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The use of SSRIs in children and adolescentsSarah E. Hetricka, Joanne E. McKenzieb and Sally N. Merryc

aOrygen Yoof MedicineVictoria, bMMelbourne,DepartmenUniversity of Auckland, Auckland, New Zealand

CorrespondCentre, CeSciences, TE-mail: she

Current O

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day-to-day basis [17]. There was no evidence that SSRIswere effective in improving functioning.

7 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/YCO.0b013e328334bc92ence to Sarah E. Hetrick, MA, DPsych, Orygen Youth Health Researchntre for Youth Mental Health, Faculty of Medicine, Dentistry and Healthhe University of Melbourne, Parkville, Victoria 3052, Australiatrick@unimelb.edu.au

pinion in Psychiatry 2010, 23:5357

uctionive disorders are prevalent among young peopleare frequently untreated or inadequately treated

e use of antidepressants in the management ofion in children and adolescents is contentious.e serotonin reuptake inhibitors (SSRIs) had beensed in paediatric depression until warnings aboutwere issued following concerns that children andnts who had participated in trials evaluating theeness of SSRIs were at an increased risk of self-his resulted in comprehensive reviews of the trialsrnment regulatory agencies which all concludedy fluoxetine should be recommended for use inand adolescents with depressive disorders [47].

and counter claims about the effectiveness ofnd risk related to their use have followed [8cerns have been raised that if antidepressant used young people could be deprived of effectivents for a condition that carries with it considerablety and mortality [8,9,14]. Recent research hased that pessimism about effective treatmentslted in reluctance on the part of patients to seek5]. Further, lower rates of depressive disorderes [15] may indicate that clinicians are reluctantthis diagnosis, perhaps due to uncertainty aboute treatments.

o key questions when considering the use ofn the treatment of children and adolescents withive disorder are, do they work and are they welld? Answering these questions requires considera-the evidence.

ective serotonin reuptake inhibitors

ertook a Cochrane systematic review to evaluate

SSRIstrateSSRI[relat1.17,

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Funcyounworkuth Health Research Centre, Centre for Youth Mental Health, Faculty, Dentistry and Health Services, The University of Melbourne, Parkville,onash Institute of Health Sciences Research, Monash University,Australia and cWerry Centre for Child and Adolescent Mental Health,t of Psychological Medicine, Faculty of Medical and Health Sciences,

TweThewascontiht Lippincott Williams & Wilkins. Unauthorizedtrials met the inclusion criteria for our review.tcome response was reported in all trials. Thisinary outcome created from a cut-point on aous depression scale. Both the scale and cut-pointetween trials. The pooled treatment effect of allompounds on the outcome response demon-that a greater percentage of participants receivingesponded compared with those receiving placeborisk (RR) 1.28; 95% confidence interval (CI)1] (Fig. 1).

was evidence that effectiveness of SSRIs onse varied by compound (with 81.3% of then across SSRI compound effect estimates dueogeneity rather than chance; P 0.001). Theretatistically significant difference in the percen-children and adolescents who responded wheng fluoxetine compared with placebo (RR 1.86;1.49, 2.32). The percentage of those respond-ile on fluoxetine ranged between 41 and 61%ed with a range of 2035% in those on placebo.sive symptom scores [Childrens DepressionScale-Revised scale (CDRS-R); range 17113]lso statistically significantly lower for thoseg fluoxetine compared with placebo at thetreatment [ranging between 8 and 12 weeksment; treatment effect 5.63 (95% CI 7.38,.

roxetine, there was no statistically significantce in the percentage of children and adolescentssponded to paroxetine compared with those whoed to placebo (RR 1.09; 95% CI 0.95, 1.26).as a lack of consistency for both sertraline and

am. There was no statistically significant differ-response rate between the sertraline and controlRR 1.17; 95%CI 1.00, 1.36). However, depressivescores were significantly lower in the sertraline

treatment effect CDRS-R 3.56; 95% CI 6.69,There was a statistically significant differencepercentage of children and adolescents whoed when receiving citalopram/escitalopram0; 95% CI 1.02, 1.67), compared with placeboignificant difference in depressive symptom score-R).

ning is perhaps the most relevant outcome foreople as it measures their ability to sustain school/terpersonal relations, and social functioning on a reproduction of this article is prohibited.

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Whatthe evIt is imresultscome the clinissues osiderati

OutcoIn the sresolutinormalfunctionnot colequatedremissioment scdefinitiocult to isensusscale to

meaningful improvement on these scales. In addition,varying cut-points for dichotomizing a continuous mea-

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54 Psychiatry forum

Figure 1 Relative risk of response to selective serotoninreuptake inhibitors compared with placebo

Statisticaand barsof freedoreuptakewith

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are the strengths and weaknesses ofidence base?portant to be cautious when interpreting theof our review. The interpretation of the out-response, the selection of patient outcomes,ical significance of treatment effects, and otherf internal and external validity all need con-on.

me measurementearch for effective treatments, the ideal goal is aon of symptoms (i.e., remission) and a return tofunction. In the trials in our review, remission oring were inconsistently reported, not reported, orlected. Most trials reported response whichto a reduction in symptoms that fell short ofn. Inconsistencies in the choice of measure-ale used between trials coupled with varyingns of response (e.g., [13,18,19]) make it diffi-nterpret this outcome. It highlights a lack of con-over both the most appropriate measurementuse in trials, and what is considered a clinically

221). Hranging40% inthis attrthe clinprimaryparticipparticipside eff

ExternGeneraltrials excomorbidity, and those at risk of suicide so that parti-cipantsIt is unfor suchshort duthe effe612 mmendedpossibleperiod onot eva

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l pooling used fixed effects statistical model for this outcomeindicate 95% CIs. Test for heterogeneity x218.80, degreesm (df)8 (P0.02), I257%. SSRIs, selective serotonininhibitors.f those presenting in clinical practice is unknown.se young people with uncomplicated depressionay be a small advantage to using fluoxetine in thewere not typical of those seen in clinical practice.clear how effective these medications would beyoung people. In addition, the trials were ofration, spanning only 712 weeks. Therefore,ctiveness and risks of these medications over aonth time period, which is the typically recom-treatment duration [23,24], is unknown. It is, for example, that functioning may take a longerf time to return to normal, but these trials haveluated this.

lusion, the effectiveness of SSRIs in patientsy also be indicative of a form of within studye reporting bias in which the most favourablet is chosen on the basis of the results [20].

ical versus clinical significancee of the difference in improvements betweenis of questionable clinical significance. For, for fluoxetine, the average CDRS-R score atp was 5.63 lower for those in the treatment groupd with the placebo group, with both groupsng substantially. A difference of 25 points onRS-R scale has been shown to differentiateand nonclinical groups, whereas a difference ofts has been shown to differentiate clinical groupsd without depressive disorder [21].

l validityas generally limited information reported about

duct of the trials, so it was difficult to assess theirvalidity. However, two methodological com-which were reported, attrition and blinding,

d cause for concern. These have empirically beeno be associated with bias ([22], chapter 8, pp. 217igh attrition rates were observed in all trials;from 17 to 46% in the control groups and 17the intervention groups. The bias associated withition may be substantial. In the included trials,icians were also the outcome assessors for theoutcomes. It is possible that clinicians and

ants may have been able to guess whether theants were on active treatment or placebo fromect profiles.

al validityizability of the included trials is limited. Mostcluded placebo responders, those with complexreproduction of this article is prohibited.

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short-term. However, there is no evidence that treatmentwith fluoxetine will improve their function.

Are selective serotonin reuptake inhibitorswell tolerated?There is conflicting evidence about the link betweenSSRIs and suicidality. Consistent with USFood andDrugAdministration (FDA) findings and other meta-analyses[25,26], our review showed an increased risk of suicidalideation and behaviour in those receiving an SSRI com-pared with those receiving a placebo (RR 1.80; 95% CI1.19, 2.72). However, compared with rates found incommunity studies [2731], the rates of these phenom-ena were very low (Fig. 2). This is likely to be because ofthe exclusion of those most at risk. These phenomenawere measured in various ways across trials, or notreported at all. The Treatment for Adolescents withDepression Study (TADs) trial was the only one to reportsuicidal ideation using a validated questionnaire (SuicideIdeation Questionnaire [32]), and in contrast to the

increased risk of suicidal ideation behaviours observedacross other trials, participants receiving fluoxetine hadlower sutreatme[33]. Asuicideincludeshort durisk fromin interpdue to itrials, thconcernmay bepopulatclinical

In contreviewslected dto 2004prescribbehavioHowever, one study suggested that increased prescribingof antidreducedsince20for younsame peNetherlthat therates ofthe linksuicide

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The use of SSRIs in children and adolescents Hetrick et al. 55

Figure 2 Relative risk of suicide-related outcomes on a selec-tive serotonin reuptake inhibitors compared with placebo

Statisticaand bars(P0.75OurevideSSRIeffecdisorwithpatedtreatlow rplaceshowDespmodesuicialthoshowprescrouti

l pooling used fixed effects statistical model for this outcomeindicate 95% CIs. Test for heterogeneity x25.09, df8), I20%. SSRIs, selective serotonin reuptake inhibitors.ht Lippincott Williams & Wilkins. Unauthorizedepressants in those years was associated withsuicide rates in some countries [34]. Further,

04 therehasbeen a reduction inSSRIprescriptionsg people due to regulatory warnings, and over theriod of time an increase in the suicide rate in theands and theUnited States of America with claimsse twophenomena are related [35].The lowoverallsuicide make these claims questionable [36] withbetween antidepressant medication use and

rates contested [37].

sionta-analysis [16] showed that there was limitede of efficacy of SSRIs. Fluoxetine was the onlyr which there was consistent evidence of itseness in improving response and depressivesymptoms in children and adolescents comparedcebo. Most children and adolescents who partici-the trials were not typical of those presenting fornt; they had low rates of comorbidity and were atof suicide or self-harm. Those who responded tohad been screened out, maximizing the chance ofa difference between placebo and medication.this, even for fluoxetine the improvement isThere was evidence of an increased risk ofideation and behaviour for those on an SSRI,h rates were low. However, one included triala reduction in suicidal ideation for those

ed fluoxetine and evidence from studies usingy collected data have shown an inverse relation-tween SSRI prescription and suicide.icidal ideation at follow-up than at the start ofnt and compared with those in the placebo grouplthough there were no reports of completedin a total sample of 2240 children and adolescentsd in our review; suicide is rare, the trials were ofration, and were not powered to assess suicideSSRIs. Although appropriate caution is requiredreting the risk of suicidal ideation and behavioursnconsistency in reporting of this outcome acrosse increased risk for those receiving SSRIs raises. Adding to this concern is the fact that the riskdifferent, perhaps larger, if SSRIs are used in aion of patients who are typical of those seen inpractice.

radiction to the FDA findings [26] and otherof SSRIs [16,25], evidence from routinely col-ata show a different story. In the decades prior, internationally, there was an increase in theing rates of SSRIs. If SSRIs do increase suicidalurs, an increase in suicide ratesmight be expected. reproduction of this article is prohibited.

Copyrigh

Clinical implicationsWhen deciding treatment options, all interventionsshouldother an

When bshould bchild ansufficientherapierange otive, at

AntideptematicHoweveclassesWithinregression to examine whether a drug class was predictiveof treatmcludedthe hyptricyclic

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Finally, it is evident from the variation in measurementinstruments used between trials included in our review

heure[46tabdo

clueatndldiat7]. Our systematic review, along with others [16,39],demonstrated the limited effectiveness of SSRIsfutiv

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56 Psychiatry forument effect for the outcome response and con-that there was no statistical evidence to supportothesis that SSRIs were more effective thanantidepressants.

ssible that medications are effective for someals including those with more severe and com-sentations. However, only a few trials (e.g. [40])cluded these participants, so there is limitede about the effectiveness and risks of treatmentssubgroups.

ns on treatment options should always be made intion with the young person and their families.he equivocal evidence base about the effective-risks of the treatments, there is a particular needde accurate information about the limits of thee base and elicit treatment preferences of thepeople and their family; allowing them to beinvolved in their treatment decision [16,4145].

rch prioritiesults of our systematic review, and others (e.g. [39]),entified the need for further research. Thisclude a systematic review that allows for directirect comparisons of various treatment options;g antidepressant medication and psychothera-nterventions. Thismay necessitate the need for aead-to-head trial testing those interventionstrated to be the most effective in the systematicSuch a trial should include young people similarseen in clinical practice and should be of at leastonths duration. Consideration should be given toely powering the trial to test whether the effec-s of the treatments differs by severity of depress-rder.

SSRIfor d[47].

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eginning treatment, interventions of least riske considered first. Standard care, typical of mostd adolescent mental health services, may bet for some to recover. Consideration to psycho-s can also be given. There is some evidence that af psychotherapeutic interventions may be effec-least in the short-term [38].

ressants potentially pose greater risks. Our sys-review examined the evidence of SSRIs [16].r, a recent review included trials comparing allof antidepressant medications with placebo [39].this review, the authors undertook a meta-

that tmeaslogyto esand a

ConUntrity ashouassoc[16,4hasand,effect Lippincott Williams & Wilkins. Unauthorized efficiency in reducing the burden of depression. J Ment Health Policy2000; 3:175186.

ittee on Safety of Medicines (CSM). Report of the CSM expert workingon the safety of selective serotonin reuptake inhibitors antidepressants:medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/nal.pdf; 4 Dec 2004.rthermore, the limited information about theireness in young people typically seen in clinical. Evidence regarding the risk of self-harm ons conflicting. The search for effective treatmentsressive disorders in young people is not over

eantime, it is essential that optimismand an activeh are maintained in the treatment of depressives in children and adolescents. Depressive dis-n young people need to be detected, and activelyd, first utilizing interventions of least risk. Manyond to simple remedies [40]. There is consider-terogeneity in young people who present withive disorder and SSRIs may be effective for sub-f these young people, which are not yet defined.ng people who have not responded to other inter-s, or those with a particularly severe or disabling, a trial of medication could be considered afterng the risks and limited evidence of effectivenessyoung person and their family. Close monitoringtoms and side effects is always crucial, but parti-nce medication is utilized. Guidelines, althoughconsistently recommendsuchanapproach, includ-e judicious use of medication [10,23,24,48]. Weupport this.

nces

her B, Ryan ND, Williamson DE, et al. Childhood and adolescentssion: a review of the past 10 years: part 1. J Am Acad Child Adolesciatry 1996; 35:14271439.

sohn PM, Hops H, Roberts RE, et al. Adolescent psychopathology: I.ence and incidence of depression and other DSM-III-R disorders in highre is a need to establish a standard set of outcomes. This has been successfully done in rheumato-]. Additional research may need to be undertakenlish what outcomes are important to childrenlescents.

sioned depressive disorder is associated with morbid-mortality; however, the argument that SSRIsbe used to reduce the morbidity and mortalityed with depressive disorders is not well foundedreproduction of this article is prohibited.

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The use of SSRIs in children andadolescentsIntroductionDo selective serotonin reuptake inhibitors work?What are the strengths and weaknesses of the evidence base?Outcome measurementStatistical versus clinical significanceInternal validityExternal validityAre selective serotonin reuptake inhibitors well tolerated?DiscussionClinical implicationsResearch prioritiesConclusion