ORIGINAL CONTRIBUTION

Switching to Another SSRI or to With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-Resistant Depression The TORDIA Randomized Controlled Trial

David Brent, MD Context Only about 60% of adolescents with depression will show an adequate clini- Graham Emslie, MD cal response to an initial treatment trial with a selective inhibitor Greg Clarke, PhD (SSRI). There are no data to guide clinicians on subsequent treatment strategy. Karen Dineen Wagner, MD, PhD Objective To evaluate the relative efficacy of 4 treatment strategies in adolescents who continued to have depression despite adequate initial treatment with an SSRI. Joan Rosenbaum Asarnow, PhD Design, Setting, and Participants Randomized controlled trial of a clinical sample Marty Keller, MD of 334 patients aged 12 to 18 years with a primary diagnosis of major depressive dis- Benedetto Vitiello, MD order that had not responded to a 2-month initial treatment with an SSRI, conducted at 6 US academic and community clinics from 2000-2006. Louise Ritz, MBA Interventions Twelve weeks of: (1) switch to a second, different SSRI (, Satish Iyengar, PhD , or , 20-40 mg); (2) switch to a different SSRI plus cognitive be- Kaleab Abebe, MA havioral therapy; (3) switch to venlafaxine (150-225 mg); or (4) switch to venlafaxine Boris Birmaher, MD plus cognitive behavioral therapy. Neal Ryan, MD Main Outcome Measures Clinical Global Impressions-Improvement score of 2 or less (much or very much improved) and a decrease of at least 50% in the Children’s Betsy Kennard, PsyD Depression Rating Scale-Revised (CDRS-R); and change in CDRS-R over time. Carroll Hughes, PhD Results Cognitive behavioral therapy plus a switch to either medication regimen showed Lynn DeBar, PhD a higher response rate (54.8%; 95% confidence interval [CI], 47%-62%) than a medi- cation switch alone (40.5%; 95% CI, 33%-48%; P=.009), but there was no differ- James McCracken, MD ence in response rate between venlafaxine and a second SSRI (48.2%; 95% CI, 41%- Michael Strober, PhD 56% vs 47.0%; 95% CI, 40%-55%; P=.83). There were no differential treatment effects on change in the CDRS-R, self-rated depressive symptoms, , Robert Suddath, MD or on the rate of harm-related or any other adverse events. There was a greater in- Anthony Spirito, PhD crease in diastolic blood pressure and pulse and more frequent occurrence of skin prob- Henrietta Leonard, MD† lems during venlafaxine than SSRI treatment. Nadine Melhem, PhD Conclusions For adolescents with depression not responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch Giovanna Porta, MS to another resulted in a higher rate of clinical response than did a medi- Matthew Onorato, LCSW cation switch alone. However, a switch to another SSRI was just as efficacious as a switch to venlafaxine and resulted in fewer adverse effects. Jamie Zelazny, MPH, RN Trial Registration clinicaltrials.gov Identifier: NCT00018902 DOLESCENTDEPRESSIONISA JAMA. 2008;299(8):901-913 www.jama.com common, chronic, recur- rent, and impairing condi- AuthorAffiliations:UniversityofPittsburgh,Pittsburgh, University, Providence, Rhode Island (Drs Keller, Spirito, Pennsylvania (Drs Brent, Iyengar, Birmaher, Ryan, and and Leonard); and National Institute of Mental Health, tion that accounts for a sub- Melhem, Messrs Abebe and Onorato, and Mss Porta Bethesda, Maryland (Dr Vitiello and Ms Ritz); Mr On- Astantial proportion of the disability and and Zelazny); University of Texas Southwestern Medi- orato is now with Nationwide Children’s Hospital, Co- 1,2 cal Center at Dallas (Drs Emslie, Kennard, and Hughes); lumbus, Ohio. mortality incurred in this age group. Kaiser Permanente Center for Health Research, Port- †Deceased. Untreated depression results in impair- land, Oregon (Drs Clarke and DeBar); The University Corresponding Author: David Brent, MD, Western of Texas Medical Branch, Galveston (Dr Wagner); Psychiatric Institute and Clinic, 3811 O’Hara St, Room ment in school, interpersonal relation- University of California, Los Angeles (Drs Rosenbaum 315 Bellefield Towers, Pittsburgh, PA 15213 (brentda ships, occupational adjustment, and in- Asarnow, McCracken, Strober, and Suddath); Brown @upmc.edu).

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creases the risk for suicidal behavior and shown to be superior to an SSRI in the participate. Potential participants tak- completed suicide.3-5 Therefore, the management of treatment-refractory ing medications with psychoactive prop- proper treatment of adolescent depres- adult depression in some but not all erties were excluded, with the excep- sion has profound public health impli- studies.10,18-26 The efficacy of adding CBT tion of those who were prescribed stable cations for youth in this critical stage to a medication switch was studied be- doses (Ն12 weeks) of , hyp- of development.6-8 cause the combination of antidepres- notics (, , zaleplon), Clinical guidelines for the acute man- sant medication and CBT has been or antianxiety agents (, lor- agement of adolescent depression rec- shown to be beneficial in acute, re- azepam). Other exclusionary criteria ommend the prescribing of selective sidual, and chronic depression in adults were diagnoses of bipolar spectrum dis- serotonin (SSRI) and in some, but not all, studies of ado- order, , pervasive developmen- medications, , or both, lescents with depression.12,13,27-34 tal disorder or , eating disorders, with the best-studied psychotherapy This article reports the relative effi- substance abuse or dependence, or hy- being cognitive behavioral therapy cacy of medication type, CBT, and the pertension (diastolic blood pressure Ͼ90 (CBT).2,9-11 While these treatments combination of both for the acute treat- mm Hg), and for females: pregnancy, alone or in combination have been ment of resistant adolescent depres- breastfeeding, or having unprotected sex. shown to be efficacious, at least 40% of sion at 12 weeks from intake into the This study was approved by each site’s adolescents with depression do not study, hypothesizing that a switch to local institutional review board. All par- show an adequate clinical response to venlafaxine would be a superior treat- ticipants gave written informed assent these interventions, and only one- ment to a switch to a second SSRI, and (and consent after they turned age 18), third show complete symptomatic re- that the addition of CBT would be su- and parents gave written informed con- mission to acute treatment.12-16 De- perior to a medication switch alone. sent in accordance with local institu- spite the high frequency of nonresponse tional review board regulations. Recruit- and the serious consequences of per- METHODS ment, outcomes, and adverse effects were sistent depression in this age group Participants monitored quarterly by a National In- (12-18 years), there are no empirical Participants were adolescents aged 12 to stitute of Mental Health–constituted data studies to guide clinicians regarding the 18 years, in active treatment for major and safety monitoring board. management adolescents with depres- depressive disorder according to the Di- sion not responsive to an initial treat- agnostic and Statistical Manual of Mental Intake and Enrollment ment with an SSRI. To address the clini- Disorders, Fourth Edition (DSM-IV),35 Participants were assessed with a diag- cal management of this clinically with a clinically significant depression nostic interview (Schedule for Affective important population, we developed a (Children’s Depression Rating Scale- Disorders and Schizophrenia for School- 6-site, National Institute of Mental Revised[CDRS-R])36 totalscoreofatleast Age Children-Present and Lifetime ver- Health–funded study, the Treatment of 40 and a Clinical Global Impressions- sion),38 interview ratings of depression SSRI-Resistant Depression in Adoles- Severity subscale of at least 4 (at least (CDRS-R) and of clinical severity (Clini- cents (TORDIA) trial, in which adoles- moderate severity),37 despite being in cal Global Impressions-Severity sub- cents with depression that did not re- treatment with an SSRI regimen for at scale), and laboratory tests (eg, electro- spond to an adequate course of an initial least 8 weeks, the last 4 of which were cardiogram, function, thyroid, SSRI were randomized to 1 of 4 treat- at a dosage of at least 40 mg per day of electrolytes, urine drug screen). Those ments in a 2ϫ2 factorial design: (1) fluoxetine or its equivalent (eg, 40 mg with abnormal laboratory test results switch to a second, different SSRI; (2) paroxetine, 40 mg citalopram, 20 mg were enrolled only if medically cleared. switch to venlafaxine; (3) switch to sec- s-citalopram, or 150 mg sertraline). We Participants then continued on the same ond SSRI plus CBT; or (4) switch to also included participants who, after at- prestudy treatment regimen (ie, initial venlafaxine plus CBT. tempting a dosage comparable to 40 mg SSRI at equivalent of 40 mg of fluox- This study focuses on nonresponse to of fluoxetine, could only tolerate a dose etine) for another 2 weeks and were re- SSRI medications rather than on non- that was the equivalent of 20 mg of fluox- assessed. At the second assessment, response to psychotherapy, because SSRI etine for at least 4 weeks (19/334 par- which served as the study baseline, the medications have been the predomi- ticipants; 5.7%). Excluded were partici- difference between the 2 CDRS-R rat- nant method of treatment for adoles- pants with 2 or more adequate trials of ings was calculated. For participants in cent depression for at least the past de- an SSRI, a history of nonresponse to ven- whom the CDRS-R decreased less than cade.17 Switch to another SSRI is lafaxine (at least 4 weeks at a dosage of 30% and who still had significant de- compared with switch to venlafaxine, a Ն150 mg), or to CBT (Ն7 sessions). Par- pressive symptoms (CDRS-R Ն40), en- selective serotonin and noradrenergic re- ticipants currently receiving CBT were rollment into the study was offered. The uptake inhibitor, because the former also excluded, whereas those with past majority (79.9%) of participants came strategy is recommended in clinical or current exposure to other forms of in- from clinical sources, and the remain- guidelines, whereas venlafaxine has been dividual psychotherapy were eligible to der (20.1%) from advertisements.

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Figure. Study Participants From Prescreening Through Analysis

3258 Adolescents prescreened

2776 Excluded 2722 Did not meet criteria 45 Not interested 9 Unable to contact

482 Assessed by diagnostic interview and medical record review

97 Excluded 52 Did not meet criteria (32 had CDRS-R <40) 37 Withdrew consent 8 Other

385 Underwent baseline assessment

51 Excluded 25 Had a change in CDRS-R ≥30% or CDRS-R ≤40 11 Refused to continue 9 Had exclusion criteria 2 Had abnormal laboratory test results 4 Other

334 Randomized

83 Randomized to receive 83 Randomized to receive 85 Randomized to receive 83 Randomized to receive venlafaxine alone venlafaxine with CBT SSRI alone SSRI with CBT 42 Randomized to receive 42 Randomized to receive fluoxetine fluoxetine 25 Randomized to receive 25 Randomized to receive paroxetine paroxetine 18 Randomized to receive 16 Randomized to receive citalopram citalopram

33 Received adjunctive treatment 25 Received adjunctive treatment 31 Received adjunctive treatment 34 Received adjunctive treatment 12 Received sleep medication 11 Received sleep medication 19 Received sleep medication 16 Received sleep medication 14 Received 9 Received stimulant 11 Received stimulant 9 Received stimulant medication medication medication medication 3 Received 4 Received anxiolytic 2 Received anxiolytic 3 Received anxiolytic medication medication medication medication 7 Received individual therapy 7 Received individual therapy 5 Received individual therapy 8 Received individual therapy

22 Withdrew from treatment 30 Withdrew from treatment 25 Withdrew from treatment 25 Withdrew from treatment 6 Serious adverse events 8 Serious adverse events 5 Serious adverse events 10 Serious adverse events 3 Adverse events 2 Adverse events 4 Adverse events 3 Adverse events 4 Nonadherence 4 Nonadherence 4 Nonadherence 1 Nonadherence 2 Withdrew consent 6 Withdrew consent 2 Withdrew consent 2 Withdrew consent 2 Lost to follow-up 2 Lost to follow-up 2 Lost to follow-up 2 Worsening depression 3 Worsening depression 4 Worsening depression 3 Worsening depression 1 Ancillary treatment–comorbidity 1 Ancillary treatment–comorbidity 3 Ancillary treatment–comorbidity 3 Ancillary treatment–comorbidity 3 Received paroxetinea 1 1 Received psychotropic 1 Substance abuse 1 Substance abuseb medication 1 Pregnancy 1 Psychosis 1 Received psychotropic medication

61 Completed treatment protocol 53 Completed treatment protocol 60 Completed treatment protocol 57 Completed treatment protocol 4 Completed <2 CBT sessions 3 Completed <2 CBT sessions 74 Completed 6-wk assessment 68 Completed 6-wk assessment 77 Completed 6-wk assessment 73 Completed 6-wk assessment 71 Completed 12-wk assessment 72 Completed 12-wk assessment 76 Completed 12-wk assessment 68 Completed 12-wk assessment

83 Included in analysis 83 Included in analysis 85 Included in analysis 83 Included in analysis

CBT indicates cognitive behavioral therapy; CDRS-R, Children’s Depression Rating Scale-Revised; SSRI, selective serotonin reuptake inhibitor. Numbers may not sum within boxes because participants could receive more than one adjunctive treatment. aParticipants were taking paroxetine at the time of the 2003 UK reports concerning paroxetine use,40 were unblinded, and tapered off of the medication. bParticipant was withdrawn from the study and unblinded after providing disclosure of having dependence, an exclusionary criterion. Participant later with- drew the claim.

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Randomization ing participants and staff not to discuss cation, which consisted of meeting with Participants were randomly assigned to CBT treatment assignment when the in- a nurse-clinician or psychiatrist who re- 1 of 4 treatment regimens (FIGURE) in a dependent evaluator was present. The viewed the symptoms of depression, its 2ϫ2 factorial design: change to second pharmacotherapists’ accuracy in guess- causes, treatments, possible adverse ef- SSRI, change to venlafaxine, change to ing medication assignment was less ac- fects, and informed parents about how a second SSRI plus CBT, or change to curate than chance (44.2%; ␹2=4.57; to cope with having a mood-disordered venlafaxine plus CBT. Randomization P=.03), whereas the independent evalu- child.42,43 Across all treatment groups, cli- wasbalancedbothwithinandacrosssites ators guessed CBT assignment at a rate nicians met with families at intake, at the withrespecttoincomingtreatmentmedi- slightly higher than chance (58.3%; 6-week midpoint, and at 12 weeks— cation, comorbid anxiety, chronic de- ␹2=5.14; P=.02). In 64 cases, the blind- the end of acute treatment. pression (duration Ն24 months), and ingoftheindependentevaluatorwascom- Cognitive Behavioral Therapy. suicidal ideation (Beck Depression In- promised,mostcommonlybecauseofpar- Therapists who facilitated CBT earned at ventory item 9 Ն2), using a variation of ticipant disclosure of receiving CBT. least a master’s degree in a mental health Efron’s biased coin toss.39 Participants field, with prior experience in CBT.CBT in the SSRI switch groups who were ini- Interventions drew upon the manuals that emphasize tiallytreatedwithcitalopram,sertraline, Medication Taper. Participants were ta- cognitive restructuring and behavior ac- or were randomized to re- pered to discontinuation from their ini- tivation, emotion regulation, social skills, ceive either fluoxetine or paroxetine. If tial medication by decreasing dosages and problem solving for participants, and theywereinitiallytreatedwithfluoxetine, over a period of 2 weeks, except for that also emphasize parent-child ses- theywereswitchedtoreceiveparoxetine those who entered the study taking sions to decrease criticism and to im- and vice versa. fluoxetine, for whom the medication prove support, family communication, was simply discontinued due to fluox- and problem solving.44-49 These differ- Change in Study Medication etine’s long half-life. ent modules were flexibly applied on the Midway through the study (after 181/ Pharmacotherapy. Pharmacothera- basis of the clinical needs of the partici- 334 participants had been enrolled), pists were either psychiatrists or mas- pant and family, with input from on- due to concerns about the efficacy and ter’s degree–prepared nurses working site and external supervisors, and re- safety of paroxetine, 1 of the treat- withthesupervisionofapsychiatrist.The view of case formulations during a CBT ment options in the SSRI group was study psychiatrist examined partici- conference call every other week. changed from paroxetine to citalo- pants at entry, 6 weeks, and 12 weeks. The protocol called for as many as 12 pram.40,41 Of the 50 participants who Medicationsessionswere30to60min- sessions (60-90 minutes each) of CBT were assigned to receive paroxetine, utesindurationandincludedassessment during the first 12 weeks, 3 to 6 of which only 3 were in active treatment at the of vital signs, adverse effects, safety,and were to be family sessions. During 6 in- time of this change. These partici- symptomatic response, and occurred stances when judged clinically neces- pants assigned to paroxetine were un- weeklyforthefirst4weeksandeveryother sary, therapists “borrowed” as many as blinded and removed from the study week thereafter during acute treatment. 3 sessions from their bank of sessions or- and 2 of the 3 were subsequently lost ThedosagescheduleforSSRIintakewas dinarily reserved for continuation treat- to follow-up. The clinical and demo- 10 mg per day for the first week and 20 ment. The mean and median number of graphic characteristics of participants mg per day for weeks 2 to 6, with an op- CBT sessions attended in the first 12 were similar before and after the an- tion to increase to 40 mg per day if there weeks was 8.3 and 9 (interquartile range, nouncement about paroxetine. was insufficient clinical improvement 5), respectively, with no differences be- (ClinicalGlobalImpressions-Severitysub- tween medication groups or across sites. Blinding Procedure scale Ն3). The venlafaxine dosages for Treatment Fidelity. Alltherapistsun- Theintentwasforstudyparticipants,cli- weeks1to4were37.5,75,112.5,and150 derwenta2-daytrainingatthebeginning nicians,andindependentevaluatorstobe mg,respectively,withanoptiontoincrease and at midpoint in the study.Pharmaco- blinded to medication treatment assign- to225mgatweek6.Ifintolerableadverse therapysessionaudiotapeswerereviewed ment and for independent evaluators to effects developed after a medication in- by the coordinating center (153 tapes), be blinded to CBT assignment. Blinding crease, the participant’s dosage was low- usingthe16-itemPharmacotherapyRat- formedicationwasmaintainedbyuseof ered to either 20 mg of an SSRI or to 150 ing Scale derived from the Clinical Man- 3encapsulatedpillsdailyforallprescrip- mgofvenlafaxine.By12weeks,themean agementScale50 toensurecoverageofas- tions,someofwhichmightbeplaceboto dosesofSSRIwere33.8mg(95%CI,32.0- sessment, safety issues, and distinctness mask drug type and dose. The blinding 35.6),andforvenlafaxinewere205.4mg fromCBT,with92.8%beingofacceptable to CBT for independent evaluators was (95% CI, 199.0-211.7). quality.CBT session audiotapes were re- maintained by scheduling the indepen- Family Psychoeducation. All par- viewedusingtheCognitiveTherapyRat- dentevaluators’assessmentsatatimenot ents of participants, regardless of treat- ing Scale51 by on-site supervisors (277 contiguouswithCBTsessionsandbyask- ment group, received family psychoedu- tapes), 2 CBT supervisors in Pittsburgh,

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Pennsylvania(351tapes),and1external cant depression. Both the Clinical Glob- age Children screen. Any posi- consultantwhohasservedasatrainerfor alImpressions-ImprovementSubscaleand tive response resulted in the adminis- theBeckCognitiveTherapyCenter,Phila- theCDRS-Rhavebeenwidelyusedinpe- tration of the full 14-item Mania Rating delphia, Pennsylvania (49 tapes), with diatric treatment trials of depression.52 Scale.56 Adverse effects were assessed 94.9%,94.0%,and93.9%ratedasaccept- These outcomes were rated by indepen- using the Form for Chil- able, respectively. dentevaluators,whohadattainedorwere dren and Adolescents.57 Treatment- Adjunctive Treatments. Adjunc- completingamaster’sdegreeinamental emergent adverse events were defined tive medications were prescribed for health field, with at least 3 years of clini- as new-onset or worsening symptoms sleep (, 25-50 mg; za- cal experience and who were trained to and were reviewed during weekly con- leplon, 5-20 mg; zolpidem, 5-10 mg; or atleast80%interraterreliabilityonthese ference calls.58 Serious adverse events trazodone [for females, 25-50 mg]), and assessments. were those that resulted in significant for anxiety (clonazepam, 0.25 mg twice Primary Outcomes. The study had 2 disability, threat to life, or emergency daily; or , 0.5 mg 3 times/ declared primary outcomes. The first, care. After the concerns about the safety day). Participants who were involved “adequate clinical response,” was de- of were raised,40,41,59 the in ongoing supportive treatment (Ն3 fined as a Clinical Global Impressions- remaining 153 participants were moni- months with no family or cognitive Improvement Subscale score of 2 or less tored weekly by clinicians for suicidal component) were allowed to continue and an improvement in the CDRS-R ideation, suicidal behavior, and ad- no more frequently than every other score of at least 50% in order to capture verse effects of antidepressants that week. These interventions occurred in both global and symptomatic improve- might be related to suicidality (eg, hos- a minority of participants (4%-21.5%) ment. The second primary outcome was tility, , lability). and were evenly distributed across treat- the trajectory of the CDRS-R over time. ment groups (Figure; ␹2Ͻ2.2; P Ͼ.14). Interrater Reliability. Interrater re- Statistical and Power Analyses Protocol Deviations. Twelve partici- liability was monitored throughout the Allprimaryanalyseswerebasedona2ϫ2 pants (3.6%) were allowed into the pro- study and remained high for diagnosis balancedfactorialdesign,wereofintent- tocoldespitemeetingexclusionarycrite- of depression and (␬=0.70; to-treat format, and in the case of those ria, if consensus of the investigators was 95% CI, 0.49-0.89; N=150), for CDRS-R using dichotomous outcomes, used the thatsuchanexceptionwaswarranted(eg, (intraclass correlation coefficient=0.85; last observation carried forward unless participantwhowas1weekyoungerthan 95% CI, 0.80-0.89; N=324), and for both stated otherwise. Similar results were 12 years, pubertal, and cognitively ma- the Clinical Global Impressions- foundusingmultipleimputationwiththe ture).Inaddition,11participants(3.3%), Severity Subscale and Clinical Global Im- assumptionofdatamissingatrandom,and after they had been enrolled and treated, pressions-Improvement Subscale (intra- therefore, this study reports only on last werefoundtohavehadashorterthanre- class correlation coefficient=0.84; 95% observation carried forward.60 Analyses quired duration of initial treatment with CI, 0.74-0.89; N=176) for each. wereconductedusingSPSS14.0(SPSSInc, anSSRI,and12(3.6%)werefoundtohave Secondary Outcomes. Self-reported Chicago,Illinois)andSTATA9.2(Stata- hadaresponsetotheinitialtreatmentbet- depression and suicide-related symp- Corp,CollegeStation,Texas).61,62 Differ- ter than allowed for entry. Results were toms were assessed by the Beck De- encesinresponsewereassessedusing␹2 unchangedwhenanalyseswerererunex- pression Inventory53 and the Suicide andlogisticregression,testingforeffects cluding these participants. Ideation Questionnaire-Jr.54 Func- for CBT (vs not), medication (switch to tional status was assessed using the an SSRI vs venlafaxine), and their inter- Assessments Children’s Global Adjustment Scale,55 action.Unlessnotedotherwise,contrasts Diagnostic and Primary Outcome a 1- to 100-point scale, with scoring of were planned, df=1, and tests were Assessments.TheScheduleforAffective at least 70 being indicative of ad- 2-sided. Logistic regression was used to DisordersandSchizophreniaforSchool- equate functioning. assess the main effects of treatment after Age Children-Present and Lifetime Ver- Follow-up Assessment Visits Dur- adjustingforbaselinedifferencesandin- sion,38 a widely used semistructured in- ing Acute Phase. The previously noted teractions with treatment, followed by terview,was used to determine DSM-IV interview and self-rated assessments of backward stepping to identify the best- diagnoses.Overallclinicalimprovement symptoms and adaptive functioning fitting, most parsimonious model. The was rated by the Clinical Global were obtained at baseline and at weeks effectoftreatmentonthetrajectoryofthe Impressions-Improvement Subscale, 6 and 12, regardless of treatment sta- CDRS and other scalar measures was as- which ranges from 1 (very much im- tus and response. sessedbyrandomeffectslinearregression, proved)to7(verymuchworse).37 Depres- Safety Assessment. Safety assess- usingalogarithmictransformationoftime, sive symptoms were rated by the CDRS- ments were completed during all phar- testing for effects of time, CBT, medica- R,36 a17-iteminterviewthatrangesfrom macotherapy visits and included a tion,site,andtheirrespectiveinteractions 17to113,withascoreof40orgreatercon- 4-item Kiddie Schedule for Affective on the scalar outcome. Effect sizes were sideredconsistentwithclinicallysignifi- Disorders and Schizophrenia for School- calculated using Hedges g.63

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The study was designed to have a RESULTS the completion rates across the 2 fac- sample size of 400 and was powered Patient Disposition torial variables (CBT [66.3%; 95% to detect a 10% difference between Of 334 participants who were ran- CI, 59%-74%] vs not [72.0%; 95% groups at power of 80%, with P=.05. domized to treatment (Figure), 292 CI, 65%-79%] ␹2 =1.30; P=.26; and This study did not meet that target (87.4%) had at least 1 postbaseline venlafaxine [68.7%; 95% CI, 62%- because at midpoint, concerns and assessment point, 287 (85.9%) were 76%] vs SSRI [69.6%; 95% CI, 63%- warnings about SSRI use in pediatric assessed from baseline through week 77%] ␹2=0.04; P=.85). populations led to a decline in use, 12, and 231 (69.2%) completed the making recruitment more difficult.64 treatment protocol through week 12. Demographic and Clinical For the actual sample of 334 partici- The remaining participants (30.8%) Characteristics pants and group sizes of 167, an effect left or were withdrawn from the pro- The treatment groups were very simi- size of d=0.31 could be detected at tocol prematurely, most commonly lar with regard to demographic and 80% power, P =.05, which corre- due to adverse effects (n=41); non- clinical baseline characteristics sponds to a 15% difference between adherence, loss to follow-up, or with- (TABLE 1) except that the venlafaxine groups for dichotomous outcomes, drawal of consent (n=31); need for group had a lower Beck Depression In- with ability to detect slightly larger out-of-protocol treatment for depres- ventory score (P=.03) and lower rates effect sizes (d=0.34; 16.5% risk differ- sion or other conditions (n=20); or of posttraumatic stress disorder (P=.04) ence) for the sample with complete development of exclusionary criteria at baseline. As race and ethnicity can follow-up data (n=287). (n=7). There were no differences in influence treatment response, these

Table 1. Baseline Variables by Treatment Groupa All Randomized Participants

SSRI Venlafaxine P No CBT CBT P (n = 168) (n = 166) Value (n = 168) (n = 166) Value Demographic characteristics Age, mean (SD), ya 16.0 (1.6) 15.8 (1.5) .22 15.8 (1.6) 16.0 (1.5) .25 White race/ethnicity, No. (%)a 138 (82.1) 139 (83.7) .70 136 (81.0) 141 (84.9) .33 Female sex, No. (%)a 121 (72.0) 112 (67.5) .37 117 (69.6) 116 (69.9) .96 Income, median (range), thousands $ 60 (8-500) 62 (0-250) .84 62.5 (8-500) 59 (0-190) .58 College graduatea 80 (50.6) 72 (45.0) .32 76 (47.2) 76 (48.4) .83 Clinical characteristics Children’s Depression Rating Scale-Revised mean (SD)a,b 59.9 (10.6) 57.8 (10.1) .07 58.4 (9.7) 59.2 (11.0) .50 Clinical Global Impressions-Severity, mean (SD)a 4.5 (0.6) 4.4 (0.7) .77 4.5 (0.6) 4.5 (0.7) .91 Children’s Global Assessment Scale, mean (SD)a 50.3 (7.8) 50.9 (7.6) .46 50.6 (7.7) 50.6 (7.7) Ͼ.99 Beck Depression Inventorya,c 21.9 (12.0) 19.1 (12.0) .03 19.6 (11.5) 21.4 (12.6) .17 Suicidal Ideation Questionnairea 27.8 (22.0) 25.4 (22.6) .31 26.9 (21.1) 26.3 (23.5) .81 Children’s Depression Rating Scale-Revised % change 6.9 (25.4) 5.3 (21.4) .77 4.9 (24.2) 6.8 (23.0) .47 between assessments, median (interquartile range) Comorbidity, No. (%) Anxiety (including posttraumatic stress disorder)a 59 (36.4) 60 (36.4) .99 60 (35.9) 59 (36.9) .86 Posttraumatic stress disorderd 17 (10.1) 7 (4.2) .04 15 (8.9) 9 (5.5) .22 -deficit/hyperactivity disordera 26 (15.8) 26 (15.7) .98 23 (13.8) 29 (17.7) .33 Oppositional/conduct 15 (9.0) 18 (11.0) .56 18 (10.8) 15 (9.2) .63 Dysthymiaa 45 (27.1) 53 (32.1) .32 51 (30.5) 47 (28.7) .71 Clinical history First episode of depression, (No. %)a 122 (74.8) 119 (73.0) .71 122 (73.5) 119 (74.4) .86 Duration current major depressive disorder episode, mean (SD), moa 23.5 (21.6) 21.4 (19.0) .36 22.6 (21.4) 22.3 (19.4) .88 Age at onset of major depressive disorder symptoms, mean (SD), ya 12.6 (2.6) 12.8 (2.4) .45 12.5 (2.6) 12.9 (2.4) .20 History of suicide attempts, No. (%)a 45 (26.9) 34 (20.5) .17 44 (26.3) 35 (21.1) .26 Concomitant treatment at intake, No. (%) Anxiety medication 1 (0.6) 3 (1.8) .31 2 (1.2) 2 (1.2) Ͼ.99 Sleep medicationa 12 (7.1) 8 (4.8) .37 11 (6.5) 9 (5.4) .67 Stimulant medicationa 13 (7.7) 20 (12.0) .19 20 (11.9) 13 (7.8) .21 Abbreviations: CBT, cognitive behavioral therapy; SSRI, selective serotonin reuptake inhibitor. aDifferent statistical significance among sites. bStatistical measures: t = 1.84; P = .07. cStatistical measures: t = 2.17; P = .03. d 2 Statistical measures: ␹1 = 4.30; P = .04.

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Table 2. Clinical Outcome by Treatment Group With Intent-to-Treat and Completer Analyses Intent-to-Treat (n = 334) Completers (n = 231)

SSRI Venlafaxine No CBT CBT SSRI Venlafaxine No CBT CBT (n = 168) (n = 166) (n = 168) (n = 166) (n = 117) (n = 114) (n = 121) (n = 110) Responsea 79 (47.0) 80 (48.2) 68 (40.5) 91 (54.8) 64 (54.7) 65 (57.0) 60 (49.6) 69 (62.7) CGI-I score Յ2, No. (%)b 86 (51.2) 92 (55.4) 80 (47.6) 98 (59.0) 70 (59.8) 76 (66.7) 72 (59.5) 74 (67.3) Change in CDRS-R score Ն50%, No. (%)c 94 (56.0) 86 (51.8) 79 (47.0) 101 (60.8) 73 (62.4) 69 (60.5) 68 (56.2) 74 (67.3) Abbreviations: CBT, cognitive behavioral therapy; CDRS-R, Children’s Depression Rating Scale-Revised; CGI-I, Clinical Global Impressions-Improvement Subscale; SSRI, selective sero- tonin reuptake inhibitor. a 2 2 2 2 Statistical measures: intent-to-treat by medication, ␹1 = .05, P = .83; intent-to-treat by CBT, ␹1 = 6.89, P = .009; completers by medication, ␹1 = .13, P = .72; completers by CBT, ␹1 = 4.04, P = .05. b 2 2 2 Statistical measures: intent-to-treat by medication, ␹1 = .60, P = .44; intent-to-treat by CBT, ␹1 = 4.37, P = .04 ; completers by medication, ␹1 = 1.16, P = .28; completers by CBT, 2 ␹1 = 1.50, P = .22. c 2 2 2 2 Statistical measures: intent-to-treat by medication, ␹1 = .58, P = .45; intent-to-treat by CBT, ␹1 = 6.42, P = .01 ; completers by medication, ␹1 = .09, P = .77; completers by CBT, ␹1 = 2.98, P = .08.

were assessed based on participants’ re- Hedges g=0.29 [95% CI, 0.07-0.51]; model 1). The main effect for CBT ports.65,66 The sample was approxi- number needed to treat=7 [95% CI, (P=.002) persisted after controlling mately 16 years of age, 70% female, 82% 4-27]), but there was no difference be- for baseline differences in the Beck white, with a median household in- tween medication groups (48.2% pre- Depression Inventory (PϽ.001) and come of $61 000. Participants had mod- scribed venlafaxine [95% CI, 41%- posttraumatic stress disorder (P=.15; erately severe (CDRS-R=59; 95% CI, 56%]; vs 47.0% prescribed SSRI [95% Table 3, model 2). Also, the main 58-60 and Children’s Global Adjust- CI, 40%-55%]; risk difference=1.2%, effect for CBT (P=.01) was still signifi- ment Scale=51; 95% CI, 50-51) and 95% CI, 9.5-11.9; ␹2=0.046; P=.83). cant after controlling for the main chronic depression (56.3% had dura- The results were similar for each of the effects of site (P=.02), baseline Beck tion Ն2 years; median duration, 17 2 components of response score (Clini- Depression Inventory (P=.001), and a months; interquartile range, 22.3 cal Global Impressions-Improvement site by CBT interaction (P = .003; months), mostly in their first episode Subscale; and a change in CDRS-R Table 3, model 3). (73.9%). Treatment duration prior to Ն50%) and also if the analyses were re- study entry was a median of 17 weeks stricted to completers (TABLE 2). There CDRS-R Trajectory of SSRI pharmacotherapy (interquar- was a significant difference in CBT re- With regard to change in the CDRS-R 2 tile range, 16.5 weeks), and a median sponse by site (␹5=11.3; PϽ.05), but (TABLE 4), there was a significant effect of 8 sessions of psychotherapy in the no site differences with regard to re- for time (z=−7.18; PϽ.001), but not 2 previous 12 weeks (interquartile range, sponse to SSRI (␹5=3.62; P=.61) or to for medication, CBT, site, or any 2- or 2 5 sessions). A high proportion of par- venlafaxine (␹5=7.22; P=.21). These 3-way interaction. ticipants showed clinically significant findings with regard to CBT response suicidal ideation (38.4%, Suicide Ide- were robust to sensitivity analyses that Self-reported Depression ation Questionnaire-Jr score Ն31), and removed 1 site at a time (risk differ- and Suicidal Ideation at least 1 additional comorbid disor- ence ranged from 8.8%-20.6%; me- There were significant effects on the der (51.7%). There were substantial site dian 13.3%) and that removed one- Beck Depression Inventory for time differences with regard to demo- sixth (n=56) of participants at random (Table 4; z=−4.92; PϽ.001) and site graphic and clinical baseline vari- (risk difference from 11.4%-17.5%; me- (z=2.82; P=.005). For the Suicide Ide- ables, although for the most part, the dian 13.4%). ation Questionnaire-Jr, there was an balance of these characteristics across Post hoc, there were no significant effect of time (z=−3.45; P=.001). No treatments was maintained within each differences among the 3 SSRI medica- other main effects or interactions were site as well. tions with regard to clinical response detected for either measure. (paroxetine, 19/50 [38.0%; 95% CI, Clinical Response 25%-52%]; fluoxetine, 41/84 [48.8%; Global Functioning A higher proportion of participants 95% CI, 38%-60%]; citalopram, 19/34 and Rating of Severity 2 treated with CBT showed an adequate [55.9%; 95% CI, 39%-73%]; ␹2=2.81; There were significant effects of time clinical response (54.8% of partici- P=.25). Logistic regression with the on the Children’s Global Adjustment pants [95% CI, 47%-62%]; Clinical outcome of clinical response showed Scale (Table 4; z=−4.31; PϽ.001) and Global Impressions-Improvement Sub- that there was a main effect for CBT on the Clinical Global Impressions- scale Յ2 and a CDRS-R decline Ն50%) (P=.03), but not for medication type Severity Subscale (z=−5.68; PϽ.001), vs not (40.5% of participants [95% CI, (P=.66), nor was there a medication but no other main effects or interac- 33%-48%]; risk difference=14.3% [95% by CBT interaction with regard to tions were detected for either mea- CI, 3.7%-24.9%]; ␹2 =6.89; P=.009; clinical response (P = .67; TABLE 3, sure.

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Relationship of Response ventory, Suicide Ideation Questionnaire- Post Hoc Sensitivity Analyses and Continuous Outcomes Jr, Children’s Global Adjustment Scale, Post hoc, we stratified our analyses of Participants who showed an adequate and Clinical Global Impressions Sever- treatment response on several vari- clinical response, compared with non- ity-Subscale (response ϫ time; z ables that might have influenced it responders, showed more rapid de- scores=–14.33 to −4.71; all P values (TABLE 5). The response rates overall cline on the CDRS, Beck Depression In- Ͻ.001). and within each treatment were simi- lar before and after the safety warn- Table 3. Logistic Regressions of Clinical Response, Adjusting for Baseline and Site Differences ings and the US Food and Drug Ad- ␤ SE Wald ␹2 df OR (95% CI) P Value ministration Antidepressant Black Box 40,41,59 Model 1a Warning. Response rates showed Medication .14 .32 .20 1 1.15 (0.62-2.13) .66 a nonsignificant trend toward being CBT .67 .31 4.60 1 1.96 (1.06-3.62) .03 higher in the unblinded participants Medication and CBT −.19 .44 .18 1 0.83 (0.35-1.98) .67 overall (P =.07) and within CBT Model 2b (PϽ.06). Using logistic regression, the Medication −.06 .23 .06 1 0.94 (0.60-1.49) .80 effects of CBT (odds ratio [OR], 1.70 CBT .74 .23 9.99 1 2.10 (1.32-3.31) .002 Sitec 5.41 5 .37 [95% CI, 1.09-2.64]; P=.02) on re- Baseline Beck Depression Inventory −.04 .01 12.54 1 0.96 (0.94-0.98) Ͻ.001 sponse persisted, even after control- Baseline posttraumatic stress disorder .68 .48 2.06 1 1.98 (0.78-5.04) .15 ling for the effect of unblinding (OR, Model 3d 1.49 [95% CI, 0.85-2.62]; P=.16; Hos- CBT 2.01 .78 6.64 1 7.43 (1.62-34.16) .01 2 mer-Lemeshow ␹2=1.87; P=.39). Par- Sitec 13.45 5 .02 ticipants who received adjunctive medi- c Site and CBT 18.33 5 .003 cation for sleep had a lower response Baseline Beck Depression Inventory −.04 .01 10.40 1 0.97 (0.95-0.99) .001 rate overall (P=.01), as well as within Abbreviations:CBT,cognitivebehavioraltherapy;CI,confidenceinterval;OR,oddsratio;PTSD,posttraumaticstressdisorder. a 2 Statistical measures: Hosmer and Lemeshow ␹2 = .00, P Ͼ .99. SSRI(P =.01) and CBT treatments b 2 P Statistical measures: Hosmer and Lemeshow ␹8 = 3.26, = .92. (P=.004). Overall results were similar c␤, SE, and OR are only calculated for individual sites. d 2 Statistical measures: Hosmer and Lemeshow ␹8 = 6.44, P = .60. with and without participants with ad-

Table 4. Changes in Total Scores During a 12-Week Treatment Period Mean (SD) [95% CI]

Baseline Week 6 Week 12 SSRI Children’s Depression Rating Scale-Reviseda 59.8 (10.6) [58.3-61.5] 42.3 (14.0) [40.1-44.6] 37.9 (13.7) [35.7-40.1] Beck Depression Inventory 21.9 (12.0) [20.1-23.8] 13.2 (11.4) [11.4-15.1] 11.5 (10.9) [9.7-13.3] Suicidal Ideation Questionnaire 27.8 (22.0) [24.5-31.2] 18.3 (20.7) [15.0-21.6] 16.6 (17.9) [13.6-19.6] Clinical Global Impressions-Severity 4.5 (0.6) [4.4-4.6] 3.5 (1.0) [3.3-3.6] 2.9 (1.2) [2.7-3.1] Children’s Global Assessment Scale 50.3 (7.8) [49.1-51.5] 58.9 (11.5) [57.1-60.8] 63.3 (11.9) [61.3-65.2] Venlafaxine Children’s Depression Rating Scale-Revised 57.8 (10.1) [56.2-59.3] 42.6 (13.2) [40.4-44.8] 37.0 (13.1) [34.9-39.2] Beck Depression Inventory 19.1 (12.0) [17.2-20.9] 13.2 (12.2) [11.3-15.3] 9.9 (10.5) [8.2-11.6] Suicidal Ideation Questionnaire 25.4 (22.6) [21.9-28.8] 20.1 (21.5) [16.5-23.7] 16.5 (19.7) [13.2-19.7] Clinical Global Impressions-Severity 4.4 (0.7) [4.4-4.6] 3.4 (1.1) [3.3-3.6] 2.8 (1.2) [2.6-3.0] Children’s Global Assessment Scale 50.9 (7.6) [49.7-52.1] 59.7 (9.7) [58.1-61.3] 64.8 (11.1) [62.9-66.6] No CBT Children’s Depression Rating Scale-Revised 58.4 (9.7) [57.0-59.9] 41.6 (13.4) [39.5-43.7] 38.1 (12.9) [36.0-40.1] Beck Depression Inventory 19.6 (11.5) [17.9-21.4] 12.3 (10.8) [10.6-14.1] 10.5 (9.8) [8.9-12.1] Suicidal Ideation Questionnaire 26.9 (21.1) [23.7-30.1] 19.3 (20.5) [16.0-22.7] 16.4 (17.5) [13.5-19.2] Clinical Global Impressions-Severity 4.5 (0.6) [4.4-4.6] 3.4 (1.0) [3.3-3.6] 3.0 (1.1) [2.8-3.2] Children’s Global Assessment Scale 50.6 (7.7) [49.4-51.8] 59.3 (10.7) [57.6-61.0] 63.0 (11.2) [61.2-64.8] CBT Children’s Depression Rating Scale-Revised 59.2 (11.0) [57.5-60.9] 43.4 (13.9) [41.1-45.7] 36.9 (13.9) [34.6-39.2] Beck Depression Inventory 21.4 (12.6) [19.5-23.4] 14.2 (12.7) [12.1-16.2] 11.0 (11.5) [9.0-12.9] Suicidal Ideation Questionnaire 26.3 (23.5) [22.7-29.9] 18.9 (21.7) [15.4-22.5] 16.7 (20.2) [13.3-20.1] Clinical Global Impressions-Severity 4.5 (0.7) [4.4-4.6] 3.5 (1.0) [3.3-3.6] 2.7 (1.2) [2.5-2.9] Children’s Global Assessment Scale 50.6 (7.7) [49.4-51.8] 59.4 (10.7) [57.6-61.1] 65.1 (11.8) [63.1-67.0] Abbreviations: CBT, cognitive behavioral therapy; CI, confidence interval; SSRI, selective serotonin reuptake inhibitor. a Lowest possible score for Children’s Depression Rating Scale. Revised is 17.

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junctive sleep medications. There was who were prescribed SSRI medica- nation of CBT and another antidepres- no relationship between outcome and tions (P=.01; Table 6). The Side Ef- sant resulted in a higher rate of clini- the use of , stimulants, ad- fects Form for Children and Adoles- cal response than switching to another junctive supportive therapy, or the pres- cents showed a similar pattern, with medication without CBT. There was no ence of comorbid attention-deficit/ 31.7% of skin problems (mostly itch- differential effect between switching to hyperactivity disorder. ing and rash) reported in the venlafax- another SSRI or to venlafaxine. Al- ine group (95% CI, 25%-39%) com- though there were considerable site dif- Adverse Events pared with 16.9% in the SSRI groups ferences in CBT treatment response, the There were no differences between treat- (95% CI, 11%-23%; ␹2=9.78; P=.002). effects of CBT on outcome were ro- ments with regard to the frequency of se- Four participants (2.4% [95% CI, 0%- bust to sensitivity analyses and per- rious adverse events, adverse events, or 5%]) assigned to venlafaxine were re- sisted after controlling for site effects. the frequency of removal from the study moved from the study for cardiovascu- There were no differential treatment ef- for such events (Figure; TABLE 6). There lar events, vs 1 who was assigned to SSRI fects on scalar measures of depres- were also no differences by treatment medications (0.6% [95% CI, 0.6%-2%]; sion, suicidal ideation, and function- group with respect to the frequency of Fisher, P=.21); these events were pro- ing, nor were there treatment effects on self-harm adverse events or related cat- longed corrected QT interval in 1 par- suicide attempts, or self-harm–related egories (increased suicidal ideation, self- ticipant, increased blood pressure in 2 adverse events in 2 participants. injurious behavior, or suicide at- participants, and increased heart rate. tempts), either when restricted to those Venlafaxine resulted in greater in- Limitations within their treatment group (Table 6), creases in diastolic blood pressure We did not control for the greater con- or based on intent-to-treat analyses. (P=.004) and pulse (P=.001; TABLE 7), tact and attention that participants in There were 18 suicide attempts among although these adverse effects were rarely the combined treatment received (eg, 17 participants, but none of the partici- of clinical impact. There were no medi- by offering supportive therapy in the pants completed suicide. Sleep difficul- cation effects on weight, systolic blood non-CBT groups. However, prior to en- ties and irritability were the only psy- pressure, or the corrected QT interval. try, these participants had not re- chiatric adverse effects that occurred in sponded to a fairly intense regimen of atleast5%ofparticipants.Therewasonly COMMENT treatment, consisting of a median of 17 1 instance of hypomania during the first Summary weeks of pharmacotherapy and 8 ses- 12 weeks. In this study of adolescents with mod- sions of psychotherapy over the previ- With regard to nonpsychiatric ad- erately severe and chronic depression ous 12 weeks. Also, 2 characteristics of verse events that occurred in at least 5% who had not responded to an ad- this sample, namely high rates of chro- of participants, only skin problems were equate course of treatment with an SSRI nicity and clinically significant suicid- more common in venlafaxine vs those antidepressant, switching to a combi- ality, have previously been shown to

Table 5. Post Hoc Sensitivity Analyses of the Impact of Different Study Conditions on Treatment Response Overall Venlafaxine SSRI CBT

Stratification Variable No. RR % (95% CI)a No. RR % (95% CI) No. RR % (95% CI)b No. RR % (95% CI)c Before warning 181 47.5 (40-55) 89 50.6 (40-61) 92 44.6 (34-55) 90 56.7 (46-67) After warning 153 47.7 (40-56) 77 45.5 (34-57) 76 50.0 (39-61) 76 52.6 (41-64) Blinded 270 45.2 (39-51) 127 44.9 (36-54) 143 45.5 (37-54) 123 50.4 (42-59) Unblinded 64 57.8 (46-70) 39 59.0 (44-74) 25 56.0 (37-76) 43 67.4 (53-81) Sleep medication 58 32.8 (21-45) 23 39.1 (19-59) 35 28.6 (16-45) 27 29.6 (15-48) No sleep medication 276 50.7 (45-57) 143 49.7 (42-58) 133 51.9 (43-60) 139 59.7 (52-68) Anxiolytic medication 12 50.0 (22-78) 7 28.6 (6-65) 5 80.0 (37-98) 7 57.1 (23-86) No anxiolytic medication 322 47.5 (42-53) 159 49.1 (41-57) 163 46.0 (38-54) 159 54.7 (47-63) Stimulant medication 43 46.5 (32-61) 23 52.2 (32-73) 20 40.0 (19-62) 18 61.1 (38-81) No stimulant medication 291 47.8 (42-54) 143 47.6 (39-56) 148 48.0 (40-56) 148 54.1 (46-62) Supportive therapy 27 51.9 (34-70) 14 64.3 (38-85) 13 38.5 (16-65) 15 53.3 (29-76) No supportive therapy 307 47.2 (42-53) 152 46.7 (39-55) 155 47.7 (40-56) 151 55.0 (47-63) ADHD 52 51.9 (39-65) 26 61.5 (42-78) 26 42.3 (25-61) 29 69.0 (51-83) No ADHD 279 46.2 (40-52) 140 45.7 (38-54) 139 46.8 (39-55) 135 51.1 (43-59) Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CBT, cognitive behavioral therapy; CI, confidence interval; RR, response rate; SSRI, selective serotonin reuptake inhibitor. a 2 2 Blind: ␹1 = 3.31, P Ͻ .07; sleep medication: ␹1 = 6.20, P = .01. b 2 Sleep medication: ␹1 = 6.04, P = .01. c 2 2 2 Blind: ␹1 = 3.73, P Ͻ .06; sleep medication: ␹1 = 8.26, P = .004; ADHD: ␹1 = 3.01, P = .08.

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predict a poor response to supportive tients with depression who did not re- tice that were not evaluated, such as a therapy in adolescents with depres- spond to citalopram showed response switch to or augmentation sion.67,68 Second, the blinding with re- to augmentation with CBT compa- with bupropion, , thyroxine, or gard to CBT was compromised in about rable to a switch in medication.26 How- atypical .18 While most of one-fifth of the sample, but since the ever, only one-third of the available these strategies were tested in adults effects of CBT persisted even after sta- participants agreed to a randomiza- with depression enrolled in the Se- tistically controlling for the effect of un- tion that included this condition,69 con- quenced Treatment Alternatives to blinding, the compromise in the blind- sistent with our concern that recruit- Relieve Depression study,26 none of ing alone does not explain our findings. ment for this treatment option would these strategies has ever been evalu- Third, due to our design, we cannot de- have been challenging. Fourth, our ated in children or adolescents with termine whether the addition of CBT sample was not ethnically diverse (17% depression. would have been beneficial even with- minority), limiting our ability to test for out making a change in medication. In ethnic differences in response.65,66 Fi- Strengths the Sequenced Treatment Alternatives nally, there are several other treat- This is the first to em- to Relieve Depression study, adult pa- ment strategies used in clinical prac- panel adolescents with depression who were not responding to a current, evi- dence-based treatment. Conse- Table 6. Proportion of Participants Who Experienced at Least 1 Adverse Event by Treatment Group quently, while the severity of depres- No. (%) sion was comparable with other studies,12,14,15,31-33 this sample had higher SSRI Venlafaxine No CBT CBT rates of 2 additional predictors of poor Total No. of participants 168 166 168 166 clinical response: chronic depression Ն 1 Serious adverse event 18 (10.7) 19 (11.4) 14 (8.3) 23 (13.9) and clinically significant suicidal ide- Ն 1 Adverse event 86 (51.2) 78 (47.0) 84 (50.0) 80 (48.2) ation.67,70 Previous clinical trials of an- Event/problem Harm-relateda 31 (18.5) 37 (22.3) 32 (19.0) 36 (21.7) tidepressants in adolescents with de- Suicide attempts 6 (3.6) 11 (6.6) 7 (4.2) 10 (6.0) pression have routinely excluded Sleep 5 (3.0) 12 (7.2) 7 (4.2) 10 (6.0) participants with active suicidal ide- Irritability 8 (4.8) 8 (4.8) 6 (3.6) 10 (6.0) ation, which belies community prac- Flu-like 31 (18.5) 21 (12.7) 26 (15.5) 26 (15.7) tice insofar as suicidal behavior is one Aches 24 (14.3) 23 (13.9) 23 (13.7) 24 (14.5) of the most common reasons for initi- Accident/injury 12 (7.1) 7 (4.2) 10 (6.0) 9 (5.4) ating antidepressant treatment for an 71 Gastrointestinal 9 (5.4) 7 (4.2) 7 (4.2) 9 (5.4) adolescent with depression. We have Skinb 3 (1.8) 13 (7.8) 7 (4.2) 9 (5.4) demonstrated that it is possible to man- Musculoskeletal 6 (3.6) 10 (6.0) 5 (3.0) 11 (6.6) age these participants in the context of Abbreviations: CBT, cognitive behavioral therapy; SSRI, selective serotonin reuptake inhibior. a clinical trial, given sufficient appro- aDefined as suicidal ideation, suicide attempt, or self-injurious behavior. b 2 priate rescue procedures. Thus, our By medication: ␹1 = 6.69, P = .01. findings could be applicable to com- munity samples, which while often Table 7. Change in Weight, Blood Pressure, Heart Rate, and Corrected QT Interval by Medication more ethnically diverse than our Mean (SD) [95% Confidence Interval] sample, have comparable clinical com- plexity. Baseline Week 12 Venlafaxine Combination Treatment Weight, kg 68.9 (19.7) [65.7-71.9] 70.7 (20.1) [66.9-74.3] Diastolic blood pressure, mm Hga 67.0 (8.8) [65.6-68.4] 70.3 (8.5) [68.8-71.9] The strategy of comparing a medica- Systolic blood pressure, mm Hg 112.3 (14.0) [110.1-114.5] 115.5 (13.6) [113.0-118.0] tion switch plus CBT to a medication Heart rate, beats/minb 76.3 (11.9) [74.4-78.1] 82.3 (12.5) [80.0-84.6] switch alone has not been previously Corrected QT interval, ms 412.7 (21.4) [409.4-416.1] 410.3 (21.3) [406.3-414.3] tested in treatment-resistant depres- Selective serotonin reuptake inhibitor sion, but combination treatment for de- Weight, kg 69.5 (19.8) [66.3-72.5] 72.4 (20.4) [68.6-76.1] pression in adults, including adults with Diastolic blood pressure, mm Hg 66.3 (9.1) [64.9-67.7] 64.7 (10.2) [62.9-66.6] chronic depression, has been shown to Systolic blood pressure, mm Hg 111.1 (13.1) [109.0-113.1] 111.5 (13.3) [109.1-113.9] be superior to either monotherapy.29,34 Heart rate, beats/min 77.6 (12.4) [75.6-79.5] 77.5 (11.4) [75.4-79.6] We obtained an effect at a relatively low Corrected QT interval, ms 413.9 (18.4) [411.1-416.8] 413.5 (17.0) [410.3-416.6] “dose” of CBT (median, 9 sessions), as aVenlafaxine vs selective serotonin reuptake inhibitor: t = 2.88; P = .004. have some other positive clinical trials bVenlafaxine vs selective serotonin reuptake inhibitor: t = 3.41; P = .001. in adolescents and adults.15,16,69,72 It is

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possible that with a higher dose, we The slightly higher rate of cardiovas- pression Study because in TORDIA, might have been able to achieve a larger cular effects associated with venlafax- participants had higher suicidality at in- effect. The Treatment of Adolescent De- ine and the relatively modest treat- take, experienced a greater number of pression Study found the strongest ad- ment effects of venlafaxine in adolescent suicidal events, and were subject to vantage for combined treatment over depression (albeit at lower doses than more intense and frequent safety moni- medication alone in less severe depres- used in TORDIA), support the choice toring. Other studies have also shown sion.70 Our results extend the Treat- of another SSRI over venlafaxine as a that reductions in depression and in sui- ment of Adolescent Depression Study second-line antidepressant.75-77 cidal behavior do not necessarily cor- findings to a more chronically de- relate, supporting the need for further pressed, treatment-resistant popula- Sleep Medication treatment development that targets the tion. and Clinical Response prevention of suicidal behavior.5,15 The use of sleep medication was asso- Different Results for Clinical ciated with a poorer response rate to Clinical Implications Response and Random Effects treatment. It is unclear if this finding On the basis of these findings, CBT- Regression is attributable to clinical features of naive adolescents with chronic, treat- While a greater proportion of partici- those who received hypnotics, incom- ment-resistant depression will be more pants who received CBT were rated as plete treatment of sleep difficulties, or likely to respond to the combination of clinically improved, there were no par- an interaction between hypnotic and CBT and a switch in antidepressant allel treatment effects found on any of antidepressant medications. Dis- medication than to a switch in medi- the scalar measures of outcome. This rupted sleep predicts onset and recur- cation alone. Even in participants who is because CBT had a modest effect and rence of depression, and in one study, did not receive CBT, 40% improved af- did not affect the speed of improve- a poorer response to CBT.78,79 These re- ter enduring an average of 2 years of un- ment, which is what is being tested in sults highlight the need to better as- remitting depression. Assuming that ap- random effects regression analyses of sess and manage sleep difficulties in proximately half of adolescents with scalar measures. In one study of adults adolescents with depression. depression will respond to an initial with chronic depression that deliv- treatment, the rate of response in our ered nearly twice the number of CBT Site Effects study is consistent with the relatively sessions that participants received in TheeffectofCBT,whilesignificantinthe high cumulative response rate re- TORDIA, a combination of psycho- aggregate,wasquitevariableacrosssites. ported in those adults with depression therapy and antidepressant adminis- However,theoveralleffectofCBTwasro- in the Sequenced Treatment Alterna- tration did result in a more rapid de- bust to sensitivity analyses and also per- tives to Relieve Depression study, who cline in depressive symptoms.29 sisted even after controlling for site and continued to pursue additional treat- CBT by site interactions. In a separate ment steps.26 Therefore, the clinician Choice of a Second-Line manuscript, we plan to examine the should convey hope to the adolescent Medication sourcesofvariabilityinCBTperformance, with depression and his or her family Contrary to our hypothesis, venlafax- bothrelatedtoqualitycontrolandthesub- that, despite a first unsuccessful treat- ine was not superior to the option of stantialsitedifferencesinclinicalvariables ment for depression, persistence with switching to another SSRI. In the Se- thatarelikelytopredictdifferentialtreat- additional appropriate interventions can quenced Treatment Alternatives to Re- ment outcomes (A.S., K.A., and S.I., un- result in substantial clinical improve- lieve Depression study, it was also found published data, 2007).67,68,70 ment. that participants who did not respond Author Contributions: Dr Brent had full access to all to citalopram were just as likely to re- Effect on Suicidal Behavior of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data mit with a switch to a second SSRI (ser- We found no advantage of the combi- analysis. traline, 17.6%) as to a switch to venla- nation of CBT and medication over Study concept and design: Brent, Emslie, Clarke, 30 Wagner, Asarnow, Keller, Iyengar, Birmaher, Ryan, faxine (24.8%). While earlier studies medication alone on the incidence of Kennard, Hughes, DeBar, McCracken, Strober, of treatment-resistant depression re- suicidal adverse events, findings which Leonard. Acquisition of data: Brent, Emslie, Clarke, Wagner, ported as much as a 19% difference in are similar to one other large study of Asarnow, Keller, Ritz, Birmaher, Ryan, Kennard, response rate between venlafaxine and combined treatment in adolescents with Hughes, McCracken, Strober, Suddath, Spirito, other antidepressants,25 more recent depression.31 In contrast, the Treat- Leonard, Onorato, Zelazny. Analysis and interpretation of data: Brent, Emslie, meta-analyses have found either no dif- ment of Adolescent Depression Study Clarke, Wagner, Asarnow, Vitiello, Iyengar, Abebe, ference or very modest advantages (ie, group found a trend toward the com- Ryan, Kennard, Hughes, Suddath, Leonard, Melhem, Porta. 5%-7%) in response and remission rates bination of CBT and medication being Drafting of the manuscript: Brent, Suddath, Spirito, over SSRI medications,73,74 differences protective against the occurrence of sui- Leonard, Porta. 80 Critical revision of the manuscript for important in- that are much smaller than could be re- cidal events. Our results might di- tellectual content: Brent, Emslie, Clarke, Wagner, liably detected with our sample sizes. verge from Treatment of Adolescent De- Asarnow, Keller, Vitiello, Ritz, Iyengar, Abebe,

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Birmaher, Ryan, Kennard, Hughes, DeBar, McCracken, cotherapist, Dawn Picotte, MD, Pharmacotherapist; cational, and social role outcomes of adolescents with Strober, Leonard, Melhem, Onorato, Zelazny. Kristin Bruning, MD, Pharmacotherapist; Marilyn depression. Arch Gen Psychiatry. 2002;59(3):225- Statistical analysis: Brent, Iyengar, Abebe, Melhem, Matzko, EdD, Project Coordinator; Mark Celio, BA, 231. Porta. Independent Evaluator; Lance Swenson, PhD, CBT 5. Bridge JA, Goldstein TR, Brent DA. Adolescent sui- Obtained funding: Brent, Clarke, Asarnow, Keller, Therapist; Wendy Hadley, PhD, CBT Therapist; Chris- cide and suicidal behavior. J Child Psychol Psychiatry. Iyengar, Ryan, Strober, Leonard, Zelazny. tie Rizzo, PhD, CBT Therapist; Christianne Esposito- 2006;47(3-4):372-394. ’ Administrative, technical, or material support: Brent, Smythers, PhD, CBT Therapist; Ellen O Brien, MA, CBT 6. Vitiello B, Rohde P, Silva S, et al; The TADS Team. Emslie, Clarke, Asarnow, Keller, Vitiello, Ritz, Birmaher, Therapist; Todd Moore, PhD, CBT Therapist; Annie Functioning and quality of life in the treatment for ado- Ryan, Kennard, Hughes, McCracken, Suddath, Spirito, Fox, MA, Data Management; Liz Rivelli, BA, Data Man- lescents with depression study (TADS). J Am Acad Child Leonard, Onorato, Zelazny. agement; Mat Arruda, BA, Independent Evaluator; and Adolesc Psychiatry. 2006;45(12):1419-1426. Study supervision: Brent, Emslie, Clarke, Rosenbaum Marguerite Lee, BA, Independent Evaluator. Univer- 7. Weissman MM, Wolk S, Goldstein RB, et al. De- Asarnow, Keller, Birmaher, Kennard, Hughes, DeBar, sity of Texas Southwestern Medical Center at Dal- pressed adolescents grown up. JAMA. 1999;281 McCracken, Strober, Suddath, Spirito, Leonard, las: Maryam Rezai, MD, Pharmacotherapist; Taryn L. (18):1707-1713. Zelazny. Mayes, MS, Project Coordinator; Jarrette Moore, MA, 8. Fombonne E, Wostear G, Cooper V, Harrington Project Coordinator; Melissa Batt, MPH, Project Co- Financial Disclosures: Dr Asarnow reports consult- R, Rutter M. The Maudsley Long-term Follow-up of ordinator; Jessica Jones, MA, Independent Evaluator; ing on cognitive behavioral therapy and cognitive be- Child and Adolescent Depression. Br J Psychiatry. 2001; Jeanne Rintelmann, BA, Independent Evaluator; havioral therapy for depression supported by an un- 179:210-217. Catherine Karni, MD, Pharmacotherapist; Sunita Stew- restricted grant from and has funding from Philip 9. Weisz JR, McCarty CA, Valeri SM. Effects of psy- art, PhD, CBT Therapist; and Avery Hoenig, PhD, CBT Morris; a family member has funding from Bristol- chotherapy for depression in children and adolescents. Therapist. University of Texas Medical Branch, Galves- Myers Squibb and has consulted for Roche. Dr Bir- Psychol Bull. 2006;132(1):132-149. ton: Nikki Amarantunge, MA, Project Coordinator; Jen- maher reports participating in forums sponsored by 10. Birmaher B, Brent D; Work Group on Quality Issues. nifer Ferguson, LMSW, Project Coordinator; Dwight Solvay Pharmaceuticals Inc and Abcomm Inc; pre- Practice parameters for the assessment and treat- Wolf, MD, Pharmacotherapist; Joan Hebeler, MD, ment of children and adolescents with depressive sented on bipolar disorders in children at a meeting Pharmacotherapist; and Aileen Oandasan, MD, CBT sponsored by Solvay; and reports receiving royalties disorders. J Am Acad Child Adolesc Psychiatry. 2007; Supervisor. University of Pittsburgh: Kim Poling, LCSW, 46(11):1503-1526. from Random House Inc. Dr Emslie reports receiving CBT Supervisor; Mary Beth Rucki, MSN, Nurse Clini- research support from Eli Lilly, Organon, Shire, Som- 11. National Institute for Health and Clinical Excel- cian; Brain McKain, MSN, Pharmacotherapist; Sue Wes- lence (NICE). Depression in children and young people: erset, Forest Laboratories, and Biobehavioral Diag- ner, MSN, Pharmacotherapist; Nancie Tormey, PhD, nostics Inc; consults for Eli Lilly, GlaxoSmithKline, Wy- identification and management in primary, commu- CBT Therapist; Travis Schermer, MSCP, Independent nity, and secondary care. http://www.nice.org.uk eth-Ayerst, Shire, and Biobehavioral Diagnostics Inc; Evaluator; Maureen Bridge, LCSW, CBT Consultant and is on the speaker’s bureau for McNeil. Dr Hughes /guidance/index.jsp?action=byID&o=10970. Ac- (service agreement with UP); Robert Berchik, PhD, CBT cessed February 4, 2008. reports being a consultant for Biobehavioral Diagnos- Consultant (service agreement with UP); and Re- , Inc. Dr Keller reported research support from Pfizer; 12. March J, Silva S, Petrycki S, et al; Treatment for becca Munnell, BA, Data Management/Analysis. Kai- Adolescents with Depression Study Team. Fluox- and consults for CENEREX, Cephalon, Cypress Bio- ser Permanente-Portland: John Gale, MD, Physician science, Cyberonics, Forest Laboratories, Janssen, JDS, etine, cognitive-behavioral therapy, and their combi- Liaison; John Stull, MD, Physician Liaison; John Pear- nation for adolescents with depression. JAMA. 2004; Organon, , Pfizer, and Wyeth. Dr Keller re- son, MD, Physician Liaison; Kristina Booker, BS, Project 292(7):807-820. ports serving on advisory boards for Abbott Labora- Management; Stephanie Hertert, MEd, CCRC Project 13. Kennard B, Silva S, Vitiello B, et al. Remission and tories, Bristol-Myers Squibb, CENEREX, Cyberonics, Cy- Management; Lynette Currie, MA, Independent Evalu- residual symptoms after acute treatment of adoles- press Bioscience, Forest Laboratories, Janssen, Novartis, ator; Kevin Rogers, MA, Independent Evaluator; Bobbi cents with major depressive disorder. J Am Acad Child Organon, and Pfizer. Dr McCracken reports receiv- Yarborough, MA, Independent Evaluator; Micah Yar- Adolesc Psychiatry. 2006;45(12):1404-1411. ing research support from Eli Lilly, McNeil, Bristol- borough, MA, Independent Evaluator; Nancy Thayer, 14. Emslie GJ, Rush AJ, Weinberg WA, et al. A double- Myers Squibb, and Shire; and consults for Shire, Eli Lilly, MA, Independent Evaluator; Carrie Smith, MA, Inde- blind, randomized -controlled trial of fluox- McNeil, Pfizer, Janssen, Johnson & Johnson, Novar- pendent Evaluator; Alison Firemark, MA, CBT Thera- etine in depressed children and adolescents with tis and Wyeth. Dr Melhem reports receiving the AFSP- pist; Sue Leung, PhD, CBT Therapist; Roger Macdon- depression. Arch Gen Psychiatry. 1997;54(11):1031- Pfizer travel award to present at the American Asso- ald, RN, ND Pharmacotherapist; Jonalyn Wallace, RN, 1037. ciation of Suicidology annual meeting in New Orleans, Pharmacotherapist; JoAnn Deutsche, RN, MS, FNP 15. Louisiana. Dr Wagner reports past research support Pharmacotherapist; Pat Smith, RN, MN, PMHNP Phar- Brent DA, Holder D, Kolko D, et al. A clinical psy- from Abbott Laboratories, AstraZeneca, Bristol- macotherapist; Jane Wallace, Data Management; Kevin chotherapy trial for adolescent depression compar- Myers Squibb, Eli Lilly, Forest Laboratories, Winn, Data Management; John Dickerson, MA, Data ing cognitive, family, and supportive treatments. Arch GlaxoSmithKline, Johnson & Johnson, Novartis, Or- Management; and Christine Jones, Laboratory. UCLA: Gen Psychiatry. 1997;54(9):877-885. ganon, Pfizer, and Wyeth-Ayerst; and is a consultant/ Caroly Pataki, MD, Pharmacotherapist; Janeen Locker, 16. Wood A, Harrington R, Moore A. Controlled trial advisory board member for Abbott Laboratories, As- PhD, CBT Therapist; Michele Berk, PhD, CBT Thera- of a brief cognitive-behavioural intervention in ado- traZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, pist; Cynthia Whitham, PhD, CBT Therapist; David lescent patients with depressive disorders. J Child Psy- Forest Laboratories, GlaxoSmithKline, Janssen, Jazz Langer, MA, CBT Therapist; Anne Bellows, MSW chol Psychiatry. 1996;37(6):737-746. Pharmaceuticals, Novartis, Ortho-McNeil, Pfizer, Or- Project Coordinator/Independent Evaluator; Analisa 17. Ma J, Lee KV, Stafford RS. Depression treatment ganon, Otsuka, Solvay, UCB Pharma, Wyeth Ayerst. Enrile, MSW Project Coordinator/Independent Evalu- during outpatient visits by US children and adolescents. No other financial disclosures were reported. ator; Mona Navarro, PhD, Independent Evaluator; J Adolesc Health. 2005;37(6):434-442. Funding/Support: This work was supported by Na- Veronica Barbery, BA, Project Coordinator; Natalie To- 18. Hughes CW, Emslie GJ, Crismon ML, et al; Texas tional Institute of Mental Health grants MH61835 jarieh, BA, Research Assistant; Kelly Burns, BA, JD Consensus Conference Panel on Medication Treat- (Pittsburgh, Pennsylvania site); MH61856 (Galves- Project Coordinator; Heather Jones, MD, Pharmaco- ment of Childhood Major Depressive Disorder. Texas ton, Texas site); MH61864 (UCLA site); MH61869 therapist; and Eliana Santoro, MD, Data Manage- Children’s Medication Algorithm Project: update from (Portland, Oregon site); MH61958 (Dallas, Texas site); ment. Texas consensus conference panel on medication treat- and MH62014 (Brown), and the Advanced Center for ment of childhood major depressive disorder. 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