Psychiatric Times May 2005 Vol. XXII Issue 6
The prevalence of smoking in severe mental disorders is higher than the normal population. In worldwide schizophrenia studies, the rate is approximately six times higher than in the general population (de Leon and Diaz, in press). Many patients with severe mental disorders are heavy smokers (Dalack et al., 1998; de Leon et al., 2002). Patients with severe mental disorders also tend to have high intake of caffeine (Hughes et al., 1998). This may, in part, be explained by the high coprevalence of heavy smoking, which increases caffeine metabolism (Gurpegui et al., 2004). Smoking and caffeine intake can affect the metabolism of some psychotropic medications with implications for clinical dosage adjustment.
Nicotine is mainly metabolized to cotinine by cytochrome P450 (CYP) 2A6 (CYP2A6) (Nakajima et al., 2002). Byproducts of tobacco smoke such as polycyclic aromatic hydrocarbons are inducers of cytochrome P450 isoenzyme 1A2 (CYP1A2) and of the less-understood UDP-glucuronosyl-transferases (UGTs) (de Leon, 2003; Zevin and Benowitz, 1999). This enzyme induction occurs with marijuana smoking as well. The effects of these inducers depend on the turnover of the hepatic enzymes and production of new enzymes. Thus, it takes several weeks for their maximum effect to occur and, similarly, for their enzyme-inducing effect to resolve after cessation of smoking.
Caffeine is highly dependent (>90%) on CYP1A2 for its metabolism (de Leon et al., 2003). It competitively inhibits CYP1A2 and increases the levels of medications metabolized by this enzyme. Thus the effects of caffeine are opposite that of smoking. Due to the metabolic inductive effects of smoking, smokers require three to four times the caffeine doses compared to non-smokers to get similar plasma caffeine levels and hence caffeine intake is usually higher in smokers (de Leon et al., 2003).
Second-generation antipsychotics that are not metabolized by CYP1A2 should not be affected by either smoking or caffeine. Thus, smoking or caffeine intake should not influence dosing of aripiprazole (Abilify) and risperidone (Risperdal) (the metabolism of both depends on CYP2D6 and CYP3A4) (Prior and Baker, 2003; Swainston Harrison and Perry, 2004), quetiapine (Seroquel) (mainly metabolized by CYP3A4), and ziprasidone (Geodon) (mainly metabolized by an aldehyde oxidase and CYP3A4) (Prior and Baker, 2003). On the other hand, the metabolism of clozapine (Clozaril) and olanzapine (Zyprexa) is mainly dependent on CYP1A2 and UGTs, and hence their levels are affected by smoking and caffeine. The Table lists the effects of smoking and caffeine on second-generation antipsychotics.