Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression.

BACKGROUND: After unsuccessful treatment for depression with a selective serotonin-reuptake inhibitor (SSRI), it is not known whether switching to one antidepressant is more effective than switching to another. METHODS: We randomly assigned 727 adult outpatients with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram to receive one of the following drugs for up to 14 weeks: sustained-release bupropion (239 patients) at a maximal daily dose of 400 mg, sertraline (238 patients) at a maximal daily dose of 200 mg, or extended-release venlafaxine (250 patients) at a maximal daily dose of 375 mg. The study was conducted in 18 primary and 23 psychiatric care settings. The primary outcome was symptom remission, defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of the study. Scores on the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR-16), obtained at treatment visits, determined secondary outcomes, including remission (a score of 5 or less at exit) and response (a reduction of 50 percent or more on baseline scores). RESULTS: Remission rates as assessed by the HRSD-17 and the QIDS-SR-16, respectively, were 21.3 percent and 25.5 percent for sustained-release bupropion, 17.6 percent and 26.6 percent for sertraline, and 24.8 percent and 25.0 percent for extended-release venlafaxine. QIDS-SR-16 response rates were 26.1 percent for sustained-release bupropion, 26.7 percent for sertraline, and 28.2 percent for extended-release venlafaxine. These treatments did not differ significantly with respect to outcomes, tolerability, or adverse events. CONCLUSIONS: After unsuccessful treatment with an SSRI, approximately one in four patients had a remission of symptoms after switching to another antidepressant. Any one of the medications in the study provided a reasonable second-step choice for patients with depression. (ClinicalTrials.gov number, NCT00021528.).

Medication augmentation after the failure of SSRIs for depression.

BACKGROUND: Although clinicians frequently add a second medication to an initial, ineffective antidepressant drug, no randomized controlled trial has compared the efficacy of this approach. METHODS: We randomly assigned 565 adult outpatients who had nonpsychotic major depressive disorder without remission despite a mean of 11.9 weeks of citalopram therapy (mean final dose, 55 mg per day) to receive sustained-release bupropion (at a dose of up to 400 mg per day) as augmentation and 286 to receive buspirone (at a dose of up to 60 mg per day) as augmentation. The primary outcome of remission of symptoms was defined as a score of 7 or less on the 17-item Hamilton Rating Scale for Depression (HRSD-17) at the end of this study; scores were obtained over the telephone by raters blinded to treatment assignment. The 16-item Quick Inventory of Depressive Symptomatology--Self-Report (QIDS-SR-16) was used to determine the secondary outcomes of remission (defined as a score of less than 6 at the end of this study) and response (a reduction in baseline scores of 50 percent or more). RESULTS: The sustained-release bupropion group and the buspirone group had similar rates of HRSD-17 remission (29.7 percent and 30.1 percent, respectively), QIDS-SR-16 remission (39.0 percent and 32.9 percent), and QIDS-SR-16 response (31.8 percent and 26.9 percent). Sustained-release bupropion, however, was associated with a greater reduction (from baseline to the end of this study) in QIDS-SR-16 scores than was buspirone (25.3 percent vs. 17.1 percent, P<0.04), a lower QIDS-SR-16 score at the end of this study (8.0 vs. 9.1, P<0.02), and a lower dropout rate due to intolerance (12.5 percent vs. 20.6 percent, P<0.009). CONCLUSIONS: Augmentation of citalopram with either sustained-release bupropion or buspirone appears to be useful in actual clinical settings. Augmentation with sustained-release bupropion does have certain advantages, including a greater reduction in the number and severity of symptoms and fewer side effects and adverse events. (ClinicalTrials.gov number, NCT00021528.).

Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial.

CONTEXT: Only about 60% of adolescents with depression will show an adequate clinical response to an initial treatment trial with a selective serotonin reuptake inhibitor (SSRI). There are no data to guide clinicians on subsequent treatment strategy. OBJECTIVE: To evaluate the relative efficacy of 4 treatment strategies in adolescents who continued to have depression despite adequate initial treatment with an SSRI. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of a clinical sample of 334 patients aged 12 to 18 years with a primary diagnosis of major depressive disorder that had not responded to a 2-month initial treatment with an SSRI, conducted at 6 US academic and community clinics from 2000-2006. INTERVENTIONS: Twelve weeks of: (1) switch to a second, different SSRI (paroxetine, citalopram, or fluoxetine, 20-40 mg); (2) switch to a different SSRI plus cognitive behavioral therapy; (3) switch to venlafaxine (150-225 mg); or (4) switch to venlafaxine plus cognitive behavioral therapy. MAIN OUTCOME MEASURES: Clinical Global Impressions-Improvement score of 2 or less (much or very much improved) and a decrease of at least 50% in the Children's Depression Rating Scale-Revised (CDRS-R); and change in CDRS-R over time. RESULTS: Cognitive behavioral therapy plus a switch to either medication regimen showed a higher response rate (54.8%; 95% confidence interval [CI], 47%-62%) than a medication switch alone (40.5%; 95% CI, 33%-48%; P = .009), but there was no difference in response rate between venlafaxine and a second SSRI (48.2%; 95% CI, 41%-56% vs 47.0%; 95% CI, 40%-55%; P = .83). There were no differential treatment effects on change in the CDRS-R, self-rated depressive symptoms, suicidal ideation, or on the rate of harm-related or any other adverse events. There was a greater increase in diastolic blood pressure and pulse and more frequent occurrence of skin problems during venlafaxine than SSRI treatment. CONCLUSIONS: For adolescents with depression not responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch to another antidepressant resulted in a higher rate of clinical response than did a medication switch alone. However, a switch to another SSRI was just as efficacious as a switch to venlafaxine and resulted in fewer adverse effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00018902.

Risperidone in children with autism and serious behavioral problems.

BACKGROUND: Atypical antipsychotic agents, which block postsynaptic dopamine and serotonin receptors, have advantages over traditional antipsychotic medications in the treatment of adults with schizophrenia and may be beneficial in children with autistic disorder who have serious behavioral disturbances. However, data on the safety and efficacy of atypical antipsychotic agents in children are limited. METHODS: We conducted a multisite, randomized, double-blind trial of risperidone as compared with placebo for the treatment of autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior in children 5 to 17 years old. The primary outcome measures were the score on the Irritability subscale of the Aberrant Behavior Checklist and the rating on the Clinical Global Impressions - Improvement (CGI-I) scale at eight weeks. RESULTS: A total of 101 children (82 boys and 19 girls; mean [+/-SD] age, 8.8+/-2.7 years) were randomly assigned to receive risperidone (49 children) or placebo (52). Treatment with risperidone for eight weeks (dose range, 0.5 to 3.5 mg per day) resulted in a 56.9 percent reduction in the Irritability score, as compared with a 14.1 percent decrease in the placebo group (P<0.001). The rate of a positive response, defined as at least a 25 percent decrease in the Irritability score and a rating of much improved or very much improved on the CGI-I scale, was 69 percent in the risperidone group (34 of 49 children had a positive response) and 12 percent in the placebo group (6 of 52, P<0.001). Risperidone therapy was associated with an average weight gain of 2.7+/-2.9 kg, as compared with 0.8+/-2.2 kg with placebo (P<0.001). Increased appetite, fatigue, drowsiness, dizziness, and drooling were more common in the risperidone group than in the placebo group (P<0.05 for each comparison). In two thirds of the children with a positive response to risperidone at eight weeks (23 of 34), the benefit was maintained at six months. CONCLUSIONS: Risperidone was effective and well tolerated for the treatment of tantrums, aggression, or self-injurious behavior in children with autistic disorder. The short period of this trial limits inferences about adverse effects such as tardive dyskinesia.

Maximizing the adequacy of medication treatment in controlled trials and clinical practice: STAR(*)D measurement-based care.

The success of well-developed protocols has been limited in real-world practice, where even effective strategies have not been sufficient to meet patient needs in routine clinical care owing to Axis I and III comorbidities. The Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) trial required that antidepressant medication treatment be optimal regarding dose and duration, yet accommodate flexibility to ensure safety given the wide range of comorbid general medical and psychiatric disorders allowed in the trial. The objective of this study was to develop a measurement-based care (MBC) approach and an automated feedback system to ensure adequate and safe antidepressant treatment delivery suitable for both clinical research and routine practice. Ratings of depressive symptom severity and side-effect frequency, intensity, and burden were obtained at each treatment visit using the MBC system that (1) guided medication dose adjustments and treatment duration, (2) documented clinician adherence to treatment recommendations, and (3) provided prompt feedback to clinicians to enhance appropriate treatment decisions. Physician adherence to protocol-specific treatment was monitored based on measured symptoms and side-effect burden, and dose and duration of antidepressant at each critical decision point during the acute phase treatment of major depression. Feedback was provided at the point of care by the clinical coordinators, assisted by Web-based reports following each treatment visit. On the basis of the first treatment step with citalopram, over 85% of treatment encounters had appropriate fidelity to recommendations. Most deviations from treatment recommendations occurred late in treatment and were often justifiable. MBC proved to be feasible and effective in busy primary and psychiatric settings. This approach signals a paradigm shift toward the use of measurement-based clinical decisions, both at the point of care and following each visit, to deliver optimal pharmacotherapy for depression.

Electronic source materials in clinical research: acceptability and validity of symptom self-rating in major depressive disorder.

OBJECTIVES: Clinical research projects gather large amounts of data. Typically, information is captured on paper source documents for later transcription to an electronic format, where responses can be checked, and errors, omissions, and inconsistencies can be resolved. These steps contribute delays, cost, and complexity to clinical research, particularly in large-scale multi-site investigations. To address these issues, we used a mobile computing device with a touch-screen display ("tablet PC") to capture clinical data from depressed patients directly into electronic format. We then examined ease of use, the equivalence of responses between paper and electronic methods, and the acceptability of the tablet PC for this clinical population. SETTINGS: Outpatient clinics at four medical centers. METHODS: 80 adults with major depressive disorder (MDD) completed the 16-item Quick Inventory of Depressive Symptomatology--Self-Rated (QIDS-SR(16)), using both traditional paper forms and an electronic representation of the same questions; participants also completed a survey to evaluate their experience. RESULTS: QIDS-SR(16) responses from paper and electronic versions were highly correlated (mean total: 15.3 (SD=5.2) electronic vs. 15.1 (SD=5.2) paper format), and showed high inter-rating reliability for overall score (intra-class correlation 0.987 (with a 95%CI [0.979,0.992])) and high degree of association for individual symptom items. Participants found both methods acceptable and overall found the electronic implementation easier to use. CONCLUSIONS: QIDS-SR(16) values collected electronically from research participants were equivalent to those collected using traditional paper self-assessment forms. Participants with MDD found the tablet PC version to be acceptable and easier to use than the paper forms.

Treatment of early-onset schizophrenia spectrum disorders (TEOSS): rationale, design, and methods.

OBJECTIVE: The Treatment of Early Onset Schizophrenia Spectrum Disorders Study is a publicly funded clinical trial designed to compare the therapeutic benefits, safety, and tolerability of risperidone, olanzapine, and molindone in youths with early-onset schizophrenia spectrum disorders. The rationale, design, and methods of the Treatment of Early Onset Schizophrenia Spectrum Disorders Study are described. METHOD: Using a randomized, double-blind, parallel-group design at four sites, youths with EOSS (ages 8-19 years) were assigned to an 8-week acute trial of risperidone (0.5-6.0 mg/day), olanzapine (2.5-20 mg/day), or molindone (10-140 mg/day). Responders continued double-blind treatment for 44 weeks. The primary outcome measure was responder status at 8 weeks, defined by a 20% reduction in baseline Positive and Negative Symptom Scale scores plus ratings of significant improvement on the Clinical Global Impressions. Secondary outcome measures included assessments of psychopathology, functional impairment, quality of life, and medication safety. An intent-to-treat analytic plan was used. RESULTS: From February 2002 to May 2006, 476 youths were screened, 173 were further evaluated, and 119 were randomized. Several significant study modifications were required to address safety, the use of adjunctive medications, and the termination of the olanzapine treatment arm due to weight gain. CONCLUSIONS: The Treatment of Early Onset Schizophrenia Spectrum Disorders Study will inform clinical practice regarding the use of antipsychotic medications for youths with early-onset schizophrenia spectrum disorders. Important safety concerns emerged during the study, including higher than anticipated rates of suicidality and problems tapering thymoleptic agents before randomization.

Treatment of early-onset schizophrenia spectrum disorders (TEOSS): demographic and clinical characteristics.

OBJECTIVE: We examined baseline demographic and clinical profiles of youths enrolled from 2001 to 2006 in the publicly funded multicenter, randomized controlled trial Treatment of Early-Onset Schizophrenia Spectrum Disorders. METHOD: Youths (8-19 years) with schizophrenia (SZ) and schizoaffective disorder were recruited at four academic sites. Diagnosis was made via structured and clinical interviews. Assessments of psychiatric symptoms and social and global functioning were included. RESULTS: A total of 119 youths were enrolled. The mean age at illness onset was 11.1 +/- 3.5 years. Patients with SZ and schizoaffective disorder had similar ratings on the Positive and Negative Symptom Scale, Brief Psychiatric Rating Scale for Children, and Clinical Global Impression-Severity Scale. The overall level of functioning was similar in the two groups. A comparison to published reports of adults with SZ indicates that these youths may have more severe symptoms based on results of the Positive and Negative Symptom Scale. CONCLUSIONS: This is one of the largest samples of youths with SZ spectrum disorders studied to date and the largest assessment of youths with schizoaffective disorder. High rates of symptoms and general psychopathology were noted. There was a substantial degree of social and functional impairment. The symptom profiles are consistent with, but more severe than, those reported in the adult literature.

Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice.

OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression, but the rates, timing, and baseline predictors of remission in "real world" patients are not established. The authors' primary objectives in this study were to evaluate the effectiveness of citalopram, an SSRI, using measurement-based care in actual practice, and to identify predictors of symptom remission in outpatients with major depressive disorder. METHOD: This clinical study included outpatients with major depressive disorder who were treated in 23 psychiatric and 18 primary care "real world" settings. The patients received flexible doses of citalopram prescribed by clinicians for up to 14 weeks. The clinicians were assisted by a clinical research coordinator in the application of measurement-based care, which included the routine measurement of symptoms and side effects at each treatment visit and the use of a treatment manual that described when and how to modify medication doses based on these measures. Remission was defined as an exit score of or=50% in baseline QIDS-SR score. RESULTS: Nearly 80% of the 2,876 outpatients in the analyzed sample had chronic or recurrent major depression; most also had a number of comorbid general medical and psychiatric conditions. The mean exit citalopram dose was 41.8 mg/day. Remission rates were 28% (HAM-D) and 33% (QIDS-SR). The response rate was 47% (QIDS-SR). Patients in primary and psychiatric care settings did not differ in remission or response rates. A substantial portion of participants who achieved either response or remission at study exit did so at or after 8 weeks of treatment. Participants who were Caucasian, female, employed, or had higher levels of education or income had higher HAM-D remission rates; longer index episodes, more concurrent psychiatric disorders (especially anxiety disorders or drug abuse), more general medical disorders, and lower baseline function and quality of life were associated with lower HAM-D remission rates. CONCLUSIONS: The response and remission rates in this highly generalizable sample with substantial axis I and axis III comorbidity closely resemble those seen in 8-week efficacy trials. The systematic use of easily implemented measurement-based care procedures may have assisted in achieving these results.

A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report.

OBJECTIVE: Few controlled studies have addressed the issue of which antidepressant medications should be recommended for outpatients who have not responded to multiple treatment trials. This study compared the efficacy of switching to mirtazapine to that of switching to a tricyclic antidepressant (nortriptyline) following two prospective, consecutive, unsuccessful medication treatments for nonpsychotic major depressive disorder. METHOD: Following lack of remission or an inability to tolerate an initial trial of citalopram for up to 12 weeks (first step) and a second trial with either monotherapy involving another antidepressant or augmentation of citalopram with bupropion or buspirone (second step), adult outpatients (N=235) with nonpsychotic major depressive disorder were randomly assigned to 14 weeks of treatment with mirtazapine (up to 60 mg/day) (N=114) or nortriptyline (up to 200 mg/day) (N=121). The primary outcome, symptom remission, was defined a priori as a total exit score of /=50% reduction in score from baseline). RESULTS: For mirtazapine, remission rates were 12.3% and 8.0% per the Hamilton and QIDS-SR(16) scores, respectively. For nortriptyline, remission rates were 19.8% and 12.4%, respectively. QIDS-SR(16) response rates were 13.4% for mirtazapine and 16.5% for nortriptyline. Neither response nor remission rates statistically differed by treatment, nor did these two treatments differ in tolerability or adverse events. CONCLUSIONS: Switching to a third antidepressant monotherapy regimen after two consecutive unsuccessful antidepressant trials resulted in low remission rates (<20%) among patients with major depressive disorder.

Children's Yale-Brown Obsessive Compulsive Scale modified for pervasive developmental disorders.

OBJECTIVE: To examine the psychometric properties of the Children's Yale-Brown Obsessive Compulsive Scales (CYBOCS) modified for pervasive developmental disorders (PDDs). METHOD: Raters from five Research Units on Pediatric Psychopharmacology (RUPP) Autism Network were trained to reliability. The modified scale (CYBOCS-PDD), which contains only the five Compulsion severity items (range 0-20), was administered to 172 medication-free children (mean 8.2 +/- 2.6 years) with PDD (autistic disorder, n = 152; Asperger's disorder, n = 6; PDD not otherwise specified, n = 14) participating in RUPP clinical trials. Reliability was assessed by intraclass correlation coefficient (ICC) and internal consistency by Cronbach's alpha coefficient. Correlations with ratings of repetitive behavior and disruptive behavior were examined for validity. RESULTS: Eleven raters showed excellent reliability (ICC = 0.97). The mean CYBOCS score was 14.4 (+/- 3.86) with excellent internal consistency (alpha = .85). Correlations with other measures of repetitive behavior ranged from r = 0.11 to r = 0.28 and were similar to correlations with measures of irritability (r = 0.24) and hyperactivity (r = 0.25). Children with higher scores on the CYBOCS-PDD had higher levels of maladaptive behaviors and lower adaptive functioning. CONCLUSIONS: The five-item CYBOCS-PDD is reliable, distinct from other measures of repetitive behavior, and sensitive to change.

Risperidone and adaptive behavior in children with autism.

OBJECTIVE: To evaluate the impact of risperidone on adaptive behavior in children with autistic disorder who have serious behavior problems and to examine different methods of scoring the Vineland Adaptive Behavior Scales to measure change. METHOD: Forty-eight children (5 years to 16 years, 5 months) who showed behavioral improvement during acute treatment with risperidone were followed for 6 months and assessed with the Vineland Scales. RESULTS: Raw scores, age-equivalents, and special norm percentile scores all showed significant increases in adaptive behavior in the areas of communication, daily living skills, and socialization (p <.01). During a period of 6 to 8 months, children gained an average of 7.8 age-equivalent months in the area of socialization, a > 6% improvement beyond what would be expected based on baseline growth rates. CONCLUSIONS: Although limited by the absence of a control group, these results suggest that risperidone may improve adaptive skills in children with autistic disorder accompanied by serious behavioral problems. Vineland age-equivalent scores appear to be most useful in assessing change with treatment over time.

A prospective open trial of guanfacine in children with pervasive developmental disorders.

OBJECTIVE: A common complaint for children with pervasive developmental disorder (PDD) is hyperactivity. The purpose of this pilot study was to gather preliminary information on the efficacy of guanfacine in children with PDD and hyperactivity. METHODS: Children with PDD accompanied by hyperactivity entered the open-label trial if there was a recent history of failed treatment with methylphenidate or the child did not improve on methylphenidate in a multisite, placebo-controlled trial. RESULTS: Children (23 boys and 2 girls) with a mean age of 9.03 (+/-3.14) years entered the open-label trial. After 8 weeks of treatment, the parent-rated Hyperactivity subscale of the Aberrant Behavior Checklist (ABC) went from a mean of 31.3 (+/-8.89) at baseline to 18.9 (+/-10.37) (effect size = 1.4; p < 0.001). The teacher-rated Hyperactivity subscale decreased from a mean of 29.9 (+/-9.12) at baseline to 22.3 (+/-9.44) (effect size = 0.83; p < 0.01). Twelve children (48%) were rated as Much Improved or Very Much Improved on the Clinical Global Impressions- Improvement. Doses ranged from 1.0 to 3.0 mg/day in two or three divided doses. Common adverse effects included irritability, sedation, sleep disturbance (insomnia or midsleep awakening), and constipation. Irritability led to discontinuation in 3 subjects. There were no significant changes in pulse, blood pressure, or electrocardiogram. CONCLUSIONS: Guanfacine may be useful for the treatment of hyperactivity in children with PDD. Placebo-controlled studies are needed to guide clinical practice.

Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology.

OBJECTIVE: Risperidone has been found efficacious for decreasing severe tantrums, aggression, and self-injurious behavior in children and adolescents with autistic disorder (autism). The authors report on whether risperidone improves the core symptoms of autism, social and communication impairment and repetitive and stereotyped behavior. METHOD: The database from an 8-week double-blind, placebo-controlled trial (N=101) and 16-week open-label continuation study (N=63) of risperidone for children and adolescents with autism was used to test for drug effects on secondary outcome measures: scores on the Ritvo-Freeman Real Life Rating Scale, the Children's Yale-Brown Obsessive Compulsive Scale, and the maladaptive behavior domain of the Vineland Adaptive Behavior Scales. RESULTS: Compared to placebo, risperidone led to a significantly greater reduction in the overall score on the Ritvo-Freeman Real Life Rating Scale, as well as the scores on the subscales for sensory motor behaviors (subscale I), affectual reactions (subscale III), and sensory responses (subscale IV). No statistically significant difference was observed, however, on the subscale for social relatedness (subscale II) or language (subscale V). Risperidone also resulted in significantly greater reductions in scores on the Children's Yale-Brown Obsessive Compulsive Scale and Vineland maladaptive behavior domain. This pattern of treatment response was maintained for 6 months. CONCLUSIONS: Risperidone led to significant improvements in the restricted, repetitive, and stereotyped patterns of behavior, interests, and activities of autistic children but did not significantly change their deficit in social interaction and communication. Further research is necessary to develop effective treatments for the core social and communicative impairments of autism.

Sequential pharmacotherapy for children with comorbid attention-deficit/hyperactivity and anxiety disorders.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by clinically significant anxiety, but few empirical data guide treatment of children meeting full DSM-IV criteria for ADHD and anxiety disorders (ADHD/ANX). This study examined the efficacy of sequential pharmacotherapy for ADHD/ANX children. METHOD: Children, age 6 to 17 years, with ADHD/ANX were titrated to optimal methylphenidate dose and assessed along with children who entered the study on a previously optimized stimulant. Children with improved ADHD who remained anxious were randomly assigned to 8 weeks of double-blind stimulant + fluvoxamine (STIM/FLV) or stimulant + placebo (STIM/PL). Primary efficacy measures were the Swanson, Nolan, Atkins, and Pelham IV Parent and Teacher Rating Scale ADHD score and the Pediatric Anxiety Rating Scale total score. ADHD, ANX, and overall Clinical Global Impressions-Improvement scores were also obtained. RESULTS: Of the 32 medication-naive children openly treated with methylphenidate, 26 (81%) improved as to ADHD. Twenty-five children entered the randomized trial. Intent-to-treat analysis indicated no differences between the STIM/FLV (n = 15) and STIM/PL groups on the Pediatric Anxiety Rating Scale or Clinical Global Impressions-Improvement-defined responder rate. Medications in both arms were well tolerated. CONCLUSIONS: Children with ADHD/ANX have a response rate to stimulants for ADHD that is comparable with that of children with general ADHD. The benefit of adding FLV to stimulants for ANX remains unproven.

Quality improvement methods as applied to a multicenter effectiveness trial--STAR*D.

In multicenter clinical trials, important aspects of trial performance (e.g., the number of participants who enter the trial within the required time frame, the number of participants who remain in the trial, and/or the completeness of the outcome data collected) directly affect the extent to which the study can achieve its aims. Obtaining the maximum amount of data from the maximum number of participants at each step in the trial increases the likelihood of identifying real differences in outcome. These aspects of trial performance can, therefore, be considered intermediate performance goals of the study since success in achieving each of them is directly related to success in achieving study aims. A quality improvement system was introduced to improve efficiency and performance in the multicenter Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Four intermediate performance goals were targeted for quality improvement efforts: (1) initial enrollment of subjects, (2) collection of entry/exit primary outcome data, (3) retention of subjects to enter subsequent "levels" of the trial, and (4) collection of blood samples for genetics studies. The identification of numerical targets for these goals provides a basis for monitoring performance and for implementing attempts to improve performance, since success in achieving each goal is directly related to success in achieving the study aims. This paper describes the background, rationale, development, and potential utility of implementing a quality improvement system to improve the performance and efficiency of the trial.

Acute and long-term safety and tolerability of risperidone in children with autism.

Treatment-emergent adverse events (AEs) were monitored during an 8-week, double-blind, placebo-controlled trial of risperidone (0.5-3.5 mg/day) in 101 children and adolescents with a lifetime diagnosis of autistic disorder. In addition, 37 placebo nonresponders received open-label risperidone for another 8 weeks. Of all the risperidone responders (n=65), 63 entered an open extension of another 16 weeks (6 months total risperidone exposure), and 32 of them were rerandomized to either continued risperidone therapy (n=16) or gradual replacement with placebo (n=16) over 8 weeks. We collected the following measures of safety and tolerability: (1) laboratory blood assessments (CBC with differential, electrolytes, and liver function tests) and urinalyses, (2) vital signs, (3) Side Effects Review of AEs thought to be associated with risperidone, (4) sleep records, (5) Simpson Angus Neurological Rating Scale (SARS), (6) Abnormal Involuntary Movement Scale (AIMS), and (7) height and weight. No clinically significant changes were found on the lab tests. During the 8-week acute trial, the most common AEs on the Side Effects Review, scored as moderate or higher, were as follows (placebo and risperidone, respectively): Somnolence (12% and 37%), enuresis (29% and 33%), excessive appetite (10% and 33%), rhinitis (8% and 16%), difficulty waking (8% and 12%), and constipation (12% and 10%). "Difficulty falling asleep" and anxiety actually favored the risperidone condition at statistically significant levels. The same AEs tended to recur through 6 months of treatment, although often at reduced levels. Using Centers for Disease Control (CDC) standardized scores, both weight and body mass index (BMI) increased with risperidone during the acute trial (0.5 and 0.6 SDs, respectively, for risperidone; 0.0 and 0.1 SDs, respectively, for placebo) and into open-label extension (0.19 and 0.16 SDs, respectively), although the amount of gain decelerated with time. Extrapyramidal symptoms, as assessed by the SARS, were no more common for drug than placebo, although drooling was reported more often in the risperidone group. There were no differences between groups on the AIMS. Two subjects had seizures (one taking placebo), but these were considered unrelated to active drug. Most AEs were mild to moderate and failed to interfere with therapeutic changes; there were no unanticipated AEs. The side effects of most concern were somnolence and weight gain.

Suicide risk management for the sequenced treatment alternatives to relieve depression study: applied NIMH guidelines.

NIMH guidelines to manage subjects who are suicidal during their participation in clinical trials include a full range of procedures to minimize suicidal risk, yet no reports to date have shown how researchers should best implement these guidelines. The architects of the sequenced treatment alternatives to relieve depression (STAR*D) study operationalized and implemented the NIMH guidelines by developing a comprehensive set of procedures to detect, monitor, and manage suicidal subjects during a large, complex, multisite clinical trial. Because of the large size of the study (anticipated n = 4000), the wide geographic distribution, the large number of treating STAR*D clinicians, the broad array of subjects with psychiatric and medical comorbidities, and the focus on treatment-resistant depression, along with the complexity of multiple treatment steps and randomization points in STAR*D, the risk of suicide, safety monitoring of suicidal subjects presented a unique challenge. This paper describes methods derived from the NIMH guidelines used to manage suicidal risk in STAR*D including the use of an interactive voice response system to alert clinicians, regional center directors, and safety officers.

Searching for moderators and mediators of pharmacological treatment effects in children and adolescents with anxiety disorders.

OBJECTIVE: To examine whether age, gender, ethnicity, type of anxiety disorder, severity of illness, comorbidity, intellectual level, family income, or parental education may function as moderators and whether treatment adherence, medication dose, adverse events, or blinded rater's guess of treatment assignment may function as mediators of pharmacological treatment effect in children and adolescents with anxiety disorders. METHOD: The database of a recently reported double-blind placebo-controlled trial of fluvoxamine in 128 youths was analyzed. With a mixed-model random-effects regression analysis of the Pediatric Anxiety Rating Scale total score, moderators and mediators were searched by testing for a three-way interaction (strata by treatment by time). A two-way interaction (strata by time) identified predictors of treatment outcome. RESULTS: No significant moderators of efficacy were identified, except for lower baseline depression scores, based on parent's (but not child's) report, being associated with greater improvement (p < .001). Patients with social phobia (p < .05) and greater severity of illness (p < .001) were less likely to improve, independently of treatment assignment. Blinded rater's guess of treatment assignment acted as a possible mediator (p < .001), but improvement was attributed to fluvoxamine, regardless of actual treatment assignment. Treatment adherence tended to be associated (p = .05) with improvement. CONCLUSIONS: In this exploratory study, patient demographics, illness characteristics, family income, and parental education did not function as moderators of treatment effect. Social phobia and severity of illness predicted less favorable outcome. Attribution analyses indicated that study blindness remained intact. The presence of concomitant depressive symptoms deserves attention in future treatment studies of anxious children.

Treatment of pediatric anxiety disorders: an open-label extension of the research units on pediatric psychopharmacology anxiety study.

BACKGROUND: An 8-week placebo-controlled study, the Research Units on Pediatric Psychopharmacology Anxiety Study, documented beneficial effects of fluvoxamine in the treatment of pediatric social anxiety, separation anxiety, or generalized anxiety disorders. Following completion of this study, participants were invited to enter a 6-month open-label treatment phase designed to examine three issues: (a) long-term maintenance of response in fluvoxamine responders, (b) acute response to fluoxetine in fluvoxamine nonresponders, and (c) acute response to fluvoxamine in placebo nonresponders. METHODS: Participants aged 6-17 years meeting criteria for social anxiety, separation anxiety, or generalized anxiety disorders previously treated in an 8-week placebo-controlled trial (n = 128) were offered open treatment. Changes in symptoms of anxiety during open treatment were assessed in three groups: (a) fluvoxamine responders maintained on fluvoxamine, (b) fluvoxamine nonresponders changed to fluoxetine, and (c) placebo nonresponders changed to fluvoxamine. Response was defined based on Clinical Global Impression criteria. RESULTS: During 6 months of continued open treatment, anxiety symptoms remained low in 33 of 35 (94%) subjects who initially responded to fluvoxamine. Among 14 fluvoxamine nonresponders switched to fluoxetine, anxiety symptoms appeared significantly improved in 10 (71%) subjects. Finally, among 48 placebo nonresponders, 27 (56%) showed clinically significant improvement in anxiety on fluvoxamine. CONCLUSION: The current findings concerning extended treatment of pediatric anxiety disorders are only preliminary, because treatment was uncontrolled. Results suggest that an initial fluvoxamine response is likely to be retained with continued treatment, that some fluvoxamine nonresponders may respond to fluoxetine, and that some placebo nonresponders may respond to fluvoxamine.