Cheung, Amy H., Emslie, Graham J., Mayes, Taryn L.

Review of the efficacy and safety of antidepressants in youth depression

BACKGROUND: Depression in children and adolescents is a cause of substantial morbidity and mortality in this population. It is a common disorder that affects 2% of children and up to 6% of adolescents. Although antidepressants are used frequently for the treatment of this disorder, there has been recent controversy about the efficacy and safety of these medications in this population. This review examined the available evidence from clinical trials of antidepressants in adolescents and children with depression. METHODS: Clinical trial data reviewed were obtained from published reports, including peer review journals and meeting abstracts, as well as unpublished data in the public domain. Clinical trials in this review included large RCTs of antidepressants in youth under the age of 19 with depression. Studies were identified in 2 stages: 1) all RCTs included in the 2004 FDA safety report were reviewed; and 2) to ensure that no additional studies not reported to the FDA were missed, MEDLINE and PSYCH Info were searched from inception until December 2004. A total of 8 published studies and 9 unpublished studies were identified and reviewed. RESULTS: Efficacy and safety results from each study are reviewed in detail. There are significant differences in remission and response rates between different antidepressants but also between placebo groups across studies. Adverse events are common in clinical trials involving children and adolescents with depression. Due to lack of access to full data sets, effect sizes could not be calculated. CONCLUSIONS: With the variability in trial methodology and the variation in the drug/placebo response rates within a single trial, clinicians need to be judicious in their interpretation of research data on pediatric antidepressant trials. Significant methodological issues may also have affected the efficacy and safety results from these clinical trials. [References: 32]

Journal of Child Psychology & Psychiatry & Allied Disciplines, 46(7) : 735- 54

Asarnow, Joan Rosenbaum, Jaycox, Lisa H., Duan, Naihua, LaBorde, Anne P., Rea, Margaret M., Murray, Pamela, Anderson, Martin, Landon, Christopher, Tang, Lingqi, Wells, Kenneth B.

Effectiveness of a quality improvement intervention for adolescent depression in primary care clinics: A randomized controlled trial.[see comment]

CONTEXT: Depression is a common condition associated with significant morbidity in adolescents. Few depressed adolescents receive effective treatment for depression in primary care settings. OBJECTIVE: To evaluate the effectiveness of a quality improvement intervention aimed at increasing access to evidence-based treatments for depression (particularly cognitive-behavior therapy and antidepressant medication), relative to usual care, among adolescents in primary care practices. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial conducted between 1999 and 2003 enrolling 418 primary care patients with current depressive symptoms, aged 13 through 21 years, from 5 health care organizations purposively selected to include managed care, public sector, and academic medical center clinics in the United States. INTERVENTION: Usual care (n = 207) or 6-month quality improvement intervention (n = 211) including expert leader teams at each site, care managers who supported primary care clinicians in evaluating and managing patients' depression, training for care managers in manualized cognitive-behavior therapy for depression, and patient and clinician choice regarding treatment modality. Participating clinicians also received education regarding depression evaluation, management, and pharmacological and psychosocial treatment. MAIN OUTCOME MEASURES: Depressive symptoms assessed by Center for Epidemiological Studies-Depression Scale (CES-D) score. Secondary outcomes were mental health- related quality of life assessed by Mental Health Summary Score (MCS-12) and satisfaction with mental health care assessed using a 5-point scale. RESULTS: Six months after baseline assessments, intervention patients, compared with usual care patients, reported significantly fewer depressive symptoms (mean [SD] CES-D scores, 19.0 [11.9] vs 21.4 [13.1]; P = .02), higher mental health-related quality of life (mean [SD] MCS-12 scores, 44.6 [11.3] vs 42.8 [12.9]; P = .03), and greater satisfaction with mental health care (mean [SD] scores, 3.8 [0.9] vs 3.5 [1.0]; P = .004). Intervention patients also reported significantly higher rates of mental health care (32.1% vs 17.2%, P<.001) and psychotherapy or counseling (32.0% vs 21.2%, P = .007). CONCLUSIONS: A 6-month quality improvement intervention aimed at improving access to evidence-based depression treatments through primary care was significantly more effective than usual care for depressed adolescents from diverse primary care practices. The greater uptake of counseling vs medication under the intervention reinforces the importance of practice interventions that include resources to enable evidence-based psychotherapy for depressed adolescents.

JAMA, 293(3) : 311- 9

Bond, L., Patton, G., Glover, S., Carlin, J. B., Butler, H., Thomas, L., Bowes, G.

The Gatehouse Project: Can a multilevel school intervention affect emotional well-being and health risk behaviours?

STUDY OBJECTIVE:\r \rThe aim of this study was to determine the effect of a multilevel school based intervention on adolescents' emotional wellbeing and health risk behaviours.\rDESIGN:\r\rSchool based cluster randomised controlled trial. Students were surveyed using laptop computers, twice in the first year of intervention and annually thereafter for a further two years.\rSETTING:\r\rSecondary schools.\rPARTICIPANTS:\r\r2678 year 8 students (74%) participated in the first wave of data collection. Attrition across the waves was less than 3%, 8%, and 10% respectively with no differential response rate between intervention and control groups at the subsequent waves (98% v 96%; 92% v 92%, and 90% v 89% respectively).\rMAIN RESULTS:\r\rA comparatively consistent 3% to 5% risk difference was found between intervention and control students for any drinking, any and regular smoking, and friends' alcohol and tobacco use across the three waves of follow up. The largest effect was a reduction in the reporting of regular smoking by those in the intervention group (OR 0.57, 0.62, and 0.72 at waves 2, 3, and 4 respectively). There was no significant effect of the intervention on depressive symptoms, and social and school relationships.\rCONCLUSIONS:\r\rWhile further research is required to determine fully the processes of change, this study shows that a focus on general cognitive skills and positive changes to the social environment of the school can have a substantial impact on important health risk behaviours

, 58 : 997- 1003

Emslie, Graham J., Hughes, Carroll W., Crismon, M. Lynn, Lopez, Molly, Pliszka, Steve, Toprac, Marcia G., Boemer, Christine, TexasChildren'sMedicationAlgorithm,Project

A feasibility study of the childhood depression medication algorithm: the Texas Children's Medication Algorithm Project (CMAP)

OBJECTIVE: To evaluate the feasibility and impact on clinical response and function associated with the use of an algorithm-driven disease management program (ALGO) for children and adolescents treated for depression with or without attention-deficit/hyperactivity disorder (ADHD) in community mental health centers. METHOD: Interventions included (1). medication algorithms, (2). clinical and technical support for the physician, (3). uniform chart documentation of outcomes, and (4). a patient/family psychoeducation program. Children eligible for entry into the study were referred to the child psychiatrist for initiation or change in medicine. Outcomes of treatment with the ALGO for up to 4 months are presented. Measures of change included clinical symptoms, functioning, and global improvement (Clinical Global Impression Scale). A historical chart cohort from the same clinics was used as a quasi-control. RESULTS: Thirty-nine individuals (depression = 24; comorbid depression with ADHD = 15) were enrolled for treatment with ALGO. One hundred fourteen children were in the control cohort (74 depressed, 40 comorbid). For the ALGO groups, Children's Depression Rating Scale-Revised depression severity scores decreased from 48.2 to 32.5 and Child Adolescent Functioning Assessment Scale function scores improved from 70.3 to 40.9 (all p < or =.0005). Clinical Global Impression Scale severity scores decreased from 5.7 to 3.7 in ALGO compared to only 5.8 to 4.8 in the control (p <.003). CONCLUSIONS: There was clear improvement in clinical symptoms, functioning, and global response with ALGO treatment. The magnitude of the improvement was greater in children and adolescents treated with the ALGO program compared with a historical cohort. These data support the need for controlled studies in larger populations examining the effects of algorithm-driven disease management programs on the clinical outcomes of children with mental illness.

Journal of the American Academy of Child & Adolescent Psychiatry, 43(5) : 519- 27

Woolery, A., Myers, H., Sternlieb, B., Zeltzer, L.

A yoga intervention for young adults with elevated symptoms of depression

Alternative therapies in health and medicine, 10(2) : 60-63

March, John, Silva, Susan, Petrycki, Stephen, Curry, John, Wells, Karen, Fairbank, John, Burns, Barbara, Domino, Marisa, McNulty, Steven, Vitiello, Benedetto, Severe, Joanne, TADSTeam

Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial.[see comment]

CONTEXT: Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor (SSRI). However, little is known about their relative or combined effectiveness. OBJECTIVE: To evaluate the effectiveness of 4 treatments among adolescents with major depressive disorder. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of a volunteer sample of 439 patients between the ages of 12 to 17 years with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder. The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003. INTERVENTIONS: Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone, (3) CBT with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10 to 40 mg/d). Placebo and fluoxetine alone were administered double-blind; CBT alone and CBT with fluoxetine were administered unblinded. MAIN OUTCOME MEASURES: Children's Depression Rating Scale-Revised total score and, for responder analysis, a (dichotomized) Clinical Global Impressions improvement score. RESULTS: Compared with placebo, the combination of fluoxetine with CBT was statistically significant (P =.001) on the Children's Depression Rating Scale-Revised. Compared with fluoxetine alone (P =.02) and CBT alone (P =.01), treatment of fluoxetine with CBT was superior. Fluoxetine alone is a superior treatment to CBT alone (P =.01). Rates of response for fluoxetine with CBT were 71.0% (95% confidence interval [CI], 62%-80%); fluoxetine alone, 60.6% (95% CI, 51%-70%); CBT alone, 43.2% (95% CI, 34%- 52%); and placebo, 34.8% (95% CI, 26%-44%). On the Clinical Global Impressions improvement responder analysis, the 2 fluoxetine-containing conditions were statistically superior to CBT and to placebo. Clinically significant suicidal thinking, which was present in 29% of the sample at baseline, improved significantly in all 4 treatment groups. Fluoxetine with CBT showed the greatest reduction (P =.02). Seven (1.6%) of 439 patients attempted suicide; there were no completed suicides. CONCLUSION: The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder.

JAMA, 292(7) : 807- 20

Merry, Sally, McDowell, Heather, Wild, Chris J., Bir, Julliet, Cunliffe, Rachel

A randomized placebo-controlled trial of a school-based depression prevention program

OBJECTIVE: To conduct a placebo-controlled study of the effectiveness of a universal school-based depression prevention program. METHOD: Three hundred ninety-two students age 13 to 15 from two schools were randomized to intervention (RAP-Kiwi) and placebo programs run by teachers. RAP-Kiwi was an 11-session manual-based program derived from cognitive-behavioral therapy. The placebo was similar but with cognitive components removed. Outcomes were self-rated depression scales, the Reynolds Adolescent Depression Scale (RADS), and the Beck Depression Inventory II (BDI-II). Follow-up was to 18 months. Analysis was done on an intent-to-treat basis. RESULTS: Immediately after the intervention, depression scores were reduced significantly more by RAP-Kiwi than by placebo, with a mean difference in change from baseline between groups of 1.5 on BDI-II (CI > 0.38, p =.01) and 2.24 on RADS (CI > 0.22, p =.04). Categorical analysis confirmed significant clinical benefit with an absolute risk reduction of 3% (95% CI, 1-11%, McNemar chi, p =.03), with the \"number needed to treat\" for short-term benefit of 33. Group differences in depression scores averaged across time to 18 months were significant on RADS but not on BDI-II. Retention rates were 91% at 6 months and 72% at 18 months. CONCLUSIONS: The RAP-Kiwi program is a potentially effective public health measure. Confirmation of effectiveness measuring episodes of depressive illness and broader measures of adjustment is warranted.

Journal of the American Academy of Child & Adolescent Psychiatry, 43(5) : 538- 47

Jureidini, J. N., Doecke, C. J., Mansfield, P. R., Haby, M. M., Menkes, D. B., Tonkin, A. L.

Efficacy and safety of antidepressants for children and adolescents

How safe and effective are antidepressants in children and adolescents? The authors of this review have found disturbing shortcomings in the methods and reporting of trials of newer antidepressants in this patient group.

British Medical Journal, 328(7444) : 879-883

DeCuyper, S., Timbremont, B., Braet, C., DeBacker, V., Wullaert, T.

Treating depressive symptoms in schoolchildren: A pilot study

Although studies on sub-threshold depression in childhood and adolescence have demonstrated an at risk profile that merits further attention, only few investigators examined the impact of therapy with these children. In this study, twenty elementary schoolchildren (aged 10-12) with moderate depressive symptoms were randomly assigned to an eighteen-session cognitive- behavioural treatment programme or to a waiting list (WL) control group (= Study 1). The key components of the programme 'Taking Action' used in the study were: affective education, problem-solving, cognitive restructuring and engaging in enjoyable activities. Child self-reports and parent reports were used to evaluate the outcome. Paired t-tests comparing the 4-months follow-up results with baseline measurements, revealed a significant improvement on the Children Depression Inventory and on the Self-Perception Profile for Children, but only in the treatment group. Afterwards, the WL control group was treated as well. All children were followed in a long-term follow-up study (= Study 2). Analyses at the 12 month stage of the follow-up study showed a further improvement of the scores on the Self-Perception Profile. Moreover, a significant decrease was found on the Children Depression Inventory, the State-Trait Anxiety Inventory and the Child Behaviour Checklist parent measure. It was concluded that the protocol is suitable for European children. The most remarkable findings in this pilot study are discussed.

European Child & Adolescent Psychiatry., 13(2) : 105-114

Emslie, Graham J., Heiligenstein, John H., Hoog, Sharon L., Wagner, Karen Dineen, Findling, Robert L., McCracken, James T., Nilsson, Mary E., Jacobson, Jennie G.

Fluoxetine treatment for prevention of relapse of depression in children and adolescents: A double-blind, placebo-controlled study.[see comment]

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

Journal of the American Academy of Child & Adolescent Psychiatry, 43(11) : 1397- 405

Courtney, Darren B.

Selective serotonin reuptake inhibitor and venlafaxine use in children and adolescents with major depressive disorder: A systematic review of published randomized controlled trials

OBJECTIVE: This review critiques published randomized placebo-controlled trials pertaining to the efficacy and safety of selective serotonin reuptake inhibitors (SSRIs) and venlafaxine in the treatment of major depressive disorder in children and adolescents. METHOD: Medline was searched for articles meeting defined inclusion criteria. The following key terms were used: depressive disorders, antidepressive agents, fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine, venlafaxine, child, and adolescent. RESULTS: Six articles met inclusion criteria. Only 2 studies claim efficacy by significant results in primary outcomes; both have since been contested in further analysis. Not one study adequately examines safety, particularly with respect to whether a link exists between antidepressant use and induction of suicidal ideation or attempts. CONCLUSION: Published studies on SSRI or venlafaxine use in children and adolescents are inconclusive with respect to safety and efficacy, owing to inappropriate claims of efficacy, lack of improvement in global functioning scores, nonstandardized data collection regarding adverse effects, exclusion of suicidal subjects in the recruitment process, grouping of children and adolescents together, small sample sizes, conflict of interest posed by pharmaceutical company sponsorship, and publishing bias. Future investigators should consider these factors when developing study designs. [References: 24]

Canadian Journal of Psychiatry, 49(8) : 557- 63

Cohen, David, Gerardin, Priscille, Mazet, Philippe, Purper-Ouakil, Diane, Flament, Martine F.

Pharmacological treatment of adolescent major depression

Antidepressant agents are widely prescribed for adolescents, although specific data regarding their efficacy in this age range are limited. The aims of the present article are to review research findings regarding the use of antidepressant drugs for adolescent depression and to discuss the main results in light of our clinical experience. Only 13 controlled trials on the use of antidepressant drugs for adolescent major depression are available in the literature. Six studies evaluated the efficacy of tricyclic antidepressants, yet they only included 196 adolescents altogether. Seven studies, including a total of 1,403 patients, evaluated the efficacy of three specific serotonin reuptake inhibitors: fluoxetine, paroxetine, and sertraline. Based on published data, serotonin reuptake inhibitors appear to be the first-line psychopharmacologic treatment for adolescent depression, as three compounds (fluoxetine, paroxetine, and sertraline) appeared to be effective in this indication. Conversely, all published studies failed to demonstrate that the tricyclic antidepressants were superior to placebo. Several questions remain open and are discussed: How should we use available scientific data in clinical practice? Are there nonspecific factors implicated in treatment response? Is there a serotonin hypothesis for juvenile depression? What are the priorities for future research? [References: 75]

Journal of Child & Adolescent Psychopharmacology, 14(1) : 19 -31