Brand Name:¹ Lexapro®
Generic Name:¹ Escitalopram Oxalate
Manufacturer:¹ Forest Pharmaceuticals, Inc.
Drug Class:¹ Selective serotonin reuptake inhibitor (SSRI)
Labeled Uses:¹ Treatment of major depressive disorder
Mechanism of Action:¹ Escitalopram works by inhibiting serotonin reuptake. This action enhances the serotonergic activity in the CNS, which relieves depression symptoms.

Metabolism:^1,2 Escitalopram is hepatically metabolized to S-demethylcitalopram (S-DCT) and S-didemethylcitalopram (S-DDCT). Studies show that escitalopram is at least 7 and 27 times more potent than S-DCT and S-DDCT, respectively, in the inhibition of serotonin reuptake. This suggests that the metabolites are relatively inactive.¹ CYP3A4, CYP2C19, and CYP2D6 are the enzymes involved in escitalopram metabolism.

Excretion:¹ Escitalopram is renally excreted. Following oral administration, the fraction of drug recovered in the urine as escitalopram and S-DCT is approximately 8% and 10%, respectively.

Efficacy:

This was an 8-week, double-blind, parallel-group, fixed-dose study comparing escitalopram with placebo. This study took place from August 1999 to August 2000 in 40 primary care centers in Canada, Estonia, France, the Netherlands, and the UK. A total of 380 patients were randomized to receive a fixed, 10 mg dose of placebo (n=189) or escitalopram (n=191). The primary outcome measured was the change from baseline to the final assessment of the Montgomery-Asberg Depression Rating Scale (MADRS) score.

The results showed that escitalopram consistently produced a greater reduction in antidepressant scores when compared to placebo. The difference in MADRS baseline to week 8 score favored escitalopram over placebo and was statistically significant (P = 0.002). When examining the weekly assessments, escitalopram was statistically significantly better than placebo from week 2 onwards. Escitalopram was statistically significantly better than placebo on the Clinical Global Impression- Severity Score (CGI-S) from week 3 onwards and on the CGI-Improvement Score (CGI-I) at all weeks post-baseline. Results showed that escitalopram 10 mg was more efficacious in the moderately depressed as opposed to the severely depressed subjects. This suggests that more severely depressed patients may need a higher dose of the drug. Escitalopram was well tolerated, with only mild to moderate adverse events. Nausea was the only adverse event that occurred more often in the escitalopram group compared to placebo (P < 0.05). The withdrawal rate was similar in both the escitalopram and placebo groups.

The baseline characteristics could limit the generalizability of the results. There was a 3:1 ratio of women to men and 97% of the participants were Caucasian. Thus, the results can be applied to mainly Caucasians and women.

In conclusion, this study shows that 10 mg of escitalopram is effective and tolerable in the patient population that was studied.³

This was an 8-week, randomized, double-blind, placebo controlled study that took place at 35 centers in the United States. This study was conducted to measure the safety and tolerability of escitalopram. A total of 491 patients entered the study and were randomized into four groups: 119 received escitalopram 10 mg/day, 125 received escitalopram 20 mg/day, 125 received citalopram 40 mg/day, and 122 received placebo.

The MADRS, the 24-item Hamilton Rating Scale for Depression (HAM-D), the CGI scales, and the Hamilton Rating Scale for Anxiety (HAM-A) measured the outcomes.

At the end of the 8-week study period, change from baseline on the MADRS, HAM, and CGI scores were statistically better for both escitalopram groups when compared to placebo. Citalopram also produced significant improvement in all efficacy measures when compared to placebo when examining the change from baseline. There were no significant differences in change from baseline between the escitalopram 20 mg group and the citalopram 40 mg group on the MADRS and the CGI-S. Citalopram 40 mg/day was not more effective than escitalopram 10 mg/day using any scale. Both doses of escitalopram significantly improved anxiety symptoms according to the HAM-A. The rate of discontinuation due to adverse events and the overall occurrence of adverse events was the same for the escitalopram 10 mg group compared to the placebo group and for the escitalopram 20 mg group compared to the citalopram 40 mg group.

This study was supported by a grant from Forest Pharmaceuticals, Inc., the manufacturer of Lexapro® (escitalopram oxalate). This could result in a potential study bias with the researchers, which may affect the outcome of the study. There was no mention of power in the study, so there is a chance that a Type 2 error may have occurred as a result of not having enough subjects.

The study results conclude that escitalopram is efficacious and well tolerated at even the lowest dose of 10 mg per day.⁴

This was a two part study that first measured both escitalopram and citalopram efficacy in a mild stress model with rats. A control group was included. Over a five-week period, the rats were trained to consume a 1% sucrose solution after 14 hours without food or water, on two occasions per week. Over the next nine weeks, the rats experienced two 10-14 hour stress periods per week, enduring cage tilting, soiling of the bedding, and strobe lights. The intake of sucrose was measured 14 hours after the stressful periods. Before the stress periods in weeks 4-9, rats were pre-medicated with 1.0 mL/kg of saline (control) and the study group received citalopram 10 mg/kg or escitalopram 5 or 10 mg/kg. The sucrose tests were then performed 24 hours after the drugs were administered. The results showed that the chronic stress lead to a decrease in the consumption of the sucrose solution. Before the stress tests began, the rats were consuming about 15 g of sucrose per day. After the first three weeks of stress, the consumption rate dropped to 8 g per day (P=0.001). Neither citalopram nor escitalopram affected sucrose consumption in the control or unstressed group. However, both citalopram and escitalopram increased sucrose consumption in the stressed group.

Next, a multi-national, parallel-group study, was conducted in 69 primary care centers with a total of 471 patients. Four-week data that was part of an 8-week, double-blind, placebo-controlled, flexible-dose study was presented. The study compared the safety and efficacy of escitalopram 10 mg/day to citalopram 20 mg/day and placebo, and compared the onset of efficacy of escitalopram to citalopram. Only data from the first 4 weeks was presented because doses were fixed to that point. The change in depressive symptoms from baseline was measured with the MADRS, CGI-I, and CGI-S scales.

The results showed that improvement with escitalopram was greater than improvement with placebo from week 1 to week 4. Improvement with citalopram 20 mg was not different from placebo. Escitalopram had a similar adverse affect profile as citalopram and seemed to be well-tolerated. The results also showed that escitalopram exhibited a faster onset of efficacy (efficacy shown in week 1) versus citalopram.

The length of time for antidepressants to be effective is usually 4 to 6 weeks. Since the study period was only 4 weeks, the drugs may not have demonstrated their full effects, but the results do suggest a faster onset of action with escitalopram. Also, the ratio of women to men was 3:1 and most of the patients were Caucasian. This would limit the applicability of these results to mainly women and Caucasians.

In conclusion, escitalopram has proved be safe and efficacious for the treatment of depression and it also has a faster onset of action than citalopram.⁵

Incidence of Adverse Effects in Placebo-Controlled Clinical Trials:¹

*Indicates incidence of 5% or greater and occurred twice as often in Lexapro® versus placebo group.

Monoamine Oxidase Inhibitors (MAOI) and SSRI’s may synergistically elevate blood pressure possibly resulting in serious events, even death. Lexapro® and MAOI’s should not be used in combination, unless Lexapro® is given after 14 days of discontinuing the MAOI. A MAOI should also not be started until 14 days after stopping Lexapro® treatment.

Alcohol may potentiate cognitive and motor effects when given with Lexapro® so it should be avoided.

Lithium and Sumatriptan may enhance the serotonergic effects of Lexapro® which may produce weakness, hyperreflexia, and incoordination, so patients should be educated about this issue.

Warfarin administered with Lexapro® resulted in a 5% increase in prothrombin time, but significance is unknown.

Carbamazepine may increase the clearance of escitalopram.

Metoprolol plasma levels may be increased when used with Lexapro, so metoprolol levels should be monitored.

CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of escitalopram. Because various enzymes metabolize escitalopram, the inhibition of only one enzyme may not affect escitalopram clearance.

CYP2D6 inhibitors may have some clinical effects on escitalopram metabolism. Caution should be advised when using CYP2D6 metabolized drugs with escitalopram.

Usual Dose: Lexapro® is available in 10 mg or 20 mg tablets. The recommended starting dose of Lexapro® is 10 mg/day. If the dose is increased to 20 mg, this should occur after at least one week. It should only be given once daily, either morning or evening, with no regard to meals.

Geriatric Dose: 10 mg /day is recommended for most elderly patients.

Pediatric Dose: Safety and efficacy in pediatric patients have not been studied.

Hepatic Impairment: 10 mg/day is recommended for those with hepatic dysfunction.

Renal Impairment: No dosage adjustment is needed for mild or moderate renal dysfunction, but caution is advised with severely renal impaired patients.

Conclusion:^1,4 Lexapro® demonstrates the potential that resolution of enantiomers have for improving therapeutic outcomes. Lexapro® 10 mg/day, is at least as effective as Celexa®, 40 mg/day. This indicates that the patient can be exposed to less than half the amount of drug and get the same benefits. Citalopram may also have a faster onset of action than citalopram. Incidence of adverse effects was not different for Lexapro® when compared to Celexa®.

1. Package Insert. Lexapro®. http://www.lexapro.com. Accessed on Sept 25, 2002.

2. Lundbeck H. Escitalopram oxalate. Drugs of the Future 2001:115-20.

3. Wade A, Lemming OM, Hedegaard KB. Escitalopram 10 mg/day is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol 2002 May; 17(3):95-102.

4. Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 2002 Apr; 63(4):331-6.

5. Montgomery SA, Loft H, Sanchez C, Reines EH, Papp M. Escitalopram (S-enantiomer of citalopram): Clinical efficacy and onset of action predicted from a rat model. Pharmacol Toxicol 2001 May; 88(5):282-6.

Lori R. Griffin, Pharm D. candidate

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