02. Impact of Smoking Behavior on Clozapine Blood Levels—A Systematic Review and Meta-Analysis

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What could be the impact of intermittent cigarette smoking on the blood levels of clozapine or olanzapine? Does it matter?

Hi! Jim Phelps here for the Psychopharmacology Institute. Let’s start with the “Does it matter?” question. How big a reduction in clozapine levels would you expect in a cigarette smoker? It’s big. According to a new meta-analysis of 23 studies with more than 7000 patients, the reduction in clozapine levels associated with cigarette smoking is about 30%. Previous reviews have reported much higher blood level reductions associated with smoking, as much as 2.5-fold. If you’ve been operating on that assumption, then this new meta-analytic review should be interpreted in such a way that the impact of cigarette smoking on clozapine levels is not as big as you previously thought.

Does a 30% impact on blood levels matter? Well, if you’re old school like me and not using the cytochrome P450 genotyping yet, maybe you just handle possible variations in the activity of cytochrome 1A2, which is the major metabolic pathway for clozapine, by titration. Slow metabolizers will respond sooner while rapid metabolizers and cigarette smokers will require higher doses. No big deal? If you know your patient smokes cigarettes, then in theory, you could go a little faster with the titration by factoring in the 30% reduction in levels. But be careful. That 30% figure is an average shift, and the range was large—from about 20% to 50% reductions in clozapine levels with cigarette smoking. Perhaps the most important implication is to be aware that if the patient stops smoking, blood levels are going to go up substantially, perhaps by 20% to 50%.

Note, though, that it’s not the nicotine; it’s the polycyclic aromatic hydrocarbons in cigarette smoke that are responsible for the effects on 1A2 activity. So, electronic cigarettes don’t induce it to the same degree, and nicotine replacement not at all. Therefore, during a somewhat extended hospital stay, patients could experience drug toxicity if their outpatient dosage is maintained because the new 1A2 steady state activity will be reached in about a week. Conversely, a carefully tuned blood level achieved in an inpatient stay might prove inadequate after discharge and resumption of cigarette smoking.

How about olanzapine? While the careful meta-analytic study of blood levels that we have in this current article for clozapine is not available for olanzapine, it’s clear that the same considerations apply. There is even a case of drug-induced parkinsonism associated with smoking cessation in a 77-year-old patient on 20 mg of olanzapine, where the apparent movement disorder resolved when olanzapine was switched carefully to aripiprazole. In another study, duloxetine levels were 38% lower in smokers than in nonsmokers. Notice that that closely parallels the 30% effect on clozapine levels that we see in this new meta-analysis.

So, when using medications metabolized by CYP1A2, pay attention to cigarette smoking, and be prepared to proactively adjust dosing if your patient is going to change their behavior.

For more on this, you could review an online table of the cytochrome inhibitors and substrates focusing on CYP1A2.

Abstract

Impact of Smoking Behavior on Clozapine Blood Levels – A Systematic Review and Meta-Analysis

E Wagner, L McMahon, P Falkai, A Hasan, D Siskind

Objective: Tobacco smoking significantly impacts clozapine blood levels and has substantial implications on individual efficacy and safety outcomes. By investigating differences in clozapine blood levels in smoking and non-smoking patients on clozapine, we aim to provide guidance for clinicians how to adjust clozapine levels for patients on clozapine who change their smoking habits.

Methods: We conducted a meta-analysis on clozapine blood levels, norclozapine levels, norclozapine/clozapine ratios, and concentration to dose (C/D) ratios in smokers and non-smokers on clozapine. Data were meta-analyzed using a random-effects model with sensitivity analyses on dose, ethnic origin, and study quality.

Results: Data from 23 studies were included in this meta-analysis with 21 investigating differences between clozapine blood levels of smokers and non-smokers. In total, data from 7125 samples were included for the primary outcome (clozapine blood levels in ng/ml) in this meta-analysis. A meta-analysis of all between-subject studies (N = 16) found that clozapine blood levels were significantly lower in smokers compared with non-smokers (Standard Mean Difference (SMD) -0.39, 95% confidence interval (CI) -0.55 to -0.22, P < 0.001, I2 = 80%). With regard to the secondary outcome, C/D ratios (N = 16 studies) were significantly lower in the smoker group (n = 645) compared with the non-smoker group (n = 813; SMD -0.70, 95%CI -0.84 to -0.56, P < 0.00001, I2 = 17%).

Conclusion: Smoking behavior and any change in smoking behavior is associated with a substantial effect on clozapine blood levels. Reductions of clozapine dose of 30% are recommended when a patient on clozapine stops smoking. Reductions should be informed by clozapine steady-state trough levels and a close clinical risk-benefit evaluation.

Reference

Wagner, E., McMahon, L., Falkai, P., Hasan, A., & Siskind, D. (2020). Impact of smoking behavior on clozapine blood levels – A systematic review and meta-analysis. Acta Psychiatrica Scandinavica, 142(6), 456–466.