Citalopram and escitalopram

Citalopram

Citalopram is a racemic bicyclic phthalane derivative and is a highly selective serotonin re-uptake inhibitor with minimal effects on noradrenaline and dopamine neuronal reuptake. Inhibition of 5-HT re-uptake by citalopram is primarily due to escitalopram, the active S-enantiomer of citalopram [ ]. One would expect escitalopram to be twice as potent as citalopram but otherwise not to differ significantly from the racemic mixture. However, escitalopram is marketed as being more efficacious than citalopram because, it is argued, the inactive R-isomer present in the racemate actually inhibits binding of the S-enantiomer to its site of action, the serotonin transporter. In some, but not all, clinical trials escitalopram has been statistically superior to citalopram in terms of speed of onset of therapeutic action and improvement on depression rating scales. The clinical significance of these differences is debatable [ ].

The single and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in the range 10–60 mg/day. Citalopram is metabolized to demethylcitalopram, didemethylcitalopram, citalopram-N-oxide, and a deaminated propionic acid derivative. Citalopram has a mean half-life of about 35 hours [ ]. Racemic citalopram is several times more potent than its metabolites in inhibiting serotonin reuptake [ ].

In a systematic review of clinical trials the therapeutic efficacy of citalopram was significantly greater than that of placebo and comparable with that of other antidepressants [ ].

Escitalopram

Escitalopram oxalate is the S -enantiomer of citalopram [ ]. The therapeutic activity of citalopram resides in the S -isomer and escitalopram binds with high affinity to the human serotonin transporter; R -citalopram is about 30-fold less potent. Escitalopram is extensively metabolized in the liver by CYP2C19, CYP3A4, and CYP2D6, and its blood concentrations are increased by drugs that inhibit one or more of these enzymes. The half-life of escitalopram is 27–32 hours. Citalopram has negligible effects on CYP isoenzymes. In vitro, escitalopram is a weak inhibitor of CYP2D6. Drugs that are substrates for CYP2D6 and that have a narrow therapeutic index (for example, flecainide and metoprolol) should be prescribed with caution in conjunction with escitalopram. As with other SSRIs, escitalopram should not be co-administered with monoamine oxidase inhibitors.

General adverse effects and adverse reactions

The most frequent adverse reactions to citalopram and escitalopram (nausea, somnolence, dry mouth, increased sweating) are mainly transient and mostly mild to moderate [ ]. Escitalopram appears to be equivalent to citalopram. For example, in placebo-controlled trials, escitalopram produced unwanted effects typical of the SSRI class, including nausea (15%), ejaculation disorders (9%), insomnia (9%), diarrhea (8%), somnolence (7%), dry mouth (6%), and dizziness (6%).

Placebo-controlled studies

Escitalopram was efficacious in patients with major depressive disorder in short-term, placebo-controlled trials, three of which included citalopram as an active control, and in a 36-week study in the prevention of relapse in depression [ ]. It has also been used to treat generalized anxiety disorder, panic disorder, and social anxiety disorder. Results also suggest that, at comparable doses, escitalopram demonstrates clinically relevant and statistically significant superiority to placebo treatment earlier than citalopram. The most common adverse events associated with escitalopram include nausea, insomnia, disorders of ejaculation, diarrhea, dry mouth, and somnolence. Only nausea occurred in more than 10% of patients taking escitalopram.

Systematic reviews

In a meta-analysis of 20 short-term studies of five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) there were no overall differences in efficacy, but fluoxetine had a slower onset of action [ ]. Citalopram and sertraline were least likely to cause drug interactions, but citalopram was implicated more often in fatal overdoses.

Cardiovascular

There has been some concern about the cardiovascular safety of citalopram, mainly because of animal studies showing effects on cardiac conduction. These most commonly occur in large overdoses, in which a variety of cardiac abnormalities, including QT _c prolongation, have been noted. However, this can occur with therapeutic doses too.

• Bradycardia (34/minute) with a prolonged QT _c interval of 463 ms occurred in a patient taking citalopram 40 mg/day [ ]. The bradycardia resolved when citalopram was withdrawn. The patient also had alcohol dependence and evidence of cardiomyopathy; presumably this may have potentiated the effect of citalopram on cardiac conduction.

• A 21-year-old woman developed QT _c prolongation (457 ms) after taking a fairly modest overdose (400 mg) of citalopram (usual daily dose 20–60 mg) [ ]. The QT _c prolongation resolved uneventfully over the next 30 hours.

This suggests that even modest overdoses of citalopram can cause QT _c prolongation and that cardiac monitoring should be considered. Based on the pharmacokinetic profile of citalopram and the temporal pattern of QT _c change, the authors suggested that the effect of citalopram on the QT _c interval was mediated by one of its metabolites, dimethylcitalopram.

Prolongation of the QT _c interval has been reported in five patients who made non-fatal suicide attempts by taking large amounts of citalopram. Their electrocardiograms showed other conduction disorders, including sinus tachycardia and inferolateral repolarization disturbances [ ].