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• W2172000844 abstract "Back to table of contents Previous article Next article ColumnsFull AccessPsychopharmacology: Atypical Antipsychotic Dosing: The Effect of Smoking and CaffeineJose de Leon, M.D.Jose de LeonSearch for more papers by this author, M.D.Published Online:1 May 2004https://doi.org/10.1176/appi.ps.55.5.491AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail A previous Psychopharmacology column focused on the effect of co-prescribing anticonvulsant inducers with atypical antipsychotics and argued that the dosing recommendations for atypical antipsychotics that are provided on package inserts do not apply well to patients with unusual genetic profiles or to patients who are exposed to environmental factors that change the concentration-dose ratio (C/D) (1).Severe mental illnesses are associated with tobacco smoking and, among smokers, with heavy smoking. Is smoking relevant to atypical antipsychotic dosing? Certainly. Byproducts of tobacco smoking, particularly the polycyclic aromatic hydrocarbons, are metabolic inducers. These byproducts are inducers of the cytochrome P450 isoenzyme 1A2 (CYP1A2) and of the less understood UDP-glucuronosyltransferases (UGTs). The metabolic inductive effects are not specific to tobacco smoking; they can also be expected from marijuana smoking. Because inducers require the synthesis of new enzymes, several weeks are usually needed before the maximum effects of inducers are seen. Inducers' effects may take a few weeks to disappear as well. The case reports of clozapine's toxicity after smoking cessation suggest that the inductive effects of smoking take at least two to four weeks to disappear (Table 1).The studies listed in Table 1 suggest that smoking's inductive effects may be relevant for clinicians who prescribe atypical antipsychotics. Additional pharmacologic support of the relevance of smoking's inductive effects comes from caffeine intake studies. Caffeine, a drug that is more than 90 percent dependent on CYP1A2 for its metabolism and that is widely used in the United States, can exemplify smoking's effects on drug metabolism. The C/D of caffeine appears to be threefold to fourfold as high among nonsmokers compared with smokers. This higher ratio means that smokers need three to four times the caffeine dosage as nonsmokers on average to get the same plasma caffeine levels. In a caffeine intake study of 147 outpatients with schizophrenia who drank caffeine, the average caffeine intake was 1.3 mg per kg a day for nonsmokers, 2.7 mg per kg a day for nonheavy smokers (less than 1.5 packs a day), and 3.4 mg per kg a day for heavy smokers (1.5 packs a day or more) (2).A limited amount of literature has been published that suggests that atypical antipsychotics that are not dependent on CYP1A2 or UGT for their metabolism should not be influenced by smoking or caffeine intake. Thus smoking or caffeine intake should not influence the dosing of risperidone and aripiprazole (metabolized by CYP2D6 and CYP3A), quetiapine (mainly metabolized by CYP3A), and ziprasidone (mainly metabolized by an aldehyde oxidase and CYP3A). On the other hand, the metabolism of clozapine and olanzapine is mainly dependent on CYP1A2 and UGTs. Table 1 summarizes studies that describe smoking's effects on the dosing of clozapine and olanzapine. Because caffeine has the opposite effect of smoking and increases the levels of clozapine and olanzapine, studies of caffeine interactions are also reviewed in the table. The effects of caffeine on CYP1A2 are explained by competitive inhibition. The effects of inhibitors are seen sooner than those of inducers, which require CYP1A2 synthesis. The chronology of maximum inhibition and its disappearance depends on the half-life of the inhibitor—that is, caffeine.The width of the therapeutic window determines the clinical significance of the plasma level changes associated with smoking and caffeine intake. Compared with olanzapine, clozapine has a much narrower therapeutic window. Several of clozapine's side effects are dose related: plasma levels higher than 1,000 ng per milliliter have been associated with toxicity, including seizure risk and severe sedation.Table 1 provides an average smoking correction factor of 1.5 for clozapine. If a patient who is taking clozapine smokes, smoking cessation would probably cause an average patient's plasma clozapine level to increase by 1.5 two to four weeks later. Similarly, if a patient who is stabilized in a nonsmoking environment starts to smoke more than one pack a day, the clinician may need to consider increasing the clozapine dose by a factor of 1.5 over two to four weeks. Checking for side effects and measuring the clozapine level may then be prudent, because the 1.5 factor is a gross approximation.Gender may also influence clozapine metabolism. The limited information available (3,4) suggests that an average female nonsmoker requires low clozapine dosages (around 300 mg per day) to reach therapeutic levels, whereas an average male heavy smoker requires high dosages (around 600 mg per day). The required dosages for male nonsmokers and female smokers fall in between these numbers. Obviously, these are average results and may not apply to specific individuals. In the future, it is hoped that a better understanding of genetics may help to individualize clozapine doses. A CYP1A2 genetic variation may influence how patients respond to smoking's inductive effects. However, in a recent study this variation did not have any effects on clozapine levels in the clinical environment (5).Table 1 shows that the average caffeine correction factor is .6 for clozapine. Assuming other variables are stable, including no changes in smoking patterns, if a patient whose clozapine dose is stabilized in a caffeine-free environment begins to regularly consume high quantities of caffeine, it may be safest to decrease the clozapine dose—for example, from 400 to 250 mg a day (400 mg a day × .6=240 mg a day). Only high quantities of caffeine seem to have significant clinical interactions with clozapine.In the United States, brewed coffee is estimated to contain 85 mg of caffeine per 5 oz cup; instant coffee, 65 mg per 5 oz cup; decaffeinated coffee, 3 mg per 5 oz cup; tea, 40 mg per 5 oz cup; and caffeinated sodas, including caffeinated colas, 40 mg per 12 oz can. In Europe, brewed coffee is estimated to contain more caffeine (100 mg per 150 cc cup). Obviously, caffeinated over-the-counter medicines in pill form may have much more caffeine than caffeinated beverages (up to 200 mg per pill). No data are available that show what level of caffeine intake is safe for patients who are taking clozapine. Steady caffeine dosages for a patient who is stabilized and is taking clozapine should not be of concern for clinicians. However, it may be important to warn the patient to avoid dramatic changes—either up or down —in caffeine intake. However, no published data define dramatic change in caffeine intake.Using a table from a mathematical model that was developed in a sample of volunteers without mental illness, one can grossly estimate that one cup of coffee or two cans of caffeinated soda per day provide caffeine plasma concentrations as high as 2 mg per liter among nonsmokers, whereas three cups of coffee per day or six cans of caffeinated soda per day provide concentrations lower than 2 mg per liter among smokers (6). On the basis of that volunteer study and earlier clozapine studies, caution is recommended when nonsmoking patients who take clozapine increase or decrease their daily caffeine intake by more than one cup of coffee or two cans of caffeinated soda or when smoking patients who take clozapine increase or decrease their daily caffeine intake by more than three cups of coffee or six cans of caffeinated soda. For example, when a smoker who takes clozapine increases caffeine intake by three cups of coffee—for example, from two to five cups per day—clinicians should watch for increased side effects that are caused by an increased clozapine level. When a nonsmoker who takes clozapine decreases caffeine intake by two cans of soda—for example, from four to two cans per day—clinicians should watch for a possible loss of clozapine response that results from decreased clozapine levels.In reviewing Table 1, the reader should remember that limited information exists about olanzapine. The pharmacologic information suggests that smoking's inductive effects and caffeine's inhibiting effects may be similar for olanzapine and clozapine. However, it may not be as relevant clinically to determine the effects of smoking and caffeine intake on olanzapine, because olanzapine's therapeutic window is much wider and high olanzapine levels lack the toxicity of high clozapine levels. The clinical environment is a dirty world, and it may be difficult to prove pharmacologic facts that have been established in a laboratory.Hospital restrictions on smoking and caffeine intake may have clinical importance. Smoking is banned inside hospitals in the United States. Thus, when stabilizing patients who are taking clozapine, clinicians need to carefully question them and consider the different effects of smoking for patients in the hospital, where no or limited smoking is allowed, and for patients in the community, where smoking is not restricted. The hospital may also restrict caffeinated beverages. No easy recipes or correction factors exist for patients who are stabilized in a nonsmoking and caffeine-free hospital environment when they go to other environments. The correction factors shown in the table can be used for orientation, but clinicians need to remember the pharmacologic principles of induction and inhibition as well as their timing. New studies should establish the effects of gender and smoking status on clozapine and olanzapine dosing. Real-world pharmacokinetic studies on the effects of changing smoking patterns and caffeine intake after hospital discharge need to be conducted. Until these studies are available, clinicians should be aware that important variations in smoking and caffeine intake may cause changes in the plasma levels of clozapine and olanzapine.Dr. de Leon is affiliated with the University of Kentucky Mental Health Research Center at Eastern State Hospital, 627 West Fourth Street, Lexington, Kentucky 40508 (e-mail, [email protected]). George M. Simpson, M.D., is editor of this column.Table 1. Recommended correction factors for smoking or using caffeine with clozapine and olanzapine and supporting dataaa A list with complete reference information is available from the author.Table 1. Recommended correction factors for smoking or using caffeine with clozapine and olanzapine and supporting dataaa A list with complete reference information is available from the author.Enlarge tableReferences1. De Leon J: Atypical antipsychotic dosing: the effect of co-medication with anticonvulsants. Psychiatric Services 55:125–128, 2004Link, Google Scholar2. Gurpegui M, Aguilar MC, Martinez-Ortega JM, et al: Caffeine intake in outpatients with schizophrenia. Schizophrenia Bulletin, in pressGoogle Scholar3. Perry PJ, Bever KA, Arndt S, et al: Relationship between patient variables and plasma clozapine concentrations: a dosing nomogram. Biological Psychiatry 44:733–738, 1998Crossref, Medline, Google Scholar4. Rostami-Hodjegan A, Amin AM, Spencer EP, et al: Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. Journal of Clinical Psychopharmacology 24:70–78, 2004Crossref, Medline, Google Scholar5. Van der Weide J, Steijns LS, van Weelden MJ: The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement. Pharmacogenetics 13:169–172, 2003Crossref, Medline, Google Scholar6. De Leon J, Diaz FJ, Rogers T, et al: A pilot study of plasma caffeine concentrations in a US sample of smoker and nonsmoker volunteers. Progress in Neuro-Psychopharmacology and Biological Psychiatry 27:165–171, 2003Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byEffects of smoking cessation on plasma clozapine concentrations in male patients with schizophrenia during the COVID-19 pandemic15 September 2023 | Frontiers in Psychiatry, Vol. 14Guía internacional para una dosificación más segura de la clozapina en adultos mediante el uso de 6 titulaciones personalizadas de dosis basados en la etnicidad, la proteína C reactiva y los niveles de clozapinaPsiquiatría Biológica, Vol. 55Impact of a Caffeine Restriction Policy on Inpatients With SchizophreniaJournal of Clinical Psychopharmacology, Vol. 43, No. 2Neurobiological Perspective and Personalized Treatment in Schizophrenia11 January 2023Comorbidities and the right dose: antipsychotics22 August 2022 | Expert Opinion on Drug Metabolism & Toxicology, Vol. 18, No. 7-8Clozapine’s multiple cellular mechanisms: What do we know after more than fifty years? A systematic review and critical assessment of translational mechanisms relevant for innovative strategies in treatment-resistant schizophreniaPharmacology & Therapeutics, Vol. 236An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels15 December 2021 | Pharmacopsychiatry, Vol. 55, No. 02Pharmacokinetic drug interactions with oral haloperidol in adults: dose correction factors from a combined weighted analysis19 April 2022 | Expert Opinion on Drug Metabolism & Toxicology, Vol. 18, No. 2Clozapine's Multiple Cellular Mechanisms: What Do We Know after More than Fifty Years? a Systematic Review and Critical Assessment of Translational Mechanisms Relevant for Innovative Strategies in Treatment-Resistant SchizophreniaSSRN Electronic Journal, Vol. 4Anticholinergic Burden and Cognitive Performance in Patients With Schizophrenia: A Systematic Literature Review28 December 2021 | Frontiers in Psychiatry, Vol. 12Psychotropics and COVID-19: An analysis of safety and prophylaxisL'Encéphale, Vol. 47, No. 6Caffeine-clozapine interaction associated with severe toxicity and multiorgan system failure: a case report13 April 2021 | BMC Psychiatry, Vol. 21, No. 1The impact of caffeine consumption on clinical symptoms in patients with bipolar disorder: A systematic review28 September 2020 | Bipolar Disorders, Vol. 23, No. 3An update on the complex relationship between clozapine and pneumonia24 January 2021 | Expert Review of Clinical Pharmacology, Vol. 89Pseudo-Resistant Schizophrenia: Non-Adherence to TreatmentKorean Journal of Schizophrenia Research, Vol. 23, No. 2Caffeine Restrictions in Inpatient Psychiatric Settings: Precipitating Withdrawal?11 October 2019 | Journal of Addiction Medicine, Vol. 14, No. 4Informations relatives aux psychotropes et à leurs adaptations éventuelles pour les patients souffrant de troubles psychiques en France pendant l’épidémie à SARS-CoV-2L'Encéphale, Vol. 46, No. 3Using therapeutic drug monitoring to personalize clozapine dosing in Asians2 March 2020 | Asia-Pacific Psychiatry, Vol. 12, No. 2Pharmacotherapy for smoking cessation in schizophrenia: a systematic review3 February 2020 | Expert Opinion on Pharmacotherapy, Vol. 21, No. 5Simultaneous determination of six antipsychotics, two of their metabolites and caffeine in human plasma by LC-MS/MS using a phospholipid-removal microelution-solid phase extraction method for sample preparationTalanta, Vol. 198BJPsych Bulletin, Vol. 43, No. 6Switching From Tobacco Smoking to Electronic Cigarettes and the Impact on Clozapine LevelsJournal of Clinical Psychopharmacology, Vol. 38, No. 5Elevated clozapine levels associated with infection: A systematic reviewSchizophrenia Research, Vol. 192Drug and Alcohol Dependence, Vol. 185Frontiers in Psychiatry, Vol. 9Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia26 October 2017 | Acta Psychiatrica Scandinavica, Vol. 137, No. 1A Pilot Study of the Usefulness of a Single Olanzapine Plasma Concentration as an Indicator of Early Drug Effect in a Small Sample of First-Episode Psychosis PatientsJournal of Clinical Psychopharmacology, Vol. 37, No. 5The Role of Antipsychotic Plasma Levels in the Treatment of SchizophreniaMarcela Horvitz-Lennon, M.D., M.P.H., Soeren Mattke, M.D., D.Sc., Zachary Predmore, B.A., Oliver D. 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