An often overlooked facet in clinical pharmacotherapy is the significance of smoking as a potential source of drug interactions, especially when using antipsychotic medications. A recent study by Sagud et al. highlighted the prevalence of smoking on a daily basis in schizophrenic patients is more than 60%, compared to the general population prevalence of approximately 16% in males and 14% in females in Australia, according to the latest statistics from the Cancer Council.

Smoking cigarettes releases a multitude of chemicals and some of these chemicals have been shown to induce important metabolic liver enzymes, especially cytochrome P450 1A2 (CYP1A2). Inducing this enzyme leads to increased metabolism of drugs usually processed by this enzyme, resulting in greater clearance rates of these drugs from the body. Some drugs that are processed by CYP1A2 include: fluvoxamine, haloperidol, imipramine, amitriptyline, and duloxetine. Most significantly, CYP1A2 is a major enzyme in the metabolism of olanzapine and clozapine, two important atypical antipsychotic drugs that are widely used, sometimes as an agent of last resort, in schizophrenic patients.

The combination of a higher prevalence of smoking in schizophrenic patients, together with the resultant increase in CYP1A2 enzyme activity that reduces the concentrations of drugs, like olanzapine and clozapine, used to treat the condition can lead to widespread suboptimal therapy and increased risk of uncontrolled symptoms. Studies by Ghotbi et al and Laika et al suggest that the plasma concentration of olanzapine may be decreased by between 21-28% in smoking patients compared with non-smokers. Other studies show that significant decreases in olanzapine levels from smoking lead to increased symptoms of suspiciousness, hallucinations, and blunted-affect. Prior et al described decreased levels of clozapine in smokers compared to non-smokers, and that smoking cessation led to seizures that were attributed to the resultant toxicity from increased clozapine plasma concentration.

Even though clozapine is routinely monitored, this often relates to picking up early signs of blood dyscrasias. Serum clozapine levels in relation to its efficacy in treating symptoms of schizophrenia do not always correlate to the same scale in different people. That is, some people with average serum levels have well controlled symptoms, where other people would have significant side effects, and others have no perceived clinical benefit. Smoking may affect clinical therapy and may be an oft overlooked aspect when something unexpected occurs, such as toxicity, seizures, increased symptoms, or decreased control.

For any setting that uses these medications, it is important to be vigilant about a patient’s smoking status, as any acute changes such as abrupt smoking cessation or initiation of antipsychotic medication in smokers may lead to either unintended toxicity or suboptimal therapy.

For more information on therapeutic drug monitoring and dosing, contact your HPS Pharmacies pharmacist.


  1. Sagud M, Mihaljevic-Peles A, Muck-Seler D, Pivac N, Vuksan-Cusa B & Brataljenovic T. Smoking and Schizophrenia. Psychiatria Danubina. 2009; 21(3): 371-375.
  2. Cancer Council NSW. Statistics on Smoking in Australia. Woolloomooloo: Cancer Council NSW; 2012.
  3. Zhou SF, Yang LP, Zhou ZW, Liu YH & Chan E. Insights into the Substrate Specificity, Inhibitors, Regulation, and Polymorphisms and the Clinical Impact of Human Cytochrome P450 1A2. AAPS J. 2009; 11(3): 481-494.
  4. Rossi S, ed. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd; 2011.
  5. Ghotbi R, Mannheimer B, Aklillu E, Suda A, Bertilsson L & Eliasson E. Carriers of the UGT1A4 142T>G gene variant are predisposed to reduced olanzapine exposure–an impact similar to male gender or smoking in schizophrenic patients. Eur J Clin Pharmacol. 2010; 66(5): 465-74.
  6. Laika B, Leucht S, Hersa S, Schneider H & Steimer W. Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome. Pharmacogenomics J. 2010; 10(1): 20-9.
  7. Nozawa M, Ohnuma T, Matsubara Y, Sakai Y, Hatano T & Hanzawa R. The relationship between the response of clinical symptoms and plasma olanzapine concentration, based on pharmacogenetics: Juntendo University Schizophrenia Projects (JUSP). Ther Drug Monit. 2008; 30(1): 35-40.
  8. Prior TI & Baker GB. Interactions between the cytochrome P450 system and the second-generation antipsychotics. J Psychiatry Neurosci. 2003; 28(2): 99-112.

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