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Escitalopram in Adolescent Major Depression

James L. Schaller, MD, PA; David B. Rawlings, PhD, PA

Medscape General Medicine. 2005;7(1):6. Posted 01/31/2005

Abstract and Introduction

Abstract

Escitalopram is the purified functional isomer contained in citalopram. Escitalopram is now prescribed in 26 countries. In the United States, the only US Food and Drug Administration (FDA)-approved selective serotonin reuptake inhibiter (SSRI) for adolescents is fluoxetine. However, in clinical practice all antidepressants are used in adolescents. Five patients had parents who opted for the use of escitalopram instead of other treatments. Reasons included poor response and side effects from other SSRIs. Specifically, escitalopram was considered possibly less likely to cause obesity than paroxetine. It also caused a lower frequency of akathisia than fluoxetine, more stable blood levels over years than sertraline, very low drug interactions, and a low onset of anxiety if using a 5-mg starting dose. Although studies in adolescents are very limited for escitalopram, its parent medication — citalopram — has been used in over 40 million patients. Parents and adolescent patients should be made aware of all antidepressant options, if psychopharmacology is indicated. In some patients, escitalopram may have use.

Introduction

Escitalopram is the purified functional isomer contained in citalopram. Specifically, escitalopram is the S-enantiomer of citalopram. The latter is used worldwide in 89 countries and in approximately 40 million patients. Since it was first approved in Denmark in 1989, escitalopram has been prescribed in 26 countries.[1-3]

In the United States, the only FDA-approved selective serotonin reuptake inhibiter (SSRI) for adolescents is fluoxetine.[4] It is preferred if caretakers wish an FDA-approved SSRI for their adolescents. Also, fluoxetine typically does not have withdrawal symptoms if a dose is missed. However, this SSRI may not always be functional or optimal. We describe some cases in which escitalopram may be considered a useful alternative.

After our treatment of these 5 patients, it seemed appropriate to report our retrospective experience for a number of reasons. First, clinically, escitalopram is not a clone of any other SSRI. Second, we had some reasonable success with escitalopram in youth who had poor experiences with other SSRIs. Third, we had previously studied citalopram in youth[5] and believed that the purified functional isomer may make less demands on the liver and require less liver-detoxification chemicals for excretion. Finally, escitalopram is prescribed by child and adolescent psychiatrists, with little published discussion. We hoped that presenting these patients would initiate discussion of the strengths and weaknesses of escitalopram and lead to more sophisticated studies in adolescents.

Methods

Patients were seen in a private practice outpatient center. They dealt entirely with the treating child and adolescent psychiatrist. This treatment took place at the Chester County Research Center in Pennsylvania from 2002 to 2003 and Professional Medical Services of Naples, Florida, in 2003. Patients were diagnosed by a routine, 3-hour interview performed over 2 weeks, which involved 1 hour with the parents, 1 hour with the adolescent patients, and a final hour to present the diagnosis and treatment options.

Occasionally, escitalopram was offered as a treatment, especially after other SSRIs caused problems. Both the parents and the patients were aware that escitalopram was not FDA-approved for adolescents. They understood that the parent drug had some use in adolescents worldwide, but that both the parent compound and escitalopram had minimal publications in youth depression treatment. However, because these 5 subsequent patients had problems with other SSRI options, they did not rule out escitalopram due to adolescent publication number.

Informed consent was a copy of the medical information provided on escitalopram from the Mayo Clinic, Rochester, Minnesota.[6] An Institutional Review Board was not involved because these were merely individual clinical patients, with their parents, deciding what was the best antidepressant option. Escitalopram was never the only medication offered, and typically at least 3 options were offered. With only 1 FDA-approved antidepressant for adolescents, it was believed that parents and their children would be best suited to make a medication choice. Over time when it appeared that some youth had a positive experience, this retrospective, small case series was believed to be worthy to advance discussions on escitalopram in adolescents. Does it have a place in adolescent psychopharmacology?

Case 1

A 16-year-old girl with 2, mildly obese parents had a body mass index of 34 and a 37-in waist. She was diagnosed with major depression (MD) from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria via a clinical interview and by the inventory to diagnose depression (IDD).[7] Her symptoms included fatigue, sadness, anhedonia, new restlessness, and social anxiety. Paroxetine was started by her behavioral pediatrician in an effort to simultaneously treat her social anxiety and MD. She was started on 5 mg without side effects, but at 3 weeks she had no MD improvement. She was subsequently increased to 25 mg over 3 months. She demonstrated a reduction in her MD from an IDD of 36 to 13 (0-10 is normal), but she gained 12-15 lb.

As a result of her demoralization and frustration from her weight gain, paroxetine was decreased to 10 mg and she was placed on escitalopram 7.5 mg. Her IDD scores were 11, 14, and 9 spaced over 4 weeks. She lost 6 lb in a month. The following month escitalopram was raised up to 20 mg. After the removal of the paroxetine and the addition of the escitalopram, she lost an additional 10-12 lb over 2 months. It appears that paroxetine may increase weight in some patients, and this probably includes adolescent patients.[8]

Case 2

A 15-year-old boy with a DSM-IV-TR diagnosis of MD reported feeling "uncomfortable, and miserable" and needing "to move" daily, after being on fluoxetine 20 mg/day for 3 weeks. He had no baseline anxiety disorder or anxious cognitions — only new body restlessness. Upon starting the fluoxetine, his discomfort was reported to his pediatrician, who told his mother, "It would go away." When his status remained unchanged over 5 weeks, the youth was reduced to 10 mg with a partial decrease in his agitation that was still very unacceptable to the boy.

The youth was diagnosed by a child psychiatrist as having fluoxetine-induced akathisia. He was placed on escitalopram 5 mg with subsequent cessation of his agitation and restlessness in 2 days. He reported "mild" headaches, during his first 36 hours, and escitalopram was increased to 10 mg on day 7. He was increased to 20 mg escitalopram due to residual anhedonia and a sad mood. He had complete remission of his MD in 6 weeks, with no symptoms of restlessness, akathisia, parkinsonian symptoms, dystonia, or bruxism.

We did a literature search of PubMed, specifically searching each movement disorder mentioned above with common antidepressants. We found extensive studies of SSRI-induced movement disorders associated with fluoxetine, sertraline, and paroxetine.[9] However, fluvoxamine and escitalopram/citalopram had only a few incidents in the literature. We hypothesize that this is not due to a shortage of studies, because each medication mentioned has thousands of publications in PubMed. And although nefazodone and venlafaxine had minimal reports of movement disorders, they also had fewer references — nefazodone with 515 references and venlafaxine with 1045 references. Differing receptor affinities may play a role in movement disorder variation.

Case 3

A 17-year-old girl was successfully treated for DSM-IV-TR MD for approximately 2.5 years on increasing doses of sertraline. The patient initially had a 4-month remission of MD on 75 mg of sertraline. She then required an increase of 37.5 mg over 12 weeks in the winter while residing in the Northeast of the United States. She was diagnosed as having a seasonal affective disorder in addition to her MD. A steady-state, "peak" blood level was drawn 5-7 hours after morning dosing, which was 61 ng/mL.

The following winter she had a relapse of MD, in the absence of any significant psychosocial stressors, and required 200 mg of sertraline. Her peak, steady-state level was 174 ng/mL. A year later, she had a sertraline level of 93 ng/mL and was judged as having another relapse of MD. (No medications, nutrients, herbs, or foods could be identified as confounders of sertraline metabolism.)

Her family, the treating physician, and the patient were concerned about continuous relapses and possible serum level drift. As a result, she was started at 5 mg of escitalopram in addition to her sertraline 200 mg with full remission. She was weaned to 25 mg of escitalopram and terminated sertraline over 2 months. She has had no relapse in 7 months, and without need for a medication increase. We hypothesize that sertraline has a possible downward serum level drift each year. This drift may allow for a breakthrough in seasonal affective disorder symptoms during the winter months in the Northern United States. It is unclear whether this exists in other SSRIs over years in treatment.

Case 4

A 14-year-old girl had migraines, MD, and impulse disorder not otherwise specified by the DSM-IV-TR criteria. Her mother found various drug interactions with SSRIs on the Internet. Specifically, she read that risperdal and propranolol, 2 medications her daughter was currently receiving, could interact with many SSRI options. She asked for the antidepressant with the lowest possible interactions. Because escitalopram's preliminary data have markedly low interactions at the CP450 system[9-12] and were reported to have no discernable interactions with over 125 neurologically relevant ligands (including the receptors associated with common SSRI side effects),[13] it was her mother's choice for treatment. Her daughter was started on 5 mg at night. After 1 week, escitalopram was raised to 10 mg, and in a month she was placed on 15 mg, where she has remained MD-free for 4 months.

Case 5

A 15-year-old girl was diagnosed with MD by the DSM-IV-TR and was reported to have borderline personality traits by her psychologist. On intake, her mother and maternal aunt volunteered that they both had good responses to citalopram for their own MD. They wanted their genetic experience considered in any medication choice. The mother added that she had "a panic attack on paroxetine" starting at 10 mg, and the aunt also had panic symptoms when started on fluoxetine at 20 mg.

The youth was started on one fourth of 10 mg of escitalopram for 2 days and then increased to 5 mg without side effects. In 7 days she was raised to 10 mg of escitalopram and judged to be in full remission 3 weeks later; her IDD decreased from 28 to 6. Against medical advice, the patient reduced her dose to 5 mg for 2 days and skipped 1 dose, because "it was a foreign chemical." She reported a return of her depressive symptoms and took 10 mg of her mother's old paroxetine. She had a panic attack within hours, yet was able to soothe herself by saying to herself, "This happened to my mom, it will go away."

The mother discarded her own paroxetine, and the patient was restarted on 5 mg of escitalopram for 2 days and then subsequently 10 mg. She remained symptom-free of MD. She was rigorously educated on MD, as well as antidepressant functioning, and her psychologist addressed her acting out with medications. In the last 5 months, the patient has been stable, without any MD. Some studies report that escitalopram may reduce anxiety at onset.[14-16] Such claims seem consistent with this adolescent patient's experience.

Discussion

Escitalopram is one of many medications used in our adolescent patients, when psychopharmacology is considered prudent. In treatment sessions, the differences between antidepressants are discussed, so that patients with their parents can make informed choices. Over the years, other patients have been treated with escitalopram, and yet those patients had not been studied or quantified in any way. No retrospective chart review has been conducted or is planned. So we are unable to offer any discussion on the percentage and degree of favorable responses. These cases are meant to merely show illustrations of escitalopram's functionality in some patients.

However, we have noticed that escitalopram can require a very wide dose range for use, which is consistent with our clinical experience with other antidepressants. Some patients apparently required doses that are not part of the manufacturer's dosing range. Specifically, in patients with a history of significant allergy problems with fatigue and "sensitivity to medications," we found nausea and headaches at doses of only 5 mg. Reductions to 2.5 mg were often helpful. Surprisingly, dose increases were rarely needed.

Other adolescent patients were at the other dosage extreme. In individuals with an elevated tumor necrosis factor-alpha, an elevated sensitive C-reactive protein, an elevated matrix metalloproteinase-9, or a decreased alpha-melanocyte stimulating hormone, they generally needed doses higher than those FDA-approved, eg, 50-60 mg/day. Generally, these individuals were eventually found to have a significant inflammatory source, such as severe chronic sinus infections without pain, multiple tooth cavitations, or neurologic Borrelia burgdorferi infection confirmed by an erythema migrans rash, laboratory results, a clinical history, and positive single photon emission computerized tomographic (SPECT) scans. With treatment of the offending disease, dosages were universally lowered to common ranges, eg, 5-20 mg/day. But sometimes finding the inflammatory cause took up to 8 months.

Conclusion

Current antidepressant options available to child and adolescent psychiatrists are very diverse and are increasing. Current practitioners use a variety of FDA-approved medications in an off-label manner with adolescents. Choosing a medication for an adolescent is a complex decision. First, who should lead in the decision? We lean toward allowing patients and parents to be given the information available to make the decision, because the weight given to a medication's strengths and weaknesses is a value judgment. Escitalopram has proposed possible benefits in obesity problems, low rates of akathisia and dystonia, possible stable dosing and blood levels, a low drug-interaction profile, and low anxiety at onset. However, these proposed strengths need to be balanced by the medication's smaller adolescent patient numbers and fewer advanced escitalopram studies in adolescents compared with other antidepressants.

Modern, new-generation antidepressants are not clones, and have meaningful differences. These cases highlight some of the possible differences offered by escitalopram that will be clarified by future studies.

References

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  2. Psychotropics. Citalopram. Available at: http://www.psychotropics.dk/usr_view_molecule.asp Accessed July 25, 2003.
  3. H. Lundbeck A/S corporation Web site. 2004. List of product trademarks. Available at: http://www.lundbeck.com/investor/Productsandmarkets/Launchedproducts/Default.asp Accessed July 25, 2003.
  4. US Food and Drug Administration. Prozac for pediatric use. Available at: http://www.fda.gov/fdac/departs/2003/203_upd.html#prozac Accessed June 13, 2004.
  5. Schaller J, Behar D. Citalopram in child and adolescent depression with anxiety. Medscape General Medicine. 2001;3(4). Available at: http://www.medscape.com/viewarticle/408189 Accessed January 18, 2005.
  6. MayoClinic.com. Available at: http://www.mayoclinic.com Accessed January 18, 2005.
  7. Zimmerman M, Coryell W. The validity of a self-report questionnaire for diagnosing major depressive disorder. Arch Gen Psychiatry. 1988;45:738-740. Abstract
  8. Bandelow B, Behnke K, Lenoir S, et al. Sertraline versus paroxetine in the treatment of panic disorder: an acute, double-blind noninferiority comparison. J Clin Psychiatry. 2004;65:405-413. Abstract
  9. Schaller JL. Celexa and Lexapro vs regular SSRI's. Available at: http://www.personalconsult.com/articles/ssricme1.html Accessed June 2, 2004.
  10. Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI. Human cytochromes and some newer antidepressants: kinetics, metabolism, and drug interactions. J Clin Psychopharmacol. 1999;19:23S-35S.
  11. von Moltke LL, Greenblatt DJ, Giancarlo GM, Granda BW, Harmatz JS, Shader RI. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metab Dispos. 2001;29:1102-1109. Abstract
  12. Greenblatt DJ, Hesse LM, Giancarlo GM, Harmatz JS, Shader RI. The S-entantiomer of citalopram: cytochromes P450 mediating metabolism and cytochrome inhibitory effects. Program and abstracts of the 56th Annual Scientific Convention of the Society of Biological Psychiatry; May 3-5, 2001; New Orleans, Louisiana.
  13. Sanchez C, Brennum L. Escitalopram is a highly selective and potent serotonin reuptake inhibitor. In vitro studies. Program and abstracts of the 1st Annual Meeting of the Scandinavian College of Neuropsychopharmacology; April 18-20, 2001; Juan-Les-Pins, France.
  14. Gorman JM, Korotzer A, Su G. Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials. CNS Spectr. 2002;7:40-44. Abstract
  15. Fish EW, Faccidomo S, Gupta S, Miczek KA. Anxiolytic-like effects of escitalopram, citalopram, and R-citalopram in maternally separated mouse pups. J Pharmacol Exp Ther. 2004;308:474-480. Abstract
  16. Stahl SM, Gergel I, Li D. Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2003;64:1322-1327. Abstract

James L. Schaller, MD, Director, Professional Medical Services of Naples, Naples, Florida

David B. Rawlings, PhD, PA, Private Practice, Department of Psychiatry, Naples Community Hospital, Naples, Florida

Disclosure: James L. Schaller, MD, has disclosed that he has received unrestricted research grants from Forest, Cephalon, Wyeth, BioRay, Vitacost.com, and Zeneca. Forest is the manufacturer of escitalopram. Dr. Schaller is an educational materials consultant for AstraZeneca; a medical advisory board consultant with stock ownership for Nutraceutical Sciences Institute; and the inventor of a nutraceutical transdermal bioidentical antidepressant with a patent pending.

Disclosure: David B. Rawlings, PhD, PA, has disclosed no significant financial interests or relationships.


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