Impact of smoking behavior on clozapine blood levels - a systematic review and meta-analysis

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.

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.

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%).

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.