Escitalopram

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Abstract
Escitalopram (Cipralex®, Lexapro®, Seroplex®, Sipralexa®), the therapeutically active S-enantiomer of racemic citalopram (RS-citalopram), is a potent and highly selective serotonin reuptake inhibitor. It is effective and generally well tolerated in the treatment of moderate to severe generalised anxiety disorder (GAD) or social anxiety disorder (SAD), panic disorder (with or without agoraphobia) as well as obsessive-compulsive disorder (OCD). Moreover, escitalopram is at least as effective as paroxetine for the treatment of GAD, SAD or OCD and appears to achieve a more rapid response than racemic citalopram in the management of panic disorder. Generally, it has a more favourable tolerability profile than paroxetine in terms of fewer discontinuation symptoms. In addition, a favourable pharmacokinetic profile permits once-daily administration of the drug. Additional comparative studies are required to definitively position escitalopram with respect to other SSRIs and venlafaxine. Nevertheless, available clinical data indicate that escitalopram is an effective first-line treatment option for the management of GAD, SAD, panic disorder and OCD. Escitalopram is unique among SSRIs in that it stabilises its binding to the high-affinity binding site of the serotonin transporter protein via an allosteric effect at the low-affinity binding site. In vivo and in vitro studies have shown escitalopram to be approximately twice as potent as citalopram in inhibiting serotonin reuptake. It is highly selective for the serotonin transporter protein and shows no or very low affinity for other receptors or ion channels. In vivo, escitalopram was four times more potent than citalopram in reducing firing activity of presumed serotonergic neurons in rat brain. Single and multiple once-daily oral doses of escitalopram 10–30 mg/day show linear, dose-proportional pharmacokinetics in healthy volunteers. The steady-state plasma concentration of the drug was reached within 7–10 days. Escitalopram is largely metabolised in the liver, mainly into S-demethylcitalopram (S-DCT) and S-didemethylcitalopram (S-DDCT). Cytochrome P450 (CYP) isozymes CYP2C19, 3A4 and 2D6 contribute equally to the metabolism of escitalopram into S-DCT, whereas only CYP2D6 was involved in the second demethylation of S-DCT to S-DDCT. Neither metabolite has significant serotonin reuptake activity in vivo. Escitalopram and its metabolites are excreted primarily via the kidneys, with a small percentage of the drug excreted unchanged. The mean plasma elimination half-life (t1/2) of escitalopram is 27–33 hours. Escitalopram dosage adjustments are recommended in elderly patients and patients with impaired hepatic function, and caution is advised in patients with severe renal impairment. In well designed, double-blind, comparative, 8- to 24-week studies in patients with moderate to severe GAD, escitalopram was more effective than placebo and at least as effective as paroxetine in reducing the mean Hamilton Rating Scale for Anxiety total score (primary efficacy parameter). Escitalopram demonstrated continued efficacy in a 24-week open-label extension study of three 8-week double-blind trials and a ≤76-week placebo-controlled, double-blind, relapse-prevention study. Moreover, in the relapse-prevention study, escitalopram recipients showed a significantly longer time to relapse and reduced risk of relapse than placebo recipients, and fewer escitalopram than placebo recipients relapsed. Escitalopram was also associated with better mental health-related quality of life than placebo in a subgroup of patients from the relapse-prevention study. In two randomised, double-blind, 12- and 24-week studies in patients with moderate to severe SAD, apart from escitalopram 10 mg/day at 12 weeks, escitalopram was significantly more effective than placebo and at least as effective as paroxetine in reducing the mean Liebowitz Social Anxiety Scale total scores (primary efficacy parameter). In a 24-week double-blind, placebo-controlled relapse-prevention study, escitalopram recipients had a longer time to relapse and reduced risk of relapse compared with placebo recipients, and significantly fewer escitalopram than placebo recipients relapsed. Escitalopram was significantly more effective than placebo in reducing the panic attack frequency (primary efficacy parameter) with a faster onset of action than citalopram in a randomised, double-blind trial in patients with panic disorder. In an open-label study in elderly (>65 years) patients with panic disorder, improvement in panic attack frequency (primary efficacy parameter) and secondary efficacy variables occurred more quickly in escitalopram than citalopram recipients. In patients with OCD, escitalopram 20 mg/day for 12 weeks was more effective than placebo, and at least as effective as paroxetine 40 mg/day, with respect to a mean reduction from baseline in the Yale-Brown Obsessive Scale total score (primary efficacy parameter). In a relapse-prevention study, escitalopram recipients showed a longer time to relapse and a significantly reduced risk of relapse compared with those receiving placebo. In addition, the proportion of patients who relapsed in the escitalopram group was significantly lower than in the placebo group. Escitalopram was generally well tolerated in adult patients with GAD, SAD, panic disorder or OCD. Withdrawal rates due to treatment-emergent adverse events in escitalopram recipients were 6.0–11.8%. The profile of treatment-emergent adverse events was generally similar in escitalopram recipients irrespective of the type of anxiety disorder in placebo-controlled short-term trials. The most common adverse event in escitalopram and placebo recipients was headache (15–25% of patients). Other common adverse events in escitalopram recipients with GAD include nausea (18.2%), ejaculation disorder (14.3%), insomnia (11.9%), fatigue (7.7%), decreased libido (6.8%) and anorgasmia (5.7%). Withdrawal rates during the 12-week open-label period of three relapse-prevention studies were 7.7–20.0%, whereas 2.6–7.9% withdrew from the study during the ≤76-week double-blind period. Furthermore, the overall incidence of adverse events was numerically lower during the double-blind period than the initial 12-week open-label period. Escitalopram recipients generally reported more discontinuation symptoms than placebo recipients after switching to placebo in two fixed-dose studies, whereas patients continuing escitalopram treatment generally reported fewer discontinuation symptoms than those switching to placebo in the relapse-prevention studies. The tolerability profile of escitalopram was generally similar to those of paroxetine or citalopram. However, in one study, paroxetine recipients showed significantly higher rates of withdrawal due to treatment-emergent adverse events than escitalopram recipients, and more paroxetine than escitalopram recipients appeared to experience sexual adverse events (ejaculation disorder [30.0% vs 14.8%], anorgasmia [26.2% vs 5.9%] and decreased libido [22.6% vs 4.9%]). Some discontinuation symptoms were reported in significantly fewer escitalopram than paroxetine recipients, and escitalopram recipients showed significantly lower mean changes in discontinuation emergent signs and symptoms scores than paroxetine recipients. In large analyses of placebo-controlled and relapse-prevention studies in patients with major depressive disorder or anxiety disorders, there was no indication of increased risk of suicidal behaviour in escitalopram or placebo recipients, with no completed suicides during the first 2 weeks of escitalopram or placebo therapy. Moreover, in an analysis of pharmacovigilance post-marketing surveillance information, escitalopram recipients had a low suicide rate (1.8 per million prescriptions).

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