Personalized Antipsychotic Therapy Based on Smoking Status: A Review of Olanzapine and Clozapine

##plugins.themes.academic_pro.article.sidebar##

Published Feb 15, 2026
https://doi.org/10.62438/tunismed.v103i6.5394
Download
PDF
Vol. 103 No. 12 (2025): Tunis Med Dec 2025

##plugins.themes.academic_pro.article.main##

Mohamed Ferhi
Psychiatry Department, Ibn El Jazzar University Hospital, Kairouan, Tunisia
https://orcid.org/0000-0002-3621-3230
Moujib Omri
Psychiatry and Psychotherapy Department, KlinkumMutterhaus der Borromäerinnen, Trier, Germany
Malek Ben Mamia
Psychiatry Department, Farhat Hached University Hospital, Sousse, Tunisia
Jihenne Mannai
Psychiatry Department, Ibn El Jazzar University Hospital, Kairouan, Tunisia

Abstract

Smoking influences the pharmacokinetics of antipsychoticmedications, particularly olanzapine and clozapine, through the induction of cytochrome P450 1A2 (CYP1A2). This narrative review explores its impact on the metabolism, efficacy, and safety of olanzapine and clozapine. Current evidence demonstrates that smokers require higher doses of theseantipsychotics to achieve the rapeutic serum concentrations due to accelerateddrug clearance, while non-smokers and thosewhocease smoking are at risk of adverse effects from elevated drug levels. Genetic variations in CYP1A2 activityfurthercomplicate dose recommendations, emphasizing the importance of individualizedtreatmentstrategies. The reviewunderlines the importance of careful monitoring and dose adjustments in smokers, non-smokers, and patients undergoing smoking cessation to prevent adverse effects and ensuretherapeuticefficacy. It also highlights the need for individualizedapproaches, consideringboth smoking habits and metabolic variations.

Keywords:

Olanzapine, Clozapine, Schizophrenia, Bipolardisorder, Psychosis, Smoking, Genetics, Pharmacology

##plugins.themes.academic_pro.article.details##

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

References

  1. Dickerson F, Schroeder J, Katsafanas E, Khushalani S, Origoni AE, Savage C, et al. Cigarette Smoking by Patients With Serious Mental Illness, 1999-2016: An Increasing Disparity. Psychiatr Serv. 2018 Feb 1;69(2):147–53.
  2. Robinson M, Reid G. Population cigarette consumption in Great Britain: novel insights usingretail sales data. BMC Public Health. 2017 Dec 20;17(1):941.
  3. Mucha L, Stephenson J, Morandi N, Dirani R. Meta-analysis of diseaseriskassociatedwith smoking, by gender and intensity of smoking. Gend Med. 2006 Dec;3(4):279–91.
  4. Batail JM, Langrée B, Robert G, Bleher S, Verdier MC, Bellissant E, et al. Use of very-high-dose olanzapine in treatment-resistantschizophrenia. SchizophrRes. 2014 Nov;159(2–3):411–4.
  5. Hálfdánarson Ó, Zoëga H, Aagaard L, Bernardo M, Brandt L, Fusté AC, et al. International trends in antipsychotic use: A study in 16 countries, 2005-2014. EurNeuropsychopharmacol. 2017 Oct;27(10):1064–76.
  6. Skogh E, Reis M, Dahl M-L, Lundmark J, Bengtsson F. Therapeuticdrug monitoring data on olanzapine and its N-demethylmetabolite in the naturalisticclinical setting. Ther Drug Monit. 2002 Aug;24(4):518–26.
  7. Bishara D, Olofinjana O, Sparshatt A, Kapur S, Taylor D, Patel MX. Olanzapine: asystematicreview and meta-regression of the relationshipsbetween dose, plasma concentration, receptoroccupancy, and response. J Clin Psychopharmacol. 2013 Jun;33(3):329–35.
  8. Mauri MC, Paletta S, Maffini M, Colasanti A, Dragogna F, Di Pace C, et al. Clinicalpharmacology of atypicalantipsychotics: an update. EXCLI J. 2014 Oct 13;13:1163–91.
  9. Si T-M, Zhang Y-S, Shu L, Li K-Q, Liu X-H, Mei Q-Y, et al. Use of clozapine for the treatment of schizophrenia: findings of the 2006 research on the china psychotropic prescription studies. Clin PsychopharmacolNeurosci. 2012 Aug 31;10(2):99–104.
  10. Bersani FS, Capra E, Minichino A, Pannese R, Girardi N, Marini I, et al. Factorsaffectinginterindividualdifferences in clozapine response: areview and case report. Hum Psychopharmacol. 2011 Apr;26(3):177–87.
  11. Morisano D, Wing VC, Sacco KA, Arenovich T, George TP. Effects of tobacco smoking on neuropsychologicalfunction in schizophrenia in comparison to otherpsychiatricdisorders and non-psychiatriccontrols. Am J Addict. 2013 Jan;22(1):46–53.
  12. Diaz FJ, Velásquez DM, Susce MT, de Leon J. The association betweenschizophreniaand smoking: unexplained by either the illnessor the prodromalperiod. SchizophrRes. 2008 Sep;104(1–3):214–9.
  13. Mann-Wrobel MC, Bennett ME, Weiner EE, Buchanan RW, Ball MP. Smoking history and motivation to quit in smokerswithschizophrenia in a smoking cessation program. SchizophrRes. 2011 Mar;126(1–3):277–83.
  14. de Leon J, Diaz FJ. A meta-analysis of worldwidestudiesdemonstrates an association betweenschizophrenia and tobacco smoking behaviors. SchizophrRes. 2005 Jul 15;76(2–3):135–57.
  15. Djordjevic N, Ghotbi R, Bertilsson L, Jankovic S, Aklillu E. Induction of CYP1A2 by heavy coffee consumption in Serbs and Swedes. Eur J Clin Pharmacol. 2008 Apr;64(4):381–5.
  16. Sachse C, Brockmöller J, Bauer S, Roots I. Functionalsignificance of a C-->A polymorphism in intron 1 of the cytochrome P450 CYP1A2 genetestedwithcaffeine. Br J Clin Pharmacol. 1999 Apr;47(4):445–9.
  17. Tsuda Y, Saruwatari J, Yasui-Furukori N. Meta-analysis: the effects of smoking on the disposition of twocommonlyusedantipsychotic agents, olanzapine and clozapine. BMJ Open. 2014 Mar 4;4(3):e004216.
  18. Haslemo T, Refsum H, Molden E. The effect of ethinylestradiol-containing contraceptives on the serum concentration of olanzapine and N-desmethyl olanzapine. Br J Clin Pharmacol. 2011 Apr;71(4):611–5.
  19. Laika B, Leucht S, Heres S, Schneider H, Steimer W. Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergicpolymorphisms influence therapeuticoutcome. Pharmacogenomics J. 2010 Feb 1;10(1):20–9.
  20. Citrome L, Stauffer VL, Chen L, Kinon BJ, Kurtz DL, Jacobson JG, et al. Olanzapine plasma concentrations aftertreatmentwith 10, 20, and 40 mg/d in patients withschizophrenia: an analysis of correlationswithefficacy, weight gain, and prolactin concentration. J Clin Psychopharmacol. 2009 Jun;29(3):278–83.
  21. Zang Y-N, Dong F, Li A-N, Wang C-Y, Guo G-X, Wang Q, et al. The impact of smoking, sex, infection, and comedication administration on oral olanzapine: A population pharmacokinetic model in chinesepsychiatric patients. Eur J Drug Metab Pharmacokinet. 2021 May;46(3):353–71.
  22. Spina E, D’Arrigo C, Santoro V, Muscatello MR, Pandolfo G, Zoccali R, et al. Effect of valproate on olanzapine plasma concentrations in patients withbipolar or schizoaffectivedisorder. Ther Drug Monit. 2009 Dec;31(6):758–63.
  23. Skogh E, Sjödin I, Josefsson M, Dahl M-L. High correlationbetweenserum and cerebrospinalfluid olanzapine concentrations in patients withschizophrenia or schizoaffectivedisordermedicatingwith oral olanzapine as the onlyantipsychoticdrug. J Clin Psychopharmacol. 2011 Feb;31(1):4–9.
  24. Haslemo T, Eikeseth PH, Tanum L, Molden E, Refsum H. The effect of variable cigarette consumption on the interaction with clozapine and olanzapine. Eur J Clin Pharmacol. 2006 Dec;62(12):1049–53.
  25. Bigos KL, Pollock BG, Coley KC, Miller DD, Marder SR, Aravagiri M, et al. Sex, race, and smoking impact olanzapine exposure. J Clin Pharmacol. 2008 Feb;48(2):157–65.
  26. Djordjevic N, Radmanovic B, Cukic J, Baskic D, Djukic-Dejanovic S, Milovanovic D, et al. Cigarette smoking and heavy coffee consumptionaffectingresponse to olanzapine: The role of geneticpolymorphism. World J Biol Psychiatry. 2020 Jan;21(1):29–52.
  27. Moschny N, Hefner G, Grohmann R, Eckermann G, Maier HB, Seifert J, et al. Therapeutic Drug Monitoring of Second- and Third-GenerationAntipsychoticDrugs-Influence of Smoking Behavior and Inflammation on Pharmacokinetics. Pharmaceuticals (Basel). 2021 May 27;14(6).
  28. Carrillo JA, Herráiz AG, Ramos SI, Gervasini G, Vizcaíno S, Benítez J. Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol. 2003 Apr;23(2):119–27.
  29. Nozawa M, Ohnuma T, Matsubara Y, Sakai Y, Hatano T, Hanzawa R, et al. The relationshipbetween the response of clinicalsymptoms and plasma olanzapine concentration, based on pharmacogenetics: JuntendoUniversitySchizophreniaProjects (JUSP). Ther Drug Monit. 2008 Feb;30(1):35–40.
  30. Li L, Shang D, Li W, Guo W, Wang X, Ren Y, et al. Population pharmacokinetics of clozapine and itsprimarymetabolitenorclozapine in Chinese patients withschizophrenia. Acta Pharmacol Sin. 2012 Nov;33(11):1409–16.
  31. Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ. Influence of dose, cigarette smoking, age, sex, and metabolicactivity on plasma clozapine concentrations: apredictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol. 2004 Feb;24(1):70–8.
  32. Palego L, Biondi L, Giannaccini G, Sarno N, Elmi S, Ciapparelli A, et al. Clozapine, norclozapine plasma levels, theirsum and ratio in 50 psychotic patients. Progress in Neuro-Psychopharmacology and BiologicalPsychiatry. 2002 Apr;26(3):473–80.
  33. Seppälä NH, Leinonen EV, Lehtonen ML, Kivistö KT. Clozapine serum concentrations are lower in smoking than in non-smoking schizophrenic patients. PharmacolToxicol. 1999 Nov;85(5):244–6.
  34. Dettling M, Sachse C, Brockmöller J, Schley J, Müller-Oerlinghausen B, Pickersgill I, et al. Long-termtherapeuticdrug monitoring of clozapine and metabolites in psychiatric in- and outpatients. Psychopharmacology (Berl). 2000 Sep;152(1):80–6.
  35. van der Weide J, Steijns LS, van Weelden MJ. The effect of smoking and cytochrome P450 CYP1A2 geneticpolymorphism on clozapine clearance and dose requirement. Pharmacogenetics. 2003 Mar;13(3):169–72.
  36. Meyer JM. Individual changes in clozapine levelsafter smoking cessation: results and a predictive model. J Clin Psychopharmacol. 2001 Dec;21(6):569–74.
  37. Roth MD, Marques-Magallanes JA, Yuan M, Sun W, Tashkin DP, Hankinson O. Induction and regulation of the carcinogen-metabolizing enzyme CYP1A1 by marijuana smoke and delta (9)-tetrahydrocannabinol. Am J Respir Cell Mol Biol. 2001 Mar;24(3):339–44.
  38. Yamamoto I, Watanabe K, Matsunaga T, Kimura T, Funahashi T, Yoshimura H. Pharmacology and toxicology of major constituents of marijuana—on the metabolic activation of cannabinoids and itsmechanism. Journal of Toxicology: ToxinReviews. 2003 Jan;22(4):577–89.
  39. Bornheim LM, Lasker JM, Raucy JL. Human hepatic microsomal metabolism of delta 1-tetrahydrocannabinol. Drug Metab Dispos. 1992;20(2):241–6.
  40. Zullino DF, Delessert D, Eap CB, Preisig M, Baumann P. Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Int Clin Psychopharmacol. 2002 May;17(3):141–3.
  41. Lowe EJ, Ackman ML. Impact of tobacco smoking cessation on stable clozapine or olanzapine treatment. Ann Pharmacother. 2010 Apr;44(4):727–32.
  42. Brownlowe K, Sola C. Clozapine toxicity in smoking cessation and withciprofloxacin. Psychosomatics. 2008 Apr;49(2):176.
  43. McCarthy RH. Seizuresfollowing smoking cessation in a clozapine responder. Pharmacopsychiatry. 1994 Sep;27(5):210–1.
  44. Skogh E, Bengtsson F, Nordin C. Coulddiscontinuing smoking behazardous for patients administered clozapine medication? A case report. Ther Drug Monit. 1999 Oct;21(5):580–2.
  45. Carrillo JA, Herraiz AG, Ramos SI, Benítez J. Effects of caffeinewithdrawalfrom the diet on the metabolism of clozapine in schizophrenic patients. J Clin Psychopharmacol. 1998 Aug;18(4):311–6.
  46. Odom-White A, de Leon J. Clozapine levels and caffeine. J Clin Psychiatry. 1996 Apr;57(4):175–6.
  47. Lawn S, Pols R. Smoking bans in psychiatricinpatient settings? A review of the research. Aust N Z J Psychiatry. 2005 Oct;39(10):866–85.
  48. Haller E, Binder RL. Clozapine--a new and differentneuroleptic. West J Med. 1990 Jul;153(1):62–4.
  49. Djordjevic N, Milovanovic DD, Radovanovic M, Radosavljevic I, Obradovic S, Jakovljevic M, et al. CYP1A2 genotype affects carbamazepinepharmacokinetics in childrenwithepilepsy. Eur J Clin Pharmacol. 2016 Apr;72(4):439–45.
  50. Zhou S-F, Wang B, Yang L-P, Liu J-P. Structure, function, regulation and polymorphism and the clinicalsignificance of human cytochrome P450 1A2. Drug Metab Rev. 2010 May;42(2):268–354.
  51. Ikeya K, Jaiswal AK, Owens RA, Jones JE, Nebert DW, Kimura S. Human CYP1A2: sequence, gene structure, comparisonwith the mouse and rat orthologousgene, and differences in liver 1A2 mRNA expression. Mol Endocrinol. 1989 Sep;3(9):1399–408.
  52. Huang H-C, Lua AC, Wu LS-H, Wu B-J, Lee S-M, Liu C-Z. Cigarette smoking has a differentialeffect on the plasma level of clozapine in Taiwaneseschizophrenic patients associatedwith the CYP1A2 gene -163A/C single nucleotidepolymorphism. Psychiatr Genet. 2016 Aug;26(4):172–7.
  53. Gunes A, Ozbey G, Vural EH, Uluoglu C, Scordo MG, Zengil H, et al. Influence of geneticpolymorphisms, smoking, gender and age on CYP1A2 activity in a Turkish population. Pharmacogenomics. 2009 May;10(5):769–78.
  54. Patel MX, Bowskill S, Couchman L, Lay V, Taylor D, Spencer EP, et al. Plasma olanzapine in relation to prescribed dose and otherfactors: data from a therapeuticdrug monitoring service, 1999-2009. J Clin Psychopharmacol. 2011 Aug;31(4):411–7.
  55. Söderberg MM, Haslemo T, Molden E, Dahl M-L. Influence of CYP1A1/CYP1A2 and AHR polymorphisms on systemic olanzapine exposure. PharmacogenetGenomics. 2013 May;23(5):279–85.
  56. de Leon J, Armstrong SC, Cozza KL. The dosing of atypicalantipsychotics. Psychosomatics. 2005;46(3):262–73.
  57. Cabaleiro T, López-Rodríguez R, Ochoa D, Román M, Novalbos J, Abad-Santos F. Polymorphismsinfluencing olanzapine metabolism and adverse effects in healthysubjects. Hum Psychopharmacol. 2013 May;28(3):205–14.
  58. Ascher-Svanum H, Stensland M, Zhao Z, Kinon BJ. Acute weight gain, gender, and therapeuticresponse to antipsychotics in the treatment of patients withschizophrenia. BMC Psychiatry. 2005 Jan 13;5:3.
  59. Aklillu E, Carrillo JA, Makonnen E, Hellman K, Pitarque M, Bertilsson L, et al. Geneticpolymorphism of CYP1A2 in Ethiopiansaffecting induction and expression: characterization of novel haplotypes with single-nucleotidepolymorphisms in intron 1. Mol Pharmacol. 2003 Sep;64(3):659–69.
  60. Ghotbi R, Christensen M, Roh H-K, Ingelman-Sundberg M, Aklillu E, Bertilsson L. Comparisons of CYP1A2 geneticpolymorphisms, enzyme activity and the genotype-phenotyperelationship in Swedes and Koreans. Eur J Clin Pharmacol. 2007 Jun;63(6):537–46.
  61. DailyMed - ZYPREXA- olanzapine tablet
  62. ZYPREXA ZYDIS- olanzapine tablet, orally disintegrating
  63. ZYPREXA INTRAMUSCULAR- olanzapine injection, powder, for solution [Internet]. [cited 2024 Jul 25]. Available from: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d5051fbc-846b-4946-82df-341fb1216341
  64. Dobrinas M, Cornuz J, Oneda B, Kohler Serra M, Puhl M, Eap CB. Impact of smoking, smoking cessation, and geneticpolymorphisms on CYP1A2 activity and inducibility. Clin Pharmacol Ther. 2011 Jul;90(1):117–25.
  65. Simon T, Becquemont L, Hamon B, Nouyrigat E, Chodjania Y, Poirier JM, et al. Variability of cytochrome P450 1A2 activity over time in young and elderlyhealthyvolunteers. Br J Clin Pharmacol. 2001 Nov;52(5):601–4.
  66. Castberg I, Westin AA, Skogvoll E, Spigset O. Effects of age and gender on the serumlevels of clozapine, olanzapine, risperidone, and quetiapine. Acta Psychiatr Scand. 2017 Nov;136(5):455–64.
  67. Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, et al. Consensus guidelines for therapeuticdrug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry. 2018 Jan;51(1–02):9–62.
  68. Diaz FJ, de Leon J, Josiassen RC, Cooper TB, Simpson GM. Plasma clozapine concentration coefficients of variation in a long-termstudy. SchizophrRes. 2005 Jan 1;72(2–3):131–5.
  69. Gex-Fabry M, Balant-Gorgia AE, Balant LP. Therapeuticdrug monitoring of olanzapine: the combinedeffect of age, gender, smoking, and comedication. Ther Drug Monit. 2003 Feb;25(1):46–53.
  70. Botts S, Diaz FJ, Santoro V, Spina E, Muscatello MR, Cogollo M, et al. Estimating the effects of co-medications on plasma olanzapine concentrations by using a mixed model. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Aug 1;32(6):1453–8.
  71. Theisen FM, Haberhausen M, Schulz E, Fleischhaker C, Clement H-W, Heinzel-Gutenbrunner M, et al. Serum levels of olanzapine and its N-desmethyl and 2-hydroxymethyl metabolites in child and adolescent psychiatricdisorders: effects of dose, diagnosis, age, sex, smoking, and comedication. Ther Drug Monit. 2006 Dec;28(6):750–9.
  72. Diaz FJ, Santoro V, Spina E, Cogollo M, Rivera TE, Botts S, et al. Estimating the size of the effects of co-medications on plasma clozapine concentrations using a model thatcontrols for clozapine doses and confounding variables. Pharmacopsychiatry. 2008 May;41(3):81–91.
  73. Bergemann N, Frick A, Parzer P, Kopitz J. Olanzapine plasma concentration, averagedaily dose, and interaction withco-medication in schizophrenic patients. Pharmacopsychiatry. 2004 Mar;37(2):63–8.