Escitalopram (Lexapro): Are Antidepressant Drug Isomers In Our Future?

Firoz Munshi, M.D.
Kamalullah Yusufzie, M.D.
Mohammad Wally Nawbary, M.D.
Liouda Voronovitch, M.D.
Oxana Matsenko, M.D.
Alex Krivtsov, M.D.
Irina Gurovich, M.D.
Shazia Sheikh, M.D.
Steven Lippmann, M.D.

Department of Psychiatry and Behavioral Sciences
University of Louisville School of Medicine
Louisville, KY

INTRODUCTION
Depression is a serious medical illness associated with a high morbidity, risk of suicide, and adverse social consequences. It prevails throughout the life cycle causing abnormal development and substantial suffering. The lifetime risk of major depressive disorder in the USA varies from 10-25% for women and 5-12% for men. [1] The annual health-care cost associated with depression in this country is estimated to be near $44 billion.
New generation antidepressant drugs have largely replaced tricyclic versions and monoamine oxidase inhibitors (MAOIs). There are several categories and types of these newer pharmaceuticals, which include selective serotonin reuptake inhibitors (SSRIs), as one group. Currently, there is significant interest in evaluating isomers of existing SSRIs for their potential antidepressant qualities. [2,3]

STEREOISOMERS AND ANTIDEPRESSANT DRUGS
Stereoisomers, also called enantiomers, are mirror images of identical chemical compounds, but with different potency and toxicity, labeled in 'R' and 'S' forms (i.e., R=dextrorotatory and L=levorotatory). Stereospecificity can be observed, for example, with the anticholinergic drug L-hyoscyamine being active in the peripheral nervous system, as compared to R-hyoscyamine, which is more potent centrally; the R-enantiomer of thalidomide exerts sedative properties, while the S-version is a teratogen. [3]
There are theories, which indicate that isomers of existing antidepressant medicines may offer greater potency, reduced toxicity, less complicated pharmacodynamics, and predictable dose-response relationships. [3,4] In other cases, different isomers of some compounds exhibit similar efficacy (e.g., fluoxetine), or that R- and S- racemic isomer mixtures are more desirable than single isomers (e.g., mirtazapine). [3] Citalopram is a racemic mixture of R- and S- enantiomers. [4] Escitalopram, contrastingly, is a newly developed drug-isomer of citalopram; it contains only the S-form. [5]

ESCITALOPRAM
Escitalopram has been evaluated primarily for its potential use to combat mild to moderate depression. It is credited with antidepressant effects and declared to offer greater selectivity and potency with fewer adverse effects or drug interactions, as compared to the original compound, citalopram. [5] Forest Pharmaceuticals is offering escitalopram to the market under the brand name Lexapro. A risk-to-benefit ratio comparison between these two similar antidepressant medications remained to be fully evaluated over use and time. There exist citations claiming advantages for escitalopram over citalopram; [3,5] however, other studies suggest less difference between these two options. [6,7]

PHARMACOLOGY
Escitalopram inhibits reuptake of serotonin (5-HT) via binding to serotonin transporter (5-HTT), resulting in increased serotonin availability at the synapses. [6] Occupancy of 5-HTT increases with the drug serum level up to a plateau. Initial desensitization and then down-regulation of transporter protein occurs after long-term administration of the drug, which reduces 5-HT clearance and raises cortical serotonin concentrations. [7] It exhibits minimal to no effect on norepinephrine or dopamine reuptake. [6]

PHARMACOKINETICS
Escitalopram is well absorbed orally regardless of food intake with an effective half-life of approximately one-day. [8] It is extensively metabolized in the liver with 8% excreted unchanged by the kidneys. Transformation of escitalopram to its metabolites takes place via the hepatic cytochrome isoenzymes (CYPs), which include CYP 2C19, CYP 2D6, and CYP 3A4. [7] Metabolic products are reported to be unlikely to cause clinically important drug interactions via CYP inhibition. Table I illustrates one report on the cytochrome P450 profile of six different SSRI drugs. [3]

INDICATIONS
The primary indication for escitalopram is mild to moderate major depression. [5,9] It is reputed to be effective for patients with comorbid depression and anxiety. [4,9] These dual expressions of illness are presently of active clinical interest. This medication is also suggested to be of benefit in the treatment of anxiety disorders without affective illness, including panic attacks, social phobia, premenstrual dysphoria, and obsessive-compulsive disorders. [10]
SOME CLINICAL RESEARCH
A randomized, placebo-controlled study was conducted on 491 subjects with major depression. [5] Following a single-blind placebo lead-in period, participants were randomly assigned to receive eight weeks of double-blind oral treatment with placebo, escitalopram 10 mg/day, escitalopram 20 mg/day, or citalopram 40 mg/day. Escitalopram, 10mg/day, reportedly had a better therapeutic effect as compared to placebo from the first week onward. Escitalopram was well tolerated with a side effect pattern similar to citalopram. A faster onset of action as compared to citalopram was announced. Escitalopram, at 10 mg/day, was considered to be as effective as citalopram 40 mg/day.
Another investigation reviewed the efficacy of escitalopram and citalopram as compared to placebo treatment for anxiety symptoms in depressed subjects. [11] Escitalopram appeared to exhibit a faster onset of action at week one, while citalopram was not significantly more effective than placebo until after one month. Side effects were uncommon in all three groups.
Other research was conducted for 12 weeks in outpatients with panic disorder. [12] Subjects underwent randomized, double-blind treatment with placebo or escitalopram. Dosage for escitalopram was titrated from between 5-20 mg/day. At 10 mg/day, escitalopram was said to have produced significant relief in anxiety symptoms and better quality of life.
SIDE EFFECTS
Table II lists and contrasts the common patient complaints associated with placebo, citalopram, and escitalopram use. [5,11,12] Less than 6% of escitalopram-treated subjects
needed to stop taking this medicine due to side effects, as compared with 2% of those on placebo. However, with escitalopram 10 mg/day, the incidence of discontinuation was similar to placebo. [5] Uncommon complaints include headache, dizziness, diaphoresis, and back pain. There were no clinically remarkable changes observed in vital signs, electrocardiogram, or routine laboratory values. [5,11,12]

DOSAGE AND AVAILABILITY
The manufacturer's recommended daily oral dose is 10 mg with titration up to 20 mg/day, if needed after a period of one week. [5] In major depression, both 10 and 20 mg/day have been reported to be effective. Anxiety symptoms with major depression were said to improve with escitalopram at 10 or 20 mg/day. Escitalopram, in flexible daily doses of 10 to 20 mg, is judged as a pharmaceutical helpful in treating several anxiety disorders. [10]
Escitalopram, 10 mg daily, is the recommended starting dose for elderly people and for patients with hepatic impairment. Escitalopram is available in three different strengths, as seen in Table III; it includes white tablets in three quantities: 5 mg, 10 mg, and 20 mg.

PRECAUTIONS
Escitalopram should not be prescribed to nursing mothers since it is excreted in breast-milk. [8,13] Animal studies show teratogenic effects of escitalopram, not yet substantiated in human studies. [13] Therefore, escitalopram must not be administered to pregnant patients. Physicians must screen females for pregnancy prior to prescribing escitalopram. Concomitant use with MAOIs can produce a serotonin syndrome; escitalopram should not be initiated for at least two weeks after stopping a MAOI and vice-versa. [5,9,13]
Dosage reduction and more careful clinical monitoring are initially needed in older persons and patients with hepatic impairment. [13] Escitalopram should also be prescribed with greater caution for individuals with significant renal impairment. [13]

COMMENTS
The combination of a reported favorable efficacy and high tolerability might make escitalopram a good new therapeutic option in the treatment of depression, with or without anxiety, and may be even for anxiety disorders alone. Escitalopram is said to be the SSRI least likely to inhibit P-450 isoenzymes, which if true, would be important to patients taking multiple medications and/or those with significant other illnesses. Continuation of this pharmacotherapy is judged to reduce the risk of depression relapse. Long-term clinical use over time should better clarify the risks and benefits of this new drug. The claims of a faster onset of action, while they may well prove to be true, have often been made at the introduction of other antidepressant medications. Time will tell.

REFERENCES
1 Sampson M: Treating depression with selective serotonin reuptake inhibitors: A practical approach. Mayo Clinic Proceedings 2001;76(7):739-744
2 Everett A: Pharmacology treatment of adolescent depression (Therapeutics and toxicology). Current Opinion in Pediatrics 2002;14(2):213-218
3 Stereochemistry and the Enantiomer Escitalopram. Psychiatric Times, June 2002; (supplement)
4 Rosak J: Isolating isomer enhances antidepressant efficacy. Psych News 2002;8:17
5 Burke W, Gergel I, Bose A: Fixed-dose trial of the single isomer escitalopram in depressed outpatients. J Clin Psychiatry 2002;63(4):331-336
6 Meyer J, Wilson A, Ginovart N et al: Occupancy of serotonin transporter by paroxetine and citalopram during treatment of depression: A [11C] DASB PET Imaging study. Am J Psychiatry 2001;158(11):1843-1849
7 Von M, Greenblatt D, Giancarlo G, et al: Escitalopram (S-citalopram) and its metabolites in vitro: Cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metabolism and Distribution 2001;29(8):1102-1109
8 Thomson MICROMEDEX,2002; http://www.micromedex.com
9 Gorman J, Korotzer A, Su G: Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: Pooled analysis of placebo-controlled trials. MedWorks Media 2002;(Academic Supplement):40-44
10 Davidson J, Bose A, Su G: Escitalopram in the treatment of generalized anxiety disorder. Presentation at the 22nd National Conference of the Anxiety Disorders Association of America, March 2002, Austin, TX
11 Lydiard B: Effects of escitalopram on anxiety symptoms in depression. Presentation at the Annual Meeting of the American Psychiatric Association, May 2001; New Orleans, LA
12 Stahl S, Gergel I, Li D: Escitalopram in the treatment of Panic Disorder. Presentation at the 22nd national conference of the Anxiety Disorders Association of America, March 2002; Austin,TX
13 Lexapro current package insert. Rev. 7/02. Forest Pharmaceuticals, St. Louis, MO

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