Citalopram (Celexa, Forest Laboratories, New York, NY) is one of the most widely prescribed selective serotonin reuptake inhibitors (SSRIs) in our practice. It has had good tolerability and low discontinuation rates in practice and in clinical trials.1-3 The recent US Food and Drug Administration (FDA) recommendation to not use doses higher than 40 mg/d because of potential QTc prolongation has been causing various difficulties.4 This warning has raised concerns from both psychiatrists and generalists at our institution both in regard to continuation of therapy that has been effective for patients that have responded to doses over 40 mg/d and in regard to the potential to use this medication above that dose range in future patients. Specifically, in our practices, there are patients who are doing well on higher doses. These patients are predominantly in our general and subspecialty psychiatry practices. Further, in our primary care practices, large numbers of patients take citalopram, and drug-drug interactions with agents such as proton pump inhibitors (PPIs), which can increase blood levels in patients taking 40 mg/d or less of citalopram, have also caused substantial prescribing problems. Members of the Mayo Clinic Neurology/Psychiatry Task Force as well as selected members from the Heart Rhythm Services group reviewed factors that should be communicated to prescribers in relation to citalopram prescribing in light of these new warnings regarding QTc prolongation and the risk for potential morbidity and mortality from drug-induced arrhythmias including torsades de pointes and sudden cardiac arrest.
When we prescribe a drug for a patient, each of us must consider official warnings as well as the warnings from our electronic prescribing platforms regarding drug interactions. This becomes more complex as the body of knowledge regarding our pharmaceutical armamentarium evolves. As physician and pharmacy leaders in psychopharmacology issues at our large medical institution, we are asked to provide a framework of relevant information to groups of our prescribers in complex situations such as the recent FDA warnings on citalopram.4 Providing information that meets the needs of both primary and tertiary care populations of patients, as well as prescribers with varying degrees of knowledge, can be challenging but potentially of substantial value.
The 4 major factors the group decided to address included:
- 1Communicating information about relevant QTc prolongation monitoring and documentation to prescribers.
- 2Giving opinion on whether or not there is any likely risk for escitalopram, the active S-isomer of citalopram (ie, should we just switch all these patients to escitalopram since there is no current warning on this drug?).
- 3Discussing and documenting the risk of undertreating the various disorders for which citalopram is prescribed and the risks and benefits of alternative therapies.
- 4Outlining factors to consider and document regarding use of citalopram and escitalopram in patients also using PPIs or oral contraceptives because these clinical situations have generated the bulk of the questions from prescribers due to the potential for pharmacokinetic drug interaction ordering alerts.
The initial FDA communication was concerned principally with citalopram dosages higher than 40 mg/d. The FDA communication stated that doses above 40 mg do not provide additional benefit and are associated with an increased risk of QT prolongation and QT-triggered cardiac rhythm–related deaths. The psychiatry experts were of the opinion that in an average population, these data outlined by the FDA may be correct. However, on an individual basis, more complex patients such as those in a tertiary care environment may and do gain benefit from dosages above 40 mg/d. The FDA warning cited efficacy in major depression but did not acknowledge use of this agent for other disorders that may have different dose-response patterns. While SSRIs are equivalent in the general population, there are many individuals for whom citalopram is the most effective agent. Selective serotonin reuptake inhibitors cannot simply be substituted for one another, not even escitalopram for citalopram. Hence, considering whether patients and prescribers can make joint decisions about continued use and dosing of the drug is of potential value. Switching from one SSRI to another risks loss of efficacy, which may not be attainable with the second agent. Doses of citalopram higher than 40 mg/d have been helpful especially for patients with anxiety disorders such as obsessive-compulsive disorder, even if such dose-response effects were not evident in studies of an unselected patient population with major depressive disorder, which the FDA focused on in making the recommendations for this agent.
The group agreed that there are no particular efficacy reasons to favor one SSRI over another for the treatment of depression and anxiety. It also was of the opinion that when switched from one agent to another, approximately 10% of patients fail to respond to the new drug. While acknowledging the concerns raised by the FDA, it was noted that citalopram has certain favorable pharmacokinetic characteristics and is still an appropriate consideration for therapy for depression and anxiety disorders.
We thought that prescribers should be mindful of additional risks for QTc prolongation or drug accumulation such as those seen in patients with bradycardia, hypokalemia, hypomagnesemia, uncorrected hypothyroidism, and hepatic dysfunction or in patients over the age of 60. Concomitant drug therapy also should be reviewed.
In certain selected circumstances, the group felt that despite the FDA's recommendations, it is at times appropriate for individual prescribers to make risk-benefit decisions for individual patients that may include continuation of citalopram at doses above 40 mg/d. When prescribers and patients choose to continue doses higher than 40 mg/d, the following are recommended to be documented:
- 1A patient has achieved, or based on partial responses would be expected to achieve, additional benefit from dosing above 40 mg/d (this is variable among patients).
- 2There was a risk-benefit discussion with the patient regarding therapeutic alternatives.
- 3Electrocardiography (ECG) has been performed while the patient is receiving the maximum dose planned for their therapy and/or before starting therapy and a second ECG with the patient on therapy. An absolute QTc greater than 500 ms or a delta QTc increase greater than 60 ms (QTc on drug – QTc before drug greater than 60 ms) may represent an ECG indication for concern and should prompt further review of risks and benefits.5
- 4Confirmation of no family history of premature sudden cardiac death, no personal history of QTc prolongation, and no personal history of congenital and acquired structural and ischemic heart disease, especially recent acute myocardial infarction and uncompensated heart failure, as well as potential pharmacodynamic effects through review of concomitant drugs that also prolong the QTc, such as class I antiarrhythmics (eg, procainamide, quinidine), class III antiarrhythmics (eg, sotalol, amiodarone), erythromycin, clarithromycin, azithromycin, methadone, and antipsychotics (such potential QT-prolonging medications are listed at www.qtdrugs.org) (Table).
Notably, escitalopram (S-citalopram), the active isomer of citalopram, was not included in the FDA warnings. In its recent update, the FDA has specifically commented that “there are no changes planned for escitalopram at this time.”6 Escitalopram is also widely used for treatment of depression and anxiety disorders. Citalopram is a racemic mixture of S-citalopram (active) and R-citalopram (inactive) isomers. The group considered whether the same or similar concerns would apply to escitalopram regarding QTc prolongation, since it is also widely used for depression and anxiety disorders. The maximum FDA labeling for escitalopram is 20 mg/d, but like citalopram, doses higher than the product labeling are used in certain cases. Literature suggests that escitalopram is twice as potent as citalopram (ie, 20 mg of escitalopram is approximately equivalent to 40 mg of citalopram). Hence, unless it is the R-isomer alone or in combination with the S-isomer causing this problem, escitalopram doses higher than 20 mg/d may have some of, if lesser degrees of, the QT-prolonging potential that has already been shown for 40-mg/d doses of citalopram. Available data show that 60 mg of citalopram prolonged the QTc by 16.7 ms, while escitalopram at an equivalent dose of 30 mg prolonged the QTc by 10.7 ms.7 Hence, the group concurred that citalopram's QT-prolonging potential was not solely an effect of the inactive R-isomer found only in citalopram but that the therapeutically active S-isomer may also exert this potential and unwanted effect.8 Taken together, these data suggest that since longer QTc prolongation is seen with the racemic mixture (citalopram), that both R- and S-isomers contribute to QTc prolongation. Thus, it seems prudent to follow the same recommendations for documentation and monitoring of escitalopram in doses greater than 20 mg/d. These data also show that escitalopram has some QTc-prolongation risk, and hence, just switching patients taking citalopram to escitalopram will not fully avoid this risk.
In considering how to make use of the FDA's warning, the group considered the potential for unintended adverse health consequences, such as those that may have followed previous FDA actions. For example, the institution of black box warnings regarding increased suicide risks for the SSRI class of antidepressants not only led to the global reduction in their use but also led some investigators to conclude that this action actually may have resulted in an increased incidence of suicide in certain populations.9,10 Hence, we felt that consideration of all factors in risk-benefit decisions for prescribing this class of medication is important, including the value of treating the underlying disease state in regard to both morbidity and mortality outcomes. There is also the risk for nonresponse or unacceptable adverse effects when switching to an alternative antidepressant, along with the possibility of clinical worsening during the transition.
Citalopram and escitalopram are metabolized primarily in the liver via the cytochrome P450 (CYP) 2C19 enzyme. This could be problematic for patients who are poor metabolizers of CYP2C19 due to genetic polymorphisms. Medications that inhibit the CYP2C19 pathway have the potential to cause an increase in the serum levels of citalopram and escitalopram since they are metabolized by CYP2C19. Such “metabolic liability” from a drug-enzyme interaction could therefore increase the risk of QTc prolongation. The PPI class medications are well documented to be important inhibitors of the CYP2C19 enzyme. A number of secondary sources and electronic prescribing databases also list oral contraceptives as CYP2C19 inhibitors, although review of the available literature suggests more variable and less well documented effects of various estrogen and progesterone derivatives on CYP2C19 pathways. However, no pharmacokinetic studies have been performed with these agents to document the effect of these medications on the levels of drugs that are CYP2C19 substrates. In vitro studies with human liver microsomes suggest that oral contraceptives may vary greatly in their ability to inhibit CYP2C19, as well as CYP3A4 (eg, medroxyprogesterone is a weak inhibitor of these enzymes in vitro).11 Nevertheless, for patients taking citalopram and escitalopram who concomitantly take drugs that are known CYP2C19 inhibitors, such as PPIs or oral contraceptives, the group recommended the following:
- •For patients taking citalopram at 40 mg/d or less or escitalopram 20 mg/d or less and in combination with a PPI or an oral contraceptive, it is reasonable to continue the combination with the documentation of (1) no reported history of structural heart disease, (2) no personal or family history of sudden death or prolonged QT syndrome, and (3) a discussion with the patient regarding the risks and benefits of alternative therapies.
- •Of note, recent FDA recommendations are that patients with hepatic dysfunction, those over 60 years of age, patients who are poor metabolizers of CYP2C19, and those who are taking another CYP2C19 inhibitor such as cimetidine (Tagamet) should not use citalopram at doses higher than 20 mg/d.7
In conclusion, we believe that the FDA's action represents the best effort to monitor evolving safety concerns for the available drugs to treat depression and anxiety. We recognize that our current recommendations are less conservative than the FDA's stance on citalopram and more conservative than the FDA in regard to escitalopram.