Moderators of fluoxetine treatment response for children and adolescents with comorbid depression and substance use disorders.

Our recent 8-week, randomized, placebo-controlled trial of fluoxetine in adolescents (ages 12-17 years) with comorbid depression and substance use disorder (SUD) did not detect a significant antidepressant treatment effect. The purpose of this secondary analysis was to explore moderators of the effect of fluoxetine in this sample. Static moderators measured at baseline were depression chronicity and hopelessness severity; time-varying moderators measured at baseline and weekly during the 8-week trial period were alcohol and marijuana use severity. Treatment effects on depression outcomes were examined among moderating subgroups in random effects regression models. Subjects assigned to fluoxetine treatment with chronic depression at baseline (p = .04) or no more than moderate alcohol use during the trial (p = .04) showed significantly greater decline in depression symptoms in comparison to placebo-assigned subgroups. The current analysis suggests that youth with chronic depression and no more than moderate alcohol consumption are likely to respond better to treatment with fluoxetine compared with placebo than youth with transient depression and heavy alcohol use.

The short-term safety and efficacy of fluoxetine in depressed adolescents with alcohol and cannabis use disorders: a pilot randomized placebo-controlled trial.

BACKGROUND: The objective of this study was to examine whether fluoxetine was superior to placebo in the acute amelioration of depressive symptomatology in adolescents with depressive illness and a comorbid substance use disorder. METHODS: Eligible subjects ages 12-17 years with either a current major depressive disorder (MDD) or a depressive disorder that were also suffering from a comorbid substance-related disorder were randomized to receive either fluoxetine or placebo in this single site, 8-week double-blind, placebo-controlled study. The primary outcome analysis was a random effects mixed model for repeated measurements of Children's Depression Rating Scale-Revised (CDRS-R) scores compared between treatment groups across time. RESULTS: An interim analysis was performed after 34 patients were randomized. Based on the results of a futility analysis, study enrollment was halted. Twenty-nine males and 5 females were randomized to receive fluoxetine (n = 18) or placebo (n = 16). Their mean age was 16.5 (1.1) years. Overall, patients who received fluoxetine and placebo had a reduction in CDRS-R scores. However, there was no significant difference in mean change in CDRS-R total score in those subjects treated with fluoxetine and those who received placebo (treatment difference = 0.19, S.E. = 0.58, F = 0.14, p = .74). Furthermore, there was not a significant difference in rates of positive urine drug toxicology results between treatment groups at any post-randomization visit (F = 0.22, df = 1, p = 0.65). The main limitation of this study is its modest sample size and resulting low statistical power. Other significant limitations to this study include, but are not limited to, the brevity of the trial, high placebo response rate, limited dose range of fluoxetine, and the inclusion of youth who met criteria for depressive disorders other than MDD. CONCLUSION: Fluoxetine was not superior to placebo in alleviating depressive symptoms or in decreasing rates of positive drug screens in the acute treatment of adolescents with depression and a concomitant substance use disorder.

Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study.

OBJECTIVE: Atypical (second-generation) antipsychotics are considered standard treatment for children and adolescents with early-onset schizophrenia and schizoaffective disorder. However, the superiority of second-generation antipsychotics over first-generation antipsychotics has not been demonstrated. This study compared the efficacy and safety of two second-generation antipsychotics (olanzapine and risperidone) with a first-generation antipsychotic (molindone) in the treatment of early-onset schizophrenia and schizoaffective disorder. METHOD: This double-blind multisite trial randomly assigned pediatric patients with early-onset schizophrenia and schizoaffective disorder to treatment with either olanzapine (2.5-20 mg/day), risperidone (0.5-6 mg/day), or molindone (10-140 mg/day, plus 1 mg/day of benztropine) for 8 weeks. The primary outcome was response to treatment, defined as a Clinical Global Impression (CGI) improvement score of 1 or 2 and >or=20% reduction in Positive and Negative Syndrome Scale (PANSS) total score after 8 weeks of treatment. RESULTS: In total, 119 youth were randomly assigned to treatment. Of these subjects, 116 received at least one dose of treatment and thus were available for analysis. No significant differences were found among treatment groups in response rates (molindone: 50%; olanzapine: 34%; risperidone: 46%) or magnitude of symptom reduction. Olanzapine and risperidone were associated with significantly greater weight gain. Olanzapine showed the greatest risk of weight gain and significant increases in fasting cholesterol, low density lipoprotein, insulin, and liver transaminase levels. Molindone led to more self-reports of akathisia. CONCLUSIONS: Risperidone and olanzapine did not demonstrate superior efficacy over molindone for treating early-onset schizophrenia and schizoaffective disorder. Adverse effects were frequent but differed among medications. The results question the nearly exclusive use of second-generation antipsychotics to treat early-onset schizophrenia and schizoaffective disorder. The safety findings related to weight gain and metabolic problems raise important public health concerns, given the widespread use of second-generation antipsychotics in youth for nonpsychotic disorders.

The Collaborative Lithium Trials (CoLT): specific aims, methods, and implementation.

BACKGROUND: Lithium is a benchmark treatment for bipolar illness in adults. However, there has been relatively little methodologically stringent research regarding the use of lithium in youth suffering from bipolarity. METHODS: Under the auspices of the Best Pharmaceuticals for Children Act (BPCA), a Written Request (WR) pertaining to the study of lithium in pediatric mania was issued by the United States Food and Drug Administration (FDA) to the National Institute of Child Health and Human Development (NICHD) in 2004. Accordingly, the NICHD issued a Request for Proposals (RFP) soliciting submissions to pursue this research. Subsequently, the NICHD awarded a contract to a group of investigators in order to conduct these studies. RESULTS: The Collaborative Lithium Trials (CoLT) investigators, the BPCA-Coordinating Center, and the NICHD developed protocols to provide data that will: (1) establish evidence-based dosing strategies for lithium; (2) characterize the pharmacokinetics and biodisposition of lithium; (3) examine the acute efficacy of lithium in pediatric bipolarity; (4) investigate the long-term effectiveness of lithium treatment; and (5) characterize the short- and long-term safety of lithium. By undertaking two multi-phase trials rather than multiple single-phase studies (as was described in the WR), the feasibility of the research to be undertaken was enhanced while ensuring all the data outlined in the WR would be obtained. The first study consists of: (1) an 8-week open-label, randomized, escalating dose Pharmacokinetic Phase; (2) a 16-week Long-Term Effectiveness Phase; (3) a 28-week double-blind Discontinuation Phase; and (4) an 8-week open-label Restabilization Phase. The second study consists of: (1) an 8-week, double-blind, parallel-group, placebo-controlled Efficacy Phase; (2) an open-label Long-Term Effectiveness lasting either 16 or 24 weeks (depending upon blinded treatment assignment during the Efficacy Phase); (3) a 28-week double-blind Discontinuation Phase; and (4) an 8-week open-label Restabilization Phase. In December of 2006, enrollment into the first of these studies began across seven sites. CONCLUSION: These innovative studies will not only provide data to inform the labeling of lithium in children and adolescents with bipolar disorder, but will also enhance clinical decision-making regarding the use of lithium treatment in pediatric bipolar illness. TRIAL REGISTRATION: NCT00442039.

Early symptoms of mania and the role of parental risk.

OBJECTIVES: The objectives of this study were to: (i) describe the phenomenology of youths diagnosed with subsyndromal bipolar disorders; (ii) describe the phenomenology of youngsters who are the children of bipolar parents, who are also experiencing subsyndromal symptoms of bipolar disorder (patients with 'cyclotaxia'); and (iii) explore which symptoms may be most useful in identifying youths with cyclotaxia. METHODS: Four hundred outpatients between the ages of 5 and 17 years received a diagnostic assessment and psychometric questionnaires pertaining to mood symptomatology and psychosocial functioning. Parental diagnostic information was also obtained. Children and adolescents were assigned to one of three diagnostic groups: a 'syndromal bipolar disorder (BP)' group (n = 118), a 'sub-syndromal bipolar (SUB-BP)' group (n = 75), or a 'non-bipolar (NON-BP)' group (n = 207). In addition, based on parental diagnoses, youths were assigned to either a high genetic risk group (n = 167) or a low genetic risk group (n = 233). RESULTS: Youths with subsyndromal bipolar disorders were found to have intermediate degrees of manic symptoms than youths with bipolar disorder and youths without a bipolar diagnosis. Offspring of parents having a bipolar disorder were more likely to show symptoms of hypomania and mania than youths without a bipolar parent. Youths at genetic risk for developing a bipolar disorder were not found to be at higher risk for having a diagnosis of attention-deficit hyperactivity disorder or a disruptive behavior disorder. Finally, results suggest that elevated mood with irritability and rapid mood fluctuations are the key distinguishing characteristics of 'cyclotaxia'. CONCLUSIONS: There exists a group of youngsters who are the offspring of a parent/parents with a bipolar disorder who do not suffer from BP 1 or BP 2, yet have elevated mood symptoms and psychosocial dysfunction. As a result of these observations, treatment studies are needed for youths with 'cyclotaxia'.

Comparing the diagnostic accuracy of six potential screening instruments for bipolar disorder in youths aged 5 to 17 years.

OBJECTIVE: To compare the diagnostic efficiency of six index tests as predictors of juvenile bipolar disorder in two large outpatient samples, aged 5 to 10 and 11 to 17 years, gathered from 1997 to 2002. METHOD: DSM-IV diagnosis was based on a semistructured diagnostic interview (Schedule for Affective Disorders and Schizophrenia for School-Age Children) with the parent and youth sequentially, blind to scores on the index tests. Participants were 318 youths aged 5 to 10 (50% with bipolar diagnoses) and 324 youths aged 11 to 17 (41% with bipolar diagnoses). Areas under the curve (AUCs) from receiver operating characteristic analyses and multilevel likelihood ratios quantified test performance. RESULTS: Parent report (AUCs from 0.78 to 0.84 in both age groups) outperformed teacher (AUCs 0.57 in the younger sample and 0.70 in the older sample) or adolescent measures (AUCs 0.67 [General Behavior Inventory] and 0.71 [Youth Self-Report]) at identifying bipolar disorders. Combining tests did not produce clinically meaningful classification improvement. CONCLUSIONS: Parent report was more useful than teacher report or adolescent self-report on the index tests studied. Results generally replicated across both age groups. Parent report on these instruments could facilitate differential diagnosis of bipolar disorder in youths aged 5 to 17 years, especially by decreasing the rate of false-positive diagnoses.

Somatic treatment for depressive illnesses in children and adolescents.

Numerous somatic interventions have been studied as potential treatments of depressive disorders in children and adolescents. These include antidepressant medications, light therapy, electro-convulsive therapy, and alternative therapies. The available evidence suggests that several somatic interventions hold promise as potentially safe and effective treatments for depressed youths; however, there is still much to be learned about these interventions. This article reviews what is known and what needs to be learned about the somatic treatment of pediatric depression.

Somatic treatment for depressive illnesses in children and adolescents.

Numerous somatic interventions have been studied as potential treatments of depressive disorders in children and adolescents. These include antidepressant medications, light therapy, electro-convulsive therapy, and alternative therapies. The available evidence suggests that several somatic interventions hold promise as potentially safe and effective treatments for depressed youth; however, there is still much to be learned about these interventions. This article reviews what is known and what needs to be learned about the somatic treatment of pediatric depression.

Clinical decision-making using the General Behavior Inventory in juvenile bipolarity.

OBJECTIVE: The General Behavior Inventory (GBI) is a questionnaire that has utility in the assessment of mood disorders in adults. The purpose of this study was to examine how the GBI might optimally be used in the assessment of youths. METHOD: Children and adolescents between the ages of 5 and 17 years participated in this study. All youths were evaluated with the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS). Based on the K-SADS results, subjects were then assigned to one of four groups: a bipolar spectrum group, a depressive disorders group, a disruptive behaviors disorders group, and a no diagnosis group. Guardians completed a version of the GBI modified for parent reporting. Patients 10 years old or greater also completed the GBI as a self-report measure. RESULTS: There were 196 subjects who participated. Both parent report and youth self-report assigned patients to the appropriate diagnostic group with better than 74% accuracy. Combining information from multiple informants did not significantly improve diagnostic group assignment. CONCLUSIONS: These data suggest that the GBI may be a useful adjunct in the diagnosis of mood disorders in youths, particularly when diagnostic specificity is more important than sensitivity.