title: Dialectical behavior therapy for adolescents with repeated suicidal and self-harming behavior: a randomized trial. Impact of physical and sexual abuse on treatment response in the Treatment of Resistant Depression in Adolescent Study (TORDIA). Adjunctive sleep medications and depression outcome in the treatment of serotonin-selective reuptake inhibitor resistant depression in adolescents study. Treatment of selective serotonin reuptake inhibitor-resistant depression in adolescents: predictors and moderators of treatment response. Treatment-resistant depression in adolescents: is the addition of cognitive behavioral therapy of benefit? Treatment of Resistant Depression in Adolescents (TORDIA): week 24 outcomes. A Randomized Controlled Effectiveness Trial of Acceptance and Commitment Therapy and Cognitive Therapy for Anxiety and Depression Association of FKBP5 polymorphisms with suicidal events in the Treatment of Resistant Depression in Adolescents (TORDIA) study. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Fluoxetine 40-60 mg versus fluoxetine 20 mg in the treatment of children and adolescents with a less-than-complete response to nine-week treatment with fluoxetine 10-20 mg: a pilot study. Long-term outcome of adolescent depression initially resistant to selective serotonin reuptake inhibitor treatment: a follow-up study of the TORDIA sample. Antidepressant Exposure as a Predictor of Clinical Outcomes in the Treatment of Resistant Depression in Adolescents (TORDIA) Study The bi-directional relationship between parent-child conflict and treatment outcome in treatment-resistant adolescent depression. Anhedonia predicts poorer recovery among youth with selective serotonin reuptake inhibitor treatment-resistant depression. A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Incremental cost-effectiveness of combined therapy vs medication only for youth with selective serotonin reuptake inhibitor-resistant depression: treatment of SSRI-resistant depression in adolescents trial findings. Impact of treatments for depression on comorbid anxiety, attentional, and behavioral symptoms in adolescents with selective serotonin reuptake inhibitor-resistant depression. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. The Treatment of Adolescent Suicide Attempters study (TASA): predictors of suicidal events in an open treatment trial. Predictors and moderators of acute outcome in the Treatment for Adolescents with Depression Study (TADS). A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial. Pharmacokinetically and clinician-determined adherence to an antidepressant regimen and clinical outcome in the TORDIA trial. Efficacy of Dialectical Behavior Therapy for Adolescents at High Risk for Suicide: A Randomized Clinical Trial Do sub-syndromal manic symptoms influence outcome in treatment resistant depression in adolescents? A latent class analysis from the TORDIA study. Long-term follow-up of a randomized controlled trial comparing acceptance and commitment therapy and standard cognitive behavior therapy for anxiety and depression.
abstract: OBJECTIVE We examined whether a shortened form of dialectical behavior therapy , dialectical behavior therapy for adolescents ( DBT-A ) is more effective than enhanced usual care ( EUC ) to reduce self-harm in adolescents . METHOD This was a r and omized study of 77 adolescents with recent and repetitive self-harm treated at community child and adolescent psychiatric outpatient clinics who were r and omly allocated to either DBT-A or EUC .  Assessment s of self-harm , suicidal ideation , depression , hopelessness , and symptoms of borderline personality disorder were made at baseline and after 9 , 15 , and 19 weeks ( end of trial period ) , and frequency of hospitalizations and emergency department visits over the trial period were recorded . RESULTS Treatment retention was generally good in both treatment conditions , and the use of emergency services was low . DBT-A was superior to EUC in reducing self-harm , suicidal ideation , and depressive symptoms . Effect sizes were large for treatment outcomes in patients who received DBT-A , whereas effect sizes were small for outcomes in patients receiving EUC . Total number of treatment contacts was found to be a partial mediator of the association between treatment and changes in the severity of suicidal ideation , whereas no mediation effects were found on the other outcomes or for total treatment time . CONCLUSION DBT-A may be an effective intervention to reduce self-harm , suicidal ideation , and depression in adolescents with repetitive self-harming behavior . Clinical trial registration information-Treatment for Adolescents With Deliberate Self Harm ; http:// Clinical Trials.gov/ ; NCT00675129 OBJECTIVE We previously reported that a history of abuse was associated with a poorer response to combination treatment  in the Treatment of Resistant Depression in Adolescents study ( TORDIA ) . We now report on the nature and correlates of abuse that might explain these findings . METHOD Youth who did not benefit from an adequate selective serotonin re-uptake inhibitor ( SSRI ) trial ( N = 334 ) were r and omized to one of the following : an alternative SSRI ; an alternative SSRI plus cognitive behavior therapy ( CBT ) ; venlafaxine ; or venlafaxine plus CBT . Analyses examined the effect of history of abuse on response to the pharmacotherapy and combination therapy . RESULTS Those without a history of physical abuse ( PA ) or sexual abuse ( SA ) had a higher 12-week response rate to  combination therapy  compared with medication mono-therapy ( 62.8 % versus 37.6 % ; odds ratio [ OR ] = 2.8 , 95 % confidence interval [ CI ] = 1.6 - 4.7 , p < .001 ) . Those with a history of SA had similar response rates to combination versus medication monotherapy ( 48.3 % versus 42.3 % ; OR = 1.3 , 95 % CI = 0.4 - 3.7 ; p = .66 ) , whereas those with history of PA had a much lower rate of response to  combination therapy  ( 18.4 % versus 52.4 % , OR = 0.1 ; 95 % CI = 0.02 - 0.43 ) . Even after adjusting for other clinical predictors , a history of PA moderated treatment outcome . CONCLUSION These results should be considered within the limitations of a post hoc analysis , lack of detailed assessment of abuse and other forms of trauma , and neuropsychological status . Depressed patients with history of abuse , especially PA may require specialized clinical approaches . Further work is needed to underst and by what mechanisms a history of abuse affects treatment response OBJECTIVE In the Treatment of Resistant Depression in Adolescents , study participants who received medication for sleep  had a lower response rate . This report sought to clarify this finding . METHOD Depressed adolescents who had not responded to a previous adequate serotonin-selective reuptake inhibitor ( SSRI ) trial were r and omly assigned to another SSRI , venlafaxine , another SSRI+cognitive behavior therapy ( CBT ) , or venlafaxine+CBT . Augmentation with sleep medication was permitted as clinical ly indicated . RESULTS Youth who received trazodone  were six times less likely to respond than those with no sleep medication ( adjusted odds ratio [OR]=0.16 , 95 % confidence interval [ CI ] : 0.05 - 0.50 , p=0.001 ) and were three times more likely to experience self-harm ( OR=3.0 , 95 % CI : 1.1 - 7.9 , p=0.03 ) , even after adjusting for baseline differences associated with trazodone use . None ( 0/13 ) of those cotreated with trazodone and either paroxetine or fluoxetine responded . In contrast , those treated with other sleep medications had similar rates of response ( 60.0 % vs. 50.4 % , χ(2)=0.85 , p=0.36 ) and of self-harm events ( OR=0.5 , 95 % CI : 0.1 - 2.6 , p=0.53 ) as those who received no sleep medication . CONCLUSIONS These findings should be interpreted cautiously because these sleep agents were not assigned r and omly , but at clinician discretion . Nevertheless , they suggest that the use of trazodone for the management of sleep difficulties in adolescent depression should be re-evaluated and that future research on the management of sleep disturbance in adolescent depression is needed . The very low response rate of participants cotreated with trazodone and either fluoxetine or paroxetine could be due to inhibition of CYP 2D6 by these antidepressants OBJECTIVE To advance knowledge regarding strategies for treating selective serotonin reuptake inhibitor (SSRI)-resistant depression in adolescents , we conducted a r and omized controlled trial evaluating alternative treatment strategies . In primary analyses , cognitive-behavioral therapy ( CBT ) combined with medication change was associated with higher rates of positive response to short-term ( 12-week ) treatment than medication alone . This study examines predictors and moderators of treatment response , with the goal of informing efforts to match youths to optimal treatment strategies . METHOD Youths who had not improved during an adequate SSRI trial ( N = 334 ) were r and omized to an alternative SSRI , an alternative SSRI plus CBT , venlafaxine , or venlafaxine plus CBT . Analyses examined predictors and moderators of treatment response . RESULTS Less severe depression , less family conflict , and absence of nonsuicidal self-injurious behavior predicted better treatment response status . Significant moderators of response to CBT + medication ( combined ) treatment were number of comorbid disorders and abuse history ; hopelessness was marginally significant . The CBT/combined treatment superiority over medication alone was more evident among youths who had more comorbid disorders ( particularly attention-deficit/hyperactivity disorder and anxiety disorders ) , no abuse history , and lower hopelessness . Further analyses revealed a stronger effect of combined CBT + medication treatment among youths who were older and white and had no nonsuicidal self-injurious behavior and longer pre study pharmacotherapy . CONCLUSIONS Combined treatment with CBT and antidepressant medication may be more advantageous for adolescents whose depression is comorbid with other disorders . Given the additional costs of adding CBT to medication , consideration of moderators in clinical decision making can contribute to a more personalized and effective approach to treatment Background Many young people with major depression fail first-line treatments . Treatment-resistant depression has various definitions in the literature but typically assumes nonresponse to medication . In young people , cognitive behavioral therapy ( CBT ) is the recommended first-line intervention , thus the definition of treatment resistance should be exp and ed . Therefore , our aim was to synthesize the existing evidence of any interventions for treatment-resistant depression , broadly defined , in children and adolescents and to investigate the effectiveness of CBT in this context . Methods We used Cochrane Collaboration methodology , with electronic search es of Medline , PsycINFO , Embase , and the Cochrane Depression Anxiety and Neurosis Group trials registers . Only r and omized controlled trials were included , and were assessed for risk of bias . Meta- analysis was undertaken where possible and appropriate . Results Of 953 articles retrieved , four trials were eligible for inclusion . For one study , only the trial registration document was available , because the study was never completed . All other studies were well conducted with a low risk of bias , although one study had a high dropout rate . Two studies assessed the effect of adding CBT to medication . While an assertive trial of antidepressants does appear to lead to benefit , when compared with placebo , there was no significant advantage , in either study , or in a meta- analysis of data from these trials , that clearly demonstrated an additional benefit of CBT . The third trial showed little advantage of a tricyclic antidepressant over placebo in the context of an inpatient admission . Conclusion Few r and omized controlled trials have investigated interventions for treatment-resistant depression in young people , and results from these show modest benefit from antidepressants with no additional benefit over medication from CBT . Overall , there is a lack of evidence about effective interventions to treat young people who have failed to respond to evidence -based interventions for depression . Research in this area is urgently required OBJECTIVE The purpose of this study was to report on the outcome of participants in the Treatment of Resistant Depression in Adolescents ( TORDIA ) trial after 24 weeks of treatment , including remission and relapse rates and predictors of treatment outcome . METHOD Adolescents ( ages 12 - 18 years ) with selective serotonin reuptake inhibitor (SSRI)-resistant depression were r and omly assigned to either a medication switch alone ( alternate SSRI or venlafaxine ) or a medication switch plus cognitive-behavioral therapy ( CBT ) . At week 12 , responders could continue in their assigned treatment arm and nonresponders received open treatment ( medication and /or CBT ) for 12 more weeks ( 24 weeks total ) . The primary outcomes were remission and relapse , defined by the Adolescent Longitudinal Interval Follow-Up Evaluation as rated by an independent evaluator . RESULTS Of 334 adolescents enrolled in the study , 38.9 % achieved remission by 24 weeks , and initial treatment assignment did not affect rates of remission . Likelihood of remission was much higher ( 61.6 % versus 18.3 % ) and time to remission was much faster among those who had already demonstrated clinical response by week 12 . Remission was also higher among those with lower baseline depression , hopelessness , and self-reported anxiety . At week 12 , lower depression , hopelessness , anxiety , suicidal ideation , family conflict , and absence of comorbid dysthymia , anxiety , and drug/alcohol use and impairment also predicted remission . Of those who responded by week 12 , 19.6 % had a relapse of depression by week 24 . CONCLUSIONS Continued treatment for depression among treatment-resistant adolescents results in remission in approximately one-third of patients , similar to adults . Eventual remission is evident within the first 6 weeks in many , suggesting that earlier intervention among nonresponders could be important Acceptance and commitment therapy ( ACT ) has a small but growing data base of support . One hundred and one heterogeneous out patients reporting moderate to severe levels of anxiety or depression were r and omly assigned to traditional cognitive therapy ( CT ) or to ACT . To maximize external validity , the authors utilized very minimal exclusion criteria . Participants receiving CT and ACT  evidence d large , equivalent improvements in depression , anxiety , functioning difficulties , quality of life , life satisfaction , and clinician-rated functioning . Whereas improvements were equivalent across the two groups , the mechanisms of action appeared to differ . Changes in “ observing ” and “ describing ” one 's experiences appeared to mediate outcomes for the CT group relative to the ACT group , whereas “ experiential avoidance , ” “ acting with awareness , ” and “ acceptance ” mediated outcomes for the ACT group . Overall , the results suggest that ACT is a viable and disseminable treatment , the effectiveness of which appears equivalent to that of CT , even as its mechanisms appear to be distinct OBJECTIVE The authors sought to assess the relationship between c and i date genes and two clinical outcomes , namely , symptomatic improvement and the occurrence of suicidal events , in a sample of treatment-resistant depressed adolescents . METHOD A sub sample of depressed adolescents participating in the Treatment of SSRI-Resistant Depression in Adolescents ( TORDIA ) trial , 155 of whom were of European origin , were genotyped with respect to 21 polymorphisms on 12 genes that have a reported association with depression , treatment response , or suicidal events . Participants had not responded to a previous adequate trial with an antidepressant and were r and omized to receive either another selective serotonin reuptake inhibitor or venlafaxine , with or without cognitive-behavioral therapy ( CBT ) . Single-nucleotide polymorphism ( SNP ) analyses were conducted using PLINK with permutation procedures . RESULTS No relationship was observed between any polymorphism and response to treatment . The FKBP5 ( which codes for a protein causing subsensitivity of the glucocorticoid receptor ) rs1360780TT and rs3800373GG genotypes were associated with suicidal events ( N=18 ) , even after controlling for treatment effects and relevant covariates . These two SNPs were in significant linkage disequilibrium ( r=0.91 ) . CONCLUSIONS The FKBP5 genotypes associated with suicidal events in this study have been reported by others to cause the greatest degree of glucocorticoid receptor subsensitivity . These results are consistent with those of other studies linking alterations in the hypothalamic-pituitary-adrenal axis with suicidal behavior . The small number of events and lack of a placebo condition make these results preliminary . Replication with a larger sample and a placebo condition is needed to assess whether these events are related to treatment Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more OBJECTIVE The aim of this study was to compare fluoxetine dosage titration to 40 - 60 mg/day with fixed fluoxetine 20-mg/day treatment for an additional 10 weeks in pediatric out patients with major depressive disorder ( MDD ) who had not met protocol -defined response criteria after 9-week acute fluoxetine treatment . METHODS Patients unresponsive ( less than or equal to 30 % decrease in Children 's Depression Rating Scale-Revised [ CDRS-R ] score ) after 9-week fluoxetine treatment were r and omly reassigned to continue at 20 mg/day or to increase to 40 mg/day . After 4 weeks , patients unresponsive to 40 mg/day could receive 60 mg/day . RESULTS Twenty-nine ( 29 ) patients , 9 - 17 years of age , received fluoxetine 40 - 60 mg/day ( n = 14 ) or 20 mg/day ( n = 15 ) . At the conclusion of this study phase , 10 patients ( 71 % ) on 40 - 60 mg/day met the response criteria , versus 5 patients ( 36 % ) on 20 mg/day ( p = 0.128 ) . Mean CDRS-R scores improved in both treatment groups ( fluoxetine 40 - 60 mg/day , -9.4 ; fluoxetine 20 mg/day , -1.5 ; p = 0.099 ) . Adverse events were similar in both groups . However , this study phase was statistically underpowered for detecting differences between treatment groups . CONCLUSION More than two thirds of patients whose dosage was increased responded within 10 weeks , suggesting dose escalation may benefit some patients . Approximately one third of patients unresponsive to initial treatment with fluoxetine 20 mg responded to this fixed dosage within another 10 weeks . Fluoxetine 20 - 60 mg/day was well tolerated BACKGROUND We examined the long-term outcome of participants in the Treatment of SSRI-Resistant Depression in Adolescents ( TORDIA ) study , a r and omized trial of 334 adolescents ( aged 12 - 18 years ) with DSM-IV-defined major depressive disorder initially resistant to selective serotonin reuptake inhibitor ( SSRI ) treatment who were subsequently treated for 12 weeks with another SSRI , venlafaxine , another SSRI + cognitive-behavioral therapy ( CBT ) , or venlafaxine + CBT . Responders then continued with the same treatment through week 24 , while nonresponders were given open treatment . METHOD For the current study , patients were reassessed 48 ( n = 116 ) and 72 ( n = 130 ) weeks from intake . Data were gathered from February 2001 to February 2007 . St and ardized diagnostic interviews and measures of depression , suicidal ideation , related psychopathology , and level of functioning were periodically administered . Remission was defined as ≥ 3 weeks with ≤ 1 clinical ly significant symptom and no associated functional impairment ( score of 1 on the adolescent version of the Longitudinal Interval Follow-Up Evaluation [ A-LIFE ] ) , and relapse , as ≥ 2 weeks with probable or definite depressive disorder ( score of 3 or 4 on the A-LIFE ) . Mixed-effects regression models were applied to estimate remission , relapse , and functional recovery . RESULTS By 72 weeks , an estimated 61.1 % of the r and omized youths had reached remission . R and omly assigned treatment ( first 12 weeks ) did not influence remission rate or time to remission , but the group assigned to SSRIs had a more rapid decline in self-reported depressive symptoms and suicidal ideation than those assigned to venlafaxine ( P < .03 ) . Participants with more severe depression  ,  greater  dysfunction , and alcohol or drug use at baseline were less likely to remit . The depressive symptom trajectory of the remitters diverged from that of nonremitters by the first 6 weeks of treatment ( P < .001 ) . Of the 130 participants in remission at week 24 , 25.4 % relapsed in the subsequent year . CONCLUSIONS While most adolescents achieved remission , more than one-third did not , and one-fourth of remitted patients experienced a relapse . More effective interventions are needed for patients who do not show robust improvement early in treatment . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00018902 This paper examines the relationship between plasma concentration of antidepressant and both clinical response and adverse effects in treatment-resistant depressed adolescents . Adolescents ( n = 334 ) with major depression who had not responded to a selective serotonin reuptake inhibitor ( SSRI )  were r and omized to 1 of 4 treatments : switch to another SSRI ( fluoxetine , citalopram , or paroxetine ) , switch to venlafaxine , switch to SSRI plus cognitive behavior therapy , or switch to venlafaxine plus cognitive behavior therapy . Adolescents who did not improve by 6 weeks had their dose increased . Plasma concentrations of medication and metabolites were measured at 6 weeks in 244 participants and at 12 weeks in 204 participants . Adolescents treated with citalopram whose plasma concentration was equal to or greater than the geometric mean ( GM ) showed a higher response rate compared to those with less than the GM , with parallel but nonsignificant findings for fluoxetine . A dose increase of citalopram or fluoxetine at week 6 was most likely to result in response when it led to a change in concentration from less than the GM at 6 weeks to the GM or greater at week 12 . Plasma levels of paroxetine , venlafaxine , or O-desmethylvenlafaxine were not related to clinical response . Exposure was associated with more cardiovascular and dermatologic side effects in those receiving venlafaxine . Antidepressant concentration may be useful in optimizing treatment for depressed adolescents receiving fluoxetine or citalopram OBJECTIVE To examine the bidirectional relationship between parent-child discord and treatment outcome for adolescent treatment-resistant depression . METHOD Depressed youth who had not responded to an adequate course of a selective serotonin reuptake inhibitor ( SSRI )  were r and omized to either a switch to another SSRI or venlafaxine , with or without the addition of cognitive behavior therapy ( CBT ) in the Treatment of SSRI-Resistant Depression in Adolescents ( TORDIA ) study . The Conflict Behavior Question naire was used to assess  adolescent ( CBQ-A )  and parent-reported ( CBQ-P ) parent-child  discord . The impact of remission on parent-child conflict , and the differential impact of medication and CBT on the CBQ-A and CBQ-P , were assessed using generalized linear models . RESULTS Although there were no differential treatment effects on parent or adolescent-report of conflict , remission was associated with improvement in the CBQ-P. In general , intake family conflict did not predict remission , except in the sub-group of participants whose parents reported clinical ly significant  parent-child  conflict at intake , for whom high levels of parent-reported conflict predicted a lower likelihood of remission . Conflict also did not moderate treatment response . CONCLUSIONS Remission of depression may be sufficient to reduce parent-reported parent-child conflict . However , higher parent-reported conflict , in the clinical ly significant range , predicts a lower likelihood of remission from depression . Clinical trial registration information-Treatment of SSRI-Resistant Depression in Adolescents ( TORDIA ) ; http:// clinical trials.gov/ ; NCT00018902 OBJECTIVE To identify symptom dimensions of depression that predict recovery among  selective serotonin reuptake inhibitor ( SSRI ) treatment-resistant adolescents undergoing second-step treatment . METHOD The Treatment of Resistant Depression in Adolescents ( TORDIA ) trial included 334 SSRI treatment-resistant youth r and omized to a medication switch , or a medication switch plus CBT .  This study examined five established symptom dimensions ( Child Depression Rating Scale-Revised ) at baseline as they predicted recovery over 24 weeks of acute and continuation treatment . The two indices of recovery that were evaluated were time to remission and number of depression-free days . RESULTS Multivariate analyses examining all five depression symptom dimensions simultaneously indicated that anhedonia was the only dimension to predict a longer time to remission , and also the only dimension to predict fewer depression-free days . In addition , when anhedonia and CDRS-total score were evaluated simultaneously , anhedonia continued to uniquely predict longer time to remission and fewer depression-free days . CONCLUSIONS Anhedonia may represent an important negative prognostic indicator among treatment-resistant depressed adolescents . Further research is needed to eluci date neurobehavioral underpinnings of anhedonia , and to test treatments that target anhedonia in the context of overall treatment of depression BACKGROUND Depression is a major cause of morbidity and mortality in children and adolescents . To date , r and omized , controlled , double-blind trials of antidepressants ( largely tricyclic agents ) have yet to reveal that any antidepressant is more effective than placebo . This article is of a r and omized , double-blind , placebo-controlled trial of fluoxetine in children and adolescents with depression . METHODS Ninety-six child and adolescent out patients ( aged 7 - 17 years ) with nonpsychotic major depressive disorder were r and omized ( stratified for age and sex ) to 20 mg of fluoxetine or placebo and seen weekly for 8 consecutive weeks . R and omization was preceded by 3 evaluation visits that included structured diagnostic interviews during 2 weeks , followed 1 week later by a 1-week , single-blind placebo run-in . Primary outcome measurements were the global improvement of the Clinical Global Impressions scale and the Children 's Depression Rating Scale -- Revised , a measure of the severity depressive symptoms . RESULTS Of the 96 patients , 48 were r and omized to fluoxetine treatment and 48 to placebo . Using the intent to treat sample , 27 ( 56 % ) of those receiving fluoxetine and 16 ( 33 % ) receiving placebo were rated " much " or " very much " improved on the Clinical Global Impressions scale at study exit ( chi 2 = 5.1 , df = 1 , P = .02 ) . Significant differences were also noted in weekly ratings of the Children 's Depression Rating Scale -- Revised after 5 weeks of treatment ( using last observation carried forward ) . Equivalent response rates were found for patients aged 12 years and younger ( n = 48 ) and those aged 13 years and older ( n = 48 ) . However , complete symptom remission ( Children 's Depression Rating Scale -- Revised < or = 28 ) occurred in only 31 % of the fluoxetine-treated patients and 23 % of the placebo patients . CONCLUSION Fluoxetine was superior to placebo in the acute phase treatment of major depressive disorder in child and adolescent out patients with severe , persistent depression . Complete remission of symptoms was rare CONTEXT Many youth with depression do not respond to initial treatment with selective serotonin reuptake inhibitors ( SSRIs ) , and this is associated with higher costs . More effective treatment for these youth may be cost-effective . OBJECTIVE To evaluate the incremental cost-effectiveness over 24 weeks of combined cognitive behavior therapy plus switch to a different antidepressant medication vs medication switch only in adolescents who continued to have depression despite adequate initial treatment with an SSRI . DESIGN R and omized controlled trial . SETTING Six US academic and community clinics . PATIENTS Three hundred thirty-four patients aged 12 to 18 years with SSRI-resistant depression . INTERVENTION Participants were r and omly assigned to ( 1 ) switch to a different medication only or ( 2 ) switch to a different medication plus cognitive behavior therapy . MAIN OUTCOME MEASURES Clinical outcomes were depression-free days ( DFDs ) , depression-improvement days ( DIDs ) , and quality -adjusted life-years based on DFDs ( DFD-QALYs ) . Costs of intervention , non protocol services , and families were included . RESULTS Combined treatment achieved 8.3 additional DFDs ( P = .03 ) , 0.020 more DFD-QALYs ( P = .03 ) , and 11.0 more DIDs ( P = .04 ) . Combined therapy cost $ 1633 more ( P = .01 ) . Cost per DFD was $ 188 ( incremental cost-effectiveness ratio [ ICER ] = $ 188 ; 95 % confidence interval [ CI ] , -$22 to $ 1613 ) , $ 142 per DID ( ICER = $ 142 ; 95 % CI , -$14 to $ 2529 ) , and $ 78,948 per DFD-QALY ( ICER = $ 78,948 ; 95 % CI , -$9261 to $ 677,448 ) . Cost-effectiveness acceptability curve analyses suggest a 61 % probability that combined treatment is more cost-effective at a willingness to pay $ 100,000 per QALY . Combined treatment had a higher net benefit for subgroups of youth without a history of abuse , with lower levels of hopelessness , and with comorbid conditions . CONCLUSIONS For youth with SSRI-resistant depression , combined treatment decreases the number of days with depression and is more costly . Depending on a decision maker 's willingness to pay , combined therapy may be cost-effective , particularly for some subgroups . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00018902 OBJECTIVE To assess the relative efficacy of antidepressant medication , alone and in combination with cognitive behavioral therapy ( CBT ) , on comorbid symptoms of anxiety , attention , and disruptive behavior disorders in participants in the Treatment of Resistant Depression in Adolescents ( TORDIA ) trial . METHOD Adolescents with selective serotonin reuptake inhibitor (SSRI)-resistant depression ( N = 334 ) were r and omly assigned to a medication switch alone ( to another SSRI or to venlafaxine ) or to a medication switch plus CBT .  Anxiety , attention-deficit/hyperactivity disorder ( ADHD ) , and disruptive behavior disorder ( DBD ) symptoms were assessed by psychiatric interview and self-report at regular intervals between baseline and 24 weeks . The differential effects of medication and of CBT , and the impact of remission on the course of comorbid symptoms and diagnoses , were assessed using generalized linear mixed models . RESULTS Remission was associated with a greater reduction in scalar measures of anxiety , ADHD , and DBDs , and a greater decrease in the rate of diagnosed anxiety disorders . The correlations between the changes in symptoms of depression on the CDRS-R and anxiety , ADHD , and oppositional symptoms were modest , ranging from r = 0.12 to r = 0.28 . There were no significant differential treatment effects on diagnoses , or corresponding symptoms . CONCLUSION The achievement of remission had a beneficial effect on anxiety , ADHD , and DBD symptoms , regardless of the type of treatment received . There were no differential effects of medication or CBT on outcome , except for a nonsignificant trend that those adolescents treated with SSRIs showed a greater decrease in rates of comorbid DBDs relative to those treated with venlafaxine . Clinical trial registration information-Treatment of SSRI-Resistant Depression In Adolescents ( TORDIA ) ; http:// clinical trials.gov/ ; NCT00018902 CONTEXT Only about 60 % of adolescents with depression will show an adequate clinical response to an initial treatment trial with a selective serotonin reuptake inhibitor ( SSRI ) . There are no data to guide clinicians on subsequent treatment strategy . OBJECTIVE To evaluate the relative efficacy of 4 treatment strategies in adolescents who continued to have depression despite adequate initial treatment with an SSRI .  DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial of a clinical sample of 334 patients aged 12 to 18 years with a primary diagnosis of major depressive disorder that had not responded to a 2-month initial treatment with an SSRI , conducted at 6 US academic and community clinics from 2000 - 2006 . INTERVENTIONS Twelve weeks of : ( 1 ) switch to a second , different SSRI ( paroxetine , citalopram , or fluoxetine , 20 - 40 mg ) ; ( 2 ) switch to a different SSRI plus cognitive behavioral therapy ; ( 3 ) switch to venlafaxine ( 150 - 225 mg ) ; or ( 4 ) switch to venlafaxine plus cognitive behavioral therapy . 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 Depression Rating Scale-Revised ( CDRS-R ) ; and change in CDRS-R over time . RESULTS Cognitive behavioral therapy plus a switch to either medication regimen showed a higher response rate ( 54.8 % ; 95 % confidence interval [ CI ] , 47%-62 % ) than a medication switch alone ( 40.5 % ; 95 % CI , 33%-48 % ; P = .009 ) , but there was no difference in response rate between venlafaxine and a second SSRI ( 48.2 % ; 95 % CI , 41%-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 , suicidal ideation , or on the rate of harm-related or any other adverse events . There was a greater increase in diastolic blood pressure and pulse and more frequent occurrence of skin problems during venlafaxine than SSRI treatment . CONCLUSIONS For adolescents with depression not responding to an adequate initial treatment with an SSRI , the combination of cognitive behavioral therapy and a switch to another antidepressant result ed in a higher rate of clinical response than did a medication switch alone . However , a switch to another SSRI was just as efficacious as a switch to venlafaxine and result ed in fewer adverse effects . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00018902 OBJECTIVE To identify the predictors of suicidal events and attempts in adolescent suicide attempters with depression treated in an open treatment trial . METHOD Adolescents who had made a recent suicide attempt and had unipolar depression ( n = 124 ) were either r and omized ( n = 22 ) or given a choice ( n = 102 ) among three conditions . Two participants withdrew before treatment assignment . The remaining 124 youths received a specialized psychotherapy for suicide attempting adolescents  ( n = 17 ) , a medication algorithm ( n = 14 ) , or the combination ( n = 93 ) . The participants were followed up 6 months after intake with respect to rate , timing , and predictors of a suicidal event ( attempt or acute suicidal ideation necessitating emergency referral ) . RESULTS The morbid risks of suicidal events and attempts on 6-month follow-up were 0.19 and 0.12 , respectively , with a median time to event of 44 days . Higher self-rated depression , suicidal ideation , family income , greater number of previous suicide attempts , lower maximum lethality of previous attempt , history of sexual abuse , and lower family cohesion predicted the occurrence , and earlier time to event , with similar findings for the outcome of attempts . A slower decline in suicidal ideation was associated with the occurrence of a suicidal event . CONCLUSIONS In this open trial , the 6-month morbid risks for suicidal events and for reattempts were lower than those in other comparable sample s , suggesting that this intervention should be studied further . Important treatment targets include suicidal ideation , family cohesion , and sequelae of previous abuse . Because 40 % of events occurred with 4 weeks of intake , an emphasis on safety planning and increased therapeutic contact early in treatment may be warranted OBJECTIVE To identify predictors and moderators of response to acute treatments among depressed adolescents ( N = 439 ) r and omly assigned to fluoxetine , cognitive-behavioral therapy ( CBT ) , both fluoxetine and CBT , or clinical management with pill placebo in the Treatment for Adolescents With Depression Study ( TADS ) . METHOD Potential baseline predictors and moderators were identified by a literature review . The outcome measure was a week 12 predicted score derived from the Children 's Depression Rating Scale-Revised ( CDRS-R ) . For each c and i date moderator or predictor , a general linear model was conducted to examine main and interactive effects of treatment and the c and i date variable on the CDRS-R predicted scores . RESULTS Adolescents who were younger , less chronically depressed , higher functioning , and less hopeless with less suicidal ideation  , fewer melancholic features or comorbid diagnoses , and greater expectations for improvement were more likely to benefit acutely than their counterparts . Combined treatment , under no condition less effective than monotherapy , was more effective than fluoxetine for mild to moderate depression and for depression with high levels of cognitive distortion , but not for severe depression or depression with low levels of cognitive distortion .  Adolescents from high-income families were as likely to benefit from CBT alone as from combined treatment . CONCLUSIONS Younger and less severely impaired adolescents are likely to respond better to acute treatment than older , more impaired , or multiply comorbid adolescents .  Family income level , cognitive distortions , and severity of depression may help clinicians to choose among acute interventions , but combined treatment proved robust in the presence of moderators OBJECTIVES To determine if , in the short term , depressed adolescents attending routine NHS Child and Adolescent Mental Health Services ( CAMHS ) , and receiving ongoing active clinical care , treatment with selective serotonin reuptake inhibitors ( SSRIs ) plus cognitive behaviour therapy ( CBT ) compared with SSRI alone , results in better healthcare outcomes . DESIGN A pragmatic r and omised controlled trial ( RCT ) was conducted on depressed adolescents attending CAMHS who had not responded to a psychosocial brief initial intervention ( BII ) prior to r and omisation . SETTING Six English CAMHS participated in the study . PARTICIPANTS A total of 208 patients aged between 11 and 17 years were recruited and r and omised . INTERVENTIONS All participants received active routine clinical care in a CAMHS outpatient setting and an SSRI and half were offered CBT . MAIN OUTCOME MEASURES The duration of the trial was a 12-week treatment phase , followed by a 16-week maintenance phase . Follow-up assessment s were at 6 , 12 and 28 weeks . The primary outcome measure was the Health of the Nation Outcome Scales for Children and Adolescents ( HoNOSCA ) . Secondary outcome measures were self-report depressive symptoms , interviewer-rated depressive signs and symptoms , interviewer-rated psychosocial impairment and clinical global impression of response to treatment . Information on re source use was collected in interview at baseline and at the 12- and 28-week follow-up assessment s using the Child and Adolescent Service Use Schedule ( CA-SUS ) . RESULTS Of the 208 patients r and omised , 200 ( 96 % ) completed the trial to the primary end-point at 12 weeks . By the 28-week follow-up , 174 ( 84 % ) participants were re-evaluated . Overall , 193 ( 93 % ) participants had been assessed at one or more time points . Clinical characteristics indicated that the trial was conducted on a severely depressed group . There was significant recovery at all time points in both arms . The findings demonstrated no difference in treatment effectiveness for SSRI + CBT over SSRI only for the primary or secondary outcome measures at any time point . This lack of difference held when baseline and treatment characteristics where taken into account ( age , sex , severity , co-morbid characteristics , quality and quantity of CBT treatment , number of clinic attendances ) . The SSRI + CBT group was somewhat more expensive over the 28 weeks than the SSRI-only group ( p=0.057 ) and no more cost-effective . Over the trial period there was on average a decrease in suicidal thoughts and self-harm compared with levels recorded at baseline . There was no significant increase in disinhibition , irritability and violence compared with levels at baseline . Around 20 % ( n=40 ) of patients in the trial were non-responders . Of these , 17 ( 43 % ) showed no improvement by 28 weeks and 23 ( 57 % ) were considered minimally ( n=10 ) or moderately to severely worse ( n=13 ) . CONCLUSIONS For moderately to severely depressed adolescents who are non-responsive to a BII , the addition of CBT to fluoxetine plus routine clinical care does not improve outcome or confer protective effects against adverse events and is not cost-effective . SSRIs ( mostly fluoxetine ) are not likely to result in harmful adverse effects . The findings are broadly consistent with existing guidelines on the treatment of moderate to severe depression . Modification is advised for those presenting with moderate ( 6 - 8 symptoms ) to severe depressions ( > 8 symptoms ) and in those with either overt suicidal risk and /or high levels of personal impairment . In such cases , the time allowed for response to psychosocial interventions should be no more than 2 - 4 weeks , after which fluoxetine should be prescribed . Further research should focus on evaluating the efficacy of specific psychological treatments against brief psychological intervention , determining the characteristics of patients with severe depression who are non-responsive to fluoxetine , relapse prevention in severe depression and improving tools for determining treatment responders and non-responders OBJECTIVE Nonadherence to antidepressant treatment may contribute to poor outcome and to suicidal adverse events in adolescent depression . We examine the relationship between adherence and both clinical response and suicidal events in participants in the Treatment of Resistant Depression in Adolescents ( TORDIA ) study . METHOD The relationship between adherence to medication and clinical outcome was assessed in 190 treatment-resistant depressed adolescents who were r and omized to one of four cells : switch to another selective serotonin reuptake inhibitor ( SSRI ) , switch to venlafaxine , or either of these two medication switches plus cognitive behavioral therapy .  Plasma levels of antidepressant drug and metabolites were determined after 6 and 12 weeks of treatment . A twofold or greater variation in the dose-adjusted concentration of drug plus metabolites ( level/dose ratio [ LDR ] ) was defined as nonadherence . Nonadherence was also determined by clinician pill counts ( CPC ) of the proportion of prescribed pills that were unused and was defined as having greater than 30 % of the prescribed pills remaining . RESULTS LDR and CPC showed low concordance . LDR was unrelated to clinical response .  CPC adherence was related to a higher response rate overall ( adherent , 63.0 % versus nonadherent , 47.2 % , p = .03 ) . Approximately half ( 50.8 % ) of the sample surveyed showed evidence of nonadherence by CPC . Neither measure of adherence was related to the occurrence of suicidal events or to the pace of decline in suicidal ideation . CONCLUSIONS Clinician pill counts may be a relevant measure of adherence that is related to outcome under formal clinical trial conditions in depressed adolescents . Nonadherence appears to be a common and significant source of treatment nonresponse . Clinical Trial Registration Information-Treatment of SSRI-Resistant Depression in Adolescents ( TORDIA ) ; http://www . clinical trials.gov ; NCT00018902 Importance Suicide is a leading cause of death among 10- to 24-year-old individuals in the United States ; evidence on effective treatment for adolescents who engage in suicidal and self-harm behaviors is limited . Objective To evaluate the efficacy of dialectical behavior therapy ( DBT ) compared with individual and group supportive therapy ( IGST ) for reducing suicide attempts , nonsuicidal self-injury , and overall self-harm among high-risk youths . Design , Setting , and Participants This r and omized clinical trial was conducted from January 1 , 2012 , through August 31 , 2014 , at 4 academic medical centers . A total of 173 participants ( pool of 195 ; 22 withdrew or were excluded ) 12 to 18 years of age with a prior lifetime suicide attempt ( ≥3 prior self-harm episodes , suicidal ideation , or emotional dysregulation ) were studied . Adaptive r and omization balanced participants across conditions within sites based on age , number of prior suicide attempts , and psychotropic medication use . Participants were followed up for 1 year . Interventions Study participants were r and omly assigned to DBT or IGST . Treatment duration was 6 months . Both groups had weekly individual and group psychotherapy , therapist consultation meetings , and parent contact as needed . Main Outcomes and Measures A priori planned outcomes were suicide attempts , nonsuicidal self-injury , and total self-harm assessed using the Suicide Attempt Self-Injury Interview . Results A total of 173 adolescents ( 163 [ 94.8 % ] female and 97 [ 56.4 % ] white ; mean [ SD ] age , 14.89 [ 1.47 ] years ) were studied . Significant advantages were found for DBT on all primary outcomes after treatment : suicide attempts ( 65 [ 90.3 % ] of 72 receiving DBT vs 51 [ 78.9 % ] of 65 receiving IGST with no suicide attempts ; odds ratio [ OR ] , 0.30 ; 95 % CI , 0.10 - 0.91 ) , nonsuicidal self-injury ( 41 [ 56.9 % ] of 72 receiving DBT vs 26 [ 40.0 % ] of 65 receiving IGST with no self-injury ; OR , 0.32 ; 95 % CI , 0.13 - 0.70 ) , and self-harm ( 39 [ 54.2 % ] of 72 receiving DBT vs 24 [ 36.9 % ] of 65 receiving IGST with no self-harm ; OR , 0.33 ; 95 % CI , 0.14 - 0.78 ) . Rates of self-harm decreased through 1-year follow-up . The advantage of DBT decreased , with no statistically significant between-group differences from 6 to 12 months ( OR , 0.65 ; 95 % CI , 0.12 - 3.36 ; P = .61 ) . Treatment completion rates were higher for DBT ( 75.6 % ) than for IGST ( 55.2 % ) , but pattern-mixture models indicated that this difference did not informatively affect outcomes . Conclusions and Relevance The results of this trial support the efficacy of DBT for reducing self-harm and suicide attempts in highly suicidal self-harming adolescents . On the basis of the criteria of 2 independent trials supporting efficacy , results support DBT as the first well-established , empirically supported treatment for decreasing repeated suicide attempts and self-harm in youths . Trial Registration Clinical Trials.gov Identifier : NCT01528020 BACKGROUND To identify distinct depressive symptom trajectories in the TORDIA study and determine their correlates . METHODS Latent Class Growth Analysis ( LCGA ) using the Children 's Depression Rating Scale-Revised ( CDRS-R ) through 72 weeks from intake . RESULTS 3 classes were identified : ( 1 ) little change in symptomatic status ( " NO " ) , comprising 24.9 % of participants , with a 72-week remission rate of 25.3 % ; ( 2 ) slow , steady improvement ( " SLOW " ) , comprising 47.9 % of participants , with a remission rate of 60.0 % , and ( 3 ) rapid symptom response ( " GO " ) , comprising 27.2 % of participants , with a remission rate of 85.7 % . Higher baseline CDRS-R ( p<0.001 ) and poorer functioning ( p=0.03 ) were the strongest discriminators between NO and GO . Higher baseline CDRS ( p<0.001 ) and scores on the Mania Rating Scale ( MRS ) ( p=0.01 ) were the strongest discriminators between SLOW and GO . Other variables differentiating GO from both NO and from SLOW , were better baseline functioning , lower hopelessness , and lower family conflict . Both NO and SLOW showed increases on the MRS over time compared to GO ( ps ≤ 0.04 ) , and increasing MRS was strongly associated with lack of remission by 72 weeks ( p=0.02 ) . LIMITATIONS High rate of open treatment by the end of the follow-up period creates difficulty in drawing clear inferences about the long-term impact of initial r and omization . CONCLUSION Along with depressive severity , sub-syndromal manic symptoms , at baseline , and over time emerged as important predictors and correlates of poor outcome in this sample . Further research is needed on the treatment of severe depression , and on the assessment and management of sub-syndromal manic symptoms in treatment resistant depression The present study represents one of the first comparisons of the long-term effectiveness of traditional cognitive behavior therapy ( i.e. , Beckian cognitive therapy ; CT ) and acceptance and commitment therapy ( ACT ) .  One hundred thirty-two anxious or depressed out patients were r and omly assigned to receive either CT or ACT , and were assessed at posttreatment ( n=90 ) and at 1.5-year ( n=91 ) follow-up . As previously reported , the two treatments were equivalently effective at posttreatment according to measures of depression , anxiety , overall ( social/occupational/symptom-related ) functioning , and quality of life . However , current results suggest that treatment gains were better maintained at follow-up in the CT condition . Clinical significance analyses revealed that , at follow-up , one-third more CT patients were in the clinical ly normative range in terms of depressive symptoms and more than twice as many CT patients were in the normative range in terms of functioning levels . The possible long-term advantage of CT relative to ACT in this population is discussed
target: Multiple secondary data analyses of TORDIA have identified important predictors of treatment response and relapse .
background: To up date a comparative effectiveness review ( 1980–2011 ) of treatments for adolescents whose depressive episode or disorder ( MDE/MDD ) did not respond to one or more trials of SSRI antidepressants .