Is there an interaction between sertraline and carbamazepine?/nA 27-year-old woman with epilepsy is

Fråga: Is there an interaction between sertraline and carbamazepine?

A 27-year-old woman with epilepsy is being treated with carbamazepine 600-800 mg. Recently sertraline 100 mg was added because of depression. Plasma carbamazepine levels have since been high (50-60 umol/l) and she is dizzy and tired. Her carbamazepine levels have remained high, despite a dose reduction of both carbamazepine (to 300 mg) and sertraline (to 50 mg). Her other medications (indications) are propranolol (tremor), diazepam (anxiety) and propiomazine (insomnia).

Sammanfattning: There are no conclusive data in the literature concerning the possible interaction between carbamazepine and sertraline. The interaction did not occur in studies on healthy volunteers, but has been reported in two patients. In the present case, a sertraline-carbamazepine interaction is a possible explanation for the increased carbamazepine plasma levels, and the combination of several drugs may have contributed to this effect.

Svar: Carbamazepine is mainly metabolised by the enzyme CYP3A4 to an active epoxide metabolite, which is further hydroxylated. Minor metabolic pathways of carbamazepine include hydroxylation by CYP1A2 and direct conjugation. Carbamazepine is known to induce its own metabolism, and that of many other drugs, via CYP3A4 (1).

The data concerning the metabolism of sertraline and possible drug interactions is not very clear. Several cytochrome enzymes seem to be responsible for the metabolism of sertraline, including CYP3A4, CYP2D6, CYP2C9 and CYP2C19 (2). In different studies, in vitro or in vivo, sertraline has been shown to have weak inhibitory effects on all of these enzymes. Eg sertraline slightly decreased the clearance of diazepam (CYP2C19, CYP3A4) and tolbutamide (CYP2C9) in healthy volunteers and had a significant effect on in vitro alprazolam metabolism (CYP3A4) (3-5). On the other hand, steady state concentrations of sertraline did not influence carbamazepine pharmacokinetics in two separate studies on healthy, male subjects (6, 7).

We found two case reports describing a carbamazepine-sertraline interaction. In a 37-year-old woman treated with carbamazepine 600 mg, lamotrigine and diazepam, the plasma level of carbamazepine increased from around 40 umol/l to 62 umol/l when sertraline 50 mg daily was added, and she developed ataxia. She improved when the sertraline treatment was stopped (8).

In a 24-year-old woman who also received carbamazepine 600 mg daily and flecainide, the carbamazepine plasma level increased from 20 to 36 umol/l within 4 weeks after sertraline 100 mg was added. Two months later the plasma level was 50 umol/l and the patient had signs of bone marrow depression. Hematological parameters improved when her medications were discontinued (9). Polypharmacy, dietary effects and hormonal variation may be factors that influence drug metabolism in patients, as opposed to the contolled situation with healthy study volunteers. 1 Spina E, Pisani F, Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clin Pharmacokinet 1996; 31: 198-214 2 Kobayashi K, Ishizuka T, Shimada N, Yoshimura Y, Kamijima K, Chiba K: Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro. Drug Metab Dispos 1999; 27: 763-766 3 Gardner MJ, Baris BA, Wilner KD, Preskorn SH: Effect of sertraline on the pharmacokinetics and protein binding of diazepam in healthy volunteers. Clin Pharmacokinet 1997; 32(suppl 1): 43-49 4 Tremaine LM, Wilner KD, Preskorn SH: A study of the potential effect of sertraline on the pharmacokinetics and protein binding of tolbutamide. Clin Pharmacokinet 1997; 32(suppl 1): 31-36 5 von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, Harmatz JS, Shader RI: Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants, ketoconazole and quinidine. Br J Clin Pharmacol 1994; 38: 23-31 6 Preskorn SH, Alderman J, Greenblatt DJ, Horst D: Sertraline does not inhibit cytochrome P450 3A-mediated drug metabolism in vivo. Psychopharmacol Bull 1997; 33: 659-665 7 Rapeport WG, Williams SA, Muirhead DC, Dewland PM, Tanner T, Wesnes K: Absence of a sertraline-mediated effect on the pharmacokinetics and pharmacodynamics of carbamazepine. J Clin Psychiatry 1996; 57(suppl 1): 20-23 8 Vercueil L, Adriantseheno LM, Hirsch E: Surdosage en carbamazepine apres administration d´un comprime de sertraline: relation au syndrome serotoninergique? Therapie 1998; 53: 499-517 9 Joblin M, Ghose K: Possible interaction of sertraline with carbamazepine. N Z Med J 1994; 107: 971