Evidence-Based Reviews

Beware cytochrome P450 inducers: Prescribing tips to prevent drug-drug interactions

Current Psychiatry. 2002 November;1(11):11-16

References

1. Rosenbaum JF. Drug treatment of resistant depression: reviewing options. Boston: Harvard Psychopharmacology Review, October 21, 1990.

2. Steffens DC, Krishnan RR, Doraiswamy PM. Psychotropic drug interactions. New York: MBL Communications, 1997.

3. Gidal BE, Garnett WR, Graves N. Epilepsy. In: DiPiro JT, Talbert RL, Yee GE, et al (eds). Pharmacotherapy: A pathophysiologic approach. New York: McGraw-Hill, 2002;1031-59.

4. Preskorn SH, Burke MJ, Fast GA. Therapeutic drug monitoring: principles and practice. Psychiatric Clin North Am 1993;16(3):611-41.

5. Arana GW, Goff DC, Friedman H, et al. Does carbamazepine-induced reduction of plasma haloperidol levels worsen psychotic symptoms? Am J Psychiatry 1986;143:650-1.

6. Jann MW, Fidone GS, Hernandez JM, et al. Clinical implications of increased antipsychotic plasma concentrations upon anticonvulsant cessation. Psychiatry Res 1989;28:153-9.

7. Wilder BJ. Pharmacokinetics of valproate and carbamazepine. J Clin Psychopharmacol 1992;12(1):64S-67S.

8. Raitasuo V, Lehtovarra R, Huttunen MO. Carbamazepine and plasma levels of clozapine. Am J Psychiatry 1993;150(1):169.-

9. Nelson JC. Combined treatment strategies in psychiatry. J Clin Psychiatry 1993;54 (suppl 9):42-9.

10. Leinonen E, Lillsunde P, Laukkanen V, et al. Effects of carbamazepine on serum antidepressant concentration in psychiatric patients. J Clin Psychopharmacology 1991;11:313-18.

11. Ketter TA, Jenkins JB, Schroeder DH, et al. Carbamazepine but not valproate induces buproprion metabolism. J Clin Psychopharmacology 1995;15:327-33.

12. De la Fuente JM, Mendlewicz J. Carbamazepine addition in tricyclic antidepressant-resistant unipolar depression. Biol Psychiatry 1992;32:369-74.

13. Brown CS, Wells BG, Cold JA. Possible influence of carbamazepine on plasma imipramine concentration in children with attention deficit hyperactivity disorder. J Clin Psychopharmacol 1990;10:359-62.

14. Arana GW, Epstein S, Molloy M, et al. Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. J Clin Psychiatry 1988;49:448-9.

15. Callahan AM, Fava M, Rosenbaum JF. Drug interactions in psychopharmacology. Psychiatric Clin North Am 1993;16:647-71.

16. Physician’s Desk Reference. Montvale, NJ: Medical Economics, 2002.

17. Savasi I, Millson RC, Owen JA. Quetiapine blood level variability. Can J Psychiatry 2002;47:94.-

18. Ghaemi S, Ko J. Oxcarbazepine treatment of bipolar disorder: a review of the literature. Primary Psychiatry 2002;9:55-9.

19. Brown RA, Goldstein MG, Niaura R, et al. Nicotine dependence: assessment and management. In: Stoudemire A, Fogel BS (eds). Psychiatric care of the medical patient. New York: Oxford University Press, 1993;877-901.

20. Bauer LA. Clinical pharmacokinetics and pharmacodynamics. In: DiPiro JT, Talbert RL, Yee GC, et al (eds). Pharmacotherapy: A pathophysiologic approach. New York: McGraw Hill, 2002;33-54.

21. Franklin JE, Frances RJ. Substance-related disorders. In: Rundell JR, Wise MG (eds). Textbook of consultation-liaison psychiatry. Washington, DC: American Psychiatric Press, 1996;427-65.

22. Flockhart D. Indiana University Department of Medicine. Cytochrome P450 drug interaction table. http://www.drug-interactions.com.

23. Crisman ML, Dorson PG. Schizophrenia. In: DiPiro JT, Talbert RL, Yee GE, et al (eds). Pharmacotherapy: A pathophysiologic approach. New York: McGraw-Hill, 2002;1219-42.

The literature offers little data on timelines for the onset and reversal of hepatic enzyme induction. Induction probably begins and becomes complete within days or weeks after drug therapy is initiated and steady-state levels are achieved. Similarly, the reversal likely occurs within days or weeks after clearance of the inducer.

How plasma levels correlate with clinical findings is the key, of course, and one must account for other possible influences, such as the presence of other hepatic enzyme inducers and inhibitors, dosage adjustments, cigarette smoking, chronic alcohol abuse, and other factors.

Box

MANAGING HEPATIC ENZYME INDUCTION: FIVE PRINCIPLES

Prescription or nonprescription agents (e.g., cigarette smoking, St. John’s wort) may induce hepatic enzymes.
Inducing agents can lower plasma levels of co-administered medications that are also metabolized by the liver.
Most psychotropics are metabolized by the liver, and their therapeutic effect requires a minimum plasma concentration.
Hepatic enzyme induction can result in subtherapeutic plasma levels and inadequate drug trials of prescribed psychotropics.
Assume that any inducing agent may lower plasma levels and alter the efficacy of co-administered drugs that are also metabolized by the liver. Observe carefully, monitor plasma levels, and use incremental dosing to assess and compensate for induction effects.

Five principles

When prescribing psychotropics, careful attention to five principles for managing the effects of hepatic enzyme induction (Box ) can result in:

fewer patients with refractory symptoms
less polypharmacy
fewer sequelae of undertreated serious psychiatric illness
improved therapy of comorbid medical conditions whose therapeutic agents may be metabolized by the liver and are therefore vulnerable to the effects of hepatic enzyme induction.

Related resources

Flockhart D. Indiana University Department of Medicine. Cytochrome P450 drug interaction table. http://www.Drug-Interactions.com
DePiro JT, Talbert RL, Yee, GC, et al (eds). Pharmacotherapy: A pathophysiologic approach. New York: McGraw-Hill, 2002.
Bernstein JG. Handbook of drug therapy in psychiatry. New York: Mosby-Year Book, 1995.

Drug brand names

Alprazolam • Xanax
Amitriptyline • Elavil
Buproprion • Wellbutrin
Carbamazepine • Tegretol
Clomipramine • Anafranil
Citalopram • Celexa
Clozapine • Clozaril
Diazepam • Valium
Doxepin • Sinequan
Dexamethasone • Decadron
Fluphenazine • Prolixin
Fluoxetine • Prozac
Fluvoxamine • Luvox
Haloperidol • Haldol
Imipramine • Tofranil
Isoniazid • Rifamate
Modafinil • Provigil
Nortriptyline • Pamelor
Omeprazole • Prilosec
Oxcarbazepine • Trileptal
Paroxetine • Paxil
Perphenazine • Trilafon
Phenytoin • Dilantin
Pimozide • Orap
Primidone • Mysoline
Quetiapine • Seroquel
Rifampin • Rifadin
Risperidone • Risperdal
Trazodone • Desyrel
Valproate • Depakote
Warfarin • Coumadin
Zaleplon • Sonata

Disclosure

Dr. Baird reports that he has served as a consultant to Eli Lilly and Co.