Can fluoxetine and ziprasidone together synergistically increase the risk of seizures and/or arrhyt

Fråga: Can fluoxetine and ziprasidone together synergistically increase the risk of seizures and/or arrhythmias?

A 15-year-old girl with Tourettes syndrome and obsessive compulsive disorder, who is being treated with fluoxetine 60 mg and ziprasidone 20 mg daily, was admitted to hospital after having fainted and/or had (unwitnessed) seizures.

Sammanfattning: Both fluoxetine and ziprasidone can, in rare cases, cause seizures and/or QT-prolongation and the risk of these side-effects can be expected to be at least added when the two drugs are combined. Both types of side-effects are generally considered to be concentration dependent.

Svar: Fluoxetine is a serotonin reuptake inhibitor, which is metabolised by, and also strongly inhibits the liver enzyme CYP2D6 (1). Ziprasidone is a neuroleptic that acts as an antagonist at both dopamine type 2 and serotonin type 2A receptors, but also as an agonist at serotonin type 1A receptors and as a serotonin reuptake inhibitor. It is metabolised by several enzymes, including aldehyde oxidase, and to some extent CYP3A4 and CYP1A2 (2).

A Medline search revealed no reports of adverse drug interactions between the two substances, and as they have different metabolic pathways, there is no apparent reason to suspect a pharmacokinetic interaction. However, pharmacodynamically, it cannot be excluded that there might be at least additive effects with respect to the risk of both seizures and QT-prolongation.

A reduction of the seizure threshold is a known side-effect for many antidepressants and neuroleptics, including both fluoxetine and ziprasidone, and tonic-clonic seizures have been reported for both drugs. There is one report of seizures for ziprasidone (total number of reported side-effects 80) and 8 reports for fluoxetine (total number 248) in the Swedish adverse drug reactions register (Swedis) (3).

As for drug induced syncope from cardiac arrhytmia, or more specifically polymorphic ventricular tachycardia/torsade de pointes, pre-existing QT-prolongation, female sex, electrolyte disturbances and polypharmacy are known risk factors (4).

Ziprasidone caused a dose-related, mild to moderate prolongation of the QT-interval in 12 percent of nearly 8000 ECG´s in clinical trials concering the treatment of schizophrenia, and the manufacturer advices that ziprasidone should not be combined with any other drug known to affect the QT-interval (2). Swedis contains one report each of hypotension, QT-prolongation, AV block and arrhythmia (3). We also found a very recent case report, describing a ziprasidone treated woman with an asymptomatic episode of ventricular tachycardia preceded by QT-prolongation while monitored because of chest pain. She had systemic lupus erythematosus and a complex of psychiatric diagnoses and was at the time treated with several drugs, including fluconazole, ciprofloxacin and trazodone (a serotonin uptake inhibitor). Concomitant medication may here have contributed both pharmacodynamically and -kinetically (5).

Fluoxetine has not been reported to regularly cause a QT-prolongation, but there are several case reports in the literature, suggesting that fluoxetine might in rare cases have this side-effect (6-7). Swedis contains one report each of QT-prolongation, torsade de pointes and arrhythmia (3).

In the present case, it cannot be excluded that the combination of fluoxetine and ziprasidone caused either seizures or a cardiac arrhythmia, even though both of these side-effects are rare. From a safety point of view, it must be important to investigate any signs of ECG and/or electrolyte disturbances, and to stop the ziprasidone treatment in the presence of such. Furthermore, the concentration of fluoxetine can be analysed by our laboratory, as these side-effects are believed to be concentration dependent. We also recommend that the case be reported to the regional adverse drug reaction monitoring centre. Fontex. Summary of product characteristics (SPC Lilly). Zeldox. Summary of product characteristics (SPC Pfizer). Swedis (cited 2006-05-11) Heist EK, Ruskin JN. Drug-induced proarrhythmia and use of QTc-prolonging agents: clues for clinicians. Heart Rhythm 2005;2:S1-S8. Heinrich TW, Biblo LA, Schneider J. Torsades de pointes associated with ziprasidone. Psychosomatics 2006;47(3):264-8. Wilting I, Smals OM, Holwerda NJ, Meyboom RH, de Bruin ML, Egberts TC. QTc prolongation and torsades de pointes in an elderly woman taking fluoxetine. Am J Psychiatry 2006;163(2):325. Varriale P. Fluoxetine (Prozac) as a cause of QT prolongation. Arch Intern Med 2001;161(4):612.