The Food and Drug Administration (FDA) announced in 2011 and 2012 that citalopram had been associated with abnormal heart rhythms, informing clinicians that (R,S)-citalopram could cause dose-dependent QT interval prolongation. As a result, revised recommendations stated that the maximum dose should be restricted to 20 mg for those older than 60 years or taking cytochrome P450 (CYP) 2C19 inhibitors 1,2. However, QT interval prolongation has not been demonstrated for (S)-citalopram in a geriatric population and the clinical relevance of this side effect remains ill defined.
On the other hand, omeprazole, a known inhibitor of CYP2C19, interacts with (S)-citalopram increasing the pharmacological effects of (S)-citalopram 3, but the intensity and clinical relevance of this phenomenon are not entirely understood.
Thus, we conducted a 6 month, prospective study aimed at evaluating QT interval prolongation as a response marker for (S)-citalopram dosage during co-administration with omeprazole. We analyzed a sample of geriatric inpatients (n = 201) with QT interval measurements obtained 15 days after starting (S)-citalopram–omeprazole treatment. Based on electrocardiographic QT interval and heart rate data obtained from the patients' admission records, we calculated QT intervals using both Bazett's correction (QTcB) and Fridericia's correction (QTcF).
Prior to data evaluation, we performed one way analysis of variance (anova) tests in order to determine the effects of important pathophysiologic (gender, organic heart disease, atrial flutter, renal failure and/or diabetes mellitus) or pharmacologic factors (according to the drug list by Woosley) 4 on QT interval. As a result of this analysis, patients being treated with amiodarone (F = 2.089, P < 0.001), donepezil (F = 3.565, P < 0.001), salbutamol, (F = 1.732, P = 0.004) and venlafaxine (F = 2.118, P < 0.001) were excluded from the study, as these drugs all lengthened QT interval. In addition, those treated with digoxin were also excluded due to its ability to shorten QT interval 5. However, none of the patients was excluded based on pathophysiological status.
Among the included patients, 23 of them were taking (S)-citalopram (10 mg daily), which was co-administered with omeprazole (20 mg daily). These patients made up the final study group (n = 23), whereas the remaining patients (n = 129) constituted the comparison group.
Notably, with respect to the use of β-adrenoceptor blockers and diuretics, two important confounders that could alter conditions (i.e. heart rate and plasma electrolytic composition) for influencing the occurrence of severe arrhythmias, the prescription rates were similar between the two groups.
Results were as follows. First of all, regarding the intensity of the interaction, the patients displayed increases in both QTcB and QTcF intervals (34.0 ± 2.2 ms and 30.2 ± 6.1 ms, respectively). Based on data published by Van Gorp et al. 6, this amount of QT interval increase corresponded to an equipotent (S)-citalopram dose above 30 mg 1,2,6. Notably, this finding would suggest that the (S)-citalopram level was three-fold higher than the 10 mg administered dose in these patients. Secondly, for descriptive purposes, we calculated the likelihood that patients treated with both (S)-citalopram and omeprazole would have a QT interval prolongation greater than 450 ms, which denotes higher risk for serious cardiac arrhythmias: OR = 3.7 (95% CI 1.5, 9.4; P = 0.0059) and OR = 2.9 (95% CI 1.2, 7.4; P = 0.0228) for QTcB and QTcF, respectively. Table 1.
Table 1.
Clinical characteristics of patients included in the study (I) and comparison (II) groups
| Group I (n = 23) | Group II (n = 129) | P | |
|---|---|---|---|
| Omeprazole and (S)-citalopram | Yes | No | |
| Women (%) | 60.8 | 63.7 | |
| Age (years) | 85.9 (5.3) | 85.9 (6.9) | |
| β-adrenoceptor blockers (%) | 13.0 | 12.4 | |
| Diuretics (%) | 39.1 | 36.1 | |
| Plasma K+ (mEq l–1) | 4.2 (0.7) | 4.4 (0.8) | >0.05 |
| Plasma Na+ (mEq l–1) | 139.3 (6.1) | 140.1 (5.4) | >0.05 |
| Plasma Ca++ (mmol l–1) | 2.3 (0.2) | 2.2 (0.2) | >0.05 |
| Heart rate (beats min–1) | 84.7 (20.4) | 87.8 (24.4) | >0.05 |
| QTcB (ms) | 475.7 (55.1) | 441.2 (55.6) | 0.0067* |
| QTcF (ms) | 447.9 (41.0) | 417.8 (49.2) | 0.0063* |
All data expressed as mean value (SD), except for Women (%) and prescription rates for β-adrenoceptor blockers and diuretics (%).
Statistically significant difference (Student's t-test).
This observational pharmacosurveillance study, which involved examining geriatric inpatient health records, revealed that treatment with (S)-citalopram plus omeprazole led to a statistically significant prolongation in QT interval. Indeed, the intensity of the observed interaction between these two drugs was high and a significant proportion of individuals displayed abnormal corrected QT intervals.
In conclusion, citalopram and omeprazole are commonly co-prescribed in the elderly and our study suggests they interact significantly in this age-group to prolong the QT interval even when citalopram is dosed in accordance with revised FDA guidance.
Competing Interests
All authors have completed the Unified Competing Interest form and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.
References
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