Escitalopram

Summary

Abstract

Escitalopram (Cipralex®), a new highly selective serotonin reuptake inhibitor (SSRI), is the active S-enantiomer of RS-citalopram. It is effective in the treatment of patients with major depressive disorder (MDD) and may have a faster onset of therapeutic effect than citalopram. It has also been shown to lead to improvements in measures of QOL. Escitalopram is generally well tolerated, with nausea being the most common adverse event associated with its use.

Modelled pharmacoeconomic analyses found escitalopram to have a costeffectiveness and cost-utility advantage over other SSRIs, including generic citalopram and fluoxetine and branded sertraline, and also over the serotonin-noradrenaline reuptake inhibitor (SNRI) venlafaxine extended-release (XR). These studies used a decision-analytic approach with a 6-month time horizon and were performed in Western Europe (year of costing 2000 or 2001). Cost-effectiveness ratios for escitalopram, in terms of cost per successfully treated patient over 6 months, ranged from €871 to €2598 in different countries, based on direct costs and remission rates, and were consistently lower (i.e. more favourable) than the ratios for comparators (€970 to €3472). Outcomes similarly favoured escitalopram when indirect costs (represented by those associated with sick leave and loss of productivity) were included. The results of comparisons with citalopram, fluoxetine and sertraline were not markedly affected by changes to assumptions in sensitivity analyses, although comparisons with venlafaxine XR were sensitive to changes in the remission rate.

The mean number of QALYs gained during the 6-month period was similar for all drugs evaluated, but direct costs were lower with escitalopram, leading to lower cost-utility ratios than for comparators. Incremental analyses performed in two of the studies confirmed the cost-effectiveness and cost-utility advantage of escitalopram.

A prospective, 8-week comparative pharmacoeconomic analysis found that escitalopram achieved similar efficacy to venlafaxine XR, but was associated with 40% lower direct costs (€85 vs €142 per patient over 8 weeks; 2001 costs), although this difference did not reach statistical significance.

In both the modelled and prospective analyses, the differences in overall direct costs were mainly due to lower secondary care costs (in particular those related to hospitalisation) with escitalopram. In the prospective analysis, escitalopram had lower estimated drug acquisition costs than venlafaxine XR.

Conclusion: Escitalopram, the S-enantiomer of RS-citalopram and a highly selective SSRI, is an effective antidepressant in patients with MDD, has a favourable tolerability profile, and, on the basis of available data, appears to have a rapid onset of therapeutic effect. Modelled pharmacoeconomic analyses from Western Europe suggest that it may be a cost-effective alternative to generic citalopram, generic fluoxetine and sertraline. Although the available data are less conclusive in comparison with venlafaxine XR, escitalopram is at least as cost effective as the SNRI based on a prospective study, and potentially more cost effective based on modelled analyses. Overall, clinical and pharmacoeconomic data support the use of escitalopram as first-line therapy in patients with MDD.

Overview of Depression

Major depressive disorder (MDD) is a common condition with a lifetime prevalence of at least 5%. A chronic, recurrent illness, it is associated with significant disability, impaired health-related QOL and increased mortality, and is at least as debilitating as other chronic conditions such as diabetes mellitus and heart disease. However, it is often underdiagnosed and undertreated.

MDD imposes a significant economic burden on society. The total annual cost of depression in the UK was estimated to be £3.5 billion for 1990 (the most recent year for which this cost has been published). Most studies have shown that direct healthcare costs account for less than a third of the total costs associated with MDD. Within this, drugs account for only 2–11% of direct costs. Indirect costs account for the greater proportion of overall costs; they are harder to calculate, but in the UK have been estimated to be 7-fold greater than the direct costs of MDD.

Clinical Profile of Escitalopram in Depression

The antidepressant activity of escitalopram has been demonstrated in randomised, Escitalopram in double-blind comparative trials in patients with moderate to severe MDD. Depression Approximately half of these studies were reported as full papers and half as abstracts/posters.

Antidepressant activity was observed in patients treated with escitalopram 10–20 mg/day for 8 weeks, with significant improvements in Montgomery-Åsberg Depression Rating Scale (MADRS) scores compared with placebo being seen from as early as 1–2 weeks after starting treatment. At the end of 8 weeks, 49–64% of patients treated with escitalopram 10–20 mg/day had responded (≥50% decrease in MADRS score from baseline), compared with 28–48% of those receiving placebo (p < 0.05). Significant improvements were also seen for secondary efficacy parameters which included scores for the Clinical Global Impressions Improvement and Severity scales.

A meta-analysis found that, compared with placebo, escitalopram led to a statistically significant greater reduction in MADRS score (p < 0.01) from week 1, whereas it reached significance compared with placebo only at week 6 for citalopram.

MADRS scores continued to improve with longer-term (up to 1 year) treatment. After 36 weeks of treatment, escitalopram reduced the risk of relapse by 44% relative to placebo (p = 0.013).

Escitalopram 10–20 mg/day was at least as effective as citalopram 20–40 mg/day based on the preliminary results of a 24-week comparative study and a meta-analysis of studies of 8 weeks’ duration that included both escitalopram and citalopram arms. Response rates were 55.5% and 50.8% for escitalopram and citalopram in the latter analysis (p = 0.01), and escitalopram produced a significantly greater reduction in MADRS score from baseline than citalopram at week 1 (p = 0.02) as well as week 8 (p = 0.03). In one of the 8-week trials, time to response was 8.1 days faster with escitalopram than with citalopram (p < 0.05).

Escitalopram 10–20 mg/day had similar efficacy to venlafaxine extended-release (XR) 75–150 mg/day based on the preliminary results of an 8-week study. For those patients achieving response or remission, the mean times to response and remission were shorter with escitalopram by 4.6 (p < 0.05) and 6.6 days (p < 0.001). In a second study using fixed dosages, escitalopram 20 mg/day was as effective as venlafaxine 225 mg/day in the total patient population; in a subgroup of patients with severe MDD, escitalopram led to significantly greater reductions in MADRS scores than venlafaxine XR (p < 0.05).

Escitalopram was generally well tolerated in clinical trials, including during long-term treatment of up to 1 year, with most adverse events being mild and transient. The type of adverse events reported were similar to those recognised for citalopram. Nausea was the most common adverse event associated with escitalopram, occurring in >10% of patients. Other adverse events with a higher incidence than seen in placebo-treated patients included increased sweating, insomnia, somnolence, dizziness, diarrhoea, constipation, decreased appetite, fatigue and sexual dysfunction (all <10%).

Preliminary data from one trial suggested that escitalopram 10–20 mg/day may be associated with significantly less nausea, constipation and sweating (p = 0.02) and less marked discontinuation-emergent signs and symptoms (p < 0.01) than venlafaxine XR 75–150 mg/day.

Escitalopram 10–20 mg/day significantly improved social functioning and QOL compared with placebo, and produced similar improvements in QOL to those seen with venlafaxine XR 75–150 mg/day in patients with moderate to severe MDD.

Pharmacoeconomic Analyses of Escitalopram

One prospective pharmacoeconomic analysis has been performed comparing escitalopram with venlafaxine XR. Five modelled analyses have compared escitalopram with citalopram, fluoxetine, venlafaxine XR and (in one study) sertraline. All studies evaluated cost effectiveness and several included an assessment of cost utility. The modelled analyses also estimated the effect of escitalopram on overall healthcare budgets for the treatment of depression. All analyses were performed in Western Europe. All studies evaluated direct healthcare costs; several also assessed indirect costs, as represented by the costs of sick-leave and associated lost production.

The prospective pharmacoeconomic analysis was performed in parallel with a multinational clinical trial comparing escitalopram 10–20 mg/day with venlafaxine XR 75–150 mg/day. Both antidepressants improved MADRS scores and QOL measures to a similar extent during the 8-week study. Escitalopram was associated with 40% lower direct healthcare costs than venlafaxine XR €85 vs €142 per patient over 8 weeks; 2001 costs); however, this did not reach statistical significance. The difference in direct costs was largely due to fewer escitalopram than venlafaxine-recipients requiring hospitalisation (0 vs 4 patients) and lower drug acquisition costs with escitalopram. Multivariate analysis showed that, when adjusted to cost drivers at baseline, direct costs were significantly lower with escitalopram than venlafaxine XR (coefficient = -0.57, p = 0.03). Indirect costs per patient were similar for both groups (€680 for escitalopram and €689 for venlafaxine XR). There was no statistically significant difference between the two treatment groups in terms of incremental cost-effectiveness ratios based on direct costs and QOL outcomes.

The modelled pharmacoeconomic analyses were performed in Finland, Norway, Sweden, Belgium and the UK (year of costing 2000 or 2001). All used similar methodology, were based on a two-path decision analytic model with a 6-month time horizon, and evaluated cost effectiveness, cost utility (except the Norwegian study) and the potential effect of escitalopram on overall healthcare budgets for the treatment of depression.

In all of the modelled analyses, escitalopram was more cost effective from the healthcare provider perspective than generic citalopram, generic fluoxetine, venlafaxine XR and sertraline (assessed in the UK study only) in the treatment of MDD. Cost-effectiveness ratios based on direct healthcare costs per successfully-treated patient (MADRS score ≤12) over 6 months ranged from €871 to €2598. In each country the ratio was lower (i.e. more favourable) for escitalopram than for the comparators (range for comparators: €970–€3472). This was largely due to lower secondary care costs for escitalopram. Limitations of the analyses included a lack of direct comparative clinical trial data between escitalopram and most of the comparator agents. In the three studies in which indirect costs were evaluated, escitalopram was also more cost effective from the societal perspective. In general, the results were supported by sensitivity analyses, although the outcome against venlafaxine XR was sensitive to changes in the escitalopram remission rate at the lower boundary of probabilities tested.

Incremental analyses performed in the UK and Belgian studies confirmed the comparative cost-effectiveness advantage associated with escitalopram. In addition, although all of the evaluated drugs were considered to result in similar QALYs gained, escitalopram was associated with lower direct healthcare costs, resulting in a cost-utility advantage for escitalopram over the comparators for the 6-month study period.

Assuming a scenario in which only patients receiving branded citalopram are switched to escitalopram, the 2004 total healthcare budgets for the treatment of depression in Finland, Norway, Sweden and the UK were estimated to be reduced by 2.4–4.4%.