Drug Interactions between citalopram and clozapine

ADJUST DOSE: Citalopram can cause dose-dependent prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval such as clozapine may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In a randomized, double-blind, crossover, escalating multiple-dose study consisting of 119 healthy subjects, the maximum mean increase in corrected QT interval from placebo was 8.5 msec for citalopram 20 mg and 18.5 msec for citalopram 60 mg. Based on the established exposure-response relationship, prolongation of the corrected QT interval was estimated to be 12.6 ms for citalopram 40 mg. Cases of QT interval prolongation and torsade de pointes have been reported during postmarketing use. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Given the risk of dose-dependent QT prolongation, citalopram dosage should not exceed 40 mg/day. Studies have not shown a benefit in the treatment of depression at dosages above 40 mg/day. Hypokalemia and hypomagnesemia should be corrected prior to initiation of citalopram treatment and periodically monitored. ECG monitoring is recommended with concomitant medications that have demonstrated prolongation of the QT interval and/or underlying risk factors such as heart failure or bradyarrhythmia. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, irregular heartbeat, shortness of breath, or syncope.

MONITOR CLOSELY: Coadministration with citalopram may increase the plasma concentrations of clozapine. The mechanism may involve inhibition of the CYP450 2C19- and 2D6-mediated metabolism of clozapine, although citalopram has generally been considered a weak inhibitor of CYP450 isoenzymes. In one case report, a 39-year-old patient with schizoaffective disorder treated with clozapine (400 mg/day) developed evidence of clozapine toxicity shortly after the addition of citalopram (20 mg/day initially, then increased to 40 mg/day). Sedation, fatigue, enuresis, hypersalivation, and confusion occurred in association with elevated serum concentrations of clozapine and norclozapine. Clozapine levels decreased and adverse reactions resolved within 2 weeks after citalopram dosage was reduced to 20 mg/day.

MANAGEMENT: Pharmacologic response and serum clozapine concentrations should be monitored more closely following initiation, discontinuation or change of dosage of citalopram in patients who are stabilized on their antipsychotic regimen, and the clozapine dosage adjusted as necessary.

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