Escitalopram (S‐Enantiomer of Citalopram): Clinical Efficacy and Onset of Action Predicted from a Rat Model

Abstract

Escitalopram is the active S-enantiomer of citalopram. In a chronic mild stress model of depression in rats, treatments with both escitalopram and citalopram were effective; however, a faster time to onset of efficacy compared to vehicle treatment was observed for escitalopram-treated (5 mg/kg/day) than for citalopram-treated (10 mg/kg/day) rats at Week 1. To study the predictability of this observation in the clinic, we analysed 4-week data from an 8-week, doubleblind, randomised, placebo-controlled, flexible-dose study that compared escitalopram and citalopram to placebo in primary care patients with major depressive disorder (baseline Montgomery and Åsberg Depression Rating Scale (MADRS) scores Ø22 and AE40). Since the flexible dosing started after Week 4, analysis of 4-week data ensured that the patients received fixed doses of 10 mg/day escitalopram (155 patients), 20 mg/day citalopram (160 patients), or placebo (154 patients). The efficacy analysis showed a significantly superior therapeutic effect for escitalopram versus placebo from Week 1 onwards (observed cases) with an adjusted mean change in MADRS at Week 4 (last observation carried forward) of 2.7 points (PΩ0.002). By comparison, 20 mg/day citalopram did not demonstrate a statistically significant effect compared to placebo. Escitalopram was well tolerated with an adverse event profile similar to that of citalopram. The preclinical observation that escitalopram possesses a faster time to onset of efficacy than citalopram was also seen in primary care patients with major depressive disorder. Thus, escitalopram is efficacious in depression and the effect occurs earlier than for citalopram.Currently, citalopram is one of the most widely prescribed antidepressants. It is a potent, highly selective serotonin reuptake inhibitor with high affinity for serotonin reuptake sites and low affinity for noradrenaline and dopamine reuptake sites. Citalopram exists as a chiral compound that is a racemic mixture of R-and S-enantiomers in a 1:1 ratio. Escitalopram, the active S-enantiomer of citalopram, mediates serotonin reuptake inhibition (Hyttel et al. 1992;Owens et al. 2001) and antidepressant activity (Hogg & Sánch-ez 1999), and has increased selectivity and potency compared to citalopram.Depression is a very common and widespread disorder with an estimated lifetime prevalence of 16 to 17% in both Europe and the United States (Kessler et al. 1994;Lépine et al. 1997). According to the World Health Organisation (Murray & Lopez 1997), depression is now associated with more years of disability than any other chronic disorder. Some common complicating factors in the treatment of depression are that the therapy itself may be associated with adverse drug reactions or it may fail to alleviate the condition. There is an unmet need for improvements to the currently available drugs with some of the key areas for improvement being: faster onset of action than current ther- apies, increase of the proportion of patients who respond to treatment, better long-term ef...

PET measurement of serotonin transporter occupancy: a comparison of escitalopram and citalopram

“…Interestingly, when the amounts of S-Cit are equal the onset of effect of S-Cit alone has been shown to be faster compared to that of R,S-Cit, both in a nonclinical study using a rat behavioural model and in a clinical study on patients with major depressive disorder (Montgomery et al, 2001). This difference in time to response, and in the proportion of responders has been replicated in several clinical studies Colonna et al, 2005 ;Lepola et al, 2003 ;Moore et al, 2005).…”

Behavioural and transcriptional effects of escitalopram in the chronic escape deficit model of depression

“…However, as already performed in other behavioural models of depression [15,18], ESC treated-animals (n = 38) were divided into responders (ESC/R; n = 18) and non-responders (ESC/NR; n = 20), both group possessing a definite phenotype reflecting itself in the number of escapes totalized at test session. Animals were considered ESC/R if their score in the escape test was higher than 15, while ESC/NR scored less than 9 escapes in the test (Supplementary Fig.2).…”

“…In preclinical studies, a 4-week treatment with ESC is able to normalize sucrose intake in the chronic mild stress model of depression [14][15][16][17][18]. Interestingly, the reversion of anhedonia is present only in about 50% of treated animals, thus leading to a subdivision of animals according to their behaviour into responders and non-responders [14].…”

In vivo imaging of serotonin transporter occupancy by means of SPECT and [123I]ADAM in healthy subjects administered different doses of escitalopram or citalopram

“…Escitalopram is the pure S-enantiomer of the racemic citalopram. Some clinical studies concluded that escitalopram may have some clinical advantages over citalopram (Montgomery et al 2001;Gorman et al 2002;Llorca et al 2005;Moore et al 2005;Kasper et al 2006;Lepola and Loft 2003).…”