Letters to the Editor
Methylphenidate and the Cytochrome P450 System
Dear Editor:
I reviewed with interest the case report in your journal describing unexpected grand mal seizures in a 14-year-old boy treated for attention-deficit hyperactivity disorder (ADHD) with methylphenidate (MPH) 60 mg daily, to which buproprion was added (1). The author notes, “it is also possible that the risk of seizures was amplified by the combination of buproprion and methylphenidate” (1, p 790).
This case report is of concern, insofar as a combination of buproprion and MPH, if known to be safe, would be a sensible augmented regimen for treatment-resistant or treatment-refractory cases of ADHD (2) and perhaps even depressive disorders (3).
However, the literature suggests a mechanism for possible deleterious interaction between these 2 agents; namely, it is possible that MPH inhibits a hepatic isoenzyme that contributes to the metabolic clearance of buproprion from the body. Several authors have alluded to methylphenidate’s capacity to inhibit the degradation of cyclic antidepressants (4–6). MPH has been cited as an inhibitor of CYP2D6 (7). It may also inhibit other hepatic enzymes, including perhaps CYP2B6, the isoenzyme predominantly responsible for the metabolism of buproprion (8), or other enzymes not currently known to help clear buproprion.
The net result of such a possible inter-action could be higher buproprion plasma levels and greater risk of seizure. This risk may be compounded by buproprion’s own inherently greater epileptogenic potential and the rapidity of its time to peak levels in both the older formulation and the newer slow release (SR) compound (9). It has been theorized that “rapidity of dose escalation” is a factor in the capacity for antidepressants to cause seizure (10). Peak plasma level occurs within 2 hours for buproprion (traditional preparation) and within 3 hours for the newer SR preparation after oral ingestion. This is 2 to 3 times faster than, for example, “time to peak plasma level” for fluoxetine, which requires 6 to 8 hours (9). By reducing metabolic clearance, a coadministered hepatic enzyme inhibitor such as MPH may accelerate time to peak and also amplify peak plasma con-centrations, both of which have been implicated as risks in buproprion- induced seizures (10).
References
1. Ickowicz A. Buproprion-methylphenidate combination and grand-mal seizures. Can J Psychiatry 2002;47:790–1.
2. Biederman J. Attention-deficit-hyperactivity disorder: a life-span perspective. J Clin Psychiatry 1998;59:137–49.
3. Rosenbaum JF, Fava M, Nierenberg A, Sachs GS. Treatment-resistant mood disorder. In: Gabbard, GO, editor. Treatment of psychiatric disorders. 3rd ed. Washington (DC): American Psychiatric Press; 2001. p 1307–88.
4. Potter WZ, Manji HK, Rudorfer MV. Tricyclics and tetracyclics. In: Schatzberg AF, Nemeroff CB, editors. Textbook of psychopharmacology. Washington (DC): American Psychiatric Press; 1995. p 141–60.
5. Dulcan MK, Bregman JD, Weller EB, Weller RA. Treatment of childhood and adolescent disorders. In: Schatzberg AF, Nemeroff CB, editors. Textbook of psychopharmacology. Washington (DC): American Psychiatric Press; 1995. p 669–706.
6. Stoudemire A, Moran MG, Fogen BS. Psycho-pharmacology in the medically ill patient. In: Schatzberg AF, Nemeroff CB, editors. Textbook of psychopharmacology. Washington (DC): American Psychiatric Press; 1995. p 783–801.
7. Cozza KL, Armstrong SC. The cytochrome P450 system: drug interaction principles for medical practice. Washington (DC): American Psychiatric Publishing; 2001.
8. Indiana University Department of Medicine. Cytochrome P450 Drug Interaction Table 2002. www.Drug-Interactions.Com.
9. Murray L, Kelly G, editors. Physicians’ desk reference. Montvale (NJ): Medical Economics Co; 2001.
10. Preskorn SH, Burke MJ, Fast GA. Therapeutic drug monitoring principles and practice. Psychiatr Clin North Am 1993;16:611–45.
Roger Baird, PhD, MD
Richmond, Virginia
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