An exploratory factor analysis of the children's depression rating scale-revised.

An exploratory factor analysis was performed in a clinical sample of 314 children and adolescents to investigate the factor structure of the Children's Depression Rating Scale-Revised (CDRS-R; Poznanski et al. 1984). A maximum likelihood method followed by a Promax rotation yielded five factors: observed depressive mood, anhedonia, morbid thoughts, somatic symptoms and reported depressive mood. The age group and gender differences on the factors scores are evaluated. After controlling for gender, the adolescents had more severe depression in terms of observed depressive mood, anhedonia, and somatic symptoms. After controlling for age groups, girls had higher scores for reported depressive mood.

Fluoxetine 40-60 mg versus fluoxetine 20 mg in the treatment of children and adolescents with a less-than-complete response to nine-week treatment with fluoxetine 10-20 mg: a pilot study.

OBJECTIVE: The aim of this study was to compare fluoxetine dosage titration to 40-60 mg/day with fixed fluoxetine 20-mg/day treatment for an additional 10 weeks in pediatric outpatients with major depressive disorder (MDD) who had not met protocol-defined response criteria after 9-week acute fluoxetine treatment. METHODS: Patients unresponsive (less than or equal to 30% decrease in Children's Depression Rating Scale-Revised [CDRS-R] score) after 9-week fluoxetine treatment were randomly reassigned to continue at 20 mg/day or to increase to 40 mg/day. After 4 weeks, patients unresponsive to 40 mg/day could receive 60 mg/day. RESULTS: Twenty-nine (29) patients, 9-17 years of age, received fluoxetine 40-60 mg/day (n = 14) or 20 mg/day (n = 15). At the conclusion of this study phase, 10 patients (71%) on 40-60 mg/day met the response criteria, versus 5 patients (36%) on 20 mg/day (p = 0.128). Mean CDRS-R scores improved in both treatment groups (fluoxetine 40-60 mg/day, -9.4; fluoxetine 20 mg/day, -1.5; p = 0.099). Adverse events were similar in both groups. However, this study phase was statistically underpowered for detecting differences between treatment groups. CONCLUSION: More than two thirds of patients whose dosage was increased responded within 10 weeks, suggesting dose escalation may benefit some patients. Approximately one third of patients unresponsive to initial treatment with fluoxetine 20 mg responded to this fixed dosage within another 10 weeks. Fluoxetine 20-60 mg/day was well tolerated.

The interface between publicly funded and industry-funded research in pediatric psychopharmacology: opportunities for integration and collaboration.

Pediatric psychopharmacology research is undergoing a major expansion consequent to increasing use of psychotropic medications in children and recent legislative incentives to industry. In this rapidly changing context, the interface between publicly and privately funded research needs to be reconsidered to integrate activities and avoid unnecessary duplication of efforts. Once, by default, the almost exclusive domain of public research, child research is now increasingly funded by industry. There are, however, important issues unlikely to be addressed through private funding for which public support is needed, such as direct comparisons between active medications, between pharmacological and psychosocial interventions, or between combined and single treatment modalities; development of effective treatment strategies for patients unresponsive to first-line treatments; development of better research methods to assess efficacy and safety; identification of moderators and mechanisms of treatment response; and impact of treatment on illness course and prognosis. Industry-sponsored research is limited by the restricted access to proprietary databases, which impedes independent analyses and meta-analyses. Translation of basic neuroscience discoveries into treatment applications for children with mental illness is a critical area of inquiry that can benefit from integration of efforts and collaborations among academia, government, and industry.

Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder.

The selective norepinephrine (NE) transporter inhibitor atomoxetine (formerly called tomoxetine or LY139603) has been shown to alleviate symptoms in Attention Deficit/Hyperactivity Disorder (ADHD). We investigated the mechanism of action of atomoxetine in ADHD by evaluating the interaction of atomoxetine with monoamine transporters, the effects on extracellular levels of monoamines, and the expression of the neuronal activity marker Fos in brain regions. Atomoxetine inhibited binding of radioligands to clonal cell lines transfected with human NE, serotonin (5-HT) and dopamine (DA) transporters with dissociation constants (K(i)) values of 5, 77 and 1451 nM, respectively, demonstrating selectivity for NE transporters. In microdialysis studies, atomoxetine increased extracellular (EX) levels of NE in prefrontal cortex (PFC) 3-fold, but did not alter 5-HT(EX) levels. Atomoxetine also increased DA(EX) concentrations in PFC 3-fold, but did not alter DA(EX) in striatum or nucleus accumbens. In contrast, the psychostimulant methylphenidate, which is used in ADHD therapy, increased NE(EX) and DA(EX) equally in PFC, but also increased DA(EX) in the striatum and nucleus accumbens to the same level. The expression of the neuronal activity marker Fos was increased 3.7-fold in PFC by atomoxetine administration, but was not increased in the striatum or nucleus accumbens, consistent with the regional distribution of increased DA(EX). We hypothesize that the atomoxetine-induced increase of catecholamines in PFC, a region involved in attention and memory, mediates the therapeutic effects of atomoxetine in ADHD. In contrast to methylphenidate, atomoxetine did not increase DA in striatum or nucleus accumbens, suggesting it would not have motoric or drug abuse liabilities.

Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder.

BACKGROUND: Atomoxetine is a nonstimulant drug being studied for the treatment of attention-deficit/hyperactivity disorder (ADHD). Atomoxetine is a highly specific inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other noradrenergic receptors or other neurotransmitter transporters or receptors. Results of 2 proof-of-concept studies are reported that tested the hypothesis that a selective inhibitor of presynaptic norepinephrine uptake would be effective for the treatment of ADHD in school-aged children. METHOD: Two identical 12-week, stratified, randomized, double-blind, placebo-controlled trials were conducted in children who met DSM-IV criteria for ADHD. The primary efficacy outcome measure was the mean change from baseline to endpoint in the Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD RS) total score. Secondary efficacy measures included the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) and the Conners' Parent Rating Scale-Revised: Short Form (CPRS-R:S). RESULTS: A total of 291 patients were randomized in the 2 trials combined (Study 1, N = 147; Study 2, N = 144). Stimulant-naive patients were randomized to atomoxetine, placebo, or methylphenidate. Patients with prior stimulant exposure were randomized to atomoxetine or placebo. Atomoxetine significantly reduced ADHD RS total scores compared with placebo in each study (p <.001). Changes in the CGI-ADHD-S (Study 1: p =.003; Study 2: p =.001) and CPRS-ADHD Index (Study 1: p =.023; Study 2: p <.001) also showed atomoxetine to be statistically significantly superior to placebo in reducing ADHD symptoms. Atomoxetine was found to be well tolerated in this population of pediatric patients. CONCLUSION: Two studies of atomoxetine early in its development confirmed that atomoxetine, a specific and selective inhibitor of noradrenergic uptake, was effective for the treatment of children with ADHD. In addition, atomoxetine was found to be well tolerated.

Cardiovascular effects of atomoxetine in children, adolescents, and adults.

BACKGROUND: Atomoxetine is a highly specific presynaptic inhibitor of the noradrenaline (norepinephrine) transporter that was recently approved in the US for the treatment of patients with attention-deficit/hyperactivity disorder (ADHD). Adverse effects on the cardiovascular system, including abnormalities in heart rate, blood pressure, or cardiac rhythm have been associated with several noradrenergic medications. OBJECTIVE: To further elucidate the magnitude and impact of blood pressure and pulse elevations in patients taking atomoxetine. STUDY DESIGN: Short-term cardiovascular safety in children, adolescents, and adults with ADHD was assessed in five randomised, double-blind trials (duration up to 10 weeks) with atomoxetine (n = 612) or placebo (n = 474). Long-term cardiovascular safety in children and adolescents (n = 169) was assessed in patients who entered an open-label extension or a blinded continuation following short-term treatment. METHODS: Adverse events, blood pressure, sitting pulse, and electrocardiograms (ECGs) were collected throughout the trials. QT intervals were corrected for heart rate by a data-specific correction factor (QTcD; derived from baseline ECGs) as well as standard methods. RESULTS: Atomoxetine treatment was associated with small but statistically significant increases in mean systolic blood pressure in adults and diastolic blood pressure in children and adolescents. Mean pulse rate increased for all atomoxetine treatment groups. The increases in blood pressure and pulse tended to occur early in therapy, stabilised, and returned toward baseline upon drug discontinuation. There was no significant difference between atomoxetine and placebo treatment groups in change in QTcD interval for all study populations. Palpitations in the adult patient population were the only significant cardiovascular adverse event (p = 0.037) occurring more frequently in the atomoxetine treatment group (3.7%) than in the placebo group (0.8%). Discontinuations due to cardiovascular-related events were very uncommon in the adult group, and did not occur in the child/adolescent group. CONCLUSION: While atomoxetine has noradrenergic activity, increases in pulse and blood pressure were small and of little, if any, clinical significance. Atomoxetine was not associated with QT interval prolongation. Cardiovascular effects of atomoxetine were minimal, and atomoxetine was well tolerated in short- and long-term studies.

Fluoxetine treatment for prevention of relapse of depression in children and adolescents: a double-blind, placebo-controlled study.

OBJECTIVE: To compare fluoxetine 20 to 60 mg/day with placebo for prevention of relapse of major depressive disorder in children and adolescents who had achieved Children's Depression Rating Scale, Revised scores of < or =28 during treatment with fluoxetine 20 to 60 mg. METHOD: In this 32-week relapse-prevention phase of a double-blind, multicenter, placebo-controlled 51-week study, 20 patients continued to receive their fixed dose of fluoxetine (F/F group), while 20 similar patients were switched to placebo (F/P group). Definition of relapse for the primary analysis was a Children's Depression Rating Scale, Revised score of >40 with a 2-week history of clinical deterioration or relapse in the opinion of the physician. Adverse events were compared between treatment groups to assess discontinuation-emergent adverse events. RESULTS: Mean time to relapse was longer in the F/F recipients than in the F/P recipients (p=.046). Relapse occurred in an estimated 34% in the F/F cohort and 60% in the F/P cohort. Incidence of adverse events and tolerability were similar in the F/F and F/P groups, suggesting that fluoxetine is not associated with significant discontinuation events. CONCLUSIONS: Fluoxetine 20 to 60 mg/day was well tolerated and can significantly delay relapse of major depressive disorder symptoms in children and 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 Children's 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.

Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial.

OBJECTIVE: To assess the comparability of atomoxetine, a new therapy for attention-deficit/hyperactivity disorder (ADHD) and methylphenidate. (Atomoxetine was originally called tomoxetine. The name was recently changed in order to avoid any potential confusion with tamoxifen that might lead to errors in dispensing drug.) METHOD: Children with ADHD were randomized to open-label atomoxetine or methylphenidate for 10 weeks. Response was assessed with the ADHD-IV Rating Scale. RESULTS: Two hundred twenty-eight patients were randomized (atomoxetine n = 184, methylphenidate n = 44). Both drugs were associated with marked improvement in inattentive and hyperactive-impulsive symptom clusters as assessed by parents and investigators. No statistically significant differences between treatment groups were observed on the primary outcome measure (investigator-rated ADHD-IV Rating Scale total score: atomoxetine baseline: 39.4 [8.5], endpoint: 20.0 [13.9]; methylphenidate baseline: 37.6 [9.7], endpoint: 19.8 (16.6); p = .66). Safety and tolerability were also similar between the 2 drugs. Discontinuations due to adverse events were 10/184 (5.4%) for atomoxetine and 5/44 (11.4%) for methylphenidate; p = .175. CONCLUSION: These data provide preliminary evidence that atomoxetine is associated with therapeutic effects comparable to those of methylphenidate.

AACAP 2002 research forum: placebo and alternatives to placebo in randomized controlled trials in pediatric psychopharmacology.

OBJECTIVE: The use of placebo in the pediatric age group has come under increasing scrutiny. At the 2002 Annual Meeting of the American Academy of Child and Adolescent Psychiatry, the Academy's Workgroup on Research conducted a research forum. The purpose was to identify challenges and their solutions regarding the use of placebo in randomized controlled trials in pediatric psychopharmacology. METHOD: Workgroups focused on problems and solutions in five areas: ethics and human subjects, research design and statistics, partnering with consumers, U.S. Food and Drug Administration and pharmaceutical industry perspectives, and psychosocial treatments. RESULTS: In many but not all circumstances, inclusion of a placebo control is essential to meet the scientific goals of treatment outcome research. Innovative research designs; involvement of consumers in planning and implementing research; flexibility by industry, academia, the National Institutes of Health, and regulatory agencies acting in partnership; and concomitant use of evidence-based psychosocial services can and should assist in making placebo-controlled trials acceptable. CONCLUSIONS: Properly designed placebo-controlled trials remain necessary, ethical, and feasible.

Safety of subchronic treatment with fluoxetine for major depressive disorder in children and adolescents.

OBJECTIVE: The aim of this study was to assess the safety of subchronic fluoxetine treatment for major depressive disorder (MDD) in children and adolescents. METHODS: Patients received up to 19 weeks of treatment with fluoxetine, 10 mg-60 mg daily. Safety was evaluated through the reporting of concomitant medications, vital signs, routine laboratory testing, electrocardiograms (ECGs), and adverse event data. RESULTS: Ninety-six patients, aged 9-17 years, completed 19 weeks of treatment with fluoxetine (n = 49) or placebo (n = 47). There were statistically significant differences between the fluoxetine and placebo groups in mean change from baseline for alkaline phosphatase and total cholesterol levels (p < 0.001, and p < 0.014, respectively), but there were no statistically significant differences between the incidence of abnormal laboratory values for these 2 analytes. Fluoxetine-treated patients gained statistically significantly less height (fluoxetine: 1.0 cm +/- 2.4; placebo: 2.1 cm +/- 2.6; p = 0.004) and weight (fluoxetine: 1.2 kg +/- 2.7; placebo: 2.3 kg +/- 2.6; p = 0.008) than placebo-treated patients during the 19 weeks of treatment. There was no difference in the rate of reported suicide-related events between fluoxetine and placebo. CONCLUSION: Fluoxetine was found to be safe and well tolerated in this study of children and adolescents with MDD. Clarification and determination of the clinical significance of the growth-rate reduction seen during fluoxetine treatment requires further investigation. During treatment with fluoxetine, the growth of child and adolescent patients should be monitored.

Efficacy of atomoxetine versus placebo in school-age girls with attention-deficit/hyperactivity disorder.

OBJECTIVE: The efficacy of atomoxetine was assessed in school-age girls with attention-deficit/hyperactivity disorder (ADHD). Atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters or receptors. METHODS: A total of 291 children who were 7 to 13 years of age and met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for ADHD participated in 1 of 2 combined, double-blind, placebo-controlled, multisite, identical clinical trials. This intent-to-treat subset analysis examined the effects of atomoxetine versus placebo in 51 girls who were randomized to atomoxetine (n = 30) or placebo (n = 21) for 9 weeks. ADHD symptoms were assessed using parent- and investigator-rated scales. RESULTS: Atomoxetine was superior to placebo on the following measures: the Attention-Deficit Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored Total Score; the Inattentive and Hyperactive/Impulsive subscales of the Attention-Deficit Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored Total Score; the ADHD Index subscale of the Conners' Parent Rating Scale-Revised: Short Form; and the Clinical Global Impressions of Severity of ADHD. Statistically significant efficacy was seen 1 week after randomization and remained so for the duration of the study. One patient from each of the atomoxetine and placebo groups discontinued the study as a result of an adverse event. CONCLUSION: Atomoxetine was found to be effective and well tolerated for the treatment of ADHD in school-age girls.

Changes in symptoms and adverse events after discontinuation of atomoxetine in children and adults with attention deficit/hyperactivity disorder: a prospective, placebo-controlled assessment.

Drugs that affect neurotransmitter release can induce changes in neuroregulation during chronic administration. Thus, in addition to recurrence of symptoms of the illness, discontinuation of treatment can be associated with clinical signs and symptoms related to these changes. Atomoxetine, a new drug approved in the United States for treatment of attention deficit/hyperactivity disorder (ADHD), is associated with blockade of the presynaptic norepinephrine transporter. Because treatment of ADHD typically involves chronic treatment, the potential for production of a discontinuation syndrome as well as recurrence of symptoms upon drug discontinuation were assessed as part of the clinical development process. The effects of discontinuation of atomoxetine were assessed in children and adults with ADHD following 9 to 10 weeks of continuous therapy in 4 large studies. Symptoms of ADHD worsened following drug discontinuation but did not return to pretreatment levels. The incidence of discontinuation-emergent adverse events was low and there were no statistically significant differences between the patients abruptly discontinuing from atomoxetine and those continuing on placebo. Discontinuation of atomoxetine did not result in the development of an acute discontinuation syndrome and was well tolerated. It appears that atomoxetine may be discontinued without risk for symptom rebound or discontinuation-emergent adverse effects. Tapering of doses is not necessary when atomoxetine is discontinued.