Text version
Thirty [percent] to 50% of adolescents with depression don’t respond to their first treatment, and about 10% don’t improve despite multiple trials of standard treatment. What else can you do in that case? What does work in child and adolescent depression besides the routine first-line approaches?
Hi! Jim Phelps here for the Psychopharmacology Institute. You remember, of course, the first-line approaches for depression in children and adolescents. According to several recent reviews, these are cognitive–behavioral therapy, interpersonal therapy, fluoxetine, and escitalopram. This twin pair of Quick Takes looks at treatment options for children who have not responded to these first-line treatments. The review that we’re looking at is so full of relevant options that I split this Quick Take into 2 parts.
In part 1, here, I’ll offer you a quick review of the TADS—the Treatment for Adolescents with Depression Study, one of the key studies underlying those first-line recommendations. Then we’ll look at some of the pharmaceutical options from this new article by Kathryn Cullen and colleagues. In part 2 of this Quick Take pair, we’ll look at the nonpharmaceutical approaches that Cullen et al. reviewed.
The TADS study was a head-to-head trial of cognitive–behavioral therapy alone vs fluoxetine alone vs their combination with a placebo control group for the first 3 months. In this study, CBT was designed to peak at 18 weeks. Sure enough, at that point, response rates were equivalent to fluoxetine alone, with 65% response for CBT and 69% response for fluoxetine in this study of 327 12-to-17-year-olds. The combination of CBT plus fluoxetine was significantly better than either alone, including achievement of a faster response rate of 71% at 12 weeks.
In case you have not fully developed your own version of CBT for adolescents or would like to make sure that you’re using a research-tested approach, we’ve linked a PDF of the 250-page TADS manual for CBT here at the Psychopharmacology Institute. Now, this sounds huge, but just look it over quickly. It consists of session guides, including goals, handouts, homework, and even suggested dialogue lines for crucial steps for both acute and maintenance stages of treatment. With this manual in hand and perhaps some practice, you or one of your therapist colleagues can offer something very like the CBT that was used in the TADS study.
But let’s say your child or adolescent patient has tried at least 1 of those psychotherapies and both fluoxetine and escitalopram, all with what you regard as adequate trials. This is the point in which you’d start thinking about alternatives. Don’t forget the adage that when your treatment isn’t working, reconsider your diagnosis. Is there something you’re missing?
For more treatment options, we can turn to this new review by Cullen et al, which is titled “New Somatic Therapies for Child and Adolescent Depression.” In this review, psychotherapies were not examined, but the authors reviewed 4 other classes of treatment, which were pharmaceuticals; nutraceuticals; sensorimotor interventions, like yoga, light therapy; and neuromodulation, including ECT, TMS, and vagus nerve stimulation. Inclusion of the latter gives you an idea of how widely the authors have thrown their net in this review.
To wrap up part 1 of this Quick Take, let’s take a quick look at the antidepressants. What’s new there, if anything? Well, vilazodone had one randomized trial in children in which the active treatment group did not separate from placebo, but even fluoxetine, which did well relative to placebo in the TADS Study, had in more recent studies failed to separate from placebo. It has been speculated that this is due to an increase in response rates to placebo, making it harder for a new treatment to show statistical superiority. Why the placebo response rate increase? Well, big studies can require multiple research centers to recruit a sufficient sample, and that incentivizes recruitment such that screening for really sick children who are less likely to respond to placebo is less extensive. This increases the potential for the control group to do well and thus the experimental treatment to fail to separate from placebo. A bigger sample could address the problem but increases the recruitment incentive, creating a vicious cycle. For reviews of this problem, see the article by Li in the reference list of this Quick Takes, as well as this article by Rutherford and colleagues, which is linked here in Psychopharmacology Institute.
As a further example of this problem, take desvenlafaxine, which had a randomized trial in children 7-to-17-year-olds. Neither of the desvenlafaxine doses separated from placebo. In another study, which was a head-to-head trial of desvenlafaxine vs fluoxetine, neither of these medications separated from placebo. Does that mean that antidepressants just actually don’t work so well in children and adolescents? Or is the observed lack of efficacy a research artifact? This isn’t clear and is actively debated, but perhaps you can see why I emphasized the TADS CBT manual earlier.
To conclude Cullen’s review of antidepressants for children, they noted that randomized trials of levomilnacipran and vortioxetine have randomized trials underway, including vortioxetine vs an active comparator—namely, fluoxetine. Finally, what about ketamine and esketamine in children and adolescents? There are randomized trials underway but no results yet.
In summary, new antidepressants have not shown efficacy in child and adolescent depression, although further trials are underway.
In part 2 of this Quick Take, we’ll see that the other 3 modalities they reviewed, such as nutraceuticals, sensorimotor system interventions, and neuromodulation, have randomized trials worth examining.
Abstract
New Somatic Treatments for Child and Adolescent Depression
Kathryn R Cullen, Laura E Padilla, Victoria N Papke, Bonnie Klimes-Dougan
Purpose of review: Depression is a common clinical problem in youth, with prevalence increasing significantly during the adolescent period. Although several evidence-based treatments are currently available for treating depression in adults, only a subset of these have been investigated in a pediatric sample. Unfortunately, even well-established, first-line interventions do not lead to sufficient treatment response for many children and adolescents suffering from depression. However, recent research has been conducted in the area of somatic treatments for youth with depression. This review focuses on current (past three years, including published results and ongoing studies) research on somatic treatments for adolescent depression in the following categories: psychopharmacology, nutraceuticals, interventions implicating motor and sensory systems, and neuromodulation.
Findings: Results from recent randomized, controlled trials testing psychopharmacological options suggest that while antidepressants that have been recently approved for adult patients are safe and tolerable in children and adolescents, none have yet outperformed performed placebo in efficacy. Nutraceuticals, motor-sensory interventions, and neuromodulation techniques, present safe and promising results, but few have been tested against controls to support effectiveness over current treatment options.
Summary: This review of research on pediatric depression treatment from the past 3 years highlights some disappointments (negative results following some of the well-designed clinical trials) and gaps (preliminary studies in need of follow up with robust methodology) but also some promising directions in research of the efficacyof these treatments in a pediatric sample. We offer suggestions for future research including consideration of treatment timing, sequencing, the role of symptom severity in directing treatment selection, the potential value of combined treatments, consideration of how to best account for high placebo response rates, and the incorporation of neurobiological assessments to examine mechanisms and biomarker predictors of treatment response.
Download PDF and other files
Reference
- Cullen, K. R., Padilla, L. E., Papke, V. N., & Klimes-Dougan, B. (2019). New somatic treatments for child and adolescent depression. Current Treatment Options in Psychiatry, 6(4), 380-400.
- Li, Y., Huang, J., He, Y., Yang, J., Lv, Y., Liu, H., … & Li, L. (2019). The impact of placebo response rates on clinical trial outcome: A systematic review and meta-analysis of antidepressants in children and adolescents with major depressive disorder. Journal of Child and Adolescent Psychopharmacology, 29(9), 712-720.
- Rutherford, B. R., Pott, E., Tandler, J. M., Wall, M. M., Roose, S. P., & Lieberman, J. A. (2014). Placebo response in antipsychotic clinical trials. JAMA Psychiatry, 71(12), 1409.
Related References
- Li, Y., Huang, J., He, Y., Yang, J., Lv, Y., Liu, H., … & Li, L. (2019). The impact of placebo response rates on clinical trial outcome: A systematic review and meta-analysis of antidepressants in children and adolescents with major depressive disorder. Journal of Child and Adolescent Psychopharmacology, 29(9), 712-720.
- Rutherford, B. R., Pott, E., Tandler, J. M., Wall, M. M., Roose, S. P., & Lieberman, J. A. (2014). Placebo response in antipsychotic clinical trials. JAMA Psychiatry, 71(12), 1409.
