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Objective: This article examined associations between change in youth and family characteristics during youth anxiety treatment and long-term anxiety severity and overall functioning., Method: Participants (N = 488; age 7-17 years; 45% male; 82% white) were randomized to 12 weeks of cognitive behavioral therapy ( Coping Cat ), medication (sertraline), their combination, or pill placebo in the Child/Adolescent Anxiety Multimodal Study (CAMS). A subset participated in the naturalistic follow-up Child/Adolescent Anxiety Multimodal Extended Long-term Study (CAMELS; n = 319; 3.70-11.83 years post-treatment). The current secondary analyses examined how change in anxiety severity (Child Global Impression-Severity), overall functioning (Children's Global Assessment Scale), caregiver psychopathology (Brief Symptom Inventory), caregiver strain (Family Burden Assessment Scale), and family dysfunction (Brief Family Assessment Measure) during CAMS was associated with anxiety severity and overall functioning years later (M = 7.72 years). CAMS procedures were registered on clinialtrials.gov., Results: Improvements in factors related to functioning (i.e., overall functioning, family dysfunction, caregiver strain) were associated with improvements in anxiety severity in CAMELS (|βys| ≥ .04, ps ≤ .04). Improvements in factors related to psychopathology (i.e., anxiety severity, caregiver psychopathology) were associated with improvements in overall functioning in CAMELS (|βys| ≥ .23, ps ≤ .04). It was changes in each of the variables examined (rather than baseline values) that predicted anxiety severity and overall functioning., Conclusions: Both youth and family factors play a significant role in long-term treatment outcomes. Therapists would be wise to monitor how these factors change throughout treatment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Objective: Test changes in perceived coping efficacy, negative self-statements, and interpretive biases to threat during treatment as potential mediators of the relationship between randomly assigned treatment conditions and long-term anxiety follow-ups. Age at randomization was also tested as a moderator of mediational relationships., Method: Participants included 319 youth (ages 7-17) from the Child/Adolescent Multimodal Study (CAMS) who participated in a naturalistic follow-up beginning an average of 6.5 years after the end of the CAMS intervention. The intervention conditions included cognitive behavioral therapy (CBT; Coping Cat), pharmacotherapy (sertraline), combined CBT and sertraline, and pill placebo. Putative mediators were measured four times during the intervention phase. Follow-up consisted of four annual assessments of current anxiety., Results: Reductions on a measure of interpretive bias to threat over the course of the combined condition intervention, as compared to the placebo condition, mediated anxiety outcomes at the first follow-up visit. This mediated effect was not significant for the CBT-only or sertraline-only conditions when compared to the placebo condition. No other significant mediated effects were found for putative mediators. Age did not significantly moderate any mediated effects., Conclusion: Changes in youth-reported interpretive biases to threat over the course of combined youth anxiety interventions, as compared to a placebo intervention, may be associated with lower anxiety an average of 6.5 years following treatment., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Expectancies for a favorable treatment outcome have been associated with actual favorable outcomes but have been understudied in youth with anxiety. The current study applied structural equation modeling in a sample of anxious youth (N = 488; 7-17 years, M = 10.69, SD = 2.80) to examine whether a multi-informant latent expectancies factor, indicated by youth, parent, and therapist reports, predicted a latent posttreatment anxiety factor, controlling for a latent pretreatment anxiety factor. Both anxiety latent factors were indicated by youth, parent, and independent evaluator (IE) reports. Analyses also examined whether treatment condition (cognitive behavioral therapy, sertraline, combination, pill placebo) moderated the association between expectancies and outcome, and whether this association differed across development. Findings indicated that informant reports loaded similarly onto the latent factors. Results also demonstrated that treatment expectancies were positively associated with outcomes, and that this relationship held across treatment type and age group. Treatment implications and future research directions are discussed.

Youth anxiety disorders are highly prevalent and are associated with considerable school impairment. Despite the identification of well-supported strategies for treating youth anxiety, research has yet to evaluate the differential effects of these treatments on anxiety-related school impairment. The present study leveraged data from the Child/Adolescent Anxiety Multimodal Study to examine differential treatment effects of CBT, sertraline, and their combination (COMB), relative to placebo (PBO), on anxiety-related school impairment among youth (N = 488). Latent growth modeling revealed that all three active treatments demonstrated superiority over PBO in reducing anxiety-related school impairment over time, with COMB showing the most robust effects. According to parent report, medication strategies may have stronger effects on anxiety-related school impairment among males than among females. Results were discrepant across parents and youth. Findings are discussed in terms of clinical implications for anxious youth and the need for continued research to examine treatment effects on anxiety-related school impairment.

Objective: To report functional outcomes from the multisite Child/Adolescent Anxiety Multimodal Extended Long-term Study (CAMELS), which examined the impact of youth anxiety treatment (cognitive-behavioral therapy [CBT], coping cat; Sertraline, SRT; COMB [CBT + SRT]; pill placebo) on (a) global and (b) domain-specific functioning assessed an average of 3.1 times, 3- to 12-years postrandomization (first assessment = mean 6.5 years postrandomization)., Method: Three-hundred and 19 of 488 families from the Child/Adolescent Anxiety Multimodal Study (CAMS; Walkup et al., 2008) participated. Growth curve modeling examined the impact of treatment condition and acute treatment outcomes (i.e., response, remission) on global functioning, global and domain-specific impairment, and life satisfaction across follow-up visits. Logistic regressions explored the impact of treatment remission and condition on low frequency events (arrests/convictions) and education., Results: Treatment responders and remitters demonstrated better global functioning, decreased overall impairment, and increased life satisfaction at follow-up. Treatment remission, but not response, predicted decreased domain-specific impairment (social relationships, self-care/independence, academic functioning), and maintenance of increased life satisfaction across follow-ups. Participants in the CBT condition, compared with pill placebo, demonstrated improved trajectories pertaining to life satisfaction, overall impairment, and impairment in academic functioning. Randomization to CBT or COMB treatment was associated with increasing employment rates. Trajectories for participants randomized to SRT was not significantly different from placebo. Treatment outcome and condition did not predict legal outcomes, school/work variables, or family life., Conclusion: Positive early intervention outcomes are associated with improved overall functioning, life satisfaction, and functioning within specific domains 6.5 years posttreatment. Treatment type differentially predicted trajectories of functioning. Findings support the positive impact of pediatric anxiety treatment into adolescence and early adulthood. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

This study examined (a) demographic and clinical characteristics associated with sleep-related problems (SRPs) among youth with anxiety disorders, and (b) the impact of anxiety treatment: cognitive-behavioral therapy (CBT; Coping Cat), medication (sertraline), their combination, and pill placebo on SRPs. Youth (N = 488, ages 7-17, 50% female, 79% White) with a principal diagnosis of generalized anxiety disorder, separation anxiety disorder, or social phobia participated. SRPs were reported by parents and youth. Findings differed by informant and by type of SRP, with evidence that SRPs are associated with age, anxiety severity, externalizing problems, functional impairment, and family burden at pretreatment. Anxiety treatment reduced SRPs; effect sizes were small to medium. Reductions in parent-reported separation-related sleep difficulties were significantly greater in active treatment than in the placebo condition, with the greatest reductions reported by parents of youth whose active treatment was multimodal or included sertraline. Youth whose anxiety treatment involved CBT reported significantly greater decreases in dysregulated sleep (e.g., sleeplessness). Both CBT for anxiety and sertraline appear to be somewhat effective in reducing SRPs, and multimodal treatment may be preferable depending on the symptom presentation. To inform practice, future research should examine a broad range of SRPs, incorporate objective measures of sleep, and evaluate the impact of behavioral strategies that directly target SRPs in youth with anxiety disorders.

Objective: To determine optimal percent reduction and raw score cutoffs on the parent- and child-report Screen for Child Anxiety Related Emotional Disorders (SCARED) for predicting treatment response and remission among youth with anxiety disorders., Method: Data were obtained from youth (N = 438; 7-17 years old) who completed treatment in the Child/Adolescent Anxiety Multimodal treatment Study, a multisite, randomized clinical trial that examined the relative efficacy of medication (sertraline), cognitive-behavioral therapy (Coping Cat), their combination, and pill placebo for the treatment of separation anxiety disorder, generalized anxiety disorder, and social phobia. The parent- and youth-report SCARED were administered at pre- and posttreatment. Quality receiver operating characteristic methods evaluated the performance of various SCARED percent reduction and absolute cutoff scores in predicting treatment response and remission, as defined by posttreatment ratings on the Clinical Global Impression scales and the Anxiety Disorders Interview Schedule., Results: Reductions of 55% on the SCARED-Parent and 50% on the SCARED-Youth optimally predicted treatment response. Posttreatment absolute raw scores of 10 (SCARED-Parent) and 12 (SCARED-Youth) optimally predicted remission in the total sample, although separate SCARED-Parent cutoffs for children (12-13) and adolescents (9) showed greatest quality of efficiency. Each cutoff significantly predicted response and remission at 6-month follow-up., Conclusion: Results serve as guidelines for operationalizing treatment response and remission on the SCARED, which could help clinicians systematically monitor treatment outcomes of youth with anxiety disorders in a cost- and time-efficient manner. Clinical trial registration information-Child and Adolescent Anxiety Disorders (CAMS); http://clinicaltrials.gov/; NCT00052078., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Test changes in (a) coping efficacy and (b) anxious self-talk as potential mediators of treatment gains at 3-month follow-up in the Child/Adolescent Anxiety Multimodal Treatment Study (CAMS)., Method: Participants were 488 youth (ages 7-17; 50.4% male) randomized to cognitive-behavioral therapy (CBT; Coping cat program), pharmacotherapy (sertraline), their combination, or pill placebo. Participants met Diagnostic and Statistical Manual for Mental Disorders-Fourth Edition (DSM-IV) criteria for generalized anxiety disorder, social phobia, and/or separation anxiety disorder. Coping efficacy (reported ability to manage anxiety provoking situations) was measured by youth and parent reports on the Coping Questionnaire, and anxious self-talk was measured by youth report on the Negative Affectivity Self-Statement Questionnaire. Outcome was measured using the Pediatric Anxiety Rating Scale (completed by Independent Evaluators blind to condition). For temporal precedence, residualized treatment gains were assessed at 3-month follow-up., Results: Residualized gains in coping efficacy mediated gains in the CBT, sertraline, and combination conditions. In the combination condition, some unique effect of treatment remained. Treatment assignment was not associated with a reduction in anxious self-talk, nor did anxious self-talk predict changes in anxiety symptoms., Conclusions: The findings suggest that improvements in coping efficacy are a mediator of treatment gains. Anxious self-talk did not emerge as a mediator., ((c) 2015 APA, all rights reserved).)

Objective: To evaluate the frequency of adverse events (AEs) across 4 treatment conditions in the Child/Adolescent Anxiety Multimodal Study (CAMS), and to compare the frequency of AEs between children and adolescents., Method: Participants ages 7 to 17 years (mean = 10.7 years) meeting the DSM-IV criteria for 1 or more of the following disorders: separation anxiety disorder, generalized anxiety disorder, or social phobia were randomized (2:2:2:1) to cognitive-behavioral therapy (CBT, n = 139), sertraline (SRT, n = 133), a combination of both (COMB, n = 140), or pill placebo (PBO, n = 76). Data on AEs were collected via a standardized inquiry method plus a self-report Physical Symptom Checklist (PSC)., Results: There were no differences between the double-blinded conditions (SRT versus PBO) for total physical and psychiatric AEs or any individual physical or psychiatric AEs. The rates of total physical AEs were greater in the SRT-alone treatment condition when compared to CBT (p < .01) and COMB (p < .01). Moreover, those who received SRT alone reported higher rates of several physical AEs when compared to COMB and CBT. The rate of total psychiatric AEs was higher in children (≤12 years) across all arms (31.7% versus 23.1%, p < .05). Total PSC scores decreased over time, with no significant differences between treatment groups., Conclusion: The results support the tolerability/safety of selective serotonin reuptake inhibitor (SSRI) treatment for anxiety disorders even after adjusting for the number of reporting opportunities, leading to no differences in overall rates of AEs. Few differences occurred on specific items. Additional monitoring of psychiatric AEs is recommended in children (≤12 years). Clinical trial registration information-Child and Adolescent Anxiety Disorders (CAMS); http://clinicaltrials.gov; NCT00052078., (Copyright © 2015 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

The aim of this investigation was to evaluate how parental anxiety predicted change in pediatric anxiety symptoms across four different interventions: cognitive-behavioral therapy, medication (sertraline; SRT), their combination (COMB), and pill placebo. Participants were 488 youths (ages 7-17) with separation anxiety disorder, generalized anxiety disorder, and/or social phobia and their primary caregivers. Latent growth curve modeling assessed how pre-treatment parental trait anxiety symptoms predicted trajectories of youth anxiety symptom change across 12 weeks of treatment at four time points. Interactions between parental anxiety and treatment condition were tested. Parental anxiety was not associated with youth's pre-treatment anxiety symptom severity. Controlling for parental trait anxiety, youth depressive symptoms, and youth age, youths who received COMB benefitted most. Counter to expectations, parental anxiety influenced youth anxiety symptom trajectory only within the SRT condition, whereas parental anxiety was not significantly associated with youth anxiety trajectories in the other treatment conditions. Specifically, within the SRT condition, higher levels of parental anxiety predicted a faster and greater reduction in youth anxiety over the acute treatment period compared to youths in the SRT condition whose parents had lower anxiety levels. While all active treatments produced favorable outcomes, results provide insight regarding the treatment-specific influence of parental anxiety on the time course of symptom change.

This study examined (a) demographic and clinical characteristics associated with physical symptoms in anxiety-disordered youth and (b) the impact of cognitive-behavioral therapy (Coping Cat), medication (sertraline), their combination, and pill placebo on physical symptoms. Youth (N = 488, ages 7-17 years) with a principal diagnosis of generalized anxiety disorder, separation anxiety disorder, or social phobia participated as part of a multi-site, randomized controlled trial and received treatment delivered over 12 weeks. Diagnostic status, symptom severity, and impairment were assessed at baseline and week 12. The total number and severity of physical symptoms was associated with age, principal diagnosis, anxiety severity, impairment, and the presence of comorbid internalizing disorders. Common somatic complaints were headaches, stomachaches, head cold or sniffles, sleeplessness, and feeling drowsy or too sleepy. Physical symptoms decreased over the course of treatment, and were unrelated to treatment condition. Clinical implications and directions for future research are discussed (ClinicalTrials.gov number, NCT00052078).

Objective: We sought to examine predictors and moderators of treatment outcomes among 488 youths ages 7-17 years (50% female; 74% ≤ 12 years) meeting Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; American Psychiatric Association, 2000) criteria for diagnoses of separation anxiety disorder, social phobia, or generalized anxiety disorder who were randomly assigned to receive either cognitive behavioral therapy (CBT), sertraline (SRT), their combination (COMB), or medication management with pill placebo (PBO) in the Child/Adolescent Anxiety Multimodal Study (CAMS)., Method: Six classes of predictor and moderator variables (22 variables) were identified from the literature and examined using continuous (Pediatric Anxiety Ratings Scale; PARS) and categorical (Clinical Global Impression Scale-Improvement; CGI-I) outcome measures., Results: Three baseline variables predicted better outcomes (independent of treatment condition) on the PARS, including low anxiety severity (as measured by parents and independent evaluators) and caregiver strain. No baseline variables were found to predict Week 12 responder status (CGI-I). Participants' principal diagnosis moderated treatment outcomes but only on the PARS. No baseline variables were found to moderate treatment outcomes on Week 12 responder status (CGI-I)., Discussion: Overall, anxious children responded favorably to CAMS treatments. However, having more severe and impairing anxiety, greater caregiver strain, and a principal diagnosis of social phobia were associated with less favorable outcomes. Clinical implications of these findings are discussed.

Objective: We report active treatment group differences on response and remission rates and changes in anxiety severity at weeks 24 and 36 for the Child/Adolescent Anxiety Multimodal Study (CAMS)., Method: CAMS youth (N = 488; 74% ≤ 12 years of age) with DSM-IV separation, generalized, or social anxiety disorder were randomized to 12 weeks of cognitive-behavioral therapy (CBT), sertraline (SRT), CBT+SRT (COMB), or medication management/pill placebo (PBO). Responders attended 6 monthly booster sessions in their assigned treatment arm; youth in COMB and SRT continued on their medication throughout this period. Efficacy of COMB, SRT, and CBT (n = 412) was assessed at 24 and 36 weeks postrandomization. Youth randomized to PBO (n = 76) were offered active CAMS treatment if nonresponsive at week 12 or over follow-up and were not included here. Independent evaluators blind to study condition assessed anxiety severity, functioning, and treatment response. Concomitant treatments were allowed but monitored over follow-up., Results: The majority (>80%) of acute responders maintained positive response at both weeks 24 and 36. Consistent with acute outcomes, COMB maintained advantage over CBT and SRT, which did not differ, on dimensional outcomes; the 3 treatments did not differ on most categorical outcomes over follow-up. Compared to COMB and CBT, youth in SRT obtained more concomitant psychosocial treatments, whereas those in SRT and CBT obtained more concomitant combined (medication plus psychosocial) treatment., Conclusions: COMB maintained advantage over CBT and SRT on some measures over follow-up, whereas the 2 monotherapies remained indistinguishable. The observed convergence of COMB and monotherapy may be related to greater use of concomitant treatment during follow-up among youth receiving the monotherapies, although other explanations are possible. Although outcomes were variable, most CAMS-treated youth experienced sustained treatment benefit. Clinical trial registration information-Child and Adolescent Anxiety Disorders (CAMS); URL: http://clinicaltrials.gov. Unique identifier: NCT00052078., (Copyright © 2014 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

Objective: We examined the therapeutic relationship with cognitive-behavioral therapists and with pharmacotherapists for youth from the Child/Adolescent Anxiety Multimodal Study (Walkup et al., 2008). The therapeutic relationship was examined in relation to treatment outcomes., Method: Participants were 488 youth (ages 7-17 years; 50% male) randomized to cognitive-behavioral therapy (CBT; Coping Cat), pharmacotherapy (sertraline), their combination, or placebo pill. Participants met criteria for generalized anxiety disorder, social phobia, and/or separation anxiety disorder according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994). The therapeutic relationship was assessed by youth report at Weeks 6 and 12 of treatment using the Child's Perception of Therapeutic Relationship scale (Kendall et al., 1997). Outcome measures (Pediatric Anxiety Rating Scale; Research Units on Pediatric Psychopharmacology Anxiety Study Group, 2002; and Clinical Global Impressions Scales; Guy, 1976) were completed by independent evaluators blind to condition., Results: For youth who received CBT only, a stronger therapeutic relationship predicted positive treatment outcome. In contrast, the therapeutic relationship did not predict outcome for youth receiving sertraline, combined treatment, or placebo., Conclusion: A therapeutic relationship may be important for anxious youth who receive CBT alone.

Background: To examine (1) changes in parent (global psychological distress, trait anxiety) and family (dysfunction, burden) functioning following 12 weeks of child-focused anxiety treatment, and (2) whether changes in these parent and family factors were associated with child's treatment condition and response., Methods: Participants were 488 youth ages 7-17 years (50% female; mean age 10.7 years) who met DSM-IV-TR criteria for social phobia, separation anxiety, and/or generalized anxiety disorder, and their parents. Youth were randomly assigned to 12 weeks of "Coping Cat" individual cognitive-behavioral therapy (CBT), medication management with sertraline (SRT), their combination (COMB), or medication management with pill placebo (PBO) within the multisite Child/Adolescent Anxiety Multimodal Study (CAMS). At pre- and posttreatment, parents completed measures of trait anxiety, psychological distress, family functioning, and burden of child illness; children completed a measure of family functioning. Blinded independent evaluators rated child's response to treatment using the Clinical Global Impression-Improvement Scale at posttreatment., Results: Analyses of covariance revealed that parental psychological distress and trait anxiety, and parent-reported family dysfunction improved only for parents of children who were rated as treatment responders, and these changes were unrelated to treatment condition. Family burden and child-reported family dysfunction improved significantly from pre- to posttreatment regardless of treatment condition or response., Conclusions: Findings suggest that child-focused anxiety treatments, regardless of intervention condition, can result in improvements in nontargeted parent symptoms and family functioning particularly when children respond successfully to the treatment., (© 2013 Wiley Periodicals, Inc.)

Objective: Depression and obesity are associated, but the impact of obesity on depression treatment outcome, or, conversely, the impact of treatment on body mass index (BMI) in depressed adolescents has not been reported. In this article, we examine the bidirectional relationships between BMI and treatment response in adolescents with treatment-resistant depression., Method: Participants in the Treatment of Selective Serotonin Reuptake Inhibitor (SSRI) Resistant Depression in Adolescents (TORDIA) study had height and weight assessed at baseline, weekly for the first 6 weeks, biweekly for the next 6 weeks, and monthly from weeks 12 through 24. The impact of baseline BMI as a predictor and moderator of treatment response was assessed. In addition, participants' changes in BMI were assessed as a function of specific treatment assignment and treatment response., Results: Participants assigned to SSRIs had a greater increase in BMI-for-age-sex z-score and weight than did those assigned to venlafaxine. Post-hoc, those treated with paroxetine or citalopram had the biggest increases in BMI, relative to fluoxetine or venlafaxine. Overweight or obesity was neither a predictor nor a moderator of treatment outcome, nor of subsequent BMI change., Conclusions: Overweight status does not appear to affect treatment response in adolescents with resistant depression. The successful treatment of depression does not appear to favorably affect weight or BMI. Fluoxetine and venlafaxine are less likely to cause an increase in BMI than paroxetine or citalopram.

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 randomly 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://clinicaltrials.gov/; NCT00018902., (Copyright © 2013. Published by Elsevier Inc.)

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 randomized 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 Questionnaire 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 clinically 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 clinically significant range, predicts a lower likelihood of remission from depression. Clinical trial registration information-Treatment of SSRI-Resistant Depression in Adolescents (TORDIA); http://clinicaltrials.gov/; NCT00018902., (Copyright © 2013 American Academy of Child & Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

This article reviews evidence-based pharmacotherapy for children and adolescents with depression. Several randomized controlled trials (RCTs) support the use of fluoxetine for the treatment of childhood and adolescent depression as well as escitalopram in the treatment of adolescent depression. To date, one RCT has demonstrated the effectiveness of sertraline or citalopram for the treatment of major depressive disorder in youth. Only a small number of RCTs for depression have included children, and none of these trials were adequately powered to detect differences in the efficacy of medication between children and adolescents.

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 randomized 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 elucidate neurobehavioral underpinnings of anhedonia, and to test treatments that target anhedonia in the context of overall treatment of depression., (Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

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 randomly assigned to another SSRI, venlafaxine, another SSRI+cognitive behavior therapy (CBT), or venlafaxine+CBT. Augmentation with sleep medication was permitted as clinically 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 randomly, 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: Response to treatment in child and adolescent affective disorders is variable, with limited ability of any one treatment to improve outcome across patients. Unfortunately, we know little about the factors that explain this variability in treatment response. Individual differences in the social and affective dynamics of daily life could help to elucidate the characteristics of youth who respond to treatment., Methods: We used ecological momentary assessment of negative affect, positive affect, and companions in natural settings over 4 days in a sample of young people with depressive and anxiety disorders who participated in an 8-week open trial of cognitive behavioral therapy (CBT), selective serotonin reuptake inhibitors (SSRIs), or a combination of the two. Clinicians rated participants' clinical severity at five time points, and participants reported their symptoms before and after treatment. Latent growth curve models were used to predict rate of change in clinical severity from pretreatment affect in natural settings., Results: Participants with high positive affect (PA), low negative affect (NA), and a high PA:NA ratio at baseline had lower severity, depressive symptoms, and anxiety symptoms at the end of treatment. Lower posttreatment symptoms were associated with spending more time with fathers and less time with peers before treatment. Although baseline affect was not associated with initial symptom severity, high NA and low PA:NA at baseline were related to slower rate of decline of severity during treatment. When baseline symptoms were included in models, NA and PA:NA predicted rate of decline in severity during treatment, whereas self-reported depressive and anxiety symptoms at baseline did not., Conclusion: A more typical profile of baseline affective functioning in natural settings-that is, lower NA and higher PA-and time with fathers, could provide a foundation for treatment response in children and adolescents. Affective and social dynamics in natural settings could ultimately help investigate which young people might benefit from current treatments.

Objective: To report on remission rates in anxious youth who participated in the Child/Adolescent Anxiety Multimodal Study (CAMS). The CAMS, a multisite clinical trial, randomized 488 children and adolescents (ages 7-17 years; 79% Caucasian; 50% female) with separation, social, and/or generalized anxiety disorder to a 12-week treatment of sertraline (SRT), cognitive behavioral therapy (CBT), their combination (COMB), or clinical management with pill placebo (PBO)., Method: The primary definition of remission was loss of all study-entry anxiety disorder diagnoses; additional definitions of remission were used. All outcomes were rated by independent evaluators blind to treatment assignment. Predictors of remission were also examined., Results: Remission rates after 12 weeks of treatment ranged from 46% to 68% for COMB, 34% to 46% for SRT, 20% to 46% for CBT, and 15% to 27% for PBO. Rates of remission (i.e., achieving a nearly symptom-free state) were significantly lower than rates of response (i.e., achieving a clinically meaningful improvement relative to baseline) for the entire sample. Youth who received COMB had significantly higher rates of remission compared to all other treatment groups. Both monotherapies had higher remission rates compared to PBO, but rates were not different from each other. Predictors of remission were younger age, nonminority status, lower baseline anxiety severity, absence of other internalizing disorders (e.g., anxiety, depression), and absence of social phobia., Conclusions: For the majority of children, some symptoms of anxiety persisted, even among those showing improvement after 12 weeks of treatment, suggesting a need to augment or extend current treatments for some children.

Objective: There is little work on the effect of school on response to treatment of depression, with available research suggesting that children and adolescents with school difficulties are less likely to respond to fluoxetine compared with those with no school difficulties., Method: Depressed adolescents in the Treatment of Resistant Depression in Adolescents study, who had not responded to a previous adequate selective serotonin reuptake inhibitor (SSRI) trial, were randomly assigned to one of the following: another SSRI, venlafaxine, another SSRI + cognitive behavior therapy (CBT), or venlafaxine + CBT. Participants were classified into four groups depending on whether their enrollment in the study and end of treatment was during school or summer vacation., Results: Controlling for baseline differences, adolescents ending their 12-week treatment during summer vacation had odds 1.7 times (95% confidence interval = 1.02-2.8, p = .04) greater to have an adequate response as those ending their treatment while being in school. In addition, adequate depression response was associated with fewer school problems at week 12 (scores <5 versus scores ≥5: odds ratio = 3.3, 95% confidence interval = 1.9-5.8, p < .001). There was a significant interaction between school difficulties and timing of treatment, with the lowest rates of response being among adolescents having school difficulties and ending their treatment during the active school year., Conclusion: School problems are relevant to treatment response in depressed adolescents and should be incorporated into the treatment plan. These findings also suggest that the time of the year might need to be taken into consideration for analysis of clinical trials in school-aged youth., Clinical Trial Registration Information: Treatment of SSRI-Resistant Depression in Adolescents (TORDIA); http://www.clinicaltrials.gov; NCT00018902., (Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

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 randomized 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.clinicaltrials.gov; NCT00018902., (Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

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 randomized 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 understand by what mechanisms a history of abuse affects treatment response., (Copyright © 2011 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

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: Randomized 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 randomly 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, nonprotocol 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: clinicaltrials.gov Identifier: NCT00018902.

Background: We examined the long-term outcome of participants in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study, a randomized 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. Standardized 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 clinically 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 randomized youths had reached remission. Randomly 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: clinicaltrials.gov Identifier: NCT00018902., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Objective: Despite the known association between substance use disorders and major depressive disorder (MDD) among adolescents, little is known regarding substance use among adolescents with MDD., Method: Youths with MDD who had not improved after an adequate selective serotonin reuptake inhibitor trial (N = 334) were enrolled in the Treatment of SSRI-Resistant Depression in Adolescents trial. Analyses examined substance use (via the Drug Use Severity Index) and changes therein in relation to treatment and depressive symptoms. Adolescents meeting substance use disorder criteria via the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version at baseline were excluded., Results: Substance use was common: 28.1% reported repeated experimentation at baseline. Substance-related impairment was associated with baseline depression severity, older age, physical/sexual abuse, family conflict, hopelessness, and comorbid oppositional defiant disorder/conduct disorder. There was significant improvement in substance-related impairment among adolescents who responded to MDD treatment. Baseline suicidal ideation was higher among the subjects who progressed to high substance-related impairment (≥ 75th percentile) versus those whose substance-related impairment remained low (< 75th percentile), and parental depressive symptoms predicted persistence of high substance-related impairment during the study. The MDD response was best among the adolescents with low 12 week substance-related impairment scores regardless of whether they had high or low baseline substance-related impairment. There were no significant differential effects of specific treatments, pharmacological or cognitive-behavioral therapy, on substance use., Conclusions: Substance use is common among adolescents with treatment-resistant MDD. The subjects who had persistently low substance-related impairment or who demonstrated reduced substance-related impairment had better MDD treatment response, although the direction of this association is uncertain.

Objective: The authors sought to identify predictors of self-harm adverse events in treatment-resistant, depressed adolescents during the first 12 weeks of treatment., Method: Depressed adolescents (N=334) who had not responded to a previous trial with an SSRI antidepressant were randomized to a switch to either another SSRI or venlafaxine, with or without cognitive behavior therapy. Self-harm events, i.e., suicidal and non-suicidal self-injury adverse events were assessed by spontaneous report for the first 181 participants, and by systematic weekly assessment for the last 153 participants., Results: Higher rates of suicidal (20.8% vs. 8.8%) and nonsuicidal self-injury (17.6% vs. 2.2%), but not serious adverse events (8.4% vs. 7.3%) were detected with systematic monitoring. Median time to a suicidal event was 3 weeks, predicted by high baseline suicidal ideation, family conflict, and drug and alcohol use. Median time to nonsuicidal self-injury was 2 weeks, predicted by previous history of nonsuicidal self-injury. While there were no main effects of treatment, venlafaxine treatment was associated with a higher rate of self-harm adverse events in those with higher suicidal ideation. Adjunctive use of benzodiazepines, while in a small number of participants (N=10) was associated with higher rate of both suicidal and nonsuicidal self-injury adverse events., Conclusions: Since predictors of suicidal adverse events also predict poor response to treatment, and many of these events occurred early in treatment, improving the speed of response to depression, by targeting of family conflict, suicidal ideation, and drug use may help to reduce their incidence. The relationship of venlafaxine and of benzodiazepines to self-harm events requires further study and clinical caution.

Objective: To advance knowledge regarding strategies for treating selective serotonin reuptake inhibitor (SSRI)-resistant depression in adolescents, we conducted a randomized 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 randomized 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 prestudy 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: Anxiety disorders are common psychiatric conditions affecting children and adolescents. Although cognitive behavioral therapy and selective serotonin-reuptake inhibitors have shown efficacy in treating these disorders, little is known about their relative or combined efficacy., Methods: In this randomized, controlled trial, we assigned 488 children between the ages of 7 and 17 years who had a primary diagnosis of separation anxiety disorder, generalized anxiety disorder, or social phobia to receive 14 sessions of cognitive behavioral therapy, sertraline (at a dose of up to 200 mg per day), a combination of sertraline and cognitive behavioral therapy, or a placebo drug for 12 weeks in a 2:2:2:1 ratio. We administered categorical and dimensional ratings of anxiety severity and impairment at baseline and at weeks 4, 8, and 12., Results: The percentages of children who were rated as very much or much improved on the Clinician Global Impression-Improvement scale were 80.7% for combination therapy (P<0.001), 59.7% for cognitive behavioral therapy (P<0.001), and 54.9% for sertraline (P<0.001); all therapies were superior to placebo (23.7%). Combination therapy was superior to both monotherapies (P<0.001). Results on the Pediatric Anxiety Rating Scale documented a similar magnitude and pattern of response; combination therapy had a greater response than cognitive behavioral therapy, which was equivalent to sertraline, and all therapies were superior to placebo. Adverse events, including suicidal and homicidal ideation, were no more frequent in the sertraline group than in the placebo group. No child attempted suicide. There was less insomnia, fatigue, sedation, and restlessness associated with cognitive behavioral therapy than with sertraline., Conclusions: Both cognitive behavioral therapy and sertraline reduced the severity of anxiety in children with anxiety disorders; a combination of the two therapies had a superior response rate. (ClinicalTrials.gov number, NCT00052078.), (2008 Massachusetts Medical Society)

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: Randomized 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 resulted 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 resulted in fewer adverse effects., Trial Registration: clinicaltrials.gov Identifier: NCT00018902.

Approximately 20% of adolescents experience at least one depressive episode by the time they enter their adult years. For most adolescents, depression, although serious, either remits spontaneously or responds to treatment. For a smaller but significant proportion of adolescents, however, depression can be long-lasting and relatively unresponsive to initial treatment. In this article the authors provide an operational definition of treatment-resistant depression, identify factors associated with treatment nonresponse, describe an approach to the management of treatment-resistant depression, and advance suggestions for promising avenues of research.

Objective: To assess the efficacy of fluoxetine for the long-term treatment of children and adolescents with anxiety disorders, including generalized anxiety disorder, separation anxiety disorder, and/or social phobia., Method: Children and adolescents (7-17 years old) with anxiety disorders were studied in open treatment for 1 year after they completed a randomized, controlled trial (RCT) comparing fluoxetine and placebo. The follow-up phase assessments included clinician, parent, and child ratings with measures of global severity, global improvement, and anxiety symptoms., Results: Subjects taking fluoxetine (n = 42) were compared with those taking no medication (n = 10) during follow-up on anxiety changes from the end of the RCT through the follow-up period. Statistical models included RCT assignment and follow-up psychological treatment. Excluded subjects took other medications (n = 4) or did not complete follow-up (n = 18). Compared with subjects taking no medication, subjects taking fluoxetine showed significantly superior follow-up outcomes on most measures, including clinician, parent, and child ratings., Conclusions: The results suggest that fluoxetine is clinically effective for the maintenance treatment of anxiety disorders in children and adolescents. A major limitation, however, was the lack of RCT methodology in the follow-up phase. RCTs are needed to determine the long-term risks and benefits of fluoxetine for this group.

Objective: The authors examined platelet serotonin reuptake inhibition and response to selective serotonin reuptake inhibitor (SSRI) treatment in depressed adolescents., Method: Twenty-three depressed adolescents participating in pharmacokinetic studies of SSRIs had platelet serotonin reuptake measured before and after 14-28 days of treatment. The Clinical Global Impression (CGI) improvement rating was determined on the basis of all clinical information and was performed blind to the platelet data., Results: Improvement in depressive symptoms as rated with the CGI improvement subscale was significantly associated with the percentage change in platelet serotonin reuptake inhibition from pre- to posttreatment. Improvement in depression was also associated with absolute decrease in platelet serotonin reuptake when adjusted for the magnitude of baseline reuptake., Conclusions: Platelet serotonin reuptake inhibition may be an appropriate surrogate biological marker for the pharmacodynamic activity of SSRIs in depressed adolescents.

Objective: To assess the potential efficacy, tolerability, and safety of citalopram in the treatment of functional pediatric recurrent abdominal pain and comorbid internalizing disorders., Method: Twenty-five clinically referred children and adolescents with recurrent abdominal pain aged 7 to 18 years, inclusive, participated in a 12-week, flexible-dose, open-label trial of citalopram. Primary outcome measure was the Clinical Global Impression Scale-Improvement, with responders defined by ratings of 1 (very much improved) or 2 (much improved). Secondary measures included self- and parent reports of abdominal pain, anxiety, depression, other somatic symptoms, and functional impairment. Side effects were assessed using a standardized checklist. Data were analyzed using an intent-to-treat format and the last observation carried forward procedure., Results: Twenty-one subjects (84%) were classified as responders (Clinical Global Impression Scale-Improvement score < or =2). Citalopram was generally well tolerated. Four subjects withdrew prematurely, one due to reported visual side effects. Ratings of abdominal pain, anxiety, depression, other somatic symptoms, and functional impairment all improved significantly over the course of the study compared with baseline., Conclusions: Citalopram is a promising treatment for functional pediatric recurrent abdominal pain and deserves additional study with a randomized, placebo-controlled clinical trial.

Objective: To assess the efficacy and tolerability of fluoxetine for the acute treatment of children and adolescents with generalized anxiety disorder, separation anxiety disorder, and/or social phobia., Method: Anxious youths (7-17 years old) who had significant functional impairment were randomized to fluoxetine (20 mg/day) (n = 37) or placebo (n = 37) for 12 weeks., Results: Fluoxetine was effective in reducing the anxiety symptoms and improving functioning in all measures. Using intent-to-treat analysis, 61% of patients taking fluoxetine and 35% taking placebo showed much to very much improvement. Despite this improvement, a substantial group of patients remained symptomatic. Fluoxetine was well tolerated except for mild and transient headaches and gastrointestinal side effects. Youths with social phobia and generalized anxiety disorder responded better to fluoxetine than placebo, but only social phobia moderated the clinical and functional response. Severity of the anxiety at intake and positive family history for anxiety predicted poorer functioning at the end of the study., Conclusions: Fluoxetine is useful and well tolerated for the acute treatment of anxious youths. Investigations regarding the optimization of treatment to obtain full anxiety remission and the length of treatment necessary to prevent recurrences are warranted.

Objective: To determine the pharmacokinetics of sertraline in adolescents and assess its effect on a surrogate marker of serotonin transport., Method: Pharmacokinetic parameters of a single 50-mg dose of sertraline were determined in 10 adolescents. Steady-state withdrawal kinetics were determined in 12 adolescents taking 50 mg/day and in 6 adolescents taking 100 to 150 mg/day. Platelet serotonin reuptake was measured before and after 2 weeks of daily 50-mg dosing., Results: The mean steady-state half-life of 50 mg was significantly shorter (15.3 +/- 3.5 hours) than the single-dose half-life (26.7 +/- 5.2 hours; t = 6.4, p < .001) and the steady-state half-life at 100 to 150 mg/day (20.4 +/- 3.4 hours; t = 2.9, p = .01). Platelet serotonin reuptake was inhibited by 61 +/- 15% after approximately 2 weeks of sertraline 50 mg/day., Conclusions: The half-life of sertraline 50 mg becomes significantly shorter from the initial dose to steady-state, and many adolescents may benefit from twice-per-day dosing. The steady-state half-life increases as the dose increases. The moderate levels of platelet reuptake inhibition at 50 mg/day indicate that most adolescents may need sertraline doses higher than 50 mg/day to attain a therapeutic response.

Recently, a first placebo-controlled study of an selective serotonin reuptake inhibitor (SSRI) medication was conducted among a sample of adolescents with major depression by Emslie et al. [Arch. Gen. Psychiatry 54 (1997) 1031.]. That study demonstrated efficacy for fluoxetine vs. placebo for treating adolescents with major depression. However, to date, no studies have been conducted to assess the efficacy of fluoxetine or any other SSRI medication in adolescents with major depression in combination with an alcohol use disorder (AUD). In this study, the authors investigated whether fluoxetine decreases the depressive symptoms and the drinking of adolescents with comorbid major depression and an AUD. The authors conducted a 12-week open-label study of fluoxetine (20 mg) in 13 adolescents with current comorbid major depression and an AUD. A significant within-group decrease (improvement) was found for both depressive symptoms and drinking during the course of the study. The fluoxetine was well tolerated during the study. These data suggest promise for fluoxetine for decreasing both the depressive symptoms and the drinking of adolescents with comorbid major depression and an AUD.

Objective: To compare paroxetine with placebo and imipramine with placebo for the treatment of adolescent depression., Method: After a 7- to 14-day screening period, 275 adolescents with major depression began 8 weeks of double-blind paroxetine (20-40 mg), imipramine (gradual upward titration to 200-300 mg), or placebo. The two primary outcome measures were endpoint response (Hamilton Rating Scale for Depression [HAM-D] score < or = 8 or > or = 50% reduction in baseline HAM-D) and change from baseline HAM-D score. Other depression-related variables were (1) HAM-D depressed mood item; (2) depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version (K-SADS-L); (3) Clinical Global Impression (CGI) improvement scores of 1 or 2; (4) nine-item depression subscale of K-SADS-L; and (5) mean CGI improvement scores., Results: Paroxetine demonstrated significantly greater improvement compared with placebo in HAM-D total score < or = 8, HAM-D depressed mood item, K-SADS-L depressed mood item, and CGI score of 1 or 2. The response to imipramine was not significantly different from placebo for any measure. Neither paroxetine nor imipramine differed significantly from placebo on parent- or self-rating measures. Withdrawal rates for adverse effects were 9.7% and 6.9% for paroxetine and placebo, respectively. Of 31.5% of subjects stopping imipramine therapy because of adverse effects, nearly one third did so because of adverse cardiovascular effects., Conclusions: Paroxetine is generally well tolerated and effective for major depression in adolescents.

The selective serotonin reuptake inhibitors (SSRIs) are becoming widely used in children and adolescents, with possible unexpected side effects being observed over time. SSRIs have been associated with bleeding in adults who have unremarkable routine hematologic laboratory results except abnormal bleeding time or platelet counts in few cases. Given the increase of pediatric SSRI prescriptions, in this article we describe five children, ages 8 through 15, who developed bruising or epistaxis 1 week to 3 months after starting SSRI treatment. It is possible that the effects SSRI on platelet functioning are causing the bleeding observed in some patients and/or that a separate coagulopathy is present and contributing to bleeding. The subject matter deserves future investigation.

This preliminary study examines the effectiveness and safety of selective serotonin reuptake inhibitors (SSRIs) for the treatment of panic disorder in children and adolescents. In a prospective open label study, 12 children and adolescents with panic disorder were treated with SSRIs, and if necessary, with benzodiazepines, for a period of 6-8 weeks and were followed for approximately 6 months. During the trial, clinician-based and self-report rating scales for anxiety and depression, functioning, and side effects, were administered. Using the Clinical Global Impression Scale (CGIS) 75% of patients showed much to very much improvement with SSRIs without experiencing significant side effects. After controlling for changes in depressive symptoms, self-report and clinician-based anxiety scales also showed significant improvement. At the end of the trial, 67% of patients no longer fulfilled criteria for panic disorder and 4 patients remained with significant residual symptoms. In conclusion, SSRIs appear to be a safe and promising for the treatment of children and adolescents with panic disorder, however, randomized controlled trials evaluating the effects of SSRIs and other interventions (e.g., cognitive therapy) for treating panic disorder in children and adolescents are warranted. It appears that until the SSRIs begin to exert their effects, a benzodiazepine adjunct treatment might be helpful for patients with severe panic disorder.

Pediatric anxiety disorders are common illnesses that, if left untreated, may induce academic, family, and interpersonal problems. Cognitive-behavioral techniques and other psychotherapeutic interventions may be adequate for the treatment of most anxiety disorders. For patients with severe symptoms or for whom psychotherapeutic approaches are not adequate, medications are indicated. Among the available medications, the SSRIs are currently the first choice; however, other medications, such as the benzodiazepines and the TCAs, may be used alone or sometimes in combination with the SSRIs. Caution with respect to medication interactions and side effects is indicated. In particular, long-term side effects in these medications have not been well studied.

Medication management of obsessive-compulsive disorder (OCD) has consisted of monotherapy with either clomipramine (CMI) or selective serotonin reuptake inhibitors (SSRIs) such as fluvoxamine, paroxetine, or sertraline. Frequently, OCD patients receiving monotherapy experience low treatment response rates and problematic side effects that may result in discontinuation or noncompliance. This open-label case series presents 7 patients (6 male, 1 female) ages 9 to 23 years with OCD who were effectively treated with combination of CMI plus an SSRI. Treatment effects persisted through 5 to 22 months of follow-up from onset of combination therapy. The drug combination was effective in the 2 patients with OCD and no mood/anxiety comorbidity. Side effects appeared in 5 of 7 patients; cardiovascular side effects were the most common adverse effects. Two patients had prolongation of QTc intervals and 2 developed tachycardia while taking CMI and SSRI combinations. Other risks might include serotonin syndrome, manic switch, insomnia, and possibly headaches, EPS, and sexual dysfunction. Recommendations are made to monitor electrocardiograms, CMI blood concentrations, and vital signs in all cases because SSRIs can increase the blood levels of CMI and/or its active metabolite, desmethylclomipramine (DCMI). CMI could also potentially increase SSRI absorption and/or protein binding. The use of CMI and SSRI combination therapy was found to be more effective compared with their monotherapy in all 7 cases.