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Recent NIMH Clinical Trials and Implications for Practice
PSYCHOPHARMACOLOGY PERSPECTIVES
Christopher J. Kratochvil, M.D.
Assistant Editor
Recent NIMH Clinical Trials and Implications for Practice BENEDETTO VITIELLO, M.D. KEY POINTS
1. Optimal treatment of adolescents with moderateto-severe major depressive disorder requires antidepressant medication, and adding cognitivebehavioral therapy (CBT) offers distinctive advantages over monotherapy. 2. Second-step pharmacological treatment of adolescent depression, after failing an initial course of medication, still has a success rate of approximately 50%, and a combination of medication and CBT increases the likelihood of response over medication alone. 3. Optimal treatment of children and adolescents with obsessive-compulsive disorder requires CBT, and improvement is greatest when CBT and pharmacotherapy are combined.
Psychopharmacology Perspectives aims to discuss practical approaches to everyday issues in pediatric pharmacotherapy. The discussions may address aspects of clinical care related to psychopharmacology for which we do not have adequate applicable controlled trials. Given the need to address symptoms in youths with often complex, severe, and comorbid disorders, recommendations are likely to be off-label from the perspective of the U.S. Food and Drug Administration. We fully appreciate that for virtually all disorders, medication is only one aspect of comprehensive care. This column focuses primarily on psychopharmacological management. Although it is important that clinicians address psychosocial issues in the evaluation and treatment of their patients, such discussion is beyond the specific scope of this feature. These are not meant to be practice guidelines, but rather examples of the thought process that may go into pharmacotherapy decision making. Accepted July 9, 2008. Dr. Vitiello is with the National Institute of Mental Health. The opinions and assertions contained in this article are the private views of the author and are not to be construed as official or as reflecting the views of the Department of Health and Human Services, the National Institutes of Health, or the National Institute of Mental Health. Correspondence to Benedetto Vitiello, M.D., National Institute of Mental Health, Room 7147, 6001 Executive Blvd., Bethesda, MD 20892-9633; e-mail: [email protected]. 0980-8567/08/4712-1369Ó2008 by the American Academy of Child and Adolescent Psychiatry. DOI:10.1097/CHI.0b013e31818960a7
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4. Symptoms of attention-deficit/hyperactivity disorder can be successfully treated with methylphenidate in children younger than 6 years, or in children with pervasive developmental disorder, but these patients are more sensitive to drug-induced adverse effects. More than 10 years ago, the National Institute of Mental Health (NIMH) started a program of multisite clinical trials with the purpose of providing clinicians, patients, and families with the scientific evidence necessary for making informed treatment decisions in child and adolescent psychiatry.1 The focus was on treatments already used in clinical practice but without adequate evidence of efficacy and safety. The specific aim of each trial varied according to the state of the science of the disorder being treated and the particular treatment being tested. Thus, for medications in need of efficacy evaluation, and often used off-label in the community, as was the case for the selective serotonin reuptake inhibitor (SSRI) antidepressants in pediatric anxiety disorders or for the second-generation antipsychotics in autism, straightforward placebo-controlled trials were conducted.2,3 When efficacy had been demonstrated, however, trials were launched to directly compare the relative benefits of active treatments and to assess the possible advantage of combined treatment versus monotherapy. The main findings of NIMH-funded, multisite, randomized clinical trials completed in the last 5 years are here briefly reviewed, and their implications for practice are discussed (Table 1).
TREATMENT OF ADOLESCENTS WITH DEPRESSION STUDY
Previous studies had proven the efficacy of fluoxetine and cognitive-behavioral therapy (CBT) used as monotherapy in the treatment of adolescents with major
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ADHD, hyperactive or combined
Autism and other PDDs with impairing hyperactivity and/or impulsivity
To test the efficacy and tolerability of methylphenidate in decreasing ADHD
Treatment of Hyperactivity and Impulsiveness in Children with PDD
Obsessive-compulsive disorder
N = 72; 5Y14 years old
N = 165; 3Y5 years old
Randomized; parallel groups; placebo-controlled; 12 weeks Randomized; placebo-controlled; crossover, with 4 fixed doses plus placebo (1 week for each condition), followed by a 4-week parallel group, and a 10-month naturalistic maintenance Randomized; placebo-controlled; crossover, with 3 fixed doses plus placebo; 1 week for each condition
Randomized; parallel groups; factorial with 4 parallel groups; 12 weeks of acute treatment, followed by a 12-week continuation
N = 326; 12Y18 years old
N = 112; 7Y17 years old
Randomized; parallel groups; placebo-controlled; 12 weeks of acute treatment, followed by a 24-week continuation
N = 439; 12Y17 years old
Methylphenidate was efficacious in approximately 50% of the patients; 18% of the patients discontinued treatment due to adverse effects.13
COMB was most effective; CBT found necessary for optimal effectiveness.7 Methylphenidate was efficacious starting at 7.5 mg/day; 12% of children did not tolerate adverse effects; effect on growth with 1-year treatment.8Y12
Fluoxetine was more effective than CBT alone at accelerating improvement but increased risk for suicidal events. COMB was most effective in accelerating remission and minimizing suicidality.4,5 COMB was better than medication alone at improving depression. No difference in efficacy between types of medication.6
Main Findings
Note: NIMH = National Institute of Mental Health; TADS = Treatment for Adolescents with Depression Study; CBT = cognitive-behavioral therapy; COMB = combination; TORDIA = Treatment of Resistant Depression in Adolescents; SSRI = selective serotonin reuptake inhibitor antidepressants; POTS = Pediatric Obsessive-Compulsive Treatment Study; PATS = Preschoolers with ADHD Treatment Study; PDD = pervasive developmental disorder.
PATS
POTS
Major depressive disorder nonresponsive to 1 adequate trial of antidepressant medication
To compare the effectiveness of alternative antidepressant medications (SSRI or venlafaxine) alone and in combination with CBT (COMB) To test the efficacy of sertraline and CBT, alone and in COMB To test efficacy and tolerability of methylphenidate
TORDIA
Major depressive disorder
To compare the effectiveness of fluoxetine and CBT, alone and in COMB
TADS
Study
TABLE 1 Recent NIMH-Sponsored Multisite Clinical Trials in Children and Adolescents Subjects Main AimYInterventions Psychopathology (Randomized) Design and Duration
VITIELLO
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PSYCHOPHARMACOLOGY PERSPECTIVES
depressive disorder and suggested that these treatment modalities have comparable antidepressant activity, with response rates around 55% to 65%.14,15 The Treatment for Adolescents with Depression Study (TADS) was the first study to compare psychotherapy with a purely pharmacological approach to adolescent depression, to evaluate monotherapy versus combination, and to go beyond initial efficacy by assessing treatment effects for a total period of 9 months. It is only when alternative treatments are included in the same randomized trial that their relative therapeutic value can be properly evaluated. In TADS, contrary to the expectation of equivalence between CBT and fluoxetine, the latter proved to be more effective, with response rates of 61% versus 43% at week 12.4 Surprisingly, the effects of CBT were not significantly different from those observed in the group that received nonspecific clinical contact with pill placebo. The TADS indicated that, for moderate-tosevere depression, fluoxetine, alone or in combination with CBT, is necessary for accelerating improvement.5,16 With time, CBT eventually Bcatches up.[ After 18 weeks of treatment, fluoxetine monotherapy still shows superiority over CBT, but, by 24 weeks, the difference had dissipated. Likewise, combined treatment was superior to CBT at week 24, but no longer at week 30 or 36. It should be noted that the placebo group was unblinded at week 12 and actively treated as clinically indicated, so that comparisons between active treatments and placebo cannot be made during long-term treatment. In TADS, improvement in depression symptoms was the primary outcome measure. Important secondary outcomes were remission and functional improvement. On these outcomes, only the combination of fluoxetine with CBT proved better than the placebo after 12 weeks of treatment.17,18 An added benefit was that patients in the combined treatment group achieved a high rate of response with a lower dose of fluoxetine (28 mg/day) than those on fluoxetine monotherapy (32 mg/day).4 With respect to suicidality, only the combinationtreated group decreased, in a statistically significant manner, the suicidal ideation rating scores as compared with the placebo group.4,19 Combined treatment also seemed to decrease the risk for suicidal events (a category inclusive of suicidal ideation and suicide attempt). During the 36-week treatment, the incidence of suicidal events was statistically significantly greater with fluox-
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etine (14.7%) but not with combined treatment (8.4%), compared with CBT (6.3%).5 In sum, while providing further evidence of the efficacy of SSRI treatment, TADS also showed distinctive advantages of combined treatment, especially when the aim is remission, functional recovery, and prevention of suicidality. Obviously, combined treatment is also more expensive than pharmacotherapy alone, at least when acute treatment is considered.20 These findings must be considered in the context of other controlled studies that have tested combined treatment with SSRI and CBT versus SSRI monotherapy,21,22 and in particular, the Adolescent Depression and Psychotherapy Trial (ADAPT), which was conducted in community clinical settings in the United Kingdom. In ADAPT, depressed adolescents were first treated with nonspecific psychotherapy, and nonresponders (n = 208) were randomized to treatment as usual with SSRI medication (primarily, but not exclusively, fluoxetine) or SSRI plus CBT. At the end of the 28-week treatment, patients in both groups were improved, with no differences between treatment arms in terms of symptom reduction, remission, or incidence of suicidal behavior. Thus, the superiority of combined treatment as a first-step intervention in adolescent depression is not univocally supported by existing data. TREATMENT OF RESISTANT DEPRESSION IN ADOLESCENTS STUDY
The Treatment of Resistant Depression in Adolescents Study (TORDIA) is the first multisite trial focused on second-step treatment for adolescent depression and thus greatly contributes toward building an evidencebased comprehensive approach to this condition.6 Youths who had been unsuccessfully treated with an SSRI medication were randomized to antidepressant medication alone or medication plus CBT. On a random basis, the medication consisted of another SSRI or venlafaxine. There were two primary outcome measures, both rated by the clinician: an end-of-treatment categorical responder status (defined as a rating of Bmuch[ or Bvery much[ improved and a decrease of at least 50% in the depressive symptom total score) and change over time of the depressive symptom total score. After 12 weeks of treatment, the response rate was higher in the combined treatment (55%) than in the
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VITIELLO
medication-alone groups (41%), although the change of depressive symptom total score was not statistically significantly different between treatment groups. These results are consistent with studies in adults that found that response rate to second-step treatment is not substantially different from that to first-step treatment, with no difference between antidepressant types.23 Finding a 50% success rate even after a first treatment with SSRI medication had failed is remarkable when considering that the TORDIA patients experienced prolonged depression that had persisted for an average of 2 years. The results also confirm that combination treatment offers advantages over pharmacotherapy alone and provide support for using another SSRI after one had proven ineffective. Unlike TADS, but in agreement with the ADAPT,21 the combination of CBT and medication was not better than medication alone at decreasing suicidality. The TORDIA sample was overall more severely ill than the TADS sample because of greater comorbidity, suicidality, and previous treatment resistance. These sample characteristics may have accounted for the different outcome. PEDIATRIC OBSESSIVE-COMPULSIVE DISORDER TREATMENT STUDY
This 3-site clinical trial of sertraline, CBT, and their combination versus pill placebo control in children and adolescents with obsessive-compulsive disorder (OCD) is also a unique study in that it directly evaluated the relative efficacy of state-of-the-art treatments given alone or in combination.7 Whereas both sertraline and CBT showed efficacy as monotherapy, the combination was more effective, leading to a remission rate of 54% versus 39% for CBT and 21% for sertraline after 12 weeks of treatment. In some way, the Pediatric ObsessiveCompulsive Disorder Treatment Study (POTS) results seem to be the inverse of those of TADS: although the latter found medication to be necessary for accelerating improvement in depression, POTS showed that CBT, alone or in combination, is critical for optimal treatment of pediatric OCD. PRESCHOOLERS WITH ADHD TREATMENT STUDY
The primary aim of the Preschoolers with ADHD Treatment Study (PATS) was to test the efficacy and tolerability of methylphenidate in children ages 3 to
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5 years with attention-deficit/hyperactivity disorder (ADHD). The study was characterized by multiple sequential phases aimed at informing on a number of issues, such as response to behavior treatment, acute efficacy of a range of doses ranging from a 1.25 to 7.5 mg t.i.d., and sustainability of treatment effects during long-term maintenance.8 The PATS focused on children with prominent and severe hyperactivity and impulsivity that had proven unresponsive to initial psychosocial intervention and showed that, for these children, methylphenidate at doses of 2.5 mg t.i.d. or greater is efficacious in decreasing ADHD symptoms but that young children are more sensitive to adverse effects.9,10 The main conclusion is that lower doses and slower titration are warranted in preschoolers than in schoolage children. Acute improvement is maintained and enhanced with continuous treatment,11 but methylphenidate can impair physical growth so that careful prospective assessment of weight and height is recommended.12 Designed in 1999, PATS tested immediate-release methylphenidate, whereas slowrelease formulations are now more commonly used. Despite this discrepancy, the findings are informative and provide direction for treatment of preschoolers with severe ADHD. TREATMENT OF HYPERACTIVITY AND IMPULSIVENESS IN CHILDREN WITH PERVASIVE DEVELOPMENTAL DISORDERS
Although the current nosology excludes a formal diagnosis of ADHD in the context of pervasive developmental disorder (PDD), many children with autism or other PDD have impairing ADHD symptoms. To address the clinical needs of these children, the NIMH Research Units on Pediatric Psychopharmacology autism network conducted a placebo-controlled trial of immediate-release methylphenidate at daily doses ranging from 7.5 to 50 mg.13 Treatment was found effective in approximately half of the children, whereas 18% discontinued medication because of adverse effects. Thus, methylphenidate has substantially lower efficacy and tolerability treating ADHD symptoms in children with PDD than in those without. Although stimulant treatment remains a potentially valuable treatment option for a large proportion of PDD children, clinicians should expect a high
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PSYCHOPHARMACOLOGY PERSPECTIVES
treatment dropout rate because of inefficacy and/or adverse effects. DISCUSSION
These recently reported multisite trials provide practical and useful evidence that is directly relevant to the clinical management of patients with depression, OCD, ADHD, and PDD. Data from these studies informed the most current treatment guidelines for depression and ADHD,24,25 and the TADS database also contributed to the Food and Drug Administration meta-analysis of suicidality in pediatric antidepressant trials.26 In the case of ADHD, both PATS and the methylphenidate study in PDD address specific clinical issues for which empirical evidence was scarce or absent despite decades of community use of stimulants. Notwithstanding the importance of these studies, one needs to also acknowledge their limitations. Any trial design is a compromise, trying to integrate experimental rigor with feasibility and ecological validity. Thus, some of these results generate further questions that remain unanswered, such as those about the specificity of CBT vis-a`-vis other psychotherapeutic interventions or the possible value of sequencing treatments rather than combining them from the outset (e.g., first pharmacotherapy, then adding CBT, or vice versa). Furthermore, clinical trials provide results at the group level. Translating group level information into treatment decisions for individual patients is the challenging task of the clinician. Developing more personalized approaches to treatment that take into account the substantial intersubject variability in treatment response will be an important area for future research. Some of these studies also have implications for mental health service delivery and organization of care. Thus, the results of TADS, TORDIA, and POTS call for integration of pharmacological and psychotherapeutic interventions. In these studies, patients receiving combined treatment were treated by separate and collaborating clinicians, a pharmacotherapist, and a psychotherapist. In theory, implementing these treatments in clinical practice requires the prescribing psychiatrist either to forge ongoing collaboration with a psychotherapist or to become competent in the delivery of CBT. In practice, the challenge of transporting these research findings into usual clinical care cannot be underestimated. Cognitive-behavioral therapy is not
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widely available in many communities. Few psychiatrists have received adequate training in CBT techniques and especially in CBT for adolescents. The dearth of psychiatrists specifically trained in child and adolescent psychiatry, the shift of adolescent depression care from primary care to mental health specialists following the recent regulatory warnings about antidepressants, and in general, the difficulty of changing clinician and patient behavior constitute formidable challenges to translating research findings into patient care.27
Disclosure: The author reports no conflicts of interest.
REFERENCES 1. Vitiello B, Jensen PS. Medication development and testing in children and adolescents. Arch Gen Psychiatry. 1997;54:871Y876. 2. RUPP Anxiety Study Group. Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med. 2001;344: 1279Y1285. 3. RUPP Autism Network. Risperidone in children with autism and serious behavioral problems. N Engl J Med. 2002;347:314Y321. 4. TADS Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression. JAMA. 2004;292:807Y820. 5. TADS Team. The Treatment for Adolescents with Depression Study (TADS): long-term effectiveness and safety outcomes. Arch Gen Psychiatry. 2007;64:1132Y1144. 6. Brent D, Emslie G, Clarke G et al. The Treatment of Adolescents with SSRI-Resistant Depression (TORDIA): a comparison of switch to venlafaxine or to another SSRI, with or without additional cognitive behavioral therapy. JAMA. 2008;299:901Y913. 7. Pediatric Obsessive-Compulsive Treatment Study. Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA. 2004;292: 1969Y1976. 8. Kollins SH, Greenhill LL, Swanson S et al. Rationale, design, and methods of the Preschool ADHD Treatment Study (PATS). J Am Acad Child Adolesc Psychiatry. 2006;45:1275Y1283. 9. Greenhill LL, Abikoff H, Chuang S et al. Efficacy and safety of immediate-release methylphenidate treatment for preschoolers with ADHD. J Am Acad Child Adolesc Psychiatry. 2006;45:1284Y1293. 10. Wigal T, Greenhill LL, Chuang S et al. Safety and tolerability of methylphenidate in preschool children with ADHD. J Am Acad Child Adolesc Psychiatry. 2006;45:1294Y1303. 11. Vitiello B, Abikoff HB, Chuang SZ et al. Effectiveness of methylphenidate in the 10-month continuation phase of the Preschoolers with Attention-deficit/hyperactivity disorder Treatment Study (PATS). J Child Adolesc Psychopharmacol. 2007;17:593Y603. 12. Swanson J, Greenhill L, Wigal T et al. Stimulant-related reductions of growth rates in the PATS. J Am Acad Child Adolesc Psychiatry. 2006; 45:1304Y1313. 13. RUPP Autism Network. A randomized controlled crossover trial of methylphenidate in pervasive developmental disorders and hyperactivity. Arch Gen Psychiatry. 2005;62;1266Y1274. 14. Emslie GJ, Rush AJ, Weinberg WA et al. A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry. 1997;54:1031Y1037. 15. Brent DA, Holder D, Kolko D et al. A clinical psychotherapy trial for adolescent depression comparing cognitive, family, and supportive therapy. Arch Gen Psychiatry. 1997;54:877Y885.
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VITIELLO 16. Kratochvil CJ, Emslie GJ, Silva SG et al. Time to response for depressed adolescents receiving fluoxetine, cognitive-behavioral therapy, or combined treatment. J Am Acad Child Adolesc Psychiatry. 2006;45: 1412Y1418. 17. Kennard BD, Silva S, Vitiello B et al. Remission and residual symptoms after acute treatment of adolescents with major depressive disorder. J Am Acad Child Adolesc Psychiatry. 2006;45:1404Y1411. 18. Vitiello B, Rohde P, Silva SG et al. Effects of treatment on level of functioning, global health, and quality of life in depressed adolescents. J Am Acad Child Adolesc Psychiatry. 2006;45:1419Y1426. 19. Emslie GJ, Kratochvil CJ, Vitiello B et al. Treatment for Adolescents with Depression Study (TADS): safety results. J Am Acad Child Adolesc Psychiatry. 2006;45:1440Y1455. 20. Domino M, Burns BJ, Silva SG et al. The cost-effectiveness of treatments for adolescent depression: results from the TADS randomized trial. Am J Psychiatry. 2008;165:588Y596. 21. Goodyer 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: randomized controlled trial. BMJ. 2007;335:142.
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22. Clarke G, DeBar L, Lynch F. A randomized effectiveness trial of brief cognitive-behavioral therapy for depressed adolescents receiving antidepressant medication. J Am Acad Child Adolesc Psychiatry. 2005;44: 888Y898. 23. Rush AJ. STAR*D: what have we learned? Am J Psychiatry. 2007; 164:201Y214. 24. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of children and adolescents with depression disorders. J Am Acad Child Adolesc Psychiatry. 2007; 46:1503Y1526. 25. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46:894Y921. 26. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63: 332Y339. 27. Bhatia SK, Rezac AJ, Vitiello B, Sitorius MA, Buehler BA, Kratochvil CJ. Antidepressant prescribing practices for the treatment of children and adolescents. J Child Adolesc Psychopharmacol. 2008;18:70Y80.
J. AM . ACAD . CHILD ADOLE SC. PSYCH IAT RY, 47:12, D ECEMBER 2008
Christopher J. Kratochvil, M.D.
Assistant Editor
Recent NIMH Clinical Trials and Implications for Practice BENEDETTO VITIELLO, M.D. KEY POINTS
1. Optimal treatment of adolescents with moderateto-severe major depressive disorder requires antidepressant medication, and adding cognitivebehavioral therapy (CBT) offers distinctive advantages over monotherapy. 2. Second-step pharmacological treatment of adolescent depression, after failing an initial course of medication, still has a success rate of approximately 50%, and a combination of medication and CBT increases the likelihood of response over medication alone. 3. Optimal treatment of children and adolescents with obsessive-compulsive disorder requires CBT, and improvement is greatest when CBT and pharmacotherapy are combined.
Psychopharmacology Perspectives aims to discuss practical approaches to everyday issues in pediatric pharmacotherapy. The discussions may address aspects of clinical care related to psychopharmacology for which we do not have adequate applicable controlled trials. Given the need to address symptoms in youths with often complex, severe, and comorbid disorders, recommendations are likely to be off-label from the perspective of the U.S. Food and Drug Administration. We fully appreciate that for virtually all disorders, medication is only one aspect of comprehensive care. This column focuses primarily on psychopharmacological management. Although it is important that clinicians address psychosocial issues in the evaluation and treatment of their patients, such discussion is beyond the specific scope of this feature. These are not meant to be practice guidelines, but rather examples of the thought process that may go into pharmacotherapy decision making. Accepted July 9, 2008. Dr. Vitiello is with the National Institute of Mental Health. The opinions and assertions contained in this article are the private views of the author and are not to be construed as official or as reflecting the views of the Department of Health and Human Services, the National Institutes of Health, or the National Institute of Mental Health. Correspondence to Benedetto Vitiello, M.D., National Institute of Mental Health, Room 7147, 6001 Executive Blvd., Bethesda, MD 20892-9633; e-mail: [email protected]. 0980-8567/08/4712-1369Ó2008 by the American Academy of Child and Adolescent Psychiatry. DOI:10.1097/CHI.0b013e31818960a7
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4. Symptoms of attention-deficit/hyperactivity disorder can be successfully treated with methylphenidate in children younger than 6 years, or in children with pervasive developmental disorder, but these patients are more sensitive to drug-induced adverse effects. More than 10 years ago, the National Institute of Mental Health (NIMH) started a program of multisite clinical trials with the purpose of providing clinicians, patients, and families with the scientific evidence necessary for making informed treatment decisions in child and adolescent psychiatry.1 The focus was on treatments already used in clinical practice but without adequate evidence of efficacy and safety. The specific aim of each trial varied according to the state of the science of the disorder being treated and the particular treatment being tested. Thus, for medications in need of efficacy evaluation, and often used off-label in the community, as was the case for the selective serotonin reuptake inhibitor (SSRI) antidepressants in pediatric anxiety disorders or for the second-generation antipsychotics in autism, straightforward placebo-controlled trials were conducted.2,3 When efficacy had been demonstrated, however, trials were launched to directly compare the relative benefits of active treatments and to assess the possible advantage of combined treatment versus monotherapy. The main findings of NIMH-funded, multisite, randomized clinical trials completed in the last 5 years are here briefly reviewed, and their implications for practice are discussed (Table 1).
TREATMENT OF ADOLESCENTS WITH DEPRESSION STUDY
Previous studies had proven the efficacy of fluoxetine and cognitive-behavioral therapy (CBT) used as monotherapy in the treatment of adolescents with major
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ADHD, hyperactive or combined
Autism and other PDDs with impairing hyperactivity and/or impulsivity
To test the efficacy and tolerability of methylphenidate in decreasing ADHD
Treatment of Hyperactivity and Impulsiveness in Children with PDD
Obsessive-compulsive disorder
N = 72; 5Y14 years old
N = 165; 3Y5 years old
Randomized; parallel groups; placebo-controlled; 12 weeks Randomized; placebo-controlled; crossover, with 4 fixed doses plus placebo (1 week for each condition), followed by a 4-week parallel group, and a 10-month naturalistic maintenance Randomized; placebo-controlled; crossover, with 3 fixed doses plus placebo; 1 week for each condition
Randomized; parallel groups; factorial with 4 parallel groups; 12 weeks of acute treatment, followed by a 12-week continuation
N = 326; 12Y18 years old
N = 112; 7Y17 years old
Randomized; parallel groups; placebo-controlled; 12 weeks of acute treatment, followed by a 24-week continuation
N = 439; 12Y17 years old
Methylphenidate was efficacious in approximately 50% of the patients; 18% of the patients discontinued treatment due to adverse effects.13
COMB was most effective; CBT found necessary for optimal effectiveness.7 Methylphenidate was efficacious starting at 7.5 mg/day; 12% of children did not tolerate adverse effects; effect on growth with 1-year treatment.8Y12
Fluoxetine was more effective than CBT alone at accelerating improvement but increased risk for suicidal events. COMB was most effective in accelerating remission and minimizing suicidality.4,5 COMB was better than medication alone at improving depression. No difference in efficacy between types of medication.6
Main Findings
Note: NIMH = National Institute of Mental Health; TADS = Treatment for Adolescents with Depression Study; CBT = cognitive-behavioral therapy; COMB = combination; TORDIA = Treatment of Resistant Depression in Adolescents; SSRI = selective serotonin reuptake inhibitor antidepressants; POTS = Pediatric Obsessive-Compulsive Treatment Study; PATS = Preschoolers with ADHD Treatment Study; PDD = pervasive developmental disorder.
PATS
POTS
Major depressive disorder nonresponsive to 1 adequate trial of antidepressant medication
To compare the effectiveness of alternative antidepressant medications (SSRI or venlafaxine) alone and in combination with CBT (COMB) To test the efficacy of sertraline and CBT, alone and in COMB To test efficacy and tolerability of methylphenidate
TORDIA
Major depressive disorder
To compare the effectiveness of fluoxetine and CBT, alone and in COMB
TADS
Study
TABLE 1 Recent NIMH-Sponsored Multisite Clinical Trials in Children and Adolescents Subjects Main AimYInterventions Psychopathology (Randomized) Design and Duration
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depressive disorder and suggested that these treatment modalities have comparable antidepressant activity, with response rates around 55% to 65%.14,15 The Treatment for Adolescents with Depression Study (TADS) was the first study to compare psychotherapy with a purely pharmacological approach to adolescent depression, to evaluate monotherapy versus combination, and to go beyond initial efficacy by assessing treatment effects for a total period of 9 months. It is only when alternative treatments are included in the same randomized trial that their relative therapeutic value can be properly evaluated. In TADS, contrary to the expectation of equivalence between CBT and fluoxetine, the latter proved to be more effective, with response rates of 61% versus 43% at week 12.4 Surprisingly, the effects of CBT were not significantly different from those observed in the group that received nonspecific clinical contact with pill placebo. The TADS indicated that, for moderate-tosevere depression, fluoxetine, alone or in combination with CBT, is necessary for accelerating improvement.5,16 With time, CBT eventually Bcatches up.[ After 18 weeks of treatment, fluoxetine monotherapy still shows superiority over CBT, but, by 24 weeks, the difference had dissipated. Likewise, combined treatment was superior to CBT at week 24, but no longer at week 30 or 36. It should be noted that the placebo group was unblinded at week 12 and actively treated as clinically indicated, so that comparisons between active treatments and placebo cannot be made during long-term treatment. In TADS, improvement in depression symptoms was the primary outcome measure. Important secondary outcomes were remission and functional improvement. On these outcomes, only the combination of fluoxetine with CBT proved better than the placebo after 12 weeks of treatment.17,18 An added benefit was that patients in the combined treatment group achieved a high rate of response with a lower dose of fluoxetine (28 mg/day) than those on fluoxetine monotherapy (32 mg/day).4 With respect to suicidality, only the combinationtreated group decreased, in a statistically significant manner, the suicidal ideation rating scores as compared with the placebo group.4,19 Combined treatment also seemed to decrease the risk for suicidal events (a category inclusive of suicidal ideation and suicide attempt). During the 36-week treatment, the incidence of suicidal events was statistically significantly greater with fluox-
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etine (14.7%) but not with combined treatment (8.4%), compared with CBT (6.3%).5 In sum, while providing further evidence of the efficacy of SSRI treatment, TADS also showed distinctive advantages of combined treatment, especially when the aim is remission, functional recovery, and prevention of suicidality. Obviously, combined treatment is also more expensive than pharmacotherapy alone, at least when acute treatment is considered.20 These findings must be considered in the context of other controlled studies that have tested combined treatment with SSRI and CBT versus SSRI monotherapy,21,22 and in particular, the Adolescent Depression and Psychotherapy Trial (ADAPT), which was conducted in community clinical settings in the United Kingdom. In ADAPT, depressed adolescents were first treated with nonspecific psychotherapy, and nonresponders (n = 208) were randomized to treatment as usual with SSRI medication (primarily, but not exclusively, fluoxetine) or SSRI plus CBT. At the end of the 28-week treatment, patients in both groups were improved, with no differences between treatment arms in terms of symptom reduction, remission, or incidence of suicidal behavior. Thus, the superiority of combined treatment as a first-step intervention in adolescent depression is not univocally supported by existing data. TREATMENT OF RESISTANT DEPRESSION IN ADOLESCENTS STUDY
The Treatment of Resistant Depression in Adolescents Study (TORDIA) is the first multisite trial focused on second-step treatment for adolescent depression and thus greatly contributes toward building an evidencebased comprehensive approach to this condition.6 Youths who had been unsuccessfully treated with an SSRI medication were randomized to antidepressant medication alone or medication plus CBT. On a random basis, the medication consisted of another SSRI or venlafaxine. There were two primary outcome measures, both rated by the clinician: an end-of-treatment categorical responder status (defined as a rating of Bmuch[ or Bvery much[ improved and a decrease of at least 50% in the depressive symptom total score) and change over time of the depressive symptom total score. After 12 weeks of treatment, the response rate was higher in the combined treatment (55%) than in the
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medication-alone groups (41%), although the change of depressive symptom total score was not statistically significantly different between treatment groups. These results are consistent with studies in adults that found that response rate to second-step treatment is not substantially different from that to first-step treatment, with no difference between antidepressant types.23 Finding a 50% success rate even after a first treatment with SSRI medication had failed is remarkable when considering that the TORDIA patients experienced prolonged depression that had persisted for an average of 2 years. The results also confirm that combination treatment offers advantages over pharmacotherapy alone and provide support for using another SSRI after one had proven ineffective. Unlike TADS, but in agreement with the ADAPT,21 the combination of CBT and medication was not better than medication alone at decreasing suicidality. The TORDIA sample was overall more severely ill than the TADS sample because of greater comorbidity, suicidality, and previous treatment resistance. These sample characteristics may have accounted for the different outcome. PEDIATRIC OBSESSIVE-COMPULSIVE DISORDER TREATMENT STUDY
This 3-site clinical trial of sertraline, CBT, and their combination versus pill placebo control in children and adolescents with obsessive-compulsive disorder (OCD) is also a unique study in that it directly evaluated the relative efficacy of state-of-the-art treatments given alone or in combination.7 Whereas both sertraline and CBT showed efficacy as monotherapy, the combination was more effective, leading to a remission rate of 54% versus 39% for CBT and 21% for sertraline after 12 weeks of treatment. In some way, the Pediatric ObsessiveCompulsive Disorder Treatment Study (POTS) results seem to be the inverse of those of TADS: although the latter found medication to be necessary for accelerating improvement in depression, POTS showed that CBT, alone or in combination, is critical for optimal treatment of pediatric OCD. PRESCHOOLERS WITH ADHD TREATMENT STUDY
The primary aim of the Preschoolers with ADHD Treatment Study (PATS) was to test the efficacy and tolerability of methylphenidate in children ages 3 to
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5 years with attention-deficit/hyperactivity disorder (ADHD). The study was characterized by multiple sequential phases aimed at informing on a number of issues, such as response to behavior treatment, acute efficacy of a range of doses ranging from a 1.25 to 7.5 mg t.i.d., and sustainability of treatment effects during long-term maintenance.8 The PATS focused on children with prominent and severe hyperactivity and impulsivity that had proven unresponsive to initial psychosocial intervention and showed that, for these children, methylphenidate at doses of 2.5 mg t.i.d. or greater is efficacious in decreasing ADHD symptoms but that young children are more sensitive to adverse effects.9,10 The main conclusion is that lower doses and slower titration are warranted in preschoolers than in schoolage children. Acute improvement is maintained and enhanced with continuous treatment,11 but methylphenidate can impair physical growth so that careful prospective assessment of weight and height is recommended.12 Designed in 1999, PATS tested immediate-release methylphenidate, whereas slowrelease formulations are now more commonly used. Despite this discrepancy, the findings are informative and provide direction for treatment of preschoolers with severe ADHD. TREATMENT OF HYPERACTIVITY AND IMPULSIVENESS IN CHILDREN WITH PERVASIVE DEVELOPMENTAL DISORDERS
Although the current nosology excludes a formal diagnosis of ADHD in the context of pervasive developmental disorder (PDD), many children with autism or other PDD have impairing ADHD symptoms. To address the clinical needs of these children, the NIMH Research Units on Pediatric Psychopharmacology autism network conducted a placebo-controlled trial of immediate-release methylphenidate at daily doses ranging from 7.5 to 50 mg.13 Treatment was found effective in approximately half of the children, whereas 18% discontinued medication because of adverse effects. Thus, methylphenidate has substantially lower efficacy and tolerability treating ADHD symptoms in children with PDD than in those without. Although stimulant treatment remains a potentially valuable treatment option for a large proportion of PDD children, clinicians should expect a high
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treatment dropout rate because of inefficacy and/or adverse effects. DISCUSSION
These recently reported multisite trials provide practical and useful evidence that is directly relevant to the clinical management of patients with depression, OCD, ADHD, and PDD. Data from these studies informed the most current treatment guidelines for depression and ADHD,24,25 and the TADS database also contributed to the Food and Drug Administration meta-analysis of suicidality in pediatric antidepressant trials.26 In the case of ADHD, both PATS and the methylphenidate study in PDD address specific clinical issues for which empirical evidence was scarce or absent despite decades of community use of stimulants. Notwithstanding the importance of these studies, one needs to also acknowledge their limitations. Any trial design is a compromise, trying to integrate experimental rigor with feasibility and ecological validity. Thus, some of these results generate further questions that remain unanswered, such as those about the specificity of CBT vis-a`-vis other psychotherapeutic interventions or the possible value of sequencing treatments rather than combining them from the outset (e.g., first pharmacotherapy, then adding CBT, or vice versa). Furthermore, clinical trials provide results at the group level. Translating group level information into treatment decisions for individual patients is the challenging task of the clinician. Developing more personalized approaches to treatment that take into account the substantial intersubject variability in treatment response will be an important area for future research. Some of these studies also have implications for mental health service delivery and organization of care. Thus, the results of TADS, TORDIA, and POTS call for integration of pharmacological and psychotherapeutic interventions. In these studies, patients receiving combined treatment were treated by separate and collaborating clinicians, a pharmacotherapist, and a psychotherapist. In theory, implementing these treatments in clinical practice requires the prescribing psychiatrist either to forge ongoing collaboration with a psychotherapist or to become competent in the delivery of CBT. In practice, the challenge of transporting these research findings into usual clinical care cannot be underestimated. Cognitive-behavioral therapy is not
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widely available in many communities. Few psychiatrists have received adequate training in CBT techniques and especially in CBT for adolescents. The dearth of psychiatrists specifically trained in child and adolescent psychiatry, the shift of adolescent depression care from primary care to mental health specialists following the recent regulatory warnings about antidepressants, and in general, the difficulty of changing clinician and patient behavior constitute formidable challenges to translating research findings into patient care.27
Disclosure: The author reports no conflicts of interest.
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