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Objective: To compare the safety and efficacy of atomoxetine, a selective inhibitor of the norepinephrine transporter, versus placebo in Attention-Deficit/Hyperactivity Disorder (ADHD) patients with comorbid Oppositional Defiant Disorder (ODD). Methods: A subset analysis of 98 children from two identical, multi-site, double-blind, randomized, placebo-controlled trials involving 9 weeks of treatment with atomoxetine or placebo was conducted. Patients met DSM-IV ADHD criteria. ODD was diagnosed with the Diagnostic Interview for Children and Adolescents-IV (DICA-IV; Reich, Welner, & Herjanic, 1997). ADHD severity was assessed with the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHD-RS-IV-Parent:Inv; DuPaul, Power, Anastopoulos, & Reid, 1998); the short version of the Conners’ Parent Rating Scales-Revised (CPRS-R:S; Conners, 2000); and the Clinical Global Impressions of ADHD Severity (CGI-ADHD-S; Guy, 1976). Clinical response was defined as a ≥ 25% reduction in ADHD-RS-IV-Parent:Inv total score. Results: ADHD-RS-IV-Parent:Inv, CGI-ADHD-S, and three CPRS-R:S subscale scores improved markedly with atomoxetine treatment. However, a decrease in the CPRS-R:S Oppositional subscore for atomoxetine-treated patients was not significantly greater than scores for placebo-treated patients. Clinical response rates were 65.4% in the atomoxetine group, and 36.4% in the placebo group ( p = .007). Conclusion: Atomoxetine was effective for the treatment of ADHD in patients with comorbid ODD. It did not significantly reduce the severity of ODD symptoms, and was well tolerated by the patients.

The aim of this study was to assess the safety of subchronic fluoxetine treatment for major depressive disorder (MDD) in children and adolescents.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.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 (p0.001, and p0.014, 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.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.

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.

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

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.

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).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.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 ofor =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).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.

The 1-week single-blind placebo lead-in has long been a standard in double-blind psychopharmacology clinical trials. Although a lead-in period is often necessary (e.g., to receive laboratory results before randomization), some authors have demonstrated that the standard single-blind placebo lead-in's performance was similar to having a lead-in in which placebo was not administered. The single-blind placebo lead-in did not decrease postrandomization placebo response, nor did it increase drug-placebo differences. To eliminate a higher percentage of placebo responders before randomization and to reduce potential biases in baseline ratings, the authors designed and implemented two depression studies with a double-blind variable placebo lead-in period. In these designs, both the patients and personnel at the investigative sites were blinded to the length of the placebo lead-in period and the start of the active treatment period. Approximately 28% of the patients in the double-blind placebo lead-in studies met criteria to be placebo lead-in responders, as compared with fewer than 10% from two single-blind placebo lead-in studies conducted in a similar time frame. Although all patients continued in the study (including placebo lead-in responders), the primary efficacy analysis prospectively excluded double-blind placebo lead-in responders. Analysis of postrandomization changes revealed that double-blind placebo lead-in responders, even when continuing to receive placebo treatment, maintained their response. At the study endpoint, these placebo lead-in responders had significantly lower severity scores than their counterparts who were not lead-in responders. The prospective removal of lead-in responders thus resulted in an increase in mean endpoint placebo group severity scores. This resulted in an increased drug-placebo treatment difference in one of the two studies but had no effect on the treatment difference in the other study.

There are several parent- and teacher-scored rating scales that are validated and available for assessing the severity of ADHD symptoms in pediatric populations. However, we are not aware of any symptom severity rating scales with published validation results when administered and scored by clinicians following a semi-structured interview with the parent or guardian. In a recent clinical trial, in order to have consistency in assessing entry severity criteria and changes in symptom severity over time across patients, we used the ADHD Rating Scale, administered and scored by trained clinicians. Using data from this trial, we assessed the validity and reliability of the ADHD Rating Scale when completed by trained clinicians based on interviews with parents. Results Indicate that this version of the scale has acceptable levels of inter-rater reliability, test-retest reliability, internal consistency, convergent validity, discriminant validity, and responsiveness. The psychometric properties were comparable to other validated scales for assessing ADHD symptom severity. Overall, this study supports the use of the ADHD Rating Scale as a clinician administered and scored tool for assessing the severity of ADHD symptoms in pediatric patients.

Objective This study assesses the efficacy and tolerability of fluoxetine in the acute treatment of child and adolescent obsessive-compulsive disorder (OCD) during a 13-week, double-blind, placebo-controlled study. Method Eligible patients aged 7 to 17 (N = 103) were randomized at a ratio of 2:1 to receive either fluoxetine or placebo. Dosing was initiated at 10 mg daily for 2 weeks, then increased to 20 mg daily. After 4 weeks of treatment, and again after 7 weeks of treatment, nonresponders could have their dosage increased by 20 mg daily, for a maximum possible dosage of 60 mg daily. Primary measure of efficacy was improvement in OCD symptoms as measured by the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). All analyses were intent-to-treat. Results Fluoxetine was associated with significantly greater improvement in OCD as assessed by the CY-BOCS (p = .026) and other measures than was placebo. Fluoxetine was well tolerated and had a rate of discontinuation for adverse events similar to that of placebo (p = 1.00). Conclusions Fluoxetine 20 to 60 mg daily was effective and well tolerated for treatment of OCD in this pediatric population.

Background. This study was conducted to determine the efficacy and tolerability of fluoxetine and desipramine in treating depressive symptoms in women with cancer. Method. In this prospective, 6-week, double-blind, placebo-controlled trial, we compared fluoxetine with desipramine in treating depressive symptoms in 40 women diagnosed with cancer. Scales used to measure efficacy and tolerability were the Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale (HAM-A), the Clinical and Patient's Global Impression (CGI and PGI) scales, the Functional Living Index for Cancer (FLIC), the Memorial Pain Assessment Card (MPAC), and the SF-36 Health Survey. Results. Fluoxetine and desipramine treatments improved depression and anxiety symptoms. There was a trend towards significance in improvement of FLIC scores (as evidenced by greater numerical improvements with fluoxetine treatment). Fluoxetine treatment alone was associated with statistically significant improvements in MPAC Mood scale scores. Both treatments showed statistically significant improvements in the quality of life SF-36 scores in Role Emotional, Social Functioning, Mental Health, and Vitality. Conclusions. Both fluoxetine and desipramine were effective and well-tolerated in improving depressive symptoms and quality of life in women with advanced cancer. Fluoxetine may offer greater benefit to these patients, as evidenced by greater improvements in fluoxetine-treated patients on several quality of life measures. Our results, while meaningful, should be confirmed in a larger patient sample. However, experience from studies of antidepressant use in patients with advanced cancer has shown that intercurrent disease and treatment variables make it difficult to conduct large studies. © 1998 John Wiley & Sons, Ltd.

A peripheral model for the central 5-HT neuron is the characterization of platelet imipramine binding. We studied an outpatient major depressive cohort who fulfilled Research Diagnostic Criteria for agitation. After a 1-week placebo lead-in, subjects were blindly randomized to either imipramine (IMI) of fluoxetine (FLU) during an 8-week, double-blind study period. Thirty-three subjects (15 IMI, 18 FLU) provided both baseline and endpoint samples for the platelet [3H]-IMI assay. Depression efficacy was comparable across the two treatments, whereas FLU was significantly more effective in reducing secondary anxiolysis (p = .023). Discontinuations due to an adverse event were significantly more frequent with IMI than FLU (p < .01). Baseline affinity (KD) was mildly predictive of change in the HAMD (r = -.22; p = .07). Whereas baseline to endpoint density (Bmax) changes (Δ) were similar for IMI (183 ± 329 fmol/mg) and FLU (196 ± 402 fmol/mg), a statistically significant treatment difference in ΔKD emerged (IMI -0.005 ± 0.010 pmol/ml versus FLU 0.08 ± 0.013 at p = .004). Moreover, the changes in KD and HAMD17 trended to a positive correlation among only the FLU-treated subjects (4 = 0.406, p = .095). The Clinical effects of 5-HT-based selective antidepressant may be reflected by dynamic changes in the platelet 5-HT uptake apparatus. These data suggest that the baseline confirmational status of the [3H]-IMI:5-HT transporter may reflect a "capacity" for a treatment response.

In a randomized 6-week trial comparing fluoxetine with placebo, the Medical Outcomes Study 36-Item Short-Form Health Status Survey (SF-36) scales were used to measure the effects of treatment on functional health and well-being among elderly (age ≥ 60 years) outpatients with major depression. In the fluoxetine and placebo groups, 261 and 271 patients, respectively, completed the SF-36 before treatment and at Weeks 3 and 6. Compared with national norms for individuals over age 60, study patients before treatment exhibited baseline decrements on the following SF-36 scales: mental health, role limitations due to emotional problems, social functioning, vitality, role limitations due to physical problems, and bodily pain. Analyses of SF-36 changed scores from baseline to Week 6 revealed that the fluoxetine group improved more than the placebo group across all scales. Differences in changes of scores between groups were significant (p < .05), favoring the fluoxetine group for the scales of mental health, role limitations due to emotional problems, physical functioning, and bodily pain. Improvements observed in the fluoxetine group were both clinically and socially significant.

Depression in the geriatric population is a frequents, serious, and potentially reversible disorder, yet relatively few blinded, controlled, antidepressant trial have been reported. A number of age-related issues complicate safe and effective pharmacotherapy. In a 6-week, double-blind trial in moderately to severely depressed (nonpsychotic) outpatients over age 60, fluoxetine (N = 335) was statistically significantly more efficacious than placebo (N = 336) in overall response (43.9% vs. 31.6%, p = .002) and remission (31.6% vs. 18.6%, p < .001) rates. Analyses of early discontinuations because of an adverse drug event revealed no statistically significantly greater rate with fluoxetine (n = 39; 11.6%) than was seen with placebo (n = 29; 8.6%). These results corroborate that major depression in an older population is responsive to antidepressant pharmacotherapy. Specifically, fluoxetine, at a conventional 20-mg dose, was both safe and effective relative to placebo in this special population.

Adaptive clinical trials have attracted the attention of statisticians because they allow for information accrued early in the trial to influence the allocation of treatment of later enrolled patients, thus allowing those patients an increased likelihood of receiving the better treatment. Few adaptive clinical trials have been reported in the literature; the purpose of this article is to describe the rationale, design, and analysis of a recently completed adaptive trial. Simulations to address sample size issues are presented. A Bayesian and a frequentist randomization analysis are discussed. The randomization analysis addresses the use of an adaptive allocation scheme, a delayed response, and a surrogate response. In this trial, the differences between the Bayesian and randomization inference were small. Some suggestions for future implementation of adaptive clinical trials and future research areas are provided.

Fluoxetine (20 mg/day) and placebo were compared in 89 outpatient men and women with major depression with ( n = 52) or without ( n = 37) DSM-III-R melancholia in an 8-week double-blind study to determine predictors of treatment response. Fluoxetine was statistically superior to placebo both within the melancholic subtype and in the total patient group (all measures). Response rate and mean decrease in 17-item Hamilton Depression Rating Scale total score approached statistical significance in favor of fluoxetine-treated melancholic patients compared with fluoxetine-treated non-melancholic patients. There were no statistically significant differences between fluoxetine- treated and placebo-treated non-melancholic patients. Results support DSM-III-R melancholia as a predictor of antidepressant response.

A comprehensive meta-analysis was performed to address the possible association of fluoxetine with violence or aggression. Data from the United States Investigational New Drug Clinical Trial Databases for approved and potential indications (depression, obesity, bulimia nervosa, obsessive-compulsive disorder, smoking cessation, alcoholism; n = 3992) were evaluated. Statistically significantly fewer fluoxetine-treated patients (0.15%) than placebo-treated patients (0.65%) experienced events suggestive of aggression (hostility, personality disorder, antisocial reaction). A relative risk analysis indicated that aggression events were four times more likely to occur in placebo-treated patients than in fluoxetine-treated patients. Although the possibility that some rare phenomenon was not detected cannot be excluded, this meta-analysis did not show fluoxetine to be associated with an increased risk of emergence of violent or aggressive behaviour.

Because of interest in the possible occurrence of violent 01 aggressive behavior with serotonin-enhancing drugs, three subpools of controlled clinical trial data were evaluated: fluoxetine (n = 2615) versus placebo (n = 1377) (18 trials; depression, bulimia nervosa, obesity, alcoholism, smoking cessation); fluoxetine (n = 441) versus tricyclic antidepressants (n = 445) (ten trials; depression); and fluoxetine (n = 309) versus tricyclic antidepressants (n = 308) versus placebo (n = 297) (three trials; depression, including adjustment disorder). Adverse event terms possibly involving physically assaultive acts toward another (antisocial reaction, hostility, and personality disorder, together termed the “aggression cluster”) were reviewed. Across all indications, a statistically significantly smaller proportion of fluoxetine-treated patients than placebo-treated patients experienced one or more of the events (0.15% versus 0.65%, respectively). Placebo-treated patients were four times more likely to e...

OBJECTIVE--A comprehensive meta-analysis of clinical trial data was performed to assess the possible association of fluoxetine and suicidality (suicidal acts and ideation). DESIGN--Retrospective analysis of pooled data from 17 double blind clinical trials in patients with major depressive disorder comparing fluoxetine (n = 1765) with a tricyclic antidepressant (n = 731) or placebo (n = 569), or both. MAIN OUTCOME MEASURES--Multiple data sources were searched to identify patients with suicidal acts. Suicidal ideation was assessed with item 3 of the Hamilton depression rating scale, which systematically rates suicidality. Emergence of substantial suicidal ideation was defined as a change in the rating of this item from 0 or 1 at baseline to 3 or 4 during double blind treatment; worsening was defined as any increase from baseline; improvement was defined as a decrease from baseline at the last visit during the treatment. RESULTS--Suicidal acts did not differ significantly in comparisons of fluoxetine with placebo (0.2% v 0.2%, p = 0.494, Mantel-Haenszel adjusted incidence difference) and with tricyclic antidepressants (0.7% v 0.4%, p = 0.419). The pooled incidence of suicidal acts was 0.3% for fluoxetine, 0.2% for placebo, and 0.4% for tricyclic antidepressants, and fluoxetine did not differ significantly from either placebo (p = 0.533, Pearson's chi 2) or tricyclic antidepressants (p = 0.789). Suicidal ideation emerged marginally significantly less often with fluoxetine than with placebo (0.9% v 2.6%, p = 0.094) and numerically less often than with tricyclic antidepressants (1.7% v 3.6%, p = 0.102). The pooled incidence of emergence of substantial suicidal ideation was 1.2% for fluoxetine, 2.6% for placebo, and 3.6% for tricyclic antidepressants. The incidence was significantly lower with fluoxetine than with placebo (p = 0.042) and tricyclic antidepressants (p = 0.001). Any degree of worsening of suicidal ideation was similar with fluoxetine and placebo (15.4% v 17.9%, p = 0.196) and with fluoxetine and tricyclic antidepressants (15.6% v 16.3%, p = 0.793). The pooled incidence of worsening of suicidal ideation was 15.3% for fluoxetine, 17.9% for placebo, and 16.3% for tricyclic antidepressants. The incidence did not differ significantly with fluoxetine and placebo (p = 0.141) or tricyclic antidepressants (p = 0.542). Suicidal ideation improved significantly more with fluoxetine than with placebo (72.0% v 54.8%, p less than 0.001) and was similar to the improvement with tricyclic antidepressants (72.5% v 69.8%, p = 0.294). The pooled incidence of improvement of suicidal ideation was 72.2% for fluoxetine, 54.8% for placebo, and 69.8% for tricyclic antidepressants. The incidence with fluoxetine was significantly greater than with placebo (p less than 0.001) and did not differ from that with tricyclic antidepressants (p = 0.296). CONCLUSIONS--Data from these trials do not show that fluoxetine is associated with an increased risk of suicidal acts or emergence of substantial suicidal thoughts among depressed patients.

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.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.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.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.

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 ≤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.

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.

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.

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.

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.

We describe a secondary analysis of data from a randomized trial conducted at seven primary care clinics of a Seattle area HMO. Adults with major depression (n=290) beginning antidepressant treatment completed structured interviews at baseline, 1, 3, 6, 9, 12, 18, and 24 months. Interviews examined clinical outcomes (Hamilton Depression Rating Scale and depression module of the Structured Clinical Interview for DSM-IIIR), employment status, and work days missed due to illness. Medical comorbidity was assessed using computerized pharmacy data, and medical costs were assessed using the HMO's computerized accounting data. Using data from the 12-month assessment, patients were classified as remitted (41%), improved but not remitted (47%), and persistently depressed (12%). After adjustment for depression severity and medical comorbidity at baseline, patients with greater clinical improvement were more likely to maintain paid employment (P=.007) and reported fewer days missed from work due to illness (P

BACKGROUND: The study of the duration and pattern of antidepressant use in actual clinical practice can provide important insights into how antidepressant prescribing patterns compare with recommended depression treatment guidelines. OBJECTIVE: The purpose of this study, using data available from depressed outpatients in the United States, is to assess the effects of initial SSRI antidepressant selection on the subsequent pattern and duration of antidepressant use. RESEARCH DESIGN: Multiple logistic regression analysis of data from a large prescription and medical claims database (MarketScan) for the years 1993 and 1994 were used to estimate the determinants of antidepressant drug use patterns for 1,034 patients with a "new" episode of antidepressant therapy who were prescribed one of three most often prescribed selective serotonin reuptake inhibitors (SSRIs), paroxetine, sertraline, or fluoxetine. RESULTS: Patients initiating therapy on sertraline or paroxetine were less likely than patients initiating therapy on fluoxetine to have four or more prescriptions of their initial antidepressant within the first 6 months. CONCLUSIONS: The findings suggest that antidepressant selection is an important determinant of the initial duration and pattern of antidepressant use which is consistent with current recommended depression treatment guidelines.

Background The more sedating antidepressants are often recommended for patients presenting with anxiety or insomnia. We examine whether baseline anxiety or insomnia symptoms (1) show differential response to fluoxetine or imipramine or (2) predict differences between drugs in overall clinical response or likelihood of medication discontinuation. Method 336 health maintenance organization primary care patients beginning antidepressant treatment for depression were randomly assigned to an initial prescription for fluoxetine or imipramine. All subsequent care (medication dosage, change, or discontinuation) was managed as usual by the primary care physician. The 17-item Hamilton Rating Scale for Depression (HAM-D) and the Hopkins Symptom Checklist (SCL) anxiety and depression subscales were administered prior to randomization and 1 month later. Results Rates of improvement in insomnia (HAM-D insomnia items), agitation (HAM-D agitation item), and anxiety (SCL anxiety subscale) were essentially identical in the two treatment groups. Baseline level of insomnia did not predict significant differences between randomization groups in improvement in overall HAM-D score (p = .44) or SCL depression subscale (p = .44). Similarly, baseline level of anxiety did not predict significant differences in improvement in HAM-D (p = .19) or SCL depression subscale (p = .31). Patients assigned to fluoxetine were significantly less likely to change or discontinue antidepressant medication during the first month, but this difference did not vary according to baseline level of insomnia (p = .68) or anxiety (p = .25). Conclusion Among patients with moderate depression, baseline levels of insomnia or anxiety should not influence the choice of fluoxetine or imipramine as an initial antidepressant.

Background: Providers and payers have an interest in the total health care costs following the initiation of antidepressant treatment in the real world of clinical practice. Analyses of these costs can help evaluate the economic consequences of patient management decisions associated with initial antidepressant selection. Objective: The purpose of this study was to assess the 1-year total direct health care costs for patients initiating therapy with one of the available tricyclic antidepressants (TCAs) or one of the three most often prescribed selective serotonin reuptake inhibitors (SSRIs) — paroxetine, sertraline, or fluoxetine. Method: A two-stage multivariate econometric model and data from fee-for-service private insurance claims between 1990 and 1994 were used to estimate the total direct health care costs following initial antidepressant drug selection for 2693 patients with a `new' episode of antidepressant treatment. Results: After controlling for both observed and unobserved characteristics, the 1-year total direct health care costs were found to be (1) statistically significantly lower for patients initiating therapy on fluoxetine than for patients initiating therapy on a TCA; (2) statistically significantly lower for patients who initiated therapy on fluoxetine than for patients initiating therapy on sertraline. Conclusions: Broadly considered, the findings in this study suggest that total direct health care costs differ across initial antidepressant selection after controlling for both observed and unobserved characteristics.

Fluoxetine and placebo were compared in 89 outpatients with major depression with (n = 45) or without (n = 44) a reduced or shortened rapid eye movement latency (SREML) (< or = 65 minutes) to determine whether rapid eye movement latency (REML) predicted placebo and/or antidepressant response. Men and women were stratified based on polysomnographic recordings and then randomly assigned to receive double-blind fluoxetine (20 mg/day) or placebo for 8 weeks after a 2-week, single-blind, placebo lead-in period. Fluoxetine-treated patients demonstrated a significantly greater reduction in the Hamilton Rating Scale for Depression total score and a significantly greater response rate than placebo-treated patients in both the SREML and the combined strata. Treatment differences in the non-SREML stratum were not statistically significant. Results supported REML as a predictor of placebo nonresponse but did not predict a differential fluoxetine response in patients with SREML compared with patients without SREML.

As part of a study in which reduced rapid eye movement latency was used to predict treatment response, fluoxetine and placebo were compared in 89 outpatients with major depression with (n = 52) and without (n = 37) DSM-III-R melancholia, to determine whether the presence or absence of melancholia predicted antidepressant and/or placebo response. Following a 2-week, single-blind placebo lead-in, men and women were assigned by random allocation to double-blind fluoxetine, 20 mg/day, or placebo for 8 weeks. Fluoxetine was statistically significantly superior to placebo in patients with melancholia (endpoint change in the Montgomery-Asberg Depression Rating Scale [MADRS] score, response rates and remission rates). A weekly analysis demonstrated statistical superiority of fluoxetine compared with placebo at week 3 and continuing for the remainder of the study. Fluoxetine was statistically significantly more likely to reduce suicidal ideation compared with placebo, using the MADRS item 10 (suicidal ideation question).

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.

Tomoxetine, a norepinephrine uptake inhibitor, is used to treat attention-deficit/hyperactivity disorder.

Objective. —To compare the clinical, functional, and economic outcomes of initially prescribing fluoxetine with outcomes of initially selecting imipramine or desipramine. Design. —Randomized controlled trial. Setting. —Primary care clinics of a Seattle, Wash, area staff-model health maintenance organization from 1992 through 1994. Patients. —A total of 536 adults beginning antidepressant treatment for depression. Intervention. —Random assignment of initial antidepressant prescription (desipramine, fluoxetine, or imipramine). Subsequent antidepressant treatment (doses, medication changes or discontinuation, specialty referral) was managed by the primary care physician. Main Outcome Measures. —Assessments after 1, 3, and 6 months examined clinical outcomes (Hamilton Depression Rating Scale and the depression subscale of the Hopkins Symptom Checklist) and quality-of-life outcomes (Medical Outcomes Study SF-36). Medication use and health care costs were assessed using the health maintenance organization's computerized data. Results. —Patients assigned to receive fluoxetine reported fewer adverse effects, were more likely to continue the original medication, and were more likely to reach adequate doses than patients beginning treatment with either tricyclic drug. The fluoxetine group reported marginally better clinical outcomes after 1 month, but these differences were not statistically significant and disappeared by the 3-month assessment. Quality-of-life outcomes in the 3 groups did not differ. Total health care costs over 6 months were approximately equal for the 3 groups, with higher antidepressant costs in the fluoxetine group balanced by lower outpatient visit and inpatient costs. Conclusions. —Clinical outcomes, quality-of-life outcomes, and overall treatment costs provide no clear guidance on initial selection of fluoxetine or tricyclic drugs. Thus, patients' and physicians' preferences are an appropriate basis for treatment selection. (JAMA. 1996;275:1897-1902)

A common presentation for major depression includes psychomotor agitation. However, this subtype has been the infrequent subject of controlled investigation during depression trials. Yet, the subcategorization of agitated depression has historically been associated with the belief that older, sedating compounds have a superior risk:benefit profile. In the 8-week, double-blind, randomized, parallel trial, 124 subjects with Research Diagnostic Criteria-compatible agitated depression were randomized to either imipramine (IMI) or fluoxetine (FLU). Both compounds proved to be similarly effective as measured by change in HAM-D17, HAM-D17 response, and HAM-D17 remission rates. Similar comparability was seen in secondary measures of agitation, anxiety, suicidality, and global impressions. However, of note, a statistically significant difference in early discontinuations because of intolerable adverse events emerged. Whereas 43.5% of IMI subjects discontinued early, only 9.7% of FLU subjects (p < 0.001) did. Significantly more central nervous system events characterized the IMI than the FLU subgroup (IMI, 24.2%, vs. FLU, 6.5%; p = 0.006). In conclusion, among subjects with major depression, subtype agitated, the risk:benefit profile favored FLU over IMI. This was driven by the superior tolerance of FLU. No evidence emerged in support of the clinical hypothesis that a "sedating" agent is the treatment of choice for this group. The results are important when striving to maximize compliance with pharmacotherapy in order to minimize recidivism and associated psychological and economic morbidity.

The primary objective of this article is to review information pertinent to and emphasize the seriousness of a potential adverse monoamine oxidase inhibitor (MAOI)-serotonin uptake inhibitor interaction by considering, within the context of preclinical data, clinical cases in which an MAOI and fluoxetine hydrochloride, a specific serotonin uptake inhibitor, were administered in close temporal proximity. Clinical cases were identified by a review of spontaneous adverse event reports submitted voluntarily to Eli Lilly and Company through its drug surveillance program and by a review of reports of MAOI interactions published in the scientific literature. A discussion of eight selected clinical cases of acute adverse reactions (seven with fatal outcomes; one with a favorable response after cyproheptadine therapy) reported to Eli Lilly and Company in which an MAOI was initiated concurrently or shortly after the discontinuation of fluoxetine and a review of preclinical data suggest a possible role of serotonin and/or serotonin-dopamine interactions in the hypermetabolic state that may occur when a serotonin uptake inhibitor and an MAOI are coadministered, although alternative etiologic processes are possible as well. Data reviewed reinforce the idea that the administration of an MAOI in close temporal proximity to fluoxetine is contraindicated.

The goal of this study was to evaluate the tolerability and effectiveness of the experimental, noradrenergic specific reuptake inhibitor atomoxetine in the treatment of children with attention deficit hyperactivity disorder (ADHD).This was an open, prospective, dose-ranging study of atomoxetine monotherapy in the treatment of 30 children with ADHD between the ages of 7 and 14 years. Atomoxetine was started at 10-20 mg/day and titrated weekly up to 90 mg over 11 weeks, depending on response and adverse effects. Twenty-two children completed the full 11 weeks. We assessed efficacy with weekly clinician and parent ratings of ADHD and oppositional symptoms and monitored adverse effects, laboratory findings, and cardiovascular parameters.Treatment with atomoxetine (mean final, total daily dose of 1.9 mg/kg/day) was very well tolerated without meaningful adverse effects. Atomoxetine significantly reduced core symptoms of ADHD (ADHD-Rating Scale-IV; 38.6% decrease vs. baseline, p0.001) with significant improvement (p0.05) in all but 1 of the 18 individual items in the ADHD-Rating Scale-IV. More than 75% of subjects who completed 10 weeks of treatment showed25% decrease in ADHD symptoms.These findings extend to children the positive results previously reported in adults diagnosed with ADHD who were treated with atomoxetine. These results support additional controlled trials of atomoxetine in cases of pediatric ADHD.