Clozapine Drug-Drug Interactions

Q: A 23-year-old man was admitted to the inpatient psychiatry unit after a suicide attempt 3 weeks ago. This was his second suicide attempt this year. He has a 2-year history of schizophrenia and has been tried on 3 different antipsychotic agents with breakthrough symptoms. While on the ward, he is pleasant and cooperative with, though continues to hear voices which instruct him to kill himself. The patient is a creative writer and has been coping with these voices by immersing himself in his work. He spends all day on his laptop writing and will have 8-10 cups of coffee daily to fuel his writing streak.
You would like to start the patient on clozapine but need to mindful of which of the following?

Choose your answer first before scrolling down….

Answer: CYP1A2 interaction

  • Clozapine is extensively metabolized in the liver via the cytochrome P450 system.
  • Cytochrome P450 isoenzyme 1A2 (CYP1A2) is mainly responsible for the metabolism of clozapine.
  • Caffeine is another CYP1A2 substrate.
  • Daily caffeine doses of 400-1000 mg have been shown to inhibit the metabolism of clozapine to an extent of clinical significance, hereby causing symptoms of toxicity in non-smoking patients.
  • Thus, this patient needs to be advised to limit his caffeine intake.
  • Clozapine has low CYP2D6 interaction
  • Clozapine has been shown to reduce the incidence of suicide and does not affect cognitive function.


  • Hagg, S., Spigset, O., Mjorndal, T., Dahlqvist, R. (2000). Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. Br J Clin Pharmacol

⇒ Read course chapter for details of following 12 medications interactions with clozapine:

(1) Proton pump inhibitors, Antacids, and Histamine receptor antagonists.

(2) Antibiotics and Infections.

(3) Anti-tuberculosis medications.

(4) Oral contraceptive pills.

(5) Smoking (nicotine)

(6) Caffeine

(7) St John’s Wort

(8) Amiodarone and Lisinopril

(9) Modafinil

(10) Antidepressants

(11) Antipsychotics

(12) Anticonvulsants



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