Complex drug interaction of carbamazepine, fluvoxamine and clozapine in a patient with bipolar depression

Dear Editor,

In the treatment of bipolar depression, classes of commonly used drugs include lithium, anticonvulsants and antipsychotics. Sometimes antidepressants can also be considered a choice ¹ . Some of them may induce or inhibit cytochrome P450 isoenzymes and, when combined in clinical use, may not accurately predict the effects of drug interactions. For example, previous studies have shown that carbamazepine (CBZ) can reduce plasma levels of clozapine (CLZ), while fluvoxamine (FVX) can increase plasma levels of CLZ ² . Additionally, the combined administration of FVX and CBZ may increase plasma concentrations of CBZ ³ . Here, we report the drug interaction in a patient with bipolar depression with the concomitant use of CBZ, CLZ and FVX.

A 46-year-old man with bipolar II disorder treated with 800 mg quetiapine and 400 mg CBZ controlled release daily. He was admitted to an acute psychiatric ward because of his depressed mood, insomnia, and suicidal thoughts. He maintained a blood CBZ level of 8.86 μg/mL on admission (normal range: 4 to 12 μg/mL). Initially, we added 50 mg of agomelatine for depression and insomnia, but to no avail. Therefore, we administered 100 mg FVX plus 100 mg CLZ in place of quetiapine and agomelatine. The result was wonderful in improving his depressive symptoms and insomnia, with the exception of dizziness that complained of the patient during the day. The blood level of CBZ increased to 13.83 μg/mL after re-verification. We adjusted the dose of CLZ from 100 mg to 50 mg and used fast-acting CBZ instead of controlled release without dose modification. After adjustment, her dizziiness improved and also remained effective in cases of depression and insomnia with a CBZ blood level of 10.82 μg/mL.

To our knowledge, this is the first case describing the concomitant use of CBZ, FVX and CLZ. Previous studies had suggested that FVX increased plasma levels of CLZ and CBZ as an inhibitor of CYP1A2 and 3A4, respectively ^2,3 . In contrast, CBZ decreased the plasma level of CLZ by being a CYP3A4 inducer ² . The increase in blood levels of CBZ in this patient could be explained mainly by the effect of FVX. Although FVX and CBZ have an opposite effect on CLZ, we have suggested that the effect of FVX on CLZ was much greater than that of CBZ on CLZ, which would reduce the dose of CLZ required in this patient. Formal pharmacokinetic studies examining the potential interaction between these three drugs are needed to confirm this finding. In summary, this case highlights the importance of monitoring plasma concentrations or clinical status when multiple drugs that inhibit or inhibit CYP450 are combined.

References

• ¹
  Shen YC . Treatment of acute bipolar depression . Ci Ji Yi Xue Za Zhi . 2018 ; 30 ( 3 ): 141 - 7 .
• ²
  Jerling M , Lindstrom L , Bondesson U , Bertilsson L . Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service . Ther Drug Monit . 1994 ; 16 ( 4 ): 368 - 74 .
• ³
  Cottencin O , Regnaut N , Thevenon-Gignac C , Thomas P , Goudemand M , Debruille C , et al . Carbamazepine-fluvoxamine interaction. Consequences for the carbamazepine plasma level . Encephale . 1995 ; 21 ( 2 ): 141 - 5 .

• Funding
  The authors received no financial support for the research, authorship and/or publication of this article.

Publication Dates

• Publication in this collection
  28 Nov 2019
• Date of issue
  Nov-Dec 2019

History

• Received
  26 Apr 2019
• Accepted
  21 May 2019