jurnal psikiatri

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P E R S P E C T I V E

In June 2003, the Medicine and Healthcare Prod-ucts Regulatory Agency of the British Departmentof Health warned physicians to avoid the off-labeluse of paroxetine, a selective serotonin-reuptakeinhibitor (SSRI) antidepressant, for the treatment ofdepression in children (18 years of age or younger).This action was taken in response to concern abouta possible association between SSRIs and suicidalbehavior, which includes a broad range of symp-toms ranging from fleeting thoughts of self-harmto attempted suicide. Proprietary data examined bythe United Kingdom regulatory agency showed aslight increase in suicidal behavior among patientswho were randomly assigned to SSRI treatment, ascompared with subjects who received placebo (3.7percent vs. 2.5 percent). The U.S. Food and DrugAdministration (FDA) issued a similar warning,with a note of caution that paroxetine treatmentshould not be discontinued suddenly, so that with-drawal reactions can be avoided.

The issue now is whether SSRIs increase the riskof suicidal behavior in depressed children. The FDAhas initiated its own examination of this question.At a joint meeting on February 2, 2004, of the Psy-chopharmacologic Drugs Advisory Committee andthe Pediatric Subcommittee of the Anti-InfectiveDrugs Advisory Committee, the FDAs review re-vealed several problems in the interpretation of theavailable data and outlined plans for the ongoingevaluation of the results.

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On March 22, the FDAtook the additional step of requesting that labelson SSRIs and related antidepressants include awarning that all patients should be monitoredclosely for worsening depression or the emergenceof suicidality. (Further information is available atwww.fda.gov.)

Does this mean that SSRIs are simply unsafe? Aswith any treatment, the safety of these drugs is a rel-ative concept to be examined in the light of the se-verity of the disorder being treated and the antici-pated benefits and risks of treatment.

First introduced in the late 1980s, the SSRIs areconsidered to represent an improvement over olderantidepressants because they are better toleratedand are safer in overdose an important feature

for drugs that are prescribed to patients who are atincreased risk for suicide. Over the years, the use ofSSRIs in children has increased substantially. Flu-voxamine, sertraline, and fluoxetine are approvedby the FDA for the treatment of obsessivecompul-sive disorder in children, and fluoxetine is also ap-proved for the treatment of major depressive disor-der in patients eight years of age or older. In ad-dition, other antidepressants, such as paroxetine,citalopram, and venlafaxine (a drug that is closelyrelated to the SSRIs), are prescribed to children foroff-label use.

Both obsessivecompulsive disorder and majordepressive disorder can be severe illnesses, oftenhaving a chronic or recurrent course and causingsubstantial functional impairment. Although mostchildren with depression have symptoms similarto those seen in adults, such as sad mood, apathy,lack of energy, and vegetative signs, in some chil-dren the disorder is manifested only by irritabilityor social isolation and may not be brought to clini-cal attention. Prevalence estimates suggest that upto 6 percent of adolescents currently meet the crite-ria for major depressive disorder, and up to 25 per-cent have been affected by this disorder by their lateteens.

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Depression is a major risk factor for suicide,which ranks third as a cause of death among teen-agers in the United States. The increased use of anti-depressants among children 10 to 19 years of agehas been accompanied by a significant decrease inthe suicide rate in this age group.

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For each 1 per-cent increase in the use of SSRIs among adolescents,there was a decrease of 0.23 suicide per 100,000adolescents per year.

However, these findings represent an epidemio-logic association, rather than evidence of causality.To demonstrate a causal link, either positive or neg-ative, between antidepressant treatment and suicideis an extremely difficult task. Suicide is a relativelyrare event, and controlled clinical trials with thou-sands of subjects would be required in order to de-tect a possible treatment effect. In fact, no suicidehas ever been reported among the more than 4100subjects enrolled in pediatric clinical trials of SSRIs.Nonlethal suicidal attempts and suicidal ideation

Antidepressant Medications in ChildrenBenedetto Vitiello, M.D., and Susan Swedo, M.D.

Antidepressant Medications in Children

The New England Journal of Medicine Downloaded from nejm.org by rin bata on July 15, 2014. For personal use only. No other uses without permission.

Copyright 2004 Massachusetts Medical Society. All rights reserved.

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are more common, but establishing an associationwould still require systematic, controlled studies in-volving hundreds of subjects. Controlled trials typi-cally exclude patients who are considered to be athigh risk for suicide, such as those with a history ofsuicide attempts or current suicidal ideation. (How-ever, suicidal ideation is not an accurate predictor ofsuicide, since most persons with such ideation donot attempt or die by suicide.) Data bases of spon-taneously reported adverse events among commu-nity-treated patients, such as MedWatch, are also oflimited usefulness in addressing this issue, becausesuicidal behavior can be a symptom of depressionrather than a distinct toxic effect like agranulocy-topenia or liver failure. Keeping these methodolog-ic limitations in mind, what can we say about theriskbenefit balance of SSRI use in children?

For the treatment of obsessivecompulsive dis-order, the balance appears to be favorable: fluvox-amine, sertraline, and fluoxetine have been shownto be effective, and although they have been associ-ated with an increased rate of adverse behavioralevents such as nervousness and agitation, their ben-efits seem to outweigh the associated risks. For thetreatment of depression, the picture is more equiv-ocal. The efficacy of an antidepressant is consideredto be proved if two separate, independently con-ducted, controlled clinical trials have found a sta-tistically and clinically significant improvement withthe use of the medication as compared with the useof placebo. According to this definition, efficacy hasbeen proved only for fluoxetine.

The response rate was 56 percent with fluoxe-tine treatment and 33 percent with placebo in thefirst study, which was funded by the National Insti-tute of Mental Health (NIMH), and 65 percent withfluoxetine treatment and 53 percent with placebo inthe second study, which was funded by Eli Lilly.

4,5

These data, which are not substantially differentfrom those obtained in studies involving adults, in-dicate that fluoxetine is moderately effective in chil-dren, that there is a high rate of response to placebo(between one third and one half of patients), andthat the medication has no benefit for about onethird of patients. The rate of suicidal behavior wasthe same with fluoxetine treatment as with placeboin these two controlled trials. Agitation and manicsymptoms were more common with fluoxetinetreatment, affecting about 1 in 10 children, whichis similar to the rates reported with other SSRIs. Alladverse events resolved completely after the discon-

tinuation of treatment. The other SSRIs and venla-faxine have not been proved to have a favorableriskbenefit ratio, since there have not been repli-cative trials confirming the superiority of thesemedications over placebo. The high rate of responseto placebo appears to be the primary factor contrib-uting to the lack of statistically significant differ-ences between groups, as had been previously foundin trials of antidepressant medications in adults.

It is noteworthy that adverse behavioral eventssuch as agitation, hyperkinesia, mania, and hypo-mania tended to be more frequent among patientstreated with SSRIs (including fluoxetine) thanamong those receiving placebo (1 to 6 percent vs.0 to 4 percent).

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Although a causal link betweenSSRI use and suicidal behavior has not been provedby current data, it is theoretically possible that theagitation and nervousness that occur in some chil-dren treated with SSRIs might have the potential toincrease the risk of self-injurious acts; cliniciansmust therefore monitor patients carefully for suchadverse effects.

Nonpharmacologic interventions, such as cog-nitivebehavioral therapy and other psychothera-pies, have been found to be beneficial in childrenwith depression. One means of improving the riskbenefit balance associated with SSRIs may be to re-serve medications for those children who have per-sistent or recurrent forms of depression that aredeemed, on the basis of data from studies in adults,to be unlikely to respond to psychotherapy, behav-ioral or environmental change, or general emotionalsupport. In many cases, nonpharmacologic inter-ventions accompanied by an early follow-up ap-pointment may be helpful in establishing the per-sistence of a depressive syndrome before anydecision is made regarding the introduction of anti-depressant medication. An NIMH-funded, multi-site, controlled clinical trial, the Treatment for Ad-olescents with Depression Study, with more than400 enrollees, is currently comparing the relativeefficacy of fluoxetine, cognitivebehavioral therapy,and their combination; results are expected laterthis year.

While we search for answers to the questionsraised about the safety of SSRIs, we must not ig-nore the documented link between depression andsuicide. The sad reality is that depressed childrenand adolescents are at increased risk for attemptingand committing suicide. The recognition and ap-propriate treatment of children with depressive dis-




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orders remain vitally important; unfortunately, incaring for such a patient today, when the safety ofSSRIs is still under review, physicians may some-times be forced to choose a treatment that hasproven efficacy in adults with depression but hasnot yet been tested in children.

The views expressed in this article are those of the authors and donot necessarily reflect the views of the National Institute of MentalHealth, the National Institutes of Health, or the Department ofHealth and Human Services.

From the National Institute of Mental Health, Bethesda, Md.

1.

Psychopharmacologic Drugs Advisory Committee and the Anti-Infective Drugs Advisory Committee. Briefing information. Rock-

ville, Md.: Food and Drug Administration, February 2, 2004. (Ac-cessed March 18, 2004, at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/4006b1.htm.)

2.

Kessler RC, Avenevoli S, Merikangas KR. Mood disorders inchildren and adolescents: an epidemiologic perspective. BiolPsychiatry 2001;49:1002-14.

3.

Olfson M, Gameroff MJ, Marcus SC, Waslick BD. Outpatienttreatment of child and adolescent depression in the UnitedStates. Arch Gen Psychiatry 2003;60:1236-42.

4.

Emslie GJ, Rush AJ, Weiberg WA, et al. A double-blind, ran-domized, placebo-controlled trial of fluoxetine in children andadolescents with depression. Arch Gen Psychiatry 1997;54:1031-7.

5.

Emslie GJ, Heiligenstein JH, Wagner KD, et al. Fluoxetine foracute treatment of depression in children and adolescents: a pla-cebo-controlled randomized clinical trial. J Am Acad Child Ado-lesc Psychiatry 2002;41:1205-15.

In the past decade, high-density lipoproteins (HDL)have emerged as a new potential therapeutic targetfor the treatment of cardiovascular disease. The keyrole of HDL as a carrier of excess cellular cholesterolin the reverse cholesterol transport pathway is be-lieved to provide protection against atherosclerosis.In reverse cholesterol transport, peripheral tissues(e.g., vessel-wall macrophages) remove their ex-cess cholesterol through the ATP-binding cassettetransporter 1 (ABCA1) to poorly lipidated apolipo-protein A-I, forming pre-

b

-HDL. Lecithincholes-terol acyltransferase then esterifies free cholesterolto cholesteryl esters, converting pre-

b

-HDL to ma-ture spherical

a

-HDL (see Figure). HDL cholesterol is transported to the liver by two

pathways: through the first pathway, it is delivereddirectly to the liver through interaction with thescavenger receptor, class B, type I (SR-BI); throughthe second pathway, cholesteryl esters in HDL aretransferred by the cholesteryl ester transfer protein(CETP) to very-low-density lipoproteins (VLDL) andlow-density lipoproteins (LDL) and are then re-turned to the liver through the LDL receptor. HDLcholesterol that is taken up by the liver is then ex-creted in the form of bile acids and cholesterol, com-pleting the process of reverse cholesterol transport.

1

HDL also decreases atherosclerosis by protecting

LDL from oxidation.

2

Oxidized or modified LDL,unlike normal LDL, is readily taken up by the macro-phage scavenger receptor SR-A or CD36, resultingin the formation of foam cells. HDL may also slowthe progression of lesions by selectively decreasingthe production of endothelial celladhesion mole-cules that facilitate the uptake of cells into the ves-sel wall.

3

Several lines of evidence support the concept thatincreasing the HDL level may provide protectionagainst the development of atherosclerosis. Epide-miologic studies have shown an inverse correlationbetween HDL cholesterol levels and the risk of car-diovascular disease.

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Increasing the HDL cholester-ol level by 1 mg may reduce the risk of cardiovas-cular disease by 2 to 3 percent. Overexpressing theapolipoprotein A-I gene in transgenic mice andrabbits and infusing complexes consisting of apo-lipoprotein A-I and phospholipids into hyperlipi-demic rabbits increase HDL cholesterol levels anddecrease the development of atherosclerosis.

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Inhumans, infusing either of these complexes orproapolipoprotein A-I results in short-term increas-es in HDL cholesterol, biliary cholesterol, and fecalsterol loss, reinforcing the concept that elevating theHDL cholesterol level decreases the risk of cardio-vascular disease.

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Increasing HDL Cholesterol LevelsH. Bryan Brewer, Jr., M.D.




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