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Removal from labeling of 60‐mg citalopram dose

McKean, et al.,1 have used results of a cohort study by Leonard, et al.,2 to challenge FDA’s removal of the 60-mg dose from labeling for citalopram because of dose-related QT prolongation and the absence of any added benefit. Leonard, et al. studied the rates of sudden cardiac death and ventricular arrhythmia with various antidepressants in Medicaid populations of several states, finding no increased rate with any drug. We find reliance on these epidemiologic data to conclude that citalopram 60-mg poses no risk of arrhythmia inappropriate and the reasons given by McKean, et al., for maintaining the 60-mg dose unconvincing. In August of 2011, citalopram labeling was changed at FDA’s request to recommend that doses above 40mg not be used. Labeling with respect to the 60-mg dose had previously acknowledged no evidence of greater benefit with the higher dose, but had not specifically recommended that it not be used. It should also be noted that escitalopram, the active isomer of racemic citalopram, has a recommended maximum dose of 20mg (equivalent in activity to 40mg of the racemate). The reasons for the labeling change were two: first, 60mg of citalopram produced a worrisome increase in the heart rate-corrected QT interval (QTc); second, there was no evidence that patients responded better to 60-mg citalopram than to 40mg, or that patients who were refractory to 40mg would respond to 60mg. The results of the citalopram and escitalopram thorough QT studies (QTc at 4 h post-dose). Edited for efficiency are shown in Table 1. Equally effective doses of citalopram and escitalopram are shown in the same row. The difference between the citalopram racemate and escitalopram in QT effect presumably means that, although antidepressant activity of citalopram is stereospecific and limited to the s-isomer, QT effects based on HERG channel inhibition are not stereospecific. The precise relationship between the specific magnitude of QT prolongation and risk of torsade de pointes (TdP) arrhythmia is not known. There is generally little concern at 5ms (upper bound of the 95% CI< 10ms) and substantial concern above a mean of 20ms. In a drug development assessment for a drug that prolongs the QT, the rate of patients with QT> 500ms would be also examined closely. An average QT prolongation between 10 and 20ms represents some concern.3 The QT prolongation caused by 60-mg citalopram is in the area of concern, but the 40-mg dose of citalopram and the 20-mg dose of escitalopram, having smaller effects, would not be expected to pose appreciable risk of TdP in most patients. A primary route of clearance for citalopram is metabolism by CYP 2C19, so that poor metabolizers for that enzyme would be expected to have increased blood levels, putting them at some risk even with a 40-mg dose of citalopram. Apart from the increase in mean QTc, there are persuasive reports of citalopram-caused marked QT prolongation and TdP,4,5 so that the problem is more than theoretical. Given the potential toxicity of the 60-mg dose of the racemate, to recommend use of that dose it would be important to have evidence that the 60-mg dose is more effective than the 40-mg dose, or is effective in patients who are refractory to 40 mg. No such evidence exists; a dose–response study for citalopram shows no suggestion of an enhanced effect on the 17-item Hamilton Rating Scale for Depression (HAMD-17) beyond 40mg. Escitalopram has been studied only up to 20 mg/day, and, as noted, 20 mg is the maximum recommended dose (Table 2).