Escitalopram

Escitalopram (Cipralex®, Lexapro™), the active S-enantiomer of the racemic selective serotonin reuptake inhibitor (SSRI) citalopram (RS-citalopram), is a highly selective inhibitor of the serotonin transporter protein. It possesses a rapid onset of antidepressant activity, and is an effective and generally well tolerated treatment for moderate-to-severe major depressive disorder (MDD). Pooled analyses from an extensive clinical trial database suggest that escitalopram is consistently more effective than citalopram in moderate-to-severe MDD. Preliminary studies suggest that escitalopram is as effective as other SSRIs and the extended-release (XR) formulation of the serotonin/noradrenaline (norepinephrine) reuptake inhibitor venlafaxine, and may have cost-effectiveness and cost-utility advantages. However, additional longer-term, comparative studies evaluating specific efficacy, tolerability, health-related quality of life and economic indices would be helpful in definitively positioning escitalopram relative to these other agents in the treatment of MDD. Nevertheless, available clinical and pharmacoeconomic data indicate that escitalopram is an effective first-line option in the management of patients with MDD.

Unlike other SSRIs, escitalopram appears to not only bind to a primary high-affinity site on the serotonin transporter protein, but also to a secondary, lower-affinity allosteric site that is considered to stabilise and prolong drug binding. In vitro, escitalopram was approximately twice as potent as citalopram in inhibiting serotonin reuptake and, in radioligand binding assays, it was more selective than other SSRIs, including citalopram, for the human serotonin transporter protein. Escitalopram has shown no or very low affinity for various other receptors in vitro. In vivo, escitalopram was four times more potent than citalopram at reducing firing activity of presumed serotonergic neurons in the dorsal raphe nucleus in rat brain.

The multiple-dose pharmacokinetic profile of escitalopram is linear across a 10–30 mg/day dosage (20 mg/day is the maximum approved dosage). Steady-state plasma concentrations are achieved after about 7–10 days’ administration of escitalopram 10 mg/day. The absolute oral bioavailability of escitalopram is about 80%, and protein binding, which is independent of escitalopram plasma concentrations, is ≈55%. Concurrent food ingestion has no influence on escitalopram pharmacokinetics. Escitalopram is extensively metabolised in the liver. In vitro, the cytochrome P450 isoenzymes 2C19, 3A4 and 2D6 contribute equally to its metabolism. The main metabolite is S-demethylcitalopram, which is further metabolised to S-didemethylcitalopram. Both metabolites have virtually no serotonin reuptake activity in vivo. Escitalopram and metabolites are primarily renally excreted, with only a small percentage eliminated as unchanged drug. The plasma elimination half-life is ≈27–33 hours.

Escitalopram dosage adjustments are advocated in elderly patients and those with hepatic impairment, and caution should be exercised with escitalopram use in patients with severe renal impairment.

In well designed, comparative studies with placebo and/or citalopram in patients with moderate-to-severe MDD, escitalopram was more effective than placebo and at least as effective as citalopram in reducing the mean Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline (primary efficacy parameter). In large, pooled analyses in patients with moderate-to-severe MDD, escitalopram was consistently more effective than placebo or citalopram in terms of a faster onset of antidepressant activity, greater decreases in mean MADRS total score and mean Clinical Global Impression-Severity score, and superior rates of response (percentage of patients with a ≥50% decrease in MADRS score) and remission (percentage of patients attaining a MADRS score ≤12).

Several randomised, double-blind studies in patients with moderate-to-severe MDD showed that escitalopram was as effective as paroxetine, sertraline or venlafaxine XR in reducing MADRS scores.

Escitalopram demonstrated continued efficacy in a 52-week open-label extension of two 8-week double-blind studies in primary-care patients with moderate-to-severe MDD, and significantly prevented relapse in 36- and 52-week double-blind, placebo-controlled studies.

Modelled pharmacoeconomic evaluations and a prospective pharmacoeconomic analysis suggested cost-effectiveness advantages for escitalopram relative to several other SSRIs and venlafaxine (including the XR formulation). Cost utility analyses showed that escitalopram dominated all the other treatments. A potential for cost savings (up to 4.5%) was shown in total healthcare budgets for depression when escitalopram is introduced.

In placebo-controlled studies, the most common treatment-emergent adverse events with escitalopram were nausea (15%), ejaculation disorder (9%), insomnia (9%), diarrhoea (8%), somnolence (7%), dry mouth (6%) and dizziness (6%). Nausea led to withdrawal of 2% of patients and 2% of men withdrew because of ejaculation disorder.

Large-scale comparisons of escitalopram with citalopram revealed that the overall type and incidence of adverse events were generally similar between treatments. Escitalopram demonstrated a lower incidence of nausea, increased sweating and constipation than venlafaxine XR. Discontinuation syndrome (Discontinuation Emergent Signs and Symptoms score increase of ≥4) was seen in fewer escitalopram than venlafaxine XR recipients after treatment withdrawal Likewise, in comparisons with paroxetine, fewer escitalopram recipients had discontinuation syndrome after treatment cessation. The tolerability profile of escitalopram was generally similar to that of fluoxetine in elderly patients and to that of sertraline in patients aged 18–80 years.

A large meta-analysis of data from placebo-controlled studies specific to the use of escitalopram revealed that no suicides with the drug occurred within the first 2 weeks or throughout up to 24 weeks of therapy. In addition, MADRS item-10 (‘suicidal thoughts’) scores were reduced compared with placebo from the first week in 8-week studies. Pharmacovigilance data reveal a very low suicide rate of 1.8 per 1 million patients treated with escitalopram.