Abstract
Dear Doctor Letters (DDLs, Direct Healthcare Professional Communications) from 2011 provided guidance regarding QTcprolonging efects with risk of torsade de pointes during treatment with citalopram and escitalopram. This study examines
the DDLs’ efects on prescription behavior. Data from 8842 inpatients treated with citalopram or escitalopram with a primary
diagnosis of major depressive disorder (MDD) were derived from a European pharmacovigilance study (Arzneimittelsicherheit in der Psychiatrie, AMSP) from 2001 to 2017. It was examined to what extent new maximum doses were adhered
to and newly contraindicated combinations with QTc-prolonging drugs were avoided. In addition, the prescriptions of psychotropic drugs before and after DDLs were compared in all 43,480 inpatients with MDD in the information set. The proportion of
patients dosed above the new limit decreased from 8 to 1% in patients≤65 years and from 46 to 23% in patients>65 years
old for citalopram versus 14–5% and 47–31% for escitalopram. Combinations of es-/citalopram with other QTc-prolonging
psychotropic drugs reduced only insignifcantly (from 35.9 to 30.9%). However, the proportion of patients with doses of
quetiapine>150 mg/day substantially decreased within the combinations of quetiapine and es-/citalopram (from 53 to 35%).
After the DDLs, prescription of citalopram decreased and of sertraline increased. The DDLs’ recommendations were not
entirely adhered to, particularly in the elderly and concerning combination treatments. This might partly be due to therapeutic
requirements of the included population. Ofcial warnings should consider clinical needs.
to reduce these risks . However, the efectiveness of
DDLs has been challenged , in part due to insufcient
quality of warning instructions in DDLs . Furthermore,
a Dutch study found that DDLs regarding the risk of hospitalization are less efective than DDLs related to the risk of
death or disability . In addition, advisories recommending
closer monitoring of patients appear not to have a large and
sustained impact on clinical practice . Since prescription
behavior is infuenced by several factors and not only by
DDLs, it is difcult to attribute potential changes in prescription behavior directly to specifc warning messages .
In 2011, DDLs (called “Rote Hand-Briefe”, RHB, in
Germany) regarding citalopram and escitalopram were sent
out by Lundbeck in the three German-speaking countries
(Germany, Austria and Switzerland; . Citalopram
and its active S-isomer escitalopram are selective serotonin
reuptake inhibitors (SSRIs) and are commonly used in the
treatment of major depressive disorder (MDD) . Due to
their efcacy and tolerability, they are widely used in adult
as well as in geriatric populations .
The DDLs recommended a reduction of the maximum
daily dose of citalopram and escitalopram due to the risk of
QTc prolongation. In addition, the DDLs advised against the
combination of es-/citalopram with other potentially QTcprolonging drugs. Similar instructions were issued by the
US Food and Drug Administration (FDA) as well as
by the European Medicines Agency (EMA) . The FDA
further recommended electrocardiogram (ECG) monitoring
in patients taking citalopram who are at particular risk of
QTc prolongation such as older patients, females, as
well as patients with a history of heart disease, hypokalemia
or hypomagnesemia