Identifying the best treatment for young people with depression

What do we know about the treatment of young people with depression? With a deceleration in the number of new studies of medication and psychotherapy, we would hope that the answer would be straightforward. However, nearly two decades into the new millennium, we continue to meta-analyse a limited body of clinical trials in the hope of providing guidance to the field. In The Lancet Psychiatry, Xinyu Zhou and colleagues¹ present the results of a network meta-analysis of 71 trials of psychotherapy, pharmacotherapy, or psycho-therapy plus pharmacotherapy in young people with major depressive disorder. Consistent with previous meta-analyses, the authors found fluoxetine (alone or in combination with cognitive behavioural therapy [CBT]) more efficacious than placebo, although, the efficacy of fluoxetine plus CBT did not differ from the efficacy of fluoxetine alone (−0·22, 95% credible Interval [CrI] −0·86 to 0·42). Also, in this analysis, only interpersonal therapy was more effective than all psychological controls (95% CrI −1·37 to −0·66). The study raises several important points for clinicians and policy makers.

First, fluoxetine was the only selective serotonin reuptake inhibitor (SSRI) that was more effective than pill placebo or psychological controls in this meta-analysis. Although SSRIs differ slightly in their chemical structure, their pharmacodynamic properties are similar.² As a class, the response rates of SSRIs are similar in paediatric depression RCTs; placebo response rates varied, but not efficacy rates.3 Therefore, fluoxetine’s effectiveness in this, and other meta-analyses, might be a historical artifact. Fluoxetine was the first SSRI to market and the first and only medication tested in US federally funded depression studies.^4,5 Emslie and colleagues⁴ and the Treatment of Adolescents with Depression Study (TADS)⁵—the only two studies in the meta-analyses that used quality implementation methods that allowed the placebo response rate to be low enough (30–35%) to identify drug–placebo differences—contributed substantially to the finding of efficacy. Other SSRIs were evaluated only in industry-sponsored studies and to a great extent under the financial incentive of the Food and Drug Administration Modernization Act of 1997. We posit that industry-sponsored trials were and continue to be associated with a myriad of implementation challenges (large number of sites, few patients per site, and prepubertal patients to name a few) that boosted placebo response, including the registration trials of escitalopram that led subsequently to approval by the US Food and Drug Administration for teens with depression. Such trials should be considered failed, not negative trials, and are not suitable to be included in meta-analyses.³ Thus, clinicians considering an SSRI for a paediatric patient with depression should not narrowly interpret meta-analytically derived estimates of effect size, but should consider key differences among SSRIs, such as tolerability6 or pharmacokinetics (eg, linear vs non-linear kinetics, half-life, and drug–drug interactions).⁷

Second, debate about the association of SSRIs and serotonin-norepinephrine reuptake Inhibitors (SNRIs) with suicidal thinking and behaviour continues, given the absence of a clear mechanism for the association. In this meta-analysis, the SNRI, venlafaxine was associated with increased suicidality (odds ratio 8·31, 95% CrI 1·92–343·17) compared with ten other interventions. This finding is consistent with evidence that venlafaxine is poorly tolerated in young people and associated with greater treatment-emergent suicidality,8 and sup-ports recommendations to use SSRIs before SNRIs in paediatric anxiety and depressive disorders.⁹ Moreover, suicidal thinking and behaviour are complex and likely associated with multiple factors: pharmacological factors (adherence and withdrawal), disorder risk (anxiety and depression), and interpersonal influences (family and peer relationships). Consideration of these factors should lead to caution not just with prescribing but with the psychological management of young people with anxiety and depression.

Third, interpersonal therapy—and not CBT—was more effective than all psychological controls. Being more generically focused on changing cognitions and behaviours, some forms of CBT might be developmentally incongruent for younger children. Including child depression CBT studies in a meta-analysis might skew the results inappropriately to favour interpersonal therapy. Although there is ongoing debate regarding whether non-specific versus specific factors make psychotherapy effective, there is an increasing focus on making psychotherapy more precise and personalised. Interpersonal therapy might inherently do this through its focus on here-and-now patient-specific factors that perpetuate depressive symptoms in adolescents (eg, grief and loss, role disputes and transitions, and interpersonal deficits) and might offer a true advantage over CBT.

At this juncture, few new paediatric pharmacotherapy studies are being done, except as regulatory agencies compel them. Innovations in psychotherapy are modest and focus largely on expanding delivery options and optimising efficiency.¹⁰ The accelerating rate at which we meta-analyse these studies and the decelerating rate of new well-controlled clinical trials in young people creates a precarious imbalance in evidence-based medicine. Meta-analysing existing data is no substitute for new and innovative intervention studies in improving outcomes in child and adolescent psychiatry. Network meta-analyses like the one by Zhou and colleagues have value in helping clinicians compare treatments. However, they might increase the risk that clinicians and policy makers misinterpret them as narrowing treatment choices and obscuring the nuance that is crucial to interpreting and contextualising findings from individual trials. It is quite likely that a properly assessed child or adolescent with depression who is well-matched to an SSRI and any evidence-based, flexible psychotherapy will do well.