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John Curry, Susan Silva,
Paul Rohde,
Golda Ginsburg,
Betsy Kennard,
Christopher Kratochvil,
Anne Simons,
Jerry Kirchner,
Diane May,
Taryn Mayes, [......],
Mark Reinecke,
Rachel Jacobs,
Emily Becker-Weidman,
Elizabeth Weller,
Graham Emslie,
John Walkup,
Elizabeth Kastelic,
Barbara Burns,
Karen Wells,
John March
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ABSTRACT: This study tested whether positive response to short-term treatment for adolescent major depressive disorder (MDD) would have the secondary benefit of preventing subsequent alcohol use disorders (AUD) or substance use disorders (SUD).
For 5 years, we followed 192 adolescents (56.2% female; 20.8% minority) who had participated in the Treatment for Adolescents with Depression Study (TADS; TADS Team, 2004) and who had no prior diagnoses of AUD or SUD. TADS initial treatments were cognitive behavior therapy (CBT), fluoxetine alone (FLX), the combination of CBT and FLX (COMB), or clinical management with pill placebo (PBO). We used both the original TADS treatment response rating and a more restrictive symptom count rating. During follow-up, diagnostic interviews were completed at 6- or 12-month intervals to assess onset of AUD or SUD as well as MDD recovery and recurrence.
Achieving a positive response to MDD treatment was unrelated to subsequent AUD but predicted a lower rate of subsequent SUD, regardless of the measure of positive response (11.65% vs. 24.72%, or 10.0% vs. 24.5%, respectively). Type of initial MDD treatment was not related to either outcome. Prior to depression treatment, greater involvement with alcohol or drugs predicted later AUD or SUD, as did older age (for AUD) and more comorbid disorders (for SUD). Among those with recurrent MDD and AUD, AUD preceded MDD recurrence in 24 of 25 cases.
Effective short-term adolescent depression treatment significantly reduces the rate of subsequent SUD but not AUD. Alcohol or drug use should be assessed prior to adolescent MDD treatment and monitored even after MDD recovery.
Journal of Consulting and Clinical Psychology 01/2012; 80(2):299-312. · 4.85 Impact Factor
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Richard E Leach,
Philip Jessmon,
Christos Coutifaris,
Michael Kruger,
Evan R Myers,
Rouba Ali-Fehmi,
Sandra A Carson,
Richard S Legro,
William D Schlaff,
Bruce R Carr,
Michael P Steinkampf, Susan Silva,
Phyllis C Leppert,
Linda Giudice,
Michael P Diamond,
D Randall Armant
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ABSTRACT: Although histological dating of endometrial biopsies provides little help for prediction or diagnosis of infertility, analysis of individual endometrial proteins, proteomic profiling and transcriptome analysis have suggested several biomarkers with altered expression arising from intrinsic abnormalities, inadequate stimulation by or in response to gonadal steroids or altered function due to systemic disorders. The objective of this study was to delineate the developmental dynamics of potentially important proteins in the secretory phase of the menstrual cycle, utilizing a collection of endometrial biopsies from women of fertile (n = 89) and infertile (n = 89) couples.
Progesterone receptor-B (PGR-B), leukemia inhibitory factor, glycodelin/progestagen-associated endometrial protein (PAEP), homeobox A10, heparin-binding EGF-like growth factor, calcitonin and chemokine ligand 14 (CXCL14) were measured using a high-throughput, quantitative immunohistochemical method. Significant cyclic and tissue-specific regulation was documented for each protein, as well as their dysregulation in women of infertile couples. Infertile patients demonstrated a delay early in the secretory phase in the decline of PGR-B (P < 0.05) and premature mid-secretory increases in PAEP (P < 0.05) and CXCL14 (P < 0.05), suggesting that the implantation interval could be closing early. Correlation analysis identified potential interactions among certain proteins that were disrupted by infertility.
This approach overcomes the limitations of a small sample number. Protein expression and localization provided important insights into the potential roles of these proteins in normal and pathological development of the endometrium that is not attainable from transcriptome analysis, establishing a basis for biomarker, diagnostic and targeted drug development for women with infertility.
Human Reproduction 01/2012; 27(3):814-28. · 4.47 Impact Factor
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Francis J Keefe,
Rebecca A Shelby,
Tamara J Somers,
Indira Varia,
Michael Blazing,
Sandra J Waters,
Daphne McKee, Susan Silva,
Lelin She,
James A Blumenthal,
John O'Connor,
Verena Knowles,
Paige Johnson,
Lawrence Bradley
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ABSTRACT: Non-cardiac chest pain (NCCP) is a common and distressing condition. Prior studies suggest that psychotropic medication or pain coping skills training (CST) may benefit NCCP patients. To our knowledge, no clinical trials have examined the separate and combined effects of CST and psychotropic medication in the management of NCCP. This randomized clinical trial examined the separate and combined effects of CST and antidepressant medication (sertraline) in participants with non-cardiac chest pain. A sample of individuals diagnosed with NCCP was randomly assigned to one of four treatments: (1) CST plus sertraline (CST+sertraline), (2) CST plus placebo (CST+placebo), (3) sertraline alone, or (4) placebo alone. Assessments of pain intensity, pain unpleasantness, anxiety, pain catastrophizing, depression, and physical disability were collected prior to treatment, and at 10- and 34-weeks following randomization. Data analyses revealed that CST and sertraline either alone or in combination significantly reduced pain intensity and pain unpleasantness. The combination of CST plus sertraline may have the greatest promise in that, when compared to placebo alone, it not only significantly reduced pain but also pain catastrophizing and anxiety. Overall, these findings support the importance of further research on the effects of CST and sertraline for non-cardiac chest pain.
Pain 02/2011; 152(4):730-41. · 5.78 Impact Factor
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John Curry, Susan Silva,
Paul Rohde,
Golda Ginsburg,
Christopher Kratochvil,
Anne Simons,
Jerry Kirchner,
Diane May,
Betsy Kennard,
Taryn Mayes, [......],
Mark Reinecke,
Rachel Jacobs,
Emily Becker-Weidman,
Elizabeth Weller,
Graham Emslie,
John Walkup,
Elizabeth Kastelic,
Barbara Burns,
Karen Wells,
John March
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ABSTRACT: Major depressive disorder in adolescents is common and impairing. Efficacious treatments have been developed, but little is known about longer-term outcomes, including recurrence.
To determine whether adolescents who responded to short-term treatments or who received the most efficacious short-term treatment would have lower recurrence rates, and to identify predictors of recovery and recurrence.
Naturalistic follow-up study.
Twelve academic sites in the United States.
One hundred ninety-six adolescents (86 males and 110 females) randomized to 1 of 4 short-term interventions (fluoxetine hydrochloride treatment, cognitive behavioral therapy, their combination, or placebo) in the Treatment for Adolescents With Depression Study were followed up for 5 years after study entry (44.6% of the original Treatment for Adolescents With Depression Study sample).
Recovery was defined as absence of clinically significant major depressive disorder symptoms on the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version interview for at least 8 weeks, and recurrence was defined as a new episode of major depressive disorder following recovery.
Almost all participants (96.4%) recovered from their index episode of major depressive disorder during the follow-up period. Recovery by 2 years was significantly more likely for short-term treatment responders (96.2%) than for partial responders or nonresponders (79.1%) (P < .001) but was not associated with having received the most efficacious short-term treatment (the combination of fluoxetine and cognitive behavioral therapy). Of the 189 participants who recovered, 88 (46.6%) had a recurrence. Recurrence was not predicted by full short-term treatment response or by original treatment. However, full or partial responders were less likely to have a recurrence (42.9%) than were nonresponders (67.6%) (P = .03). Sex predicted recurrence (57.0% among females vs 32.9% among males; P = .02).
Almost all depressed adolescents recovered. However, recurrence occurs in almost half of recovered adolescents, with higher probability in females in this age range. Further research should identify and address the vulnerabilities to recurrence that are more common among young women.
Archives of general psychiatry 11/2010; 68(3):263-9. · 12.26 Impact Factor
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ABSTRACT: In 2003, the National Institute of Mental Health funded the Child and Adolescent Psychiatry Trials Network (CAPTN) under the Advanced Center for Services and Intervention Research (ACSIR) mechanism. At the time, CAPTN was believed to be both a highly innovative undertaking and a highly speculative one. One reviewer even suggested that CAPTN was "unlikely to succeed, but would be a valuable learning experience for the field."
To describe valuable lessons learned in building a clinical research network in pediatric psychiatry, including innovations intended to decrease barriers to research participation.
The CAPTN Team has completed construction of the CAPTN network infrastructure, conducted a large, multi-center psychometric study of a novel adverse event reporting tool, and initiated a large antidepressant safety registry and linked pharmacogenomic study focused on severe adverse events. Specific challenges overcome included establishing structures for network organization and governance; recruiting over 150 active CAPTN participants and 15 child psychiatry training programs; developing and implementing procedures for site contracts, regulatory compliance, indemnification and malpractice coverage, human subjects protection training and IRB approval; and constructing an innovative electronic casa report form (eCRF) running on a web-based electronic data capture system; and, finally, establishing procedures for audit trail oversight requirements put forward by, among others, the Food and Drug Administration (FDA).
Given stable funding for network construction and maintenance, our experience demonstrates that judicious use of web-based technologies for profiling investigators, investigator training, and capturing clinical trials data, when coupled to innovative approaches to network governance, data management and site management, can reduce the costs and burden and improve the feasibility of incorporating clinical research into routine clinical practice. Having successfully achieved its initial aim of constructing a network infrastructure, CAPTN is now a capable platform for large safety registries, pharmacogenetic studies, and randomized practical clinical trials in pediatric psychiatry.
Child and Adolescent Psychiatry and Mental Health 04/2009; 3(1):12.
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Betsy D Kennard, Susan G Silva,
Simon Tonev,
Paul Rohde,
Jennifer L Hughes,
Benedetto Vitiello,
Christopher J Kratochvil,
John F Curry,
Graham J Emslie,
Mark Reinecke,
John March
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ABSTRACT: We examine remission rate probabilities, recovery rates, and residual symptoms across 36 weeks in the Treatment for Adolescents with Depression Study (TADS).
The TADS, a multisite clinical trial, randomized 439 adolescents with major depressive disorder to 12 weeks of treatment with fluoxetine, cognitive-behavioral therapy, their combination, or pill placebo. The pill placebo group, treated openly after week 12, was not included in the subsequent analyses. Treatment differences in remission rates and probabilities of remission over time are compared. Recovery rates in remitters at weeks 12 (acute phase remitters) and 18 (continuation phase remitters) are summarized. We also examined whether residual symptoms at the end of 12 weeks of acute treatment predicted later remission.
At week 36, the estimated remission rates for intention-to-treat cases were as follows: combination, 60%; fluoxetine, 55%; cognitive-behavioral therapy, 64%; and overall, 60%. Paired comparisons reveal that, at week 24, all active treatments converge on remission outcomes. The recovery rate at week 36 was 65% for acute phase remitters and 71% for continuation phase remitters, with no significant between-treatment differences in recovery rates. Residual symptoms at the end of acute treatment predicted failure to achieve remission at weeks 18 and 36.
Most depressed adolescents in all three treatment modalities achieved remission at the end of 9 months of treatment.
Journal of the American Academy of Child and Adolescent Psychiatry 02/2009; 48(2):186-95. · 4.98 Impact Factor
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ABSTRACT: Abstract
Background
The objective of this analysis was to measure changes in items on the Pediatric Adverse Event Rating Scale (PAERS) that relate to emotional well-being of children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD) during treatment with atomoxetine for up to 24 weeks from the perspective of the patient, the parent, and the physician.
Methods
Patients aged 6–17 years with ADHD were treated with atomoxetine (target dose 1.2 mg/kg/day). In the two studies on which this secondary analysis is based the PAERS was used to assess the tolerability of atomoxetine in children and adolescents. This scale has a total of 48 items. The ten items that reflect emotional well-being were selected to measure changes over time from a patient, parent, and physician perspective.
Results
421 patients were treated with atomoxetine. 355 patients completed the 8-week treatment period, and 260 patients completed the 24-week treatment period. The ten items that reflect emotional well-being were grouped in five dimensions: depressed mood, self-harm, irritability/agitation, drowsiness, and euphoria. The scores of these dimensions decreased over time, both from a patient as well as from a parent and physician perspective. Only the dimension self-harm was extremely low at baseline and stayed low over time. The mean scores for the ten items depended on the rater perspective.
Conclusion
The emotional well-being of children and adolescents with ADHD improved in terms of depressed mood, irritability/agitation, drowsiness, and euphoria during treatment with atomoxetine for up to 24 weeks.
Child and Adolescent Psychiatry and Mental Health. 01/2008;
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Benedetto Vitiello,
Christopher J Kratochvil, Susan Silva,
John Curry,
Mark Reinecke,
Sanjeev Pathak,
Bruce Waslick,
Carroll W Hughes,
Ernest D Prentice,
Diane E May,
John S March
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ABSTRACT: We examined the extent to which parents and adolescents participating in the Treatment for Adolescents With Depression Study (TADS) understood key aspects of the study.
TADS was a clinical trial comparing the effectiveness of fluoxetine, cognitive-behavioral therapy (CBT), their combination, and placebo in 439 adolescents (12-17 years old) with major depressive disorder. Six weeks after starting treatment, adolescents and their parents were asked to complete a questionnaire about critical elements of the trial.
Completion rate was 67.2% for adolescents (N = 295) and 73.6% for parents (N = 323). More than 90% of the completers knew of the main purpose of the trial, possible assignment to placebo, and their right to withdraw participation at any time. However, about one third overall (and 49% in the CBT group) described TADS as "education" rather than "research." Of 12 questions, the mean number of correct answers was 10.3 (SD 1.7) among adolescents and 11.2 (SD 1.2) among parents (p <.0001). The most frequently stated reason for TADS participation was the pursuit of high-quality care.
Most parents and adolescents were well-informed research participants. Difficulties in appreciating the research nature of the trial, however, emerged, especially among participants assigned to psychotherapy. Parents were overall better informed than adolescents.
Journal of the American Academy of Child & Adolescent Psychiatry 12/2007; 46(12):1642-50. · 6.44 Impact Factor
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John S March, Susan Silva,
Stephen Petrycki,
John Curry,
Karen Wells,
John Fairbank,
Barbara Burns,
Marisa Domino,
Steven McNulty,
Benedetto Vitiello,
Joanne Severe
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ABSTRACT: The Treatment for Adolescents With Depression Study evaluates the effectiveness of fluoxetine hydrochloride therapy, cognitive behavior therapy (CBT), and their combination in adolescents with major depressive disorder.
To report effectiveness outcomes across 36 weeks of randomized treatment.
Randomized, controlled trial conducted in 13 academic and community sites in the United States. Cognitive behavior and combination therapies were not masked, whereas administration of placebo and fluoxetine was double-blind through 12 weeks, after which treatments were unblinded. Patients assigned to placebo were treated openly after week 12, and the placebo group is not included in these analyses by design.
Three hundred twenty-seven patients aged 12 to 17 years with a primary DSM-IV diagnosis of major depressive disorder.
All treatments were administered per protocol.
The primary dependent measures rated blind to treatment status by an independent evaluator were the Children's Depression Rating Scale-Revised total score and the response rate, defined as a Clinical Global Impressions-Improvement score of much or very much improved.
Intention-to-treat analyses on the Children's Depression Rating Scale-Revised identified a significant time x treatment interaction (P < .001). Rates of response were 73% for combination therapy, 62% for fluoxetine therapy, and 48% for CBT at week 12; 85% for combination therapy, 69% for fluoxetine therapy, and 65% for CBT at week 18; and 86% for combination therapy, 81% for fluoxetine therapy, and 81% for CBT at week 36. Suicidal ideation decreased with treatment, but less so with fluoxetine therapy than with combination therapy or CBT. Suicidal events were more common in patients receiving fluoxetine therapy (14.7%) than combination therapy (8.4%) or CBT (6.3%).
In adolescents with moderate to severe depression, treatment with fluoxetine alone or in combination with CBT accelerates the response. Adding CBT to medication enhances the safety of medication. Taking benefits and harms into account, combined treatment appears superior to either monotherapy as a treatment for major depression in adolescents.
Archives of General Psychiatry 11/2007; 64(10):1132-43. · 12.02 Impact Factor
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Graham Emslie,
Christopher Kratochvil,
Benedetto Vitiello, Susan Silva,
Taryn Mayes,
Steven McNulty,
Elizabeth Weller,
Bruce Waslick,
Charles Casat,
John Walkup,
Sanjeev Pathak,
Paul Rohde,
Kelly Posner,
John March
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ABSTRACT: To compare the rates of physical, psychiatric, and suicide-related events in adolescents with MDD treated with fluoxetine alone (FLX), cognitive-behavioral therapy (CBT), combination treatment (COMB), or placebo (PBO).
Safety assessments included adverse events (AEs) collected by spontaneous report, as well as systematic measures for specific physical and psychiatric symptoms. Suicidal ideation and suicidal behavior were systematically assessed by self- and clinician reports. Suicidal events were also reanalyzed by the Columbia Group and expert raters using the Columbia-Classification Algorithm for Suicidal Assessment used in the U.S. Food and Drug Administration reclassification effort.
Depressed adolescents reported high rates of physical symptoms at baseline, which improved as depression improved. Sedation, insomnia, vomiting, and upper abdominal pain occurred in at least 2% of those treated with FLX and/or COMB and at twice the rate of placebo. The rate of psychiatric AEs was 11% in FLX, 5.6% in COMB, 4.5% in PBO, and 0.9% in CBT. Suicidal ideation improved overall, with greatest improvement in COMB. Twenty-four suicide-related events occurred during the 12-week period: 5 patients (4.7%) in COMB, 10 (9.2%) in FLX, 5 (4.5%) in CBT, and 3 (2.7%) in placebo. Statistically, only FLX had more suicide-related events than PBO (p =.0402, odds ratio (OR) = 3.7, 95% CI 1.00-63.7). Only five actual attempts occurred (2 COMB, 2 FLX, 1 CBT, 0 PBO). There were no suicide completions.
Different methods for eliciting AEs produce different results. In general, as depression improves, physical complaints and suicidal ideation decrease in proportion to treatment benefit. In this study, psychiatric AEs and suicide-related events are more common in FLX-treated patients. COMB treatment may offer a more favorable safety profile than medication alone in adolescent depression.
Journal of the American Academy of Child & Adolescent Psychiatry 01/2007; 45(12):1440-55. · 6.44 Impact Factor
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John Curry,
Paul Rohde,
Anne Simons, Susan Silva,
Benedetto Vitiello,
Christopher Kratochvil,
Mark Reinecke,
Norah Feeny,
Karen Wells,
Sanjeev Pathak,
Elizabeth Weller,
David Rosenberg,
Betsy Kennard,
Michele Robins,
Golda Ginsburg,
John March
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ABSTRACT: To identify predictors and moderators of response to acute treatments among depressed adolescents (N = 439) randomly assigned to fluoxetine, cognitive-behavioral therapy (CBT), both fluoxetine and CBT, or clinical management with pill placebo in the Treatment for Adolescents With Depression Study (TADS).
Potential baseline predictors and moderators were identified by a literature review. The outcome measure was a week 12 predicted score derived from the Children's Depression Rating Scale-Revised (CDRS-R). For each candidate moderator or predictor, a general linear model was conducted to examine main and interactive effects of treatment and the candidate variable on the CDRS-R predicted scores.
Adolescents who were younger, less chronically depressed, higher functioning, and less hopeless with less suicidal ideation, fewer melancholic features or comorbid diagnoses, and greater expectations for improvement were more likely to benefit acutely than their counterparts. Combined treatment, under no condition less effective than monotherapy, was more effective than fluoxetine for mild to moderate depression and for depression with high levels of cognitive distortion, but not for severe depression or depression with low levels of cognitive distortion. Adolescents from high-income families were as likely to benefit from CBT alone as from combined treatment.
Younger and less severely impaired adolescents are likely to respond better to acute treatment than older, more impaired, or multiply comorbid adolescents. Family income level, cognitive distortions, and severity of depression may help clinicians to choose among acute interventions, but combined treatment proved robust in the presence of moderators.
Journal of the American Academy of Child & Adolescent Psychiatry 01/2007; 45(12):1427-39. · 6.44 Impact Factor
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Betsy Kennard, Susan Silva,
Benedetto Vitiello,
John Curry,
Christopher Kratochvil,
Anne Simons,
Jennifer Hughes,
Norah Feeny,
Elizabeth Weller,
Michael Sweeney,
Mark Reinecke,
Sanjeev Pathak,
Golda Ginsburg,
Graham Emslie,
John March
[show abstract]
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ABSTRACT: To ascertain remission rates in depressed youth participating in the Treatment for Adolescents With Depression Study (TADS), a multisite clinical trial that randomized 439 adolescents with major depressive disorder (MDD) to a 12-week treatment of fluoxetine (FLX), cognitive-behavioral therapy (CBT), their combination (COMB), or clinical management with pill placebo (PBO).
Using an end-of-treatment Children's Depression Rating Scale-Revised (CDRS-R) total score of 28 or below as the criterion for remission, rates of remission were examined with logistic regression, controlling for site. Loss of MDD diagnosis and residual symptoms in responders (defined as Clinical Global Impressions-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) were also examined across treatment groups.
After 12 weeks of treatment, 102 (23%) of 439 youths had reached remission. The remission rate was significantly higher in the COMB group (37%) relative to the other treatment groups (FLX, 23%; CBT, 16%; PBO, 17%), with odds ratios of 2.1 for COMB versus FLX, 3.3 for COMB versus CBT, and 3.0 for COMB versus PBO. In addition, 71% of subjects across treatment groups no longer met criteria for MDD at the end of acute treatment. Fifty percent of the youths who responded by CGI-I criteria continued to have residual symptoms, such as sleep or mood disturbances, fatigue, and poor concentration.
The combination of FLX and CBT was superior to both monotherapy and PBO in terms of remission rates, but overall rates of remission remain low and residual symptoms are common at the end of 12 weeks of treatment.
Journal of the American Academy of Child & Adolescent Psychiatry 01/2007; 45(12):1404-11. · 6.44 Impact Factor
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ABSTRACT: Funded by the National Institute of Mental Health, the Treatment for Adolescents With Depression Study (TADS) is intended to evaluate the short-term (12 weeks) and longer-term (36 weeks) effectiveness of four treatments for adolescents with DSM-IV major depressive disorder: clinical management with fluoxetine (FLX), cognitive-behavioral therapy (CBT), FLX and CBT combined (COMB), and clinical management with placebo (PBO). We previously reported that COMB and FLX were more effective in reducing depression than CBT or PBO after 12 weeks of acute treatment. In this special section of the Journal, separate articles extend these findings to the impact of TADS treatments on remission, speed of response, function and quality of life, predictors of outcome, and safety during the first 12 weeks of treatment. To set the stage for the special section, we briefly review the rationale, design, and methods of the TADS; describe the TADS sample to which the TADS findings generalize; using all of the currently available data, summarize the intent-to-treat outcomes across multiple endpoints at 12 weeks; and consider the public health value of the TADS findings in the context of design decisions and methodological limitations of the TADS, including some that may have advantaged the combined treatment condition. Reflecting the ordering of effect sizes at week 12--COMB (0.98) > FLX (0.68) > CBT (-0.03)--combined treatment proved superior to PBO on 15 of 16 endpoints, to CBT on 14 of 16 endpoints, and to FLX on 8 of 16 endpoints, whereas FLX was superior to CBT on 8 of 14 and to PBO on 7 of 16 measures. CBT did not differ from PBO on any measure. Despite the fact that suicidality improved markedly across all of the treatment conditions, suicidal events were twice as common in patients treated with FLX alone than with COMB or CBT alone, perhaps indicating that CBT protects against suicidal events. Thus, combined treatment appears to accelerate recovery relative to CBT and, for some outcomes, FLX alone, while minimizing the risk of suicidality relative to FLX alone. Taking benefit and risk into account, we conclude that the combination of FLX and CBT appears superior to either monotherapy as a treatment for moderate to severe major depressive disorder in adolescents.
Journal of the American Academy of Child & Adolescent Psychiatry 12/2006; 45(12):1393-403. · 6.44 Impact Factor
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Christopher Kratochvil,
Graham Emslie, Susan Silva,
Steve McNulty,
John Walkup,
John Curry,
Mark Reinecke,
Benedetto Vitiello,
Paul Rohde,
Nora Feeny,
Charles Casat,
Sanjeev Pathak,
Elizabeth Weller,
Diane May,
Taryn Mayes,
Michele Robins,
John March
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ABSTRACT: To examine the time to response for both pharmacotherapy and psychotherapy in the Treatment for Adolescents with Depression Study (TADS).
Adolescents (N = 439, ages 12 to 17 years) with major depressive disorder were randomized to fluoxetine (FLX), cognitive-behavioral therapy (CBT), their combination (COMB), or pill placebo (PBO). Defining response as very much improved or much improved on the Clinical Global Impression-Improvement Scale (CGI-I), survival analyses using Cox proportional hazards models, and Kaplan-Meier curves were conducted to evaluate time to first response and time to stable response for subjects receiving pharmacotherapy (COMB, FLX, PBO) as well as for subjects receiving CBT (COMB, CBT). Direct comparisons between pharmacotherapy and CBT were not made because of differences in visit schedules.
Based on pharmacotherapist CGI-I scores, COMB and FLX showed faster onset of benefit than PBO on time to response and time to stable response (p < .001), and COMB was faster than FLX on time to stable response (p = .034). The probability of sustained early response was approximately threefold greater for COMB than PBO, twofold greater for FLX than PBO, and 1.5-fold greater for COMB than FLX. On the psychotherapist CGI-I scores, both first response and stable response occurred faster in COMB than CBT (p < .001), with a probability of sustained early response approximately threefold greater for COMB than CBT.
In the acute treatment of depressed adolescents, FLX and COMB accelerate response relative to PBO, and COMB accelerates response relative to CBT alone.
Journal of the American Academy of Child & Adolescent Psychiatry 12/2006; 45(12):1412-8. · 6.44 Impact Factor
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Benedetto Vitiello,
Paul Rohde, Susan Silva,
Karen Wells,
Charles Casat,
Bruce Waslick,
Anne Simons,
Mark Reinecke,
Elizabeth Weller,
Christopher Kratochvil,
John Walkup,
Sanjeev Pathak,
Michele Robins,
John March
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ABSTRACT: To test whether 12-week treatment of major depression improved the level of functioning, global health, and quality of life of adolescents.
The Treatment for Adolescents With Depression Study was a multisite, randomized clinical trial of fluoxetine, cognitive-behavioral therapy (CBT), their combination (COMB), or clinical management with placebo in 439 adolescents with major depression. Functioning was measured with the Children's Global Assessment Scale (CGAS), global health with the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA), and quality of life with the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q). Random-effects regression models were applied to the data.
Compared with placebo, COMB was effective on the CGAS (p < .0001), HoNOSCA (p < .05), and PQ-LES-Q (p < .001), whereas fluoxetine was superior to placebo on the CGAS only (p < .05). COMB was superior to fluoxetine on the CGAS (p < .05) and PQ-LES-Q (p = .001). Fluoxetine was superior to CBT on the CGAS (p < .01). CBT monotherapy was not statistically different from the placebo group on any of the measures assessed. Treatment effects were mediated by improvement in depressive symptoms measured on the Child Depression Rating Scale-Revised.
The combination of fluoxetine and CBT was effective in improving functioning, global health, and quality of life in depressed adolescents. Fluoxetine monotherapy improved functioning.
Journal of the American Academy of Child & Adolescent Psychiatry 12/2006; 45(12):1419-26. · 6.44 Impact Factor
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Joseph DeVeaugh-Geiss,
John March,
Mark Shapiro,
Paul J Andreason,
Graham Emslie,
Lisa M Ford,
Laurence Greenhill,
Dianne Murphy,
Ernest Prentice,
Rosemary Roberts, Susan Silva,
James M Swanson,
Barbara van Zwieten-Boot,
Benedetto Vitiello,
Karen Dineen Wagner,
Barry Mangum
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ABSTRACT: To give academic researchers, government officials, and industry scientists an opportunity to assess the state of pediatric psychopharmacology and identify challenges facing professionals in the field.
Increased federal spending and the introduction of pediatric exclusivity led to large increases in pediatric psychopharmacology research in the 1990s. Despite the increase in research, concerns exist about methods and incentives for making new medications available for use in pediatric psychiatric disorders. In recognition of these concerns, the Duke Clinical Research Institute held a roundtable in September 2004. Participants from the National Institutes of Health, regulatory agencies, academia, and the pharmaceutical industry spoke about the effects of government regulations such as the U.S. Food and Drug Administration Modernization Act and the Pediatric Research Equity Act on pediatric research from academic, clinical, and industry perspectives, and bioethical considerations of such research.
To ensure development of new drugs for treating psychiatric disorders in children and adolescents, we must address the challenges posed by the regulatory environment governing pediatric psychopharmacology research. Strategies were identified for improving the evidence base for psychopharmacologic interventions in youth before widespread use and for more effectively defining a research agenda for the future.
Journal of the American Academy of Child & Adolescent Psychiatry 04/2006; 45(3):261-70. · 6.44 Impact Factor
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ABSTRACT: Adolescents with major depressive disorder (MDD), their families and clinicians experience significant challenges when weighing the potential risks versus benefits of available choices in the treatment of MDD. Although MDD is highly prevalent in adolescents and is associated with marked suffering, impairment and risk of suicide, the scientific data regarding the safety and efficacy of treatments for pediatric depression are limited. Controlled clinical trials have provided support for the use of psychotherapy and fluoxetine for the treatment of pediatric depression, but until recently no information on the comparative efficacy of these recommended interventions alone or in combination was available. The Treatment for Adolescents with Depression Study provides a very important therapeutic advance in the field by convincingly showing that combination treatment with cognitive behavioral therapy and fluoxetine has the best benefit to risk ratio for adolescents with moderate to severe depression, and is superior to monotherapy. Moreover, the study results confirm that fluoxetine alone is effective in the treatment of depressed adolescents.
Current Psychiatry Reports 01/2006; 7(6):429-34. · 2.71 Impact Factor
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ABSTRACT: To assess effects of biopsy timing and fertility status on inter- and intraobserver variability in dating of the endometrium.
Endometrial biopsy slides randomly selected from a multicenter study testing the utility of biopsy in the diagnosis of infertility were distributed to three gynecologic pathologists, who estimated cycle day using standard criteria. Readers were blinded to the purpose of the study, patient age, fertility status, or timing of biopsy relative to LH surge or next menses.
Multicenter academic research programs in reproductive medicine.
Eighty-two women with proven fertility, 83 infertile patients.
Endometrial biopsy during midluteal (days 21-22) or late (days 26-27) luteal phase.
Intraclass correlation coefficient (ICC), kappa.
Overall agreement was excellent (ICC 0.88); addition of readings by local pathologists decreased ICC only slightly. In subgroup analyses, ICCs were lowest for infertile women during the midluteal phase (0.65 vs. 0.71 for fertile women in the midluteal phase, and 0.88-0.90 for both groups in the late luteal phase). Intraobserver reliability was excellent (0.9-0.99). Agreement for diagnoses of "out-of-phase" was only moderate, with kappa values between 0.4 and 0.6.
Observer variability in dating the endometrium was greatest in infertile women during the window of implantation.
Fertility and Sterility 12/2004; 82(5):1278-82. · 3.56 Impact Factor
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Christos Coutifaris,
Evan R Myers,
David S Guzick,
Michael P Diamond,
Sandra A Carson,
Richard S Legro,
Peter G McGovern,
William D Schlaff,
Bruce R Carr,
Michael P Steinkampf, Susan Silva,
Donna L Vogel,
Phyllis C Leppert
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ABSTRACT: To assess the ability of histological dating to discriminate between women of fertile and infertile couples. The utility of histological dating of endometrium in the evaluation of infertile couples is uncertain.
Prospective multicenter study, with subjects randomly assigned to biopsy timing. Criterion standard for infertility was 12 months of unprotected, regular intercourse without conception and for fertility at least one live birth within 2 years.
University-based infertility practices.
Volunteer subjects (847) recruited at 12 clinical sites participating in the National Institutes of Health-funded Reproductive Medicine Network. Inclusion criteria included ages 20-39 years, regular menstrual cycles, and no hormonal treatment or contraceptive use for 1 month before the study. Fertile controls were excluded if they had a history of infertility, recurrent pregnancy loss, or recent breastfeeding.
Subjects underwent daily urinary LH testing. After detection of the LH surge, subjects were randomized to biopsy in the mid (days 21-22) or the late (days 26-27) luteal phase. Pathologists at each site estimated the cycle day based on standard criteria. For the primary analysis, an out-of-phase biopsy was defined as a greater than 2-day delay in the histological maturation of the endometrium.
The proportion of out-of-phase biopsies in fertile and infertile women was compared using logistic regression models with age at randomization as a covariate. Comparisons were also made between fertile vs. infertile at the midluteal or late luteal phase time points.
Biopsies were evaluated (301 mid and 318 late; N = 619). Out-of-phase biopsy results poorly discriminated between women from fertile and infertile couples in either the midluteal (fertile: 49.4%, infertile: 43.2%) or late luteal phase (fertile: 35.3%, infertile 23.0%). Results did not substantially differ using alternative definitions of "out-of-phase" or standardized cycle day.
Histological dating of the endometrium does not discriminate between women of fertile and infertile couples and should not be used in the routine evaluation of infertility.
Fertility and Sterility 12/2004; 82(5):1264-72. · 3.56 Impact Factor
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Peter G McGovern,
Evan R Myers, Susan Silva,
Christos Coutifaris,
Sandra A Carson,
Richard S Legro,
William D Schlaff,
Bruce R Carr,
Michael P Steinkampf,
Linda C Giudice,
Phyllis C Leppert,
Michael P Diamond
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ABSTRACT: To examine the proportion of cases with proliferative endometrium on biopsies performed after positive home urine LH testing.
Multicenter clinical trial of the usefulness of endometrial biopsy in the evaluation of infertility, with women from fertile and infertile couples randomly assigned to midluteal vs. late luteal phase endometrial sampling.
Twelve clinical sites of the National Institutes of Health/National Institute of Child Health and Human Development-sponsored Reproductive Medicine Network.
All women in the study had regular menstrual cycles. Fertile volunteers who had delivered a live born infant within the past 2 years without medical intervention were recruited through advertisements at participating sites. Infertile women with regular cycles were recruited from the clinical practices of the sites' physicians.
Interview, informed consent, subject-interpreted home urine LH testing, and endometrial biopsy in either the midluteal or late luteal phase.
Proportion of cases with proliferative endometrium on biopsy.
In both fertile and infertile women, more than 7% of endometrial biopsies performed 7-13 days after a positive home urine LH test revealed proliferative endometrium.
Patient interpretation of home urine LH test kits not uncommonly results in false-positive tests. Women planning menstrual cycle testing or procedures related to ovulation may benefit from additional confirmatory testing.
Fertility and Sterility 12/2004; 82(5):1273-7. · 3.56 Impact Factor
