From efficacy to pragmatic trials: does the dodo bird verdict apply?
Authors: Joan Asarnow, Dennis Ougrin
Journal: The Lancet Psychiatry (2016)

“Everybody has won, so all shall have prizes”, concluded the dodo bird in Alice in Wonderland upon judging a race. Despite advances in treatment and the science upon which our treatments are built, the question of whether the dodo bird verdict continues to apply to our psychotherapy evidence1Luborsky L Rosenthal R Diguer L et al.The dodo bird verdict is alive and well—mostly.Clin Psychol Sci Pract. 2002; 9: 2-12Crossref Scopus (398) Google Scholar is emphasised by results of Ian Goodyer and colleagues' IMPACT trial in The Lancet Psychiatry.2Goodyer IM Reynolds S Barrett B et al.Cognitive behavioural therapy and short-term psychoanalytical psychotherapy versus a brief psychosocial intervention in adolescents with unipolar major depressive disorder (IMPACT): a multicentre, pragmatic, observer-blind, randomised controlled superiority trial.Lancet Psychiatry. 2013; (published online Nov 30.)http://dx.doi.org/10.1016/S2215-0366(16)30378-9Google Scholar This pragmatic randomised controlled superiority trial compares three treatments in adolescents with unipolar major depressive disorder as delivered across diverse specialist mental health clinics in the UK health system: cognitive behavioural therapy (CBT), short-term psychoanalytical psychotherapy, and brief psychological intervention—the comparator treatment. Results indicate improvements over time for all three treatment conditions. However, the primary outcome of self-reported depressive symptoms, measured with the Mood and Feelings Questionnaire, did not differ significantly between groups at 36, 52, or 86 weeks post-randomisation, nor did the two hypothesised effective treatments (CBT and short-term psychoanalytical psychotherapy) lead to significantly greater benefits compared with the brief psychological intervention. Total costs of the trial interventions did not differ significantly between groups. These results give the field a well needed jolt. Research advances have sparked efforts to move from bench to bedside and implement evidence-based treatments to improve patient outcomes. The long delays between scientific discoveries and translation into clinical practice have been tackled through various mechanisms, including systematic reviews, evidence-based treatment registries, and policies that encourage or incentivise evidence-based treatments.3Asarnow JR Miranda J Improving care for depression and suicide risk in adolescents: innovative strategies for bringing treatments to community settings.Annu Rev Clin Psychol. 2014; 10: 275-303Crossref PubMed Scopus (34) Google Scholar Yet results of this pragmatic trial point to similar effectiveness of three different treatment strategies varying in levels of supporting evidence. CBT for depression has strong supporting evidence and is considered a well established treatment for adolescents with depression.3Asarnow JR Miranda J Improving care for depression and suicide risk in adolescents: innovative strategies for bringing treatments to community settings.Annu Rev Clin Psychol. 2014; 10: 275-303Crossref PubMed Scopus (34) Google Scholar, 4Brent DA Emslie G Clarke G et al.Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial.JAMA. 2008; 299: 901-913Crossref PubMed Scopus (468) Google Scholar, 5Spirito A Esposito-Smythers C Wolff J Uhl K Cognitive-behavioral therapy for adolescent depression and suicidality.Child Adolesc Psychiatr Clin N Am. 2011; 20: 191-204Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar Evidence is weaker for short-term psychoanalytical psychotherapy; to our knowledge, no randomised controlled trial has shown the efficacy of this intervention relative to a control or comparator condition in adolescents with depression.2Goodyer IM Reynolds S Barrett B et al.Cognitive behavioural therapy and short-term psychoanalytical psychotherapy versus a brief psychosocial intervention in adolescents with unipolar major depressive disorder (IMPACT): a multicentre, pragmatic, observer-blind, randomised controlled superiority trial.Lancet Psychiatry. 2013; (published online Nov 30.)http://dx.doi.org/10.1016/S2215-0366(16)30378-9Google Scholar, 6Abbass AA Rabung S Leichsenring F Refseth JS Midgley N Psychodynamic psychotherapy for children and adolescents: a meta-analysis of short-term psychodynamic models.J Am Acad Child Adolesc Psychiatry. 2013; 52: 863-875Summary Full Text Full Text PDF PubMed Scopus (89) Google Scholar In the IMPACT trial, the brief psychological intervention was delivered mostly by psychiatrists (84%), included known active treatment components from CBTs (eg, problem solving, encouragement of pleasant activities), and when combined with fluoxetine yielded effects similar to those noted for CBT, fluoxetine, and brief psychological intervention combined at 28 weeks in a previous study.7Goodyer I Dubicka B Wilkinson P et al.Selective serotonin reuptake inhibitors (SSRIs) and routine specialist care with and without cognitive behaviour therapy in adolescents with major depression: randomised controlled trial.BMJ. 2007; 335: 142Crossref PubMed Scopus (291) Google Scholar The results of IMPACT raise questions about the effectiveness of all three treatments (combined with SSRIs in 36–41% of adolescents in each treatment group), and suggest that most psychotherapies will be “winners” on the basis of non-specific treatment factors, or alternatively that each treatment might contain distinct specific factors that contribute to recovery. One caveat to consider in this trial is that passage of time might have accounted for improvements in clinical symptoms. The morbidity of adolescent depression ethically precludes a no-treatment comparator, but most major depressive episodes resolve over time, with recovery estimates as high as 90–100%.8Asarnow JR Jaycox LH Tang L et al.Long-term benefits of short-term quality improvement interventions for depressed youths in primary care.Am J Psychiatry. 2009; 166: 1002-1010Crossref PubMed Scopus (61) Google Scholar, 9Kovacs M Obrosky S George C The course of major depressive disorder from childhood to young adulthood: Recovery and recurrence in a longitudinal observational study.J Affect Disord. 2016; 203: 374-381Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 10Birmaher B Brent D Bernet W et al.Practice parameter for the assessment and treatment of children and adolescents with depressive disorders.J Am Acad Child Adolesc Psychiatry. 2007; 46: 1503-1526Summary Full Text Full Text PDF PubMed Scopus (674) Google Scholar Although risk of relapse or recurrence (the study target) is high and estimated to be as high as 71%,9Kovacs M Obrosky S George C The course of major depressive disorder from childhood to young adulthood: Recovery and recurrence in a longitudinal observational study.J Affect Disord. 2016; 203: 374-381Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 10Birmaher B Brent D Bernet W et al.Practice parameter for the assessment and treatment of children and adolescents with depressive disorders.J Am Acad Child Adolesc Psychiatry. 2007; 46: 1503-1526Summary Full Text Full Text PDF PubMed Scopus (674) Google Scholar the study endpoint (86 weeks post-randomisation, 52 weeks post-treatment) might have been too short to detect these effects.8Asarnow JR Jaycox LH Tang L et al.Long-term benefits of short-term quality improvement interventions for depressed youths in primary care.Am J Psychiatry. 2009; 166: 1002-1010Crossref PubMed Scopus (61) Google Scholar Pragmatic trials, such as IMPACT, evaluate treatments as delivered in routine practice, allowing for additions to the therapy under investigation—eg, treatment protocols, manuals, and treatment adherence monitoring. Treatment dose, training, and quality assurance protocols are often weaker in these trials than in highly controlled efficacy trials.3Asarnow JR Miranda J Improving care for depression and suicide risk in adolescents: innovative strategies for bringing treatments to community settings.Annu Rev Clin Psychol. 2014; 10: 275-303Crossref PubMed Scopus (34) Google Scholar Indeed, CBT adherence in IMPACT was modest relative to that for efficacy trials (74% of IMPACT CBT sessions met fidelity criteria vs 94–95% in the TORDIA study4Brent DA Emslie G Clarke G et al.Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial.JAMA. 2008; 299: 901-913Crossref PubMed Scopus (468) Google Scholar), and the treatment adherence measure was not designed specifically for CBT. Although the tight control in efficacy trials done in highly controlled (often laboratory) settings, with rigorous therapist training and quality assurance monitoring, is crucial for identification of active treatment components and mechanisms, these controls are not generally achievable in routine specialist mental health clinics.3Asarnow JR Miranda J Improving care for depression and suicide risk in adolescents: innovative strategies for bringing treatments to community settings.Annu Rev Clin Psychol. 2014; 10: 275-303Crossref PubMed Scopus (34) Google Scholar What really matters to individuals living with depression is the benefits of treatments available in their clinics. Unfortunately, treatments as delivered in routine mental health settings and pragmatic trials might be less effective than in laboratory-based efficacy trials, with evidence pointing to stronger treatment effects when more efficacy design components are present.3Asarnow JR Miranda J Improving care for depression and suicide risk in adolescents: innovative strategies for bringing treatments to community settings.Annu Rev Clin Psychol. 2014; 10: 275-303Crossref PubMed Scopus (34) Google Scholar, 11Asarnow JR Rozenman M Integrating depression treatment within primary care improves outcomes in adolescents.Evid Based Ment Health. 2015; 18: 94Crossref PubMed Scopus (4) Google Scholar Cross-national variability could also account for some differences between the IMPACT results and those of US trials in which CBT has frequently, but not always, shown advantages over strong comparator conditions, such as supportive therapy or family therapy.3Asarnow JR Miranda J Improving care for depression and suicide risk in adolescents: innovative strategies for bringing treatments to community settings.Annu Rev Clin Psychol. 2014; 10: 275-303Crossref PubMed Scopus (34) Google Scholar, 4Brent DA Emslie G Clarke G et al.Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial.JAMA. 2008; 299: 901-913Crossref PubMed Scopus (468) Google Scholar, 5Spirito A Esposito-Smythers C Wolff J Uhl K Cognitive-behavioral therapy for adolescent depression and suicidality.Child Adolesc Psychiatr Clin N Am. 2011; 20: 191-204Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 10Birmaher B Brent D Bernet W et al.Practice parameter for the assessment and treatment of children and adolescents with depressive disorders.J Am Acad Child Adolesc Psychiatry. 2007; 46: 1503-1526Summary Full Text Full Text PDF PubMed Scopus (674) Google Scholar Variation exists across types of CBT for depression, and site differences are common in trials of depression treatment,12Spirito A Abebe KZ Iyengar S et al.Sources of site differences in the efficacy of a multisite clinical trial: the Treatment of SSRI-Resistant Depression in Adolescents.J Consult Clin Psychol. 2009; 77: 439-450Crossref PubMed Scopus (21) Google Scholar although are not apparent in the present study. The CBT given in IMPACT might have been less effective than that used in trials demonstrating efficacy. Review of the IMPACT adherence scales and CBT manual suggests that, compared with other types of CBT, the IMPACT model was more didactic, less youth friendly, and might have had less emphasis on elements viewed as preconditions for CBT efficacy (eg, therapist active listening and observation, collaborative agenda setting).4Brent DA Emslie G Clarke G et al.Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial.JAMA. 2008; 299: 901-913Crossref PubMed Scopus (468) Google Scholar, 8Asarnow JR Jaycox LH Tang L et al.Long-term benefits of short-term quality improvement interventions for depressed youths in primary care.Am J Psychiatry. 2009; 166: 1002-1010Crossref PubMed Scopus (61) Google Scholar The IMPACT trial advances our knowledge and highlights directions for future research. If many of our treatments are “winners,” then a key task is to identify the elements that contribute to this common effectiveness. In our enthusiasm for translation of science to clinical practice, we might have overemphasised evidence-based treatments and not attended sufficiently to treatment processes that lead to efficacy of diverse treatments, such as the therapeutic alliance or monitoring of patient outcomes or using tools such as clinical dashboards to guide evidence-based decision making. Identification of treatments and treatment elements with minimal adverse effects is also important, and many adolescents continue to report depressive symptoms despite diagnostic remission in IMPACT and other trials.2Goodyer IM Reynolds S Barrett B et al.Cognitive behavioural therapy and short-term psychoanalytical psychotherapy versus a brief psychosocial intervention in adolescents with unipolar major depressive disorder (IMPACT): a multicentre, pragmatic, observer-blind, randomised controlled superiority trial.Lancet Psychiatry. 2013; (published online Nov 30.)http://dx.doi.org/10.1016/S2215-0366(16)30378-9Google Scholar, 10Birmaher B Brent D Bernet W et al.Practice parameter for the assessment and treatment of children and adolescents with depressive disorders.J Am Acad Child Adolesc Psychiatry. 2007; 46: 1503-1526Summary Full Text Full Text PDF PubMed Scopus (674) Google Scholar Consistent with personalised medicine, tailoring of treatments for individual young people might be crucial to achievement of optimal benefits. Genetic, hormonal, brain-imaging, stress, and other forthcoming data from the IMPACT trial will enable analyses exploring variation and mechanisms of treatment response, enhancing knowledge for personalised approaches and the innovative contributions of this study. Finally, more research aimed at understanding key elements and mechanisms contributing to treatment effectiveness are needed in both controlled and pragmatic trials before a firm conclusion regarding the dodo bird verdict is applied. We declare no competing interests. Cognitive behavioural therapy and short-term psychoanalytical psychotherapy versus a brief psychosocial intervention in adolescents with unipolar major depressive disorder (IMPACT): a multicentre, pragmatic, observer-blind, randomised controlled superiority trialWe found no evidence for the superiority of CBT or short-term psychoanalytical therapy compared with a brief psychosocial intervention in maintenance of reduced depression symptoms 12 months after treatment. Short-term psychoanalytical therapy was as effective as CBT and, together with brief psychosocial intervention, offers additional patient choice for psychological therapy, alongside CBT, for adolescents with moderate to severe depression who are attending routine specialist CAMHS clinics. Full-Text PDF Open Access