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...
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 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...
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 x .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.
Psychopharmacology: Atypical Antipsychotic Dosing: The Effect of Smoking and Caffeine
