Graham J. Emslie

Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial

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.

Fluoxetine for acute treatment of depression in children and adolescents: A placebo-controlled, randomized clinical trial

BACKGROUND This report presents results from the acute treatment phase of a clinical trial designed to confirm efficacy of a fixed dose of 20 mg of fluoxetine in children and adolescents with major depressive disorder (MDD). METHOD After a 3-week screening period, 122 children and 97 adolescents with MDD ( ) were randomly assigned to placebo or fluoxetine. After a 1-week placebo lead-in, fluoxetine-treated patients received fluoxetine 10 mg/day for 1 week, then fluoxetine 20 mg/day for 8 weeks. RESULTS Fluoxetine was associated with greater mean improvement in Childrens Depression Rating Scale-Revised (CDRS-R) score than placebo after 1 week ( <.05) and throughout the study period. Significantly more fluoxetine-treated patients (41%) met the prospectively defined criteria for remission than did placebo-treated patients (20%) ( <.01). More fluoxetine- (65%) than placebo-treated (53%) patients met the prospectively defined response criterion of > or =30% decrease in CDRS-R score, but this difference was not significant ( =.093). Significantly more fluoxetine-than placebo-treated patients completed acute treatment ( =.001). There were no significant differences between treatment groups in discontinuations due to adverse events ( =.408). CONCLUSION Fluoxetine 20 mg daily appears to be well tolerated and effective for acute treatment of MDD in child and adolescent outpatients. Fluoxetine is the only antidepressant that has demonstrated efficacy in two placebo-controlled, randomized clinical trials of pediatric depression.

Effect Size of Lithium, Divalproex Sodium, and Carbamazepine in Children and Adolescents With Bipolar Disorder

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.

Impact of comorbidity on treatment response to paroxetine in pediatric obsessive-compulsive disorder: is the use of exclusion criteria empirically supported in randomized clinical trials?

OBJECTIVE To examine the influence of psychiatric comorbidity on response and relapse rates in children and adolescents treated with paroxetine for obsessive-compulsive disorder (OCD). METHODS Patients responding following 16 weeks of treatment (phase I) were randomized to continued paroxetine or to placebo for 16 additional weeks (phase II). OCD response (phase I) and relapse (phase II) criteria were based on the Clinical Global Impression-Improvement Scale and the Childrens Yale-Brown Obsessive Compulsive Scale. The presence of OCD and other psychiatric disorders was ascertained using the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version interview. RESULTS At entry, 193 of 335 (57.6%) patients had at least one psychiatric disorder in addition to OCD, and 102 of 335 (30.4%) had multiple other disorders. Although the response rate to paroxetine in the overall population was high (71%), the response rates in patients with comorbid attention deficit hyperactivity disorder, tic disorder, or oppositional defiant disorder (56%, 53%, and 39%, respectively) were significantly less than in patients with OCD only (75%) (intent-to-treat population, last observation carried forward analysis, p < 0.05). Psychiatric comorbidity was associated with a greater rate of relapse in the total patient population (46% for one or more comorbid disorders [p = 0.04] and 56% for two or more comorbid disorders [p < 0.05] vs. 32% for no comorbidity). CONCLUSIONS The results of these post hoc analyses show that comorbid illness adversely impacted response to pharmacotherapy with paroxetine in pediatric OCD and significantly increased risk of relapse following withdrawal from treatment. Continued paroxetine treatment reduced the relapse rates in all groups compared with placebo, including those with comorbid illness. Because pediatric OCD is frequently comorbid with other psychiatric disorders, results of randomized, controlled pediatric OCD trials that use multiple exclusion criteria may not generalize to more naturalistic OCD samples.

Treatment for Adolescents with Depression Study (TADS): Rationale, design, and methods

OBJECTIVES A rapidly growing empirical literature on the treatment of major depressive disorder (MDD) in youth supports the efficacy of short-term treatment with depression-specific cognitive-behavioral therapy or medication management with a selective serotonin reuptake inhibitor. These studies also identify a substantial probability of partial response and of relapse, which might be addressed by more intensive, longer-term treatments. METHOD Funded by the National Institute of Mental Health, the Treatment for Adolescents With Depression Study (TADS) is a multicenter, randomized, masked effectiveness trial designed to evaluate the short-term (12-week) and long-term (36-week) effectiveness of four treatments for adolescents with MDD: fluoxetine, cognitive-behavioral therapy, their combination, and, acutely, pill placebo. A volunteer sample of 432 subjects aged 12-17 years (inclusive) with a primary DSM-IV diagnosis of MDD who are broadly representative of patients seen in clinical practice will enter the study. The primary dependent measures rated blindly by an independent evaluator are the Childrens Depression Rating Scale and, for responder analysis, a dichotomized Clinical Global Impressions-Improvement score. Consistent with an intent-to-treat analysis, all patients, regardless of treatment status, return for all scheduled assessments. RESULTS This report describes the design of the trial, the rationale for the design choices made, and the methods used to carry out the trial. CONCLUSION When completed, TADS will improve our understanding of how best to initiate treatment for adolescents with MDD.

The Texas children's medication algorithm project: Report of the Texas consensus conference panel on medication treatment of childhood major depressive disorder

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.

Recurrence of Major Depressive Disorder in Hospitalized 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.

Nontricyclic antidepressants: current trends in children and adolescents.

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.

Mood disorders in children and adolescents: psychopharmacological treatment

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.

Predictors of response to treatment in children and adolescents with mood disorders

Depression and bipolar disorder are frequently chronic disorders, with onset often beginning in childhood. Mood disorders are becoming more recognized in children and adolescents, and treatment of these disorders has received much attention, particularly in the past 10 years. Recent studies have demonstrated efficacy of antidepressant medications (particularly SSRIs) and specific psychotherapies (primarily CBT). Rates of remission (little or no symptoms) in these studies, however, have remained quite low (35% to 40% in most acute studies). Furthermore, recurrence is common in this population, and affects 40% to 50%. Early onset mood disorders are also associated with increased risk of developing other psychiatric disorders, substance abuse, and suicide, and having poor academic, work, and social functioning. The lifelong implications are serious. Identifying factors that may predict response to treatment, both in general and to specific treatments, may lead to improved outcomes for these patients. Unfortunately, studies have typically been inconsistent. Most studies do not identify demographic variables as predictive of outcome, although older age has been associated with poor prognosis in several studies. Psychosocial factors have yielded some results, particularly with regard to family environments. Generally, intact families with positive interaction styles and less dysfunction have been associated with better outcomes. Psychiatric disorders among parents not only predicts the development of the disorder, but is also associated with poorer prognosis. Finally, several clinical factors have been linked to poorer outcome in children and adolescents with mood disorders. More frequent episodes, increased severity (particularly suicidality and psychosis), and comorbid disorders are likely to lead to fewer recoveries, longer episodes, and increased rate of recurrence. Recent attention has focused on mediators and moderators of outcomes to treatment. In general, the theory is that enumerable factors contribute to the course of an individuals mood disorder, but that by identifying some of the variables that have more impact may allow for more specific or modified treatments to improve outcome. Many of the predictive factors explored in this article are examples of mediators and moderators that affect outcome. Each one alone may not provide definitive answers for predicting response to treatment, but each must be taken into account at the outset of treatment. It is clear that treatments must be individualized for each patient. Furthermore, selecting only one treatment exclusively for patients may hinder progress. The first step is to attempt to identify some of the underlying causes and the consequences of the disorder itself (i.e., decreased social interaction). The next step in successful treatment is to address both the causes and consequences of the disorder, through medication, psychotherapy, skills training, family intervention, or any other methods needed to assist the child to begin functioning better in all domains (social, academic, work, family, and so forth). Such a biopsychosocial approach to treatment of these disorders will likely improve overall outcome.