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Objective: Suicide is a leading cause of death in adolescents worldwide. There is an absence of effective and low cost treatment strategies for this growing public health problem. Current practice consists of brief hospitalization of acutely suicidal youth, but many get inadequate follow-up treatment. There are few alternatives to individual outpatient services offered at too low an intensity for an acutely distressed population. This paper describes the development, feasibility, acceptability, and preliminary clinical outcomes of an intensive outpatient program (IOP) for suicidal adolescents over a two-year period., Method: 364 eligible adolescents (12-18 years) who had a worsening of suicidal ideation or a suicide attempt were enrolled in an IOP and attended at least 1 group session. Depressive symptoms and suicidality were assessed at baseline and discharge from the program and at one and six month follow-up., Results: The majority of patients completed the IOP (81.0%; average of nine sessions). Over 95% of teens and parents responded that they were mostly or very satisfied with the IOP. The condition of patients improved at the time of discharge on depressive symptoms and suicidal ideation and behavior. 286 of the 364 youth (78.6%) completed the six-month follow-up. In total, 8.7% and 27.3% of the 286 respondents reported a suicide attempt and event, respectively, within six months of discharge from the IOP., Conclusions: While limited by the lack of a control group, our findings suggest that an IOP for adolescents with suicidality is acceptable and feasible as either a step-down from or an alternative to inpatient treatment., (Copyright © 2018. Published by Elsevier Inc.)

Objective: Both the diagnosis and treatment of bipolar disorder in youth remain the subject of debate. In the Treatment of Early Age Mania (TEAM) study, risperidone was more effective than lithium or divalproex in children diagnosed with bipolar mania and highly comorbid with attention-deficit/hyperactivity disorder (ADHD). We searched for treatment moderators and predictors of outcome., Method: TEAM was a multi-site, 8-week, randomized clinical trial of risperidone, lithium, or divalproex in 279 medication-naïve patients, aged 6 through 15 years, with a DSM-IV diagnosis of bipolar disorder currently in manic or mixed phase. Outcome measures included binary end-of-treatment responder status and change in the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) Mania Rating Scale (KMRS). Baseline demographics and clinical characteristics were tested as modifiers of treatment effect and as overall predictors of outcome., Results: Moderator effects were detected for site, ADHD, and obesity. Across sites, the response ratio (RR) for risperidone versus lithium ranged from 1.2 (95% confidence interval [CI] = 0.8-1.7) to 8.3 (95% CI = 1.1-60.8), and for risperidone versus divalproex from 1.3 (95% CI = 0.8-2.2) to 10.5 (95% CI = 1.4-77.7). The RR for risperidone versus lithium was 2.1 for patients with ADHD, but 1.0 for those without ADHD, and 2.3 (95% CI = 1.6-3.3) for nonobese patients, but 1.1 (95% CI = 0.6-2.0) for obese ones. Older age and less severe ADHD symptoms were associated with greater improvement on the KMRS., Conclusions: Risperidone was more effective than lithium or divalproex across the demographics and clinical characteristics of the sample, but the magnitude of its effect was influenced by site-related characteristics and presence of ADHD. Clinical trial registration information--Treatment of Early Age Mania; http://clinicaltrials.gov/; NCT00057681., (Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

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: 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: To evaluate the clinical and prognostic significance of suicide attempts (SAs) and nonsuicidal self-injury (NSSI) in adolescents with treatment-resistant depression., Method: Depressed adolescents who did not improve with an adequate SSRI trial (N = 334) were randomized to a medication switch (SSRI or venlafaxine), with or without cognitive-behavioral therapy. NSSI and SAs were assessed at baseline and throughout the 24-week treatment period., Results: Of the youths, 47.4% reported a history of self-injurious behavior at baseline: 23.9% NSSI alone, 14% NSSI+SAs, and 9.5% SAs alone. The 24-week incidence rates of SAs and NSSI were 7% and 11%, respectively; these rates were highest among youths with NSSI+SAs at baseline. NSSI history predicted both incident SAs (hazard ratio [HR]= 5.28, 95% confidence interval [CI] = 1.80-15.47, z = 3.04, p = .002) and incident NSSI (HR = 7.31, z = 4.19, 95% CI = 2.88-18.54, p < .001) through week 24, and was a stronger predictor of future attempts than a history of SAs (HR = 1.92, 95% CI = 0.81-4.52, z = 2.29, p = .13). In the most parsimonious model predicting time to incident SAs, baseline NSSI history and hopelessness were significant predictors, adjusting for treatment effects. Parallel analyses predicting time to incident NSSI through week 24 identified baseline NSSI history and physical and/or sexual abuse history as significant predictors., Conclusions: NSSI is a common problem among youths with treatment-resistant depression and is a significant predictor of future SAs and NSSI, underscoring the critical need for strategies that target the prevention of both NSSI and suicidal behavior., Clinical Trial Registration Information: Treatment of SSRI-Resistant Depression in Adolescents (TORDIA). URL: http://www.clinicaltrials.gov. Unique Identifier: 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.)

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: To examine the course of depression during the treatment of adolescents with depression who had recently attempted suicide., Method: Adolescents (N = 124), ages 12 to 18 years, with a 90-day history of suicide attempt, a current diagnosis of depressive disorder (96.0% had major depressive disorder), and a Children's Depression Rating Scale-Revised (CDRS-R) score of 36 or higher, entered a 6-month treatment with antidepressant medication, cognitive-behavioral therapy focused on suicide prevention, or their combination (Comb), at five academic sites. Treatment assignment could be either random or chosen by study participants. Intent-to-treat, mixed effects regression models of depression and other relevant ratings were estimated. Improvement and remission rates were computed with the last observation carried forward., Results: Most patients (n = 104 or 84%) chose treatment assignment, and overall, three fourths (n = 93) received Comb. In Comb, CDRS-R declined from a baseline adjusted mean of 49.6 (SD 12.3) to 38.3 (8.0) at week 12 and to 27.0 (10.1) at week 24 (p < .0001), with a Clinical Global Impression -defined improvement rate of 58.0% at week 12 and 72.2% at week 24 and a remission (CDRS-R ≤ 28) rate of 32.5% at week 12 and 50.0% at week 24. The CDRS-R and the Scale for Suicidal Ideation scores were correlated at baseline (r = 0.43, p < .0001) and declined in parallel., Conclusions: When vigorously treated with a combination of medication and psychotherapy, adolescents with depression who have recently attempted suicide show rates of improvement and remission of depression that seem comparable to those observed in nonsuicidal adolescents with depression., (Copyright © 2009 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

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 randomized (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 samples, 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 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.

Objective: : Less than half of youths achieve remission (minimal to no symptoms) after acute antidepressant treatment. Early identification of who will or will not respond to treatment and achieve remission may help clinicians formulate treatment decisions and shorten the time spent on ineffective treatments. In a prospective open-label fluoxetine study, we investigate indicators of acute treatment response and remission., Method: : One hundred sixty-eight children and adolescents, ages 7 to 18 years, with primary diagnoses of major depressive disorder received 12 weeks of fluoxetine treatment. The youths were evaluated using the Kiddie Schedule for Affective Disorders and Schizophrenia. The outcome measure included the Children's Depression Rating Scale-Revised., Results: : Positive first-degree family history of depression was the only baseline demographic and clinical characteristic that predicted a favorable treatment response (p =.01). The rate of symptom improvement, however, is a good indicator of acute treatment response. A significant symptom reduction (approximately 50%) by week 4 is needed to achieve remission at the end of acute treatment., Conclusions: : This study demonstrated that the rate of symptom improvement during early weeks of acute fluoxetine treatment is a good indicator of remission. Treatment approach may be reevaluated and modified as early as week 4 during acute treatment.Clinical trials registration information-Determining Optimal Continuation Treatment Duration for Depressed Children and Adolescents. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00332787.

Objective: To compare the rates of physical, psychiatric, and suicide-related events in adolescents with MDD treated with fluoxetine alone (FLX), cognitive-behavioral therapy (CBT), combination treatment (COMB), or placebo (PBO)., Method: Safety assessments included adverse events (AEs) collected by spontaneous report, as well as systematic measures for specific physical and psychiatric symptoms. Suicidal ideation and suicidal behavior were systematically assessed by self- and clinician reports. Suicidal events were also reanalyzed by the Columbia Group and expert raters using the Columbia-Classification Algorithm for Suicidal Assessment used in the U.S. Food and Drug Administration reclassification effort., Results: Depressed adolescents reported high rates of physical symptoms at baseline, which improved as depression improved. Sedation, insomnia, vomiting, and upper abdominal pain occurred in at least 2% of those treated with FLX and/or COMB and at twice the rate of placebo. The rate of psychiatric AEs was 11% in FLX, 5.6% in COMB, 4.5% in PBO, and 0.9% in CBT. Suicidal ideation improved overall, with greatest improvement in COMB. Twenty-four suicide-related events occurred during the 12-week period: 5 patients (4.7%) in COMB, 10 (9.2%) in FLX, 5 (4.5%) in CBT, and 3 (2.7%) in placebo. Statistically, only FLX had more suicide-related events than PBO (p =.0402, odds ratio (OR) = 3.7, 95% CI 1.00-63.7). Only five actual attempts occurred (2 COMB, 2 FLX, 1 CBT, 0 PBO). There were no suicide completions., Conclusions: Different methods for eliciting AEs produce different results. In general, as depression improves, physical complaints and suicidal ideation decrease in proportion to treatment benefit. In this study, psychiatric AEs and suicide-related events are more common in FLX-treated patients. COMB treatment may offer a more favorable safety profile than medication alone in adolescent depression.

Objective: To examine the time to response for both pharmacotherapy and psychotherapy in the Treatment for Adolescents with Depression Study (TADS)., Method: Adolescents (N = 439, ages 12 to 17 years) with major depressive disorder were randomized to fluoxetine (FLX), cognitive-behavioral therapy (CBT), their combination (COMB), or pill placebo (PBO). Defining response as very much improved or much improved on the Clinical Global Impression-Improvement Scale (CGI-I), survival analyses using Cox proportional hazards models, and Kaplan-Meier curves were conducted to evaluate time to first response and time to stable response for subjects receiving pharmacotherapy (COMB, FLX, PBO) as well as for subjects receiving CBT (COMB, CBT). Direct comparisons between pharmacotherapy and CBT were not made because of differences in visit schedules., Results: Based on pharmacotherapist CGI-I scores, COMB and FLX showed faster onset of benefit than PBO on time to response and time to stable response (p < .001), and COMB was faster than FLX on time to stable response (p = .034). The probability of sustained early response was approximately threefold greater for COMB than PBO, twofold greater for FLX than PBO, and 1.5-fold greater for COMB than FLX. On the psychotherapist CGI-I scores, both first response and stable response occurred faster in COMB than CBT (p < .001), with a probability of sustained early response approximately threefold greater for COMB than CBT., Conclusions: In the acute treatment of depressed adolescents, FLX and COMB accelerate response relative to PBO, and COMB accelerates response relative to CBT alone.

Objective: To ascertain remission rates in depressed youth participating in the Treatment for Adolescents With Depression Study (TADS), a multisite clinical trial that randomized 439 adolescents with major depressive disorder (MDD) to a 12-week treatment of fluoxetine (FLX), cognitive-behavioral therapy (CBT), their combination (COMB), or clinical management with pill placebo (PBO)., Method: Using an end-of-treatment Children's Depression Rating Scale-Revised (CDRS-R) total score of 28 or below as the criterion for remission, rates of remission were examined with logistic regression, controlling for site. Loss of MDD diagnosis and residual symptoms in responders (defined as Clinical Global Impressions-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) were also examined across treatment groups., Results: After 12 weeks of treatment, 102 (23%) of 439 youths had reached remission. The remission rate was significantly higher in the COMB group (37%) relative to the other treatment groups (FLX, 23%; CBT, 16%; PBO, 17%), with odds ratios of 2.1 for COMB versus FLX, 3.3 for COMB versus CBT, and 3.0 for COMB versus PBO. In addition, 71% of subjects across treatment groups no longer met criteria for MDD at the end of acute treatment. Fifty percent of the youths who responded by CGI-I criteria continued to have residual symptoms, such as sleep or mood disturbances, fatigue, and poor concentration., Conclusions: The combination of FLX and CBT was superior to both monotherapy and PBO in terms of remission rates, but overall rates of remission remain low and residual symptoms are common at the end of 12 weeks of treatment.

Objective: To give academic researchers, government officials, and industry scientists an opportunity to assess the state of pediatric psychopharmacology and identify challenges facing professionals in the field., Method: Increased federal spending and the introduction of pediatric exclusivity led to large increases in pediatric psychopharmacology research in the 1990s. Despite the increase in research, concerns exist about methods and incentives for making new medications available for use in pediatric psychiatric disorders. In recognition of these concerns, the Duke Clinical Research Institute held a roundtable in September 2004. Participants from the National Institutes of Health, regulatory agencies, academia, and the pharmaceutical industry spoke about the effects of government regulations such as the U.S. Food and Drug Administration Modernization Act and the Pediatric Research Equity Act on pediatric research from academic, clinical, and industry perspectives, and bioethical considerations of such research., Conclusions: To ensure development of new drugs for treating psychiatric disorders in children and adolescents, we must address the challenges posed by the regulatory environment governing pediatric psychopharmacology research. Strategies were identified for improving the evidence base for psychopharmacologic interventions in youth before widespread use and for more effectively defining a research agenda for the future.

Objective: To determine the pharmacokinetics of fluvoxamine in children and adolescents and to compare pharmacokinetic data from adolescents to adults from a previous study., Method: Fluvoxamine was titrated to a target dose of 100 mg b.i.d. in children (6-11 years) and 150 mg b.i.d. in adolescents (12-17 years) with obsessive-compulsive disorder or other disorder requiring fluvoxamine treatment. Serum samples were collected over 12 hours after 12 or more consecutive doses of 25, 50, 100, and 150 mg., Results: Sixteen children (seven females, nine males) and 18 adolescents (nine females, nine males) were included in the pharmacokinetic analyses. Children demonstrated higher mean peak plasma concentration, higher mean area under the plasma concentration-time curve, and lower apparent oral clearance compared with adolescents. Compared with male children, female children had higher mean area under the plasma concentration-time curve, higher mean peak plasma concentration, and more reports of adverse events. However, the area under the plasma concentration-time curve was not directly correlated with frequency or severity of adverse events. Pharmacokinetics were nonlinear over the dose range studied. No pharmacokinetic differences were apparent between adolescents and adults on 150 mg b.i.d., Conclusions: These pharmacokinetic results suggest that children (especially females) have a higher exposure to fluvoxamine than adolescents, whereas adolescents and adults appear to have similar exposure to fluvoxamine.

Objective: To assess the efficacy and safety of paroxetine for the treatment of pediatric obsessive-compulsive disorder., Method: Children (7-11 years of age) and adolescents (12-17 years of age) meeting DSM-IV criteria for obsessive-compulsive disorder were randomized to paroxetine (10-50 mg/day) or placebo for 10 weeks. The primary efficacy measure was change from baseline in the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) total score at week 10 last observation carried forward end point. Safety was assessed primarily through adverse event monitoring., Results: A total of 207 patients were randomized to treatment. Of these, 203 were included in the intention-to-treat population. Adjusted mean changes from baseline at week 10 observation carried forward end point in CY-BOCS total score for patients receiving paroxetine and placebo were -8.78 (SE=0.82) and -5.34 points (SE=0.77), respectively. The adjusted mean difference, -3.45 in favor of paroxetine, was statistically significant (95% confidence interval=-5.60 to -1.29, p=.002). Adverse events were generally mild to moderate in intensity. A total of 10.2% (10/98) of patients in the paroxetine group and 2.9% (3 of 105) in the placebo group discontinued treatment because of adverse events., Conclusions: Paroxetine is an effective and generally well-tolerated treatment for obsessive-compulsive disorder in children and adolescents.

Objective: To quantify circadian rhythms in rest-activity cycles in depressed children and adolescents., Method: Rest-activity cycles were evaluated by actigraphy over five consecutive 24-hour periods in 100 children and adolescents, including 59 outpatients with major depressive disorder (MDD) and 41 healthy normal controls. Total activity, total light exposure, and time spent in light at more than 1,000 lux were averaged over the recording period for each participant. Time series analysis was used to determine the amplitude and period length of circadian rhythms in rest-activity., Results: Overall, adolescents with MDD had lower activity levels, damped circadian amplitude, and lower light exposure and spent less time in bright light than healthy controls. Among children, those with MDD showed lower light exposure and spent less time in bright light, but only depressed girls showed damped circadian amplitude. The sex differences were substantially greater in the MDD group than in the normal control group., Conclusions: These results confirm damped circadian rhythms in children and adolescents with MDD and highlight the influence of gender and age on these measures.

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.

Mood disorders are the leading causes of morbidity and mortality in children and adolescence. As a result, many adolescents are treated with psychopharmacologic agents such as antidepressants and mood stabilizers. To date, research into the safety and efficacy of these medications has lagged behind clinical practice. Several controlled trials of antidepressants in this population have recently been completed or are ongoing, yet few controlled trials of mood stabilizers have been conducted. Although acute efficacy of antidepressants is being addressed, many questions remain about pharmacological treatment of early-onset mood disorders. This article will focus on unmet research needs for the psychopharmacologic treatment of child and adolescent mood disorders.

Objective: To develop effect sizes for 3 mood stabilizers--lithium, divalproex sodium, and carbamazepine--for the acute-phase treatment of bipolar I or II disorder, mixed or manic episode, in children and adolescents aged 8 to 18 years., Method: Forty-two outpatients with a mean age of 11.4 years (20 with bipolar I disorder and 22 with bipolar II disorder) were randomly assigned to 6 weeks of open treatment with either lithium, divalproex sodium, or carbamazepine. The primary efficacy measures were the weekly Clinical Global Impression Improvement scores and the Young Mania Rating Scale (Y-MRS)., Results: Using a > or = 50% change from baseline to exit in the Y-MRS scores to define response, the effect size was 1.63 for divalproex sodium, 1.06 for lithium, and 1.00 for carbamazepine. Using this same response measure with the intent-to-treat sample, the response rates were as follows: sodium divalproex, 53%; lithium, 38%; and carbamazepine, 38% (chi 2(2) = 0.85, p = .60). All 3 mood stabilizers were well tolerated, and no serious adverse effects were seen., Conclusions: Divalproex sodium, lithium, and carbamazepine all showed a large effect size in the open treatment of children and adolescents with bipolar I or II disorder in a mixed or manic episode.

Background: It has been suggested that a primary ultradian (80-120 minute) rhythm disturbance in EEG underlies sleep abnormalities in adults with depression. The present study evaluated ultradian rhythm disturbances in childhood and adolescent depression., Methods: Sleep macroarchitecture and temporal coherence in quantitative EEG rhythms were investigated in 50 medication-free outpatients with major depression (25 children and 25 adolescents) and 15 healthy normal controls (5 children and 10 adolescents)., Results: Few of the macroarchitectural measures showed significant group effects. In fact, age and sex effects were stronger than disease-dependent components. Temporal coherence of EEG rhythms during sleep did differentiate those with MDD from controls. Both depressed children and adolescents had lower intrahemispheric coherence, whereas interhemispheric was only lower in depressed adolescents in comparison with controls. Gender differences were evident in adolescents, but not children, with MDD with lowest interhemispheric coherence in adolescent girls., Conclusions: These findings are in keeping with increased risk for depression in females beginning at adolescence and extending throughout adulthood. It was suggested that low temporal coherence in depression reflects a disruption in the fundamental basic rest-activity cycle of arousal and organization in the brain that is strongly influenced by gender.

Objectives: To develop consensus guidelines for medication treatment algorithms for childhood major depressive disorder (MDD) based on scientific evidence and clinical opinion when science is lacking. The ultimate goal of this approach is to synthesize research and clinical experience for the practitioner and to increase the uniformity of preferred treatment for childhood MDD. A final goal is to develop an approach that can be tested as to whether it improves clinical outcomes for children and adolescents with MDD., Method: A consensus conference was held. Participants included academic clinicians and researchers, practicing clinicians, administrators, consumers, and families. The focus was to review and use clinical evidence to recommend specific pharmacological approaches for treatment of MDD in children and adolescents. After a series of presentations of current research evidence and panel discussion, the consensus panel met, agreed on assumptions, and drafted the algorithms. The process initially addressed strategies of treatment and then tactics to implement the strategies., Results: Consensually agreed-upon algorithms for major depressions (with and without psychosis) and comorbid attention deficit disorders were developed. Treatment strategies emphasized the use of selective serotonin reuptake inhibitors. The algorithm consists of systematic strategies for treatment interventions and recommended tactics for implementation of the strategies, including medication augmentation and medication combinations. Participants recommended prospective evaluation of the algorithms in various public sector settings, and many volunteered as sites for such an evaluation., Conclusions: Using scientific and clinical experience, consensus-derived algorithms for children and adolescents with MDD can be developed.

Objectives: First, to review the extant data on the safety and efficacy of the use of nontricyclic antidepressants in children and adolescents; second, to identify the main limitations of our current knowledge in this area; and third, to point to future research directions., Method: A Medline search and a review of previous scientific meetings were conducted; all available reports on the efficacy and safety of nontricyclic antidepressants in children and adolescents were critically reviewed., Results: As in adults, also in children nontricyclic antidepressants are potentially useful in treating a variety of psychiatric disorders. The data supporting their efficacy, however, are quite limited. Obsessive-compulsive disorder is the only psychiatric diagnosis for which pediatric use of selective serotonin reuptake inhibitors has been approved. One placebo-controlled study in children and adolescents with major depression supports the efficacy of fluoxetine. Other clinical trials of nontricyclic antidepressants in depressed adolescents are in progress. Available data indicate that the safety of these medications is good, at least in the short term., Conclusions: The potential usefulness of nontricyclic antidepressants for children and adolescents suffering from a range of disorders is considerable. While information from adults can suggest potential areas of possible efficacy in pediatric patients suffering from similar psychopathology, further research is essential to provide the necessary information on the efficacy, safety, and pharmacokinetics of these medications in children and adolescents.

Objective: To evaluate the outcome of a sample of children and adolescents hospitalized with major depressive disorder (MDD) and to assess different duration and severity criteria to define recovery and recurrence., Method: Fifty-nine of 70 children and adolescents were reevaluated 1 to 5 years later, and the intervening course of depression and other disorders was assessed using the Kiddie-Longitudinal interval Follow-up Evaluation (K-LIFE)., Results: Ninety-eight percent of subjects had recovered from their index MDD episode within 1 year of their initial evaluation, but 61% had at least one recurrence during the follow-up period. Of those with recurrences, 47.2% had a recurrence within 1 year and 69.4% by 2 years from the offset of the index episode. Changing the criteria for recovery by increasing the length of time required to define recovery resulted in decreases in the number of episodes of recurrence reported., Conclusion: MDD in children and adolescents is often an episodic disorder. Difference in definitions of recovery and recurrence affect the data reported. Consistent definitions of remission, recovery, relapse, and recurrence are needed. These data suggest that recovery may be defined after two consecutive months without symptoms and that episodes of MDD may be briefer, but more frequent, in children and adolescents than in adults.

A substantial body of research in adults has established that certain sleep polysomnographic abnormalities are commonly found in depressed patients, including sleep continuity disturbances, reduced slow-wave sleep, shortened rapid eye movement (REM) latency and increased REM density. To date the findings in depressed adolescents are equivocal. Three consecutive nights of polysomnographic recordings were obtained in 31 hospitalized depressed adolescents and 17 age-matched normal controls. The depressed adolescents had a shorter REM latency, shorter sleep latency, more REM sleep, and less stage 3 nonREM (NREM) sleep. There was a trend for melancholic and suicidal patients to have a shorter REM latency.