ARIPIPRAZOLE

• Cytochrome P450 enzyme substrate: CYP3A4, CYP2D6
• Action to be taken: Avoid if possible. Potential adverse effects
• Rationale: Dosage adjustments are recommended in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers. In vitro studies have shown that cannabis is metabolized by CYP450 enzymes, mainly by CYP3A4 and CYP2C19. Furthermore, various in vitro studies have found cannabinoids to be weak inhibitors of CYP enzymes. However other studies have shown that CBD is a potent inhibitor of CYP3A4 and CYP2C19. Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.g., a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve a favorable clinical response.
  

OLANZAPINE

• Cytochrome P450 enzyme substrate: CYP3A4, CYP2D6
• Action to be taken: Caution. Potential adverse effects
• Rationale: In vitro studies have shown that cannabis is metabolized by CYP450 enzymes, mainly by CYP3A4 and CYP2C19. Furthermore, various in vitro studies have found synthetic cannabis to inhibit CYP1A2.  Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine.

QUATIEPINE

• Cytochrome P450 enzyme substrate: CYP3A4
• Action to be taken: Caution. Potential adverse effects
• Rationale:In vitro studies have shown that cannabis is metabolized by CYP450 enzymes, mainly by CYP3A4 and CYP2C19. Furthermore, various in vitro studies have found cannabinoids to be weak inhibitors of CYP enzymes. However other studies have shown that CBD is a potent inhibitor of CYP3A4 and CYP2C19.SEROQUEL dose should be reduced to one sixth of originaldose when co-medicated with a potent CYP3A4 inhibitor.

RISPERIDONE

• Cytochrome P450 enzyme substrate: CYP2D6
• Action to be taken: Caution. Potential adverse effects
• Rationale:Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs. In vitro studies have shown that cannabis is metabolized by CYP450 enzymes, mainly by CYP3A4 and CYP2C19. Furthermore, various in vitro studies have found cannabinoids to be weak inhibitors of CYP enzymes including CYP2D6. Drug interactions that reduce the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone

ZIPRASIDONE

• Cytochrome P450 enzyme substrate: CYP3A4, CYP1A2
• Action to be taken: Caution. Potential adverse effects
• Rationale: In vitro studies using human liver microsomes and recombinant enzymes indicate that CYP3A4 is the major CYP contributing to the oxidative metabolism of ziprasidone. CYP1A2 may contribute to a much lesser extent. An
  in vitro enzyme inhibition study utilizing human liver microsomes showed that ziprasidone had little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and thus would not likely interfere with the metabolism of drugs primarily metabolized by these enzymes.  In vitro studies have shown that cannabis is metabolized by CYP450 enzymes, mainly by CYP3A4 and CYP2C19. Furthermore, various in vitro studies have found cannabinoids to be weak inhibitors of CYP enzymes. However other studies have shown that CBD is a potent inhibitor of CYP3A4 and CYP2C19. Ketoconazole, a potent inhibitor of CYP3A4, at a dose of 400 mg QD for 5 days, increased the AUC and Cmax of ziprasidone by about 35-40%. Other inhibitors of CYP3A4 would be expected to have similar effects.

References

1. Ashino, T. Hakukawa K, et al. Inhibitory effect of synthetic cannabinoids on CYP1A activity in mouse liver microsomes. The journal of toxicological sciences. Volume 39, Issue 6, Pages 815 -820, 2014
2. Watanabe K, Yamaori S, Funahashi T, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007;80:1415-1419.
   
3. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46:86-95.​​
4. Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: Role of phenolic hydroxyl groups in the resorcinol moiety. Life Sciences. 2011;88:730-736.
5. Abilify (aripiprazole) package insert. Bristol-Myers Squibb Company, Princeton, NJ 2014
6. Xyprexa (olanzapine) package insert.Eli Lilly and Company, Indianapolis, IN 2009
7. Seroquel (quatiepine)package insert. AstraZeneca Pharmaceuticals LP Wilmington, DE, 2013
8. Risperidal (risperidone) package insert. Ortho-McNeil-Janssen Pharmaceuticals, Inc. Titusville, NJ 2009
9. Geodon (ziprasidone) package insert. Pfizer Inc. NY, NY 2008