COMMENTARY
After TADS, Can We Measure Up, Catch Up, and Ante Up? PETER S. JENSEN, M.D.
This special section, featuring the National Institute of Mental Health (NIMH) Treatment for Adolescents With Depression Study (TADS), is an extraordinary offering for careful readers, researchers, clinicians, and health care policymakers alike. An investigation of major international significance, this study will deservedly be cited for decades to come as one of the preeminent research investigations ever mounted in child and adolescent psychiatry. TADS_ significance and impact derive not just from the study_s findings, but from the many strengths characterizing TADS: its unique design, expert investigator team, careful study execution, rigorous quality controls and monitoring, and state-of-the-art data analysis. Yet surprisingly, from this commentator_s perspective, TADS has generated some modest controversy, not because of the study_s strengths, but because of the use of a psychotropic agent for a not wellunderstood condition (major depressive disorder [MDD]) and where medication use is easily depicted as malevolent. Although the various conspiracy theories do not hold much sway among the well-educated public and persons who know first-hand how MDD affects adolescentsVwhether depressed adolescents themselves, their parents and families, or those who care for themVthese notions and the larger problem of stigma (Hinshaw, 2005) pose significant, continuing distractions from our purposefully mounting a coherent national agenda to address MDD and related mental health problems in children and adolescents. Accepted July 25, 2006. Dr. Jensen is with the Center for the Advancement of Children_s Mental Health, Department of Psychiatry, Columbia University/New York State Psychiatric Institute, New York. Reprint requests to Dr. Peter S. Jensen, Center for the Advancement of Children_s Mental Health, Department of Psychiatry, Columbia University/ NYSPI, 1051 Riverside Drive, Unit #78, New York, NY 10032; e-mail:
[email protected]. 0890-8567/06/4512-1456 Ó2006 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.chi.0000237712.81378.9d
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The significance of this study resides in some basic facts, beginning with the characteristics of the sample, highlighted in the first paper in the Special Section by March et al. Note that mean depression scores on the clinician-completed Child Depression Rating Scale (CDRS) were at the 98th percentile. In addition, average Clinical Global Impressions-Severity scores were 4.77 (1 = normal, 2 = borderline, 3 = mild, 4 = moderate, 5 = marked, 6 = severe, 7 = extremely severe impairment), as judged by the clinician. These are average scores, with many children scoring at even more severely impaired levels. WHAT TADS HAS SHOWN
In response to the high level of clinical need among the TADS youth with MDD, the initially reported findings (March et al., 2004) documented the acute benefits of two of the four 12-week-long treatment groups, namely, fluoxetine alone (FLX) and FLX combined with cognitive-behavioral therapy (CBT) (COMB) versus CBT alone, and placebo (PBO). Response rates for COMB and FLX were 71% and 61%, respectively, both significantly better than CBT (43%) and PBO (35%). CBT and PBO did not differ from each other. The articles in this section extend these initial findings in important ways and underscore the public health impact of evidence-based MDD treatment options. Thus, the likelihood of complete recovery (remission rates), impact on quality of life and overall functioning, and speed of recovery were also significantly better in various treatment groups, with COMB generally offering the greatest benefits over either single form of treatment (FLX, CBT) and PBO (see articles in this special section by Kennard et al., Kratochvil et al., and Vitiello et al.). Of great interest to clinicians and families alike who are on the frontlines in considering the merits of MDD treatment options, the various treatments were differentially effective for specific
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COMMENTARY
youths, depending on age, depression severity, degree of cognitive distortion, and family income (Curry et al., 2006). In terms of risk-benefit considerations, COMB generally offered a better safety profile than FLX alone (Emslie et al., 2006). All together, the findings reported in this series will allow clinicians and families to make wiser choices for specific youths with MDD, with COMB generally offering the greatest benefit in most but not all instances, with some of the findings highlighting certain circumstances where either CBT or FLX alone may be a sensible starting point. It is heartening to note, particularly in light of the media frenzy concerning suicidal behavior presumably precipitated by selective serotonin reuptake inhibitors, that both suicidal ideation and behavior dramatically improved in all four groups, rather than being specifically worsened in the selective serotonin reuptake inhibitor-only group (Emslie et al., 2006). Although TADS analyses do suggest that suicidal ideation and behavioral incidents were greater at study endpoint in the FLX group, compared with both PBO and CBT, it should be noted that the study did not provide a notreatment control group and that, again, suicidal ideation and behavior improved across all four arms (March et al., 2004). The notion that medications increase suicidality, as is assumed in the popular press, cannot be given much credence in this study. Rather, residual levels of suicidality remained somewhat higher in the FLX group, albeit still at low levels (8% versus 2%). Only the inclusion of a no-treatment group could address the question of whether medications are specifically related to increased suicidal ideation and behavior, compared to the normal waxing and waning of depression in depressed youths at follow-up periods. As March et al. (2006) suggest, Bdoing nothing^ would certainly have proven to be the worst of all choices, had that been an acceptable and ethical study design option. WHAT TADS HAS NOT DONE
End of story? Hardly. The evidence presented here indicates that even the most effective treatment (COMB) did not achieve nearly enough for many youths. Thus, Vitiello et al. (2006) note in their report that despite COMB_s benefits, almost two thirds (65%) of COMB-treated subjects remained substantially impaired by study_s end. Even greater proportions of FLX, CBT, and PBO youth continued to experience substantial impairment (80%, 86%, and 81%, respec-
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tively). Similarly, examining remission rates, Kennard et al. (2006) found that only 37% of COMB-treated subjects had achieved full remission compared to 23%, 16%, and 17% of FLX-, CBT-, and PBO-treated youth. Thus, despite clinical improvements with active treatments, the ravages of adolescent depression remained largely unabated for most TADS youth, with the majority of treatment responders evincing significant residual symptoms despite the fact that TADS investigators provided these youths the best that science has to offer at this point. Rather than rest on our TADS laurels, let us consider these findings with several other generally well-accepted facts: most youths with MDD are not identified and receive no form of treatment within the year that their depression is identified (Leaf et al., 1996) or even by the end of adolescence (Kessler et al., 2001). MDD is the most common condition linked to suicide, the third leading cause of death among 10- to 19-year-olds in data presented by the Centers for Disease Control and Prevention in 2004. Furthermore, available data suggest that MDD rates are rising throughout the developing world, including among youth (Cross-National Collaborative Group, 1993; Kessler et al., 1994; Kessler and Walters, 1998). BEYOND TADS: CAN WE MEASURE UP?
In view of the TADS findings of less than optimal outcomes for many youths, coupled with the known impact of adolescent MDD on adult outcomes (Kessler et al., 2001), we as a field urgently need to find treatments and treatment combinations that work for more of our affected youth. Substantial impairment among two thirds of the sample after treatment is hardly the gold standard we seek. Developing more effective approaches is within our grasp. Achieving this will require a new research agenda. Less certain is whether we as a field will rise to meet this challenge. New Combinations of Existing Treatments
Quite possibly, among those youths who did not obtain an optimal response to COMB (the most effective approach for the largest proportion of TADS youth), some of them may in fact have responded had they been offered instead either a different form of medication (e.g., another selective serotonin reuptake inhibitor), a different psychotherapy (e.g., interpersonal therapy [IPT]; Mufson et al., 2004), both, or even more
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JENSEN
complex medication or therapy combinations. However, without new studies that now examine which of the other currently available treatment alternatives (alone or in combination) are effective for COMB nonresponders, many youths with MDD, along with their current and future families, will continue to experience the ravages of depression. Such strategic approaches, in other words, programmatic, National Institutes of HealthYfunded, step-by-step investigations that build on the findings of previous studies by testing new treatments and novel combinations against the currently best available methods, have yielded enormous advances in cancer, human immunodeficiency virus, and cardiovascular treatments in the past 2 decades, and from a scientific perspective could readily be applied here. New Treatments
Unfortunately, truly novel compounds for the psychiatric disorders (i.e., medications that target different receptors, or therapies that address different psychosocial risk factors) are few and far between. In this area, the search for genes may have important implications because robust and replicable genetic findings for specific disorders may lead to the development of new compounds that target those brain receptors. Likewise, identification of new psychotherapeutic strategies that target specific brain regions linked to aberrant psychosocial processes linked to depression may also prove useful. In this sense, neuroimaging studies coupled with cognitive tasks that target, elicit, and ameliorate specific cognitive and affective processes may eventually yield payoffs in identifying new MDD psychotherapeutic and pharmacological intervention strategies. Other strategies seem likely to offer high potential yield for developing newer, more effective treatments. As several commentators have noted, we do not yet know which elements of the currently available depression psychotherapies are most effective (Chorpita et al., 1998; Jensen et al., 2005; Kazdin, 2004). For example, in current approaches such as CBT and IPT that are essentially Bpackages^ of many specific procedures, what are the relative benefits of mood monitoring and psychoeducation? Of encouraging depressed youth to get out of the house and reenter peer activities? Of teaching them to dispute their negative beliefs? Or of assisting them to develop new coping strategies? We do not have firm knowledge
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about which aspects of current interventions are most effective nor of which subjects may be most responsive to cognitive-behavioral intervention versus psychopharmacologic interventions. TADS data in this special section are useful in this regard, but these interesting findings (Curry et al., 2006) are preliminary and will need replication. More targeted studies that match patients to treatments, as well as studies of which specific therapeutic processes are active (or inactive) on a subject-by-subject basis, are required. Both of these research strategiesVnew studies of existing treatments and treatment combinations and new treatments altogetherVrequire creative, committed, and well-trained researchers in an era when embarking on such careers is an increasingly uncertain life choice for would-be researchers. As a field, will we and can we measure up to this challenge? What must we do, both as individual health care professionals and as members of professional organizations committed to the mental health and well-being of children, to make this happen? This is not simply a problem for the federal government to solve, but a problem for all of us professionally committed to these youths and families. BEYOND TADS: CAN WE CATCH UP?
Given the data from TADS indicating promising treatment approaches, how do we close the research-topractice gap and encourage adoption of TADSidentified clinically effective practices so that routine practitioners can catch up? In this regard, new quality improvement studies building upon TADS and recent findings from the Youth Partners in Care study (Asarnow et al., 2005), as well as new treatment guidelines, are urgently needed. The principal question for such studies must focus on how we can better apply findings from the TADS and Youth Partners in Care studies that have shown what can be done under relatively optimal conditions, so that many more health care providers learn to effectively identify depressed youths with MDD and then apply better than Busual care^ methods for intervening with these youths and their families. In particular, given the great national shortage of child and adolescent psychiatrists (Kim, 2003), a gap not likely to be addressed anytime in the next 20 years, how might primary care providers in particular be taught these methods? Importantly, recent reviews and study data suggest that a number of reliable and valid tools and intervention
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COMMENTARY
strategies are available that can assist primary care providers to more effectively identify, support, and treat depressed youth, even within the current constraints of primary care settings (Asarnow et al., 2005; Stein et al., 2006; Zuckerbrot and Jensen, 2006). In view of the current gaps in practice, for the health care system to really Bcatch up^ and address the problem, primary care training programs will need to change, incorporating this new knowledge into their residency and postresidency training programs. Likewise, child and adolescent psychiatrist (CAP) training programs will need to place a premium on learning this kind of activity: how does one maintain effective liaisons with and offer Bbackup^ support to primary care physicians (primary care providers [PCPs], both pediatrics and family practice) in working with the bulk of depressed youth, while also assisting them to refer more complicated cases to mental health professionals? Guidelines addressing these issues, with the goal of aiding PCPs to manage adolescent depression (Guidelines for Adolescent Depression: Primary Care have recently been finalized and may help set some of the many necessary changes in motion [Cheung et al., in press]). Importantly, however, Bcatching up^ will also require training of current and future mental health professionals in the use of state-of-art treatment approaches to include new-and-improved versions of CBT, IPT, and other to-be-developed approaches. BEYOND TADS: WILL WE ANTE UP?
The TADS findings have enormous implications for allocation of scarce local, state, and national dollars. In terms of research dollars, NIMH funding decisions for current and future expenditures must be based on open discussion about how much of the federal research budget should go to long-term forays that search for genes of uncertain effect and unclear therapeutic relevance for polygenic disorders, when currently available therapeutic strategies are in hand for depressed youth and their families. Thus, publicly supported taxpayer expenditures must be carefully rethought, and long-term planning of such approaches by National Institutes of Health leaders is urgently needed with families and mental health professionals weighing in on the decision process. Coalitions of public citizens, professional organizations, and parent and family organizations must be formed to foster this agenda and help NIMH forge sustained commitments to this course.
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Changes in how dollars and time are allocated within training programs are also in order. How much of our current CAP or PCP training time is spent buttressing treatment programs that are rarely used in the Breal world,^ such as inpatient care delivered by CAP residents or neonatal intensive care unit rotations by PCP residents? This question is particularly timely, if such programs are done at the expense of teaching CAP residents how to collaborate with PCPs or teaching PCPs how to manage MDD, attention-deficit/hyperactivity disorder, and other conditions. To effectively ante up, we must also consider the larger health care dollar and financing system. Changes must be made in our financing policies and procedures so that PCPs can be reimbursed for delivering depression-related treatments, not just medication treatments, but also counseling and support (Stein et al., 2006), even though these interventions have been typically regarded as Bmental health^ interventions. Just as many PCPs are now reimbursed for delivering attention-deficit/hyperactivity disorder, asthma, or diabetes treatmentsValso easily and equally viewed as the exclusive province of specialistsVso too should our financing systems support a broader base of primary careYbased mental health interventions that are appropriately reimbursed. Given the absence of sufficient numbers of specialists, coupled with new scientific information and treatment tools that will allow more youths effective depression care among well-trained PCPs, the financing system must respond appropriately. Similarly, steps must be taken to support the reimbursement of CAPs_ provision of ongoing training and timely Bbackup^ to PCPs. For such sweeping changes to happen, concerted and sustained coalitions among the key national mental health and primary care professional organizations, family advocacy organizations, and visionary policymakers will be needed to bring about the necessary changes in states_ Medicaid policies, insurance company requirements, and purchasers_ contractual negotiations with health care provider organizations. SUMMING UP
In addition to the challenge and obstacles noted above, stigma and misinformation are rampant and are slowing progress. This misinformation is often passionate, strident, and unrelenting. Often, these voices question the existence of childhood psychiatric disorders and inflame fears of hidden harms caused by psychiatric diagnosis and treatment, medications in particular. These
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voices generally offer nothing in return, so it is instructive to contrast their messages with the facts as we know them: TADS is the largest-ever study supported by taxpayer dollars and operated under the oversight of multiple human subjects review committees, a federally chartered data safety and monitoring board, and multiple universities. The TADS was composed not just of pharmacology researchers, but also of the most experienced and expert depression psychotherapy researchers in the world. The messages emerging from TADS researchers and this special section in particular are twofold: (1) adolescent depression is often a severe, devastating illness in the lives of teens and the families who love and care for them and (2) treatments are available that are better than doing nothing and even better then simple empathy and support, but they are certainly not sufficient for many kids. Thus, we must do more, not just more basic research whose future findings may only be helpful to later generations, but we must redirect our current scientific agenda, including studies of new treatment combinations for those youths that optimal TADS treatments were unable to help, as well as studies of the best means of putting these research findings into practice. In our service system and training programs, redirection and reallocation of priorities and incentives are needed. However, the problems and obstacles are complex and interwoven, and attempts to address any problem are likely to be thwarted by seemingly intractable obstacles in another sphere. Only by strengthening our joint efforts with co-committed professional, scientific, and family advocacy partners can we change our current research, training, and service delivery programs to address these urgent public health issues. Disclosure: The author currently receives investigator-initiated grants from McNeil Pharmaceuticals and unrestricted educational grants from Pfizer, Lilly, and McNeil, participates on the speakers_ bureau of UCB Pharma, Janssen-Ortho, and the Neuroscience Education Institute, and consults with Best Practice, Inc., Janssen Pharma, Novartis, McNeil, and UCB Pharma. REFERENCES Asarnow JR, Jaycox LH, Duan N et al. (2005), Effectiveness of a quality improvement intervention for adolescent depression in primary care clinics: a randomized controlled trial. JAMA 293:311Y319 Centers for Disease Control and Prevention (2004), Unintentional injuries,
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violence, and the health of young people. Available at: http://www.cdc. gov/HealthyYouth/injury/pdf/facts.pdf. Accessed August 1, 2006 Cheung A, Zuckerbrot R, Jensen PS, Laraque D, Stein REK, GLAD-PC Steering Group (in press), Guidelines for adolescent depression in primary care (GLAD-PC). Pediatrics Chorpita BF, Barlow DH, Albano AM, Daleiden EL (1998), Methodological strategies in child clinical trials: advancing the efficacy and effectiveness of psychosocial treatments. J Abnorm Child Psychol 26:7Y16 Cross-National Collaborative Group (1993), The changing rate of major depression: cross-national comparisons. JAMA 268:3098Y3105 Curry J, Rohde P, Simon A et al. (2006), Predictors and moderators of acute outcome in the Treatment for Adolescents With Depression Study (TADS). J Am Acad Child Adolesc Psychiatry 45:1427Y1439 Emslie G, Kratochvil C, Vitiello B et al. (2006), Treatment for Adolescents With Depression Study (TADS): safety results. J Am Acad Child Adolesc Psychiatry 45:1440Y1455 Hinshaw SP (2005), The stigmatization of mental illness in children and parents: Developmental issues, family concerns, and research needs. J Child Psychol Psychiatry 46:714Y734 Jensen PS, Weersing R, Eaton-Hoagwood K, Goldman E (2005), What is the evidence for evidence-based treatments? A hard look at our soft underbelly. Ment Health Serv 7:53Y74 Kazdin AE (2004), Evidence-based treatments: challenges and priorities for practice and research. Child Adolesc Psychiatr Clin N Am 13:923Y940 Kennard B, Silva S, Vitiello B et al. (2006), Remission and residual symptoms after short-term treatment in the Treatment of Adolescents With Depression Study (TADS). J Am Acad Child Adolesc Psychiatry 45:1404Y1411 Kessler RC, Avenevoli S, Merikangas K (2001), Mood disorders in children and adolescents: an epidemiologic perspective. Biol Psychiatry 49: 1002Y1014 Kessler RC, McGonagle KA, Nelson CB, Hughes M, Swartz M, Blazer DG (1994), Sex and depression in the National Comorbidity Survey. II: Cohort effects. J Affect Disord 30:15Y26 Kessler RC, Walters EE (1998), Epidemiology of DSM-III-R major depression and minor depression among adolescents and young adults in the National Comorbidity Survey. Depress Anxiety 7:3Y14 Kim WJ, American Academy of Child and Adolescent Psychiatry Task Force on Workforce Needs (2003), Child and adolescent psychiatry workforce: a critical shortage and national challenge. Acad Psychiatry 27:277Y282 Kratochvil C, Emslie G, Silva S et al. (2006), Acute time to response in the Treatment for Adolescents With Depression Study (TADS). J Am Acad Child Adolesc Psychiatry 45:1412Y1418 Leaf P, Alegria M, Cohen P et al. (1996), Mental health service use in the community and schools: results from the four-community MECA study. J Am Acad Child Adolesc Psychiatry 35:889Y897 March J, Silva S, Petrycki S et al., Treatment for Adolescents With Depression Study (TADS) Team (2004), Fluoxetine, cognitivebehavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA 292:807Y820 March J, Silva S, Vitiello B (2006), The Treatment for Adolescents With Depression Study (TADS): methods and message at 12 weeks. J Am Acad Child Adolesc Psychiatry 45:1393Y1403 Mufson L, Dorta KP, Wickramaratne P, Nomura Y, Olfson M, Weissman MM (2004), A randomized effectiveness trial of interpersonal psychotherapy for depressed adolescents. Arch Gen Psychiatry 61: 577Y584 Stein REK, Zitner L, Jensen PS (2006), Interventions for adolescent depression in primary care. Pediatrics 118:1Y14 Vitiello B, Rohde P, Silva S et al. (2006), Functioning and quality of life in the Treatment for Adolescents With Depression Study (TADS). J Am Acad Child Adolesc Psychiatry 45:1419Y1426 Zuckerbrot RA, Jensen PS (2006), Improving recognition of adolescent depression in primary care. Arch Pediatr Adolesc Med 160:694Y704
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