;2015180921.
  2. Barton CA, Johnson NB, Mah ND, Beauchamp G, Hendrickson R. Successful treatment of a massive metoprolol overdose using intravenous lipid emulsion and hyperinsulinemia/euglycemia therapy. Pharmacotherapy. 2015;35(5):e56-60.
  3. Herring JM, McMichael MA, Corsi R, Wurlod V. Intravenous lipid emulsion therapy in three cases of canine naproxen overdose. J Vet Emerg Crit Care (San Antonio). 2015.
  4. Brull SJ. Lipid emulsion for the treatment of local anesthetic toxicity: patient safety implications. Anesthesia and analgesia. 2008;106(5):1337-9.
  5. Burch MS, McAllister RK, Meyer TA. Treatment of local-anesthetic toxicity with lipid emulsion therapy. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2011;68(2): 125-9.
  6. Cave G, Harvey M. Intravenous lipid emulsion as antidote beyond local anesthetic toxicity: a systematic review. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2009;16(9):815-24.
  7. Moshiri M, Vahabzadeh M, Mohammadpour AH, Hosseinzadeh H. Evaluation of intravenous lipid emulsion on haloperidol-induced hypotension in rabbits. Toxicology and industrial health. 2014.
  8. Fettiplace MR, Pichurko A, Ripper R, Lin B, Kowal K, Lis K, Schwartz D, Feinstein DL, Rubinstein I, Weinberg G. Cardiac depression induced by cocaine or cocaethylene is alleviated by lipid emulsion more effectively than by sulfobutylether-beta-cyclodextrin. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2015;22(5):508-17.
  9. Khlifi M, Zun L, Johnson G, Harbison R. Etiological characterization of acute poisonings in the emergency department. J Emerg Trauma Shock. 2009;2(3):159-63.
  10. Doak MW, Nixon AC, Lupton DJ, Waring WS. Self-poisoning in older adults: patterns of drug ingestion and clinical outcomes. Age Ageing. 2009;38(4):407-11.
  11. Dassa D, Kaladjian A, Azorin JM, Giudicelli S. Clozapine in the treatment of psychotic refractory depression. Br J Psychiatry. 1993;163822-4.
  12. Sajatovic M, Ramirez LF, Kenny JT, Meltzer HY. The use of clozapine in borderline-intellectual- functioning and mentally retarded schizophrenic patients. Compr Psychiatry. 1994;35(1):29-33.
  13. Cadeddu G, Deidda A, Stochino ME, Velluti N, Burrai C, Del Zompo M. Clozapine toxicity due to a multiple drug interaction: a case report. Journal of medical case reports. 2015;977.
  14. Matthews CJ, Hall TL. A clozapine conundrum: clozapine toxicity in an acute medical illness. Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists. 2014;22(6):543-5.
  15. Szymanski S, Lieberman JA, Picou D, Masiar S, Cooper T. A case report of cimetidine-induced clozapine toxicity. The Journal of clinical psychiatry. 1991;52(1):21-2.
  16. Tueth MJ. Emergencies caused by side effects of psychiatric medications. Am J Emerg Med. 1994;12(2):212-6.
  17. Hawkins DJ, Unwin P. Paradoxical and severe hypotension in response to adrenaline infusions in massive quetiapine overdose. Crit Care Resusc. 2008;10(4):320-2.
  18. Bhatia MS, Gupta R, Dhawan J. Myocarditis after overdose of conventional antipsychotics. World J Biol Psychiatry. 2009;10(4 Pt 2):606-8.
  19. Aboueid L, Toteja N. Clozapine-Induced Myocarditis: A Case Report of an Adolescent Boy with Intellectual Disability. Case reports in psychiatry. 2015;2015482375.
  20. Lee SH, Yang YY. Reversible neurotoxicity induced by a combination of clozapine and lithium: a case report. Zhonghua Yi Xue Za Zhi (Taipei). 1999;62(3):184-7.
  21. Huang CH, Fu SH, Hsu S, Huang YY, Chen ST, Hsu BR. High-fat diet aggravates islet beta-cell toxicity in mice treated with clozapine. Chang Gung Med J. 2012;35(4):318-22.
  22. Flanagan RJ. Side effects of clozapine and some other psychoactive drugs. Curr Drug Saf. 2008;3(2):115-22.
  23. Scorza MC, Castane A, Bortolozzi A, Artigas F. Clozapine does not require 5-HT1A receptors to block the locomotor hyperactivity induced by MK-801 Clz and MK-801 in KO1A mice. Neuropharmacology. 2010;59(1-2):112-20.
  24. Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Region Anesth Pain M. 2003;28(3):198-202.
  25. Bunag RD. Validation in awake rats of a tail-cuff method for measuring systolic pressure. J Appl Physiol. 1973;34(2):279-82.
  26. Joksimovic S, Varagic Z, Kovacevic J, Van Linn M, Milic M, Rallapalli S, et al. Insights into functional pharmacology of alpha(1) GABA(A) receptors: how much does partial activation at the benzodiazepine site matter? Psychopharmacology (Berl). 2013;230(1):113-23.
  27. Vafaee F, Hosseini M, Hassanzadeh Z, Edalatmanesh MA, Sadeghnia HR, Seghatoleslam M, et al. The Effects of Nigella Sativa Hydro-alcoholic Extract on Memory and Brain Tissues Oxidative Damage after Repeated Seizures in Rats. Iran J Pharm Res. 2015;14(2):547-57.
  28. Moshiri M, Mohammadpour AH, Vahabzadeh M, Etemad L, Memar B, Hosseinzadeh H. Evaluating the effects and safety of intravenous lipid emulsion on haloperidol-induced neurotoxicity in rabbit. BioMed research international. 2014;2014949262.
  29. Vahabzadeh M, Moshiri M, Mohammadpour AH, Hosseinzadeh H. Promising effects of intravenous lipid emulsion as an antidote in acute tramadol poisoning. Region Anesth Pain M. 2013;38(5):425-30.
  30. Sampson CS, Bedy SM. Lipid emulsion therapy given intraosseously in massive verapamil overdose. Am J Emerg Med. 2015.
  31. Eren Cevik S, Tasyurek T, Guneysel O. Intralipid emulsion treatment as an antidote in lipophilic drug intoxications. Am J Emerg Med. 2014;32(9):1103-8.
  32. Coward DM. General pharmacology of clozapine. Br J Psychiatry Suppl. 1992;(17):5-11.
  33. Rothschild L, Bern S, Oswald S, Weinberg G. Intravenous lipid emulsion in clinical toxicology. Scand J Trauma Resusc Emerg Med. 2010;1851.
  34. Clark MK. Lipid emulsion as rescue for local anesthetic-related cardiotoxicity. J Perianesth Nurs. 2008;23(2):111-7; quiz 8-21.
  35. Litz RJ, Roessel T, Heller AR, Stehr SN. Reversal of central nervous system and cardiac toxicity after local anesthetic intoxication by lipid emulsion injection. Anesthesia and analgesia. 2008;106(5):1575-7, table of contents.
  36. Squires RF, Saederup E. A review of evidence for GABergic predominance/glutamatergic deficit as a common etiological factor in both schizophrenia and affective psychoses: more support for a continuum hypothesis of "functional" psychosis. Neurochem Res. 1991;16(10):1099-111.
  37. Miller JW, Gray BC, Turner GM, Bardgett ME. An ascending seizure-controlling pathway in the medial brainstem and thalamus. Exp Neurol. 1993;121(1):106-12.
  38. Baskys A, Wang S, Remington G, Wojtowicz JM. Haloperidol and loxapine but not clozapine increase synaptic responses in the hippocampus. European Journal of Pharmacology. 1993;235(2-3):305-7.
  39. Lidsky TI, Yablonsky-Alter E, Zuck L, Banerjee SP. Anti-glutamatergic effects of clozapine. Neurosci Lett. 1993;163(2):155-8.
  40. Park WK, Jeong D, Cho H, Lee SJ, Cha MY, Pae AN, et al. KKHA-761, a potent D3 receptor antagonist with high 5-HT1A receptor affinity, exhibits antipsychotic properties in animal models of schizophrenia. Pharmacol Biochem Behav. 2005;82(2):361-72.
  41. Raja M, Azzoni A. A Case of Clozapine-Associated Pancreatitis. The Open Neuropsychopharmacology Journal. 2011;45-7.
  42. Gardiner TH, Lewis JM, Shore PA. Distribution of clozapine in the rat: localization in lung. The Journal of pharmacology and experimental therapeutics. 1978;206(1):151-7.
  43. Aksnes J, Eide TJ, Nordstrand K. Lipid entrapment and cellular changes in the rat myocard, lung and liver after long-term parenteral nutrition with lipid emulsion. A light microscopic and ultrastructural study. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 1996;104(7-8):515-22.
  44. Jagadheesan K, Agarwal S, Nizamie HS. Clozapine-induced Thrombocytopenia: a Pilot Study. Hong Kong J Psychiat. 2003;13(2):12-5.
  45. Aydin M, Ilhan BC, Calisir S, Yildirim S, Eren I. Continuing clozapine treatment with lithium in schizophrenic patients with neutropenia or leukopenia: brief review of literature with case reports. Therapeutic advances in psychopharmacology. 2016;6(1):33-8.
  46. Grover S, Hegde A, Agarwal M, Sachdeva MS. Olanzapine-associated leukopenia and thrombocytopenia managed with lithium in a patient who developed leukopenia with clozapine in the past: a case report. The primary care companion for CNS disorders. 2012;14(6).
  47. Bogers JP, Cohen D, Schulte PF, van Dijk D, Bakker B. Clozapine-induced leukopenia: arguments for rechallenge. Irish journal of medical science. 2012;181(1):155-6.
  48. Latif Z, Malik MA, Jabbar F, Ahmed Y, McDonough C. Clozapine-induced late leukopenia. Irish journal of medical science. 2012;181(1):139-41.
  49. Charbonneau K, Landry P. Leukopenia and neutropenia after intoxication with diphenhydramine (Nytol) during clozapine treatment. Journal of clinical psychopharmacology. 2008;28(6): 706-7.