Martha J. Ignaszewski, MD
Chief Fellow, Clinical Fellow in Psychiatry at Boston Children’s Hospital
Dr. Ignaszewski has disclosed that she has no relevant financial or other interests in any commercial companies pertaining to this educational activity.
CCPR: You recently published an article reviewing the placebo-controlled trials done over the past 10 years on depression in kids(Ignaszewski MJ and Waslick B, J Child Adolesc Psychopharmacol 2018;Epub ahead of print).Can you tell us about your findings? Dr. Ignaszewski: Historically, there’s been a lot of controversy about the effectiveness of antidepressants in children. Some studies have suggested that antidepressants work no better than placebo in depression—but it’s important to note that this has not been the case for non-depressive disorders.
CCPR: You mean they do seem to work for such things as anxiety disorders? Dr. Ignaszewski: Right. There’s more robust evidence for the use of SSRIs and other classes of antidepressants for pediatric anxiety disorders and OCD, where the active treatment actually separates from placebo. The efficacy has been demonstrated to be greatest for non-OCD anxiety, intermediate for OCD, and more modest for major depressive disorder, with numbers-needed-to-treat of 3, 6, and 10, respectively. In 2016, a huge network meta-analysis published in Lancet assessed antidepressant tolerability and comparative efficacy for depression in children and adolescents. They identified 34 studies looking at 14 antidepressant medications through randomized placebo-controlled, double-blinded trials. The researchers concluded that medications offered no clear advantage over placebo for the treatment of pediatric depression when weighed against the risk-benefit profile (Cipriani A et al, Lancet 2016;(10047)388:881–890).
CCPR: Help us understand how your more recent review is different. Dr. Ignaszewski: We based our review on an earlier meta-analysis (Bridge JA et al, JAMA 2007;297(15):1683–1696) and then looked at and compiled the data on randomized controlled trials that were published since then using stringent criteria. We found 7 relevant trials: 4 acute efficacy trials, 2 of which also looked at extension treatment; 1 separate extension trial; and 2 studies that looked at relapse prevention after acute and extended treatment.
CCPR: What were the main findings? Dr. Ignaszewski: First, and not unexpectedly, all of the treatment arms had high rates of placebo effect that likely masked the effects of active treatment. In doing our more focused review, we found that in the research over the last decade, escitalopram and fluoxetine have the best evidence as first-line treatments for pediatric depression. Second—and this was the more striking finding—we found no evidence of an increased signal of emergent suicidality when using these medications.
CCPR: No treatment-emergent suicidality when antidepressants are used with depressed kids? That’s different from what we’ve been hearing in other studies. Dr. Ignaszewski: Correct. Research in the last decade assessing the safety and tolerability of antidepressants in pediatric populations has progressed. There are now more systematic efforts to evaluate for treatment-emergent suicidality and compare to baseline suicidality. This is primarily done through the use of the C-SSRS (Columbia Suicide Severity Risk Scale). Past studies identified only spontaneously reported treatment-emergent symptoms that were not necessarily compared with symptoms at the onset of treatment. With the C-SSRS, the statistical signal that was picked up in other studies was not present in these 7 trials.
CCPR: That alone is a tremendously important finding, given the concerns raised since 2004 and the black box warning. Dr. Ignaszewski: Yes, this was the finding that I found the most compelling, given that one of the major controversies related to the use of antidepressants in this patient population is around safety concerns—specifically treatment-emergent suicidality. Treatment-emergent suicidality has been a major barrier for primary care providers in treating depression, and it also is an understandable concern for anxious parents. These worries have contributed to high rates of undertreatment in many pediatric patients.
CCPR: What about differences in clinical efficacy between different kinds of medications in the treatment of pediatric depression? Tell us about that. Dr. Ignaszewski: We looked at a number of treatments—some of which are seldom used, but these studies were ones that made the cut. For example, we looked at the selegiline transdermal patch and at fixed and flexible duloxetine dosing at acute phase and extension. Escitalopram, fluoxetine, and sertraline were active treatments, and fluoxetine was used as a comparator in some of the research we looked at, in addition to placebo.
CCPR: What did you find? Dr. Ignaszewski: Much as others have, we found really high placebo rates, from 41% at the lowest to almost 70% at the highest. That muddies any response that we’re going to see from active treatment.
CCPR: Did any of the medications show a level of efficacy or response rate greater than placebo? Dr. Ignaszewski: There were only 2 medications that actually separated from placebo. One was escitalopram, which showed better rates of response in both the acute as well as the extension phase. The other was fluoxetine, when used for relapse prevention.
CCPR: It’s interesting that fluoxetine showed separation only in relapse prevention, but not in the acute phase or the extension phase. We usually tout fluoxetine as the medication with the best overall track record. Dr. Ignaszewski: Right. And yet the relapse prevention rate was huge for fluoxetine. The odds ratio demonstrated a 3.2-fold reduction in the relapse rate for fluoxetine in pediatric depression. This might speak more to the methodology and inclusion criteria in these studies rather than the actual “effect” of the medication; there are a number of factors that can conflate the impact of active treatment. It is also important to think about who is involved in the diagnosis and treatment in a trial: Funding from NIMH may require more fidelity in assessment and diagnosis compared to industry studies that may push to rapidly recruit patients, who may not be representative of the clinical population. For example, the inclusion of pre-pubertal children in study samples has been associated with high placebo rates, which may be due to subthreshold depressive illness. Further, patients with severe depression who are at heightened risk for suicide tend to be excluded from studies. The number of study sites is also correlated with high placebo rates and tends to be lower in publicly funded trials.
CCPR: Any word on bupropion? Dr. Ignaszewski: We did not include studies on bupropion because none had been published as randomized controlled trials in the last decade. Bupropion has not been extensively studied in kids. There are a handful of open-label trials that are hard to really compare to specific randomized controlled trials. That huge network meta-analysis from 2016 didn’t include bupropion because they didn’t have any randomized controlled trials to compare it to either.
CCPR: So no help there, and then there are the 2 recent desvenlafaxine trials that were negative studies. Dr. Ignaszewski: Right. Those came after 2016, so I did not include them, but as negative studies a lot of providers may view these results as helpful in guiding us away from desvenlafaxine. Actually, this is one of the points that I talk about in the article: trying to distinguish between “negative trials” and “failed trials.”
CCPR: What do you mean? Dr. Ignaszewski: Well, there are a number of methodological challenges that may contribute to high placebo rates, and it has been suggested that trials with high placebo rates should be considered “failed” rather than “negative.” This notion is supported through differences in outcomes in industry vs publicly funded studies. For example, NIMH studies have a lower placebo response rate at 30%–35%, which is more similar to adult studies; this in turn leads to more substantial between-group differences in placebo vs active treatment. NIMH studies use a number of quality indicators to try to reduce the placebo response rates, such as collection of data about mediating and moderating variables to improve the internal validity of the study sample. Further, efficacy is only one of the major outcomes that is routinely evaluated through experimental research. Trials also provide information about safety and tolerability, which is important for providers to be able to speak about with families.
CCPR: Yes. What about side effect profiles? What did you find to help us differentiate between medications or classes of medications? Dr. Ignaszewski: Essentially, this study showed that the medications, especially the SSRIs, tend to be pretty well tolerated. They do have the expected nuisance side effects early on, such as headaches and a little bit of GI upset. But interestingly, these side effects did not consistently separate significantly from the same side effect rates with placebo treatment. Venlafaxine, on the other hand, was poorly tolerated. It had a series of side effects that really limited ongoing use, and there were higher rates of discontinuation and treatment-emergent adverse effects in comparison to any of the other medications, which is similar to the Cipriani network meta-analysis.
CCPR: How did people tolerate the selegiline patch? Dr. Ignaszewski: Pretty well. The selegiline patch also didn’t have statistically significant side effects. I’m sure that would have been different with the oral form, but I think the transdermal system mitigates a lot of the side effects that you see with oral dosing.
CCPR: Any other thoughts about how this study applies to day-to-day clinical practice? Dr. Ignaszewski: I think the part that I was most excited about, and sort of unexpectedly discovered, was the safety profile of antidepressants in kids, with the use of the C-SSRS to assess for treatment-emergent suicidality. I think it’s really important that the comparison to baseline behaviors didn’t show a statistically significant change in the signal for emergence of suicidality. We all think about the black box warning, and we absolutely need to provide that information in the process of giving informed consent to our families. But when the black box warning came out, there was a dramatic drop in antidepressant prescriptions, followed by a dramatic increase in suicidality.
CCPR: This underlines the importance of continuing research vs calling the risk of emergent suicidality “settled science.” Dr. Ignaszewski: Exactly. I think that as newer studies are pursued, we are developing more refined tools that better equip us to look carefully at issues that we are concerned about. With continued research, we may not find that same increased risk, and that’s going to actually tip the balance more in favor of treating with those medications that are also proving efficacious. As providers, this new finding really shifts the balance of safety and our efforts to weigh the balance of risks to benefits. I think this is so important because as psychiatrists, we know that the biggest risk for suicidal ideation, attempts, and completion is untreated depression—so we want to see kids receiving appropriate treatment and recovering from it.