Clinical and Health Affairs
Pediatric Depression
Issues and Treatment Recommendations
By Kathryn Cullen, M.D., Bonnie Klimes-Dougan, Ph.D., and Sanjiv Kumra, M.D.
Abstract
Major depressive disorder in adolescents is associated with severe consequences including suicide. Early intervention is crucial for preventing such outcomes. Parents may be reluctant to pursue antidepressant therapy for their children because of concerns about 1) a potential risk of increased suicidal ideation and 2) the effect of these medications on brain development. This article discusses the current data about potential risks associated with antidepressant use in children and adolescents versus the risk of untreated illness on their development. It also reviews recent research that suggests combination treatment involving antidepressant medications such as fluoxetine and cognitive behavioral therapy may be particularly helpful to patients who show poor response to only one of these treatments.
Pediatric depression is a serious public health issue. Although the prevalence of major depressive disorder (MDD) in childhood is low,1 the incidence increases significantly during adolescence.2 At its worst, MDD can be fatal in children and young adults. Suicide is the third leading cause of death among 10- to 24-year-olds,3 and MDD is the most common diagnosis associated with suicide (50%). In one prospective cohort of adolescents with MDD, 7.7% committed suicide within 15 years.4 The concern doesn’t end with adolescence. Longitudinal studies have demonstrated that depression during adolescence is a predictor for depression during adulthood.5 Among adults with depression, early onset is associated with greater symptom severity, increased likelihood of episode recurrence, increased suicidality, higher comorbidity, and lower educational attainment and marriage rates.6-8
Major depressive disorder has no single cause. The current thinking is that the risk for depressive illness results from an interaction between genetic predisposition and early adverse experiences. These factors likely disrupt early processes such as attachment and self-regulation. A child with these deficits may not have sufficient adaptive mechanisms to deal with adversity, paving the way for the onset of depression.9,10
The dramatic rise in the incidence of MDD during adolescence may be related to the developmental shifts taking place at that time. Adolescence is characterized by youths spending more time with peers (and less with family) and increased risk-taking behaviors. These behaviors are in fact crucial for becoming a competent adult.11 However, recent theories have suggested that the neurodevelopmental changes that underlie these adolescent behaviors may be partially responsible for the increased risk for depression in teens.12-15 Thus, because their brain development is still not complete, adolescents may be 1) more susceptible to stressors that can trigger MDD, and 2) more vulnerable to the effect of depressive episodes on neural circuitry.
An Untreated Illness
Most children and adolescents do not receive treatment for their depression. There are several reasons for this. For one thing, parents and other adults may not be aware that the child is suffering. Even when a child clearly exhibits depressive symptoms, concerned adults may have trouble differentiating these behaviors from those that are considered normal for their age. Also, parents may not seek care for their child because of the stigma associated with mental illness or because they lack access to care. Another reason why families are not getting mental health care for their children is because ongoing controversies regarding the use of antidepressants in children and adolescents have left them confused about their options for treatment.
♦ Risks for Suicide-Related Behaviors
One of the concerns families have is the potential increased risk for suicide-related behaviors among young people taking antidepressant medications. The Food and Drug Administration conducted a meta-analysis of studies that showed a small but significant increase in suicidal thoughts and behaviors in youths treated with antidepressants (4%) compared with placebo (2%).16 (No actual suicides were reported in any of the studies.) In response to their findings, the FDA in 2005 began requiring drug manufacturers to include a black-box warning in their prescribing information for antidepressants about the potential for suicidal thoughts and behaviors in youths. Since then, several reports have suggested that young patients, families, and clinicians are showing an increased reluctance to use these medications. Two studies have shown that antidepressant prescriptions for youths have decreased by 33% to 58%.17,18 This trend may have alarming consequences, as an increase in the rate of adolescent suicides has been noted since drug companies began using the black-box warning.19,20 Although caution and careful monitoring are needed when prescribing antidepressant medications, failure to use such medications to treat moderately and severely depressed children and adolescents also carries a risk for suicide.
♦ Risks to Neurodevelopment
Another issue parents have raised is whether there are long-term consequences associated with treatment. Specifically, they’re concerned about the potential effects antidepressants might have on the maturation of the brain, which continues into young adulthood.21 Several animal studies have suggested that early exposure to selective serotonin reuptake inhibitors (SSRIs) results in adverse outcomes. One study showed depression- and anxiety-related behaviors in adult mice that were exposed to SSRIs as neonates.22 Other research associated prepubertal exposure with increased locomotor activity and decreased sexual behavior in adult rats.23,24 Another study showed altered visual discrimination and attention in male rats exposed to SSRIs during adolescence.25 Three studies followed children up to 72 months of age who had been exposed to SSRI medications in utero; they found no behavioral differences in these children compared with those who were not exposed, although some differences in motor development and control have been observed.26-28
No data currently support the idea that antidepressants have a detrimental effect on behavior or neurodevelopment when given to children or adolescents. On the flip side, emerging evidence in depression model-adolescent mice and in human adolescents with depression suggests that disease-related alterations in the neurobiological stress system are reversed with SSRI treatment.29 Thus, although some evidence from animal studies suggests that very early exposure to antidepressants could theoretically affect neurodevelopment, emerging evidence supports the argument that treatment during childhood and adolescence restores healthy brain development.
Importance of Early Intervention
When weighing the risks and benefits of treatment, the risks of untreated illness must also be considered. Mounting evidence indicates that MDD is a disorder that may have a progressive and deteriorating course.30 In recurrent MDD, each episode increases the likelihood of a future episode.31 Although the exact neural mechanisms of this phenomenon are unknown, the kindling hypothesis suggests that a neurobiological change occurs, allowing episodes to be more easily triggered over time.32 Studies of adults with MDD have begun to examine the effect of the duration of untreated illness (DUI), defined as the interval between the onset of the first depressive episode and the first adequate antidepressant treatment, on the overall course of the disorder. In a retrospective study, Altamura and colleagues followed patients with recurrent MDD for 5 years.33 Results of this study indicated that patients with a DUI of greater than 12 months had more recurrences and new comorbid diagnoses in the follow-up period than patients with a shorter DUI. This preliminary evidence showing the negative impact of DUI on the long-term course of MDD may have important implications for youths. An early age of onset leaves children and adolescents open to more opportunities over their lifetime for recurrent episodes. If each episode is associated with further dysregulation to neurobiological systems, this may mediate the poor outcomes seen in this group.
Treatment
Treatment protocols that include psychotherapy and/or psychopharmacology are being established for children and adolescents. Individuals with mild-to-moderate depression may respond to psychotherapy alone. In particular, evidence suggests that cognitive behavioral therapy (CBT) is effective in about two-thirds of children and adolescents with mild-to-moderate depression.34 There is also some evidence to suggest interpersonal therapy is an effective approach for treating depressed youths.35
However, when depression is more severe or when psychotherapy does not prove to be effective, psychopharmacological interventions are recommended.36 Initial research into the efficacy of antidepressants in youth was disappointing: the first generation of tricyclic antidepressants was not shown to be superior to placebo in children and was only marginally beneficial to adolescents.37 These negative results may reflect high placebo response rates that are typical in pediatric depression studies. In contrast, fluoxetine, an SSRI, has received FDA approval for use in pediatric populations based on 2 studies confirming its efficacy over and above placebo.38,39 In addition, meta-analyses have indicated that to date, fluoxetine is the SSRI with the most evidence of efficacy in children age 12 and younger.40,41
Emerging evidence suggests that while both pharmacotherapy and CBT are effective, combined treatment for adolescents with depression may lead to the highest response and remission rates. In the past several years, 3 landmark studies have investigated these different approaches for the treatment of adolescents with MDD.
The Treatment of Adolescents with Depression Study (TADS) was the first large, multicenter placebo-controlled trial that compared medication, cognitive behavioral therapy, combined treatment, and placebo. Results from the initial 12 weeks of treatment showed that combination treatment was superior (a 71% response rate) to medication alone (61%) or CBT alone (43%).42 Although the 12-week results did not show CBT to be superior to placebo (which had a 35% response rate), by 18 weeks the response to CBT (65%) had caught up to fluoxetine (69%), and by 36 weeks, all treatments had approximately the same therapeutic efficacy (response rates above 80% for all 3 treatment groups). These data suggest that all 3 treatment arms have equivocal long-term outcomes, but that combination treatment seems to have an accelerated response.
The Treatment of Resistant Depression in Adolescents (TORDIA) study reported treatment of 334 patients ages 12 to 18 years with MDD who had not previously responded to 2 months of treatment with an SSRI. The study’s treatment arms included 12 weeks of treatment with a) a different SSRI (paroxetine, citalopram, or fluoxetine, 20 mg to 40 mg); b) a different SSRI plus CBT; c) venlafaxine (150 mg to 225 mg); or d) venlafaxine plus CBT. This study found that the combination of CBT and another antidepressant resulted in a higher rate of clinical response (55%) than did a medication switch alone (41%).43 It should be noted that no difference was found between venlafaxine (48%) and the second SSRI (47%). However, because venlafaxine treatment was associated with an increased rate of adverse effects, the authors concluded that CBT plus an SSRI was a safer treatment option.
The third and most recent study, the Adolescent Depression Antidepressant and Psychotherapy Trial (ADAPT), reported the results of a 12-week treatment trial of an SSRI (mainly fluoxetine) with or without CBT followed by a 16-week maintenance phase that included 208 British patients ages 11 to 17 years of age who had not responded to a brief psychosocial intervention.44 All subjects received routine care in a community setting with an SSRI (primarily fluoxetine); half were also offered CBT. The findings indicated that for these moderately to severely depressed patients, both treatment arms were effective; only 20% of the patients were considered to be nonresponders. Notably, the combined approach did not prove to be superior to medication only; given the additional cost of CBT, combined therapy for adolescents who are moderately to severely depressed was not supported. Recommendations from this study included starting treatment with a brief psychosocial intervention and, in the case of moderate-to-severe depression, prescribing fluoxetine if the patient does not respond to the psychosocial therapy during the first 2 to 4 weeks.
These large studies have demonstrated that available treatments (including medication and CBT) are effective for the majority of adolescents with mild-to-severe depression and those who have not had success with previous treatments. The TADS and ADAPT studies have demonstrated that CBT or brief psychosocial interventions are appropriate and effective for milder cases. For moderate-to-severe depression, the TADS and TORDIA studies have shown that SSRI medications combined with CBT are effective, even for those patients who have not responded to previous treatment. Further work is needed to clarify the discrepancies between the TORDIA/TADS and ADAPT studies regarding the benefit of CBT in addition to SSRI treatment for adolescents with moderate-to-severe, treatment-refractory depression.
Of critical concern is the minority of patients who remain resistant to treatment. Studies to date, especially in youths, are lacking in neurobiological correlates for treatment response. Future efforts directed toward understanding the developmental pathophysiology of depression will facilitate the development of more effective treatments for those patients who do not respond to the ones that are currently available.
Conclusion
Pediatric MDD can be severe and progress throughout adulthood. Given the potential for poor outcomes, early intervention must be a high priority. Treatment of children and adolescents should have as its goal remission from the current episode, halting the progression of neurobiological abnormalities, and promoting healthy neurodevelopment. A growing body of evidence suggests that available treatments such as SSRI medications, CBT, and particularly a combination of both are effective for treating most adolescents with MDD. However, even with optimal treatment, a subset of patients do not recover, and it’s still unclear why that is the case. Research is underway at the University of Minnesota to identify abnormalities in neural circuitry, affective processing, and stress response in adolescents who have not yet been treated for their depression. This research may help to identify neurobiological correlates of the disorder and lead to a better understanding of the disease and how to treat it. MM
Kathryn Cullen and Bonnie Klimes-Dougan are assistant professors in the Division of Child and Adolescent Psychiatry at the University of Minnesota. They also direct the university’s Child and Adolescent Mood Disorders Clinic. Sanjiv Kumra is an associate professor in and head of the Division of Child and Adolescent Psychiatry at the University of Minnesota.
References
1. Fleming JE, Offord DR. Epidemiology of childhood depressive disorders: a critical review. J Am Acad Child Adolesc Psychiatry. 1990;29(4):571-80.
2. Lewinsohn PM, Clarke GN, Seeley JR, Rohde P. Major depression in community adolescents: age at onset, episode duration, and time to recurrence. J Am Acad Child Adolesc Psychiatry. 1994;33(6):809-18.
3. Centers for Disease Control and Prevention. Suicide trends among youths and young adults aged 10-24 years—United States, 1990-2004. MMWR Morb Mortal Wkly Rep. 2007;56(35):905-8.
4. Weissman MM, Wolk S, Goldstein RB, et al. Depressed adolescents grown up. JAMA. 1999;281(18):1707-13.
5. Lewinsohn PM, Rohde P, Klein DN, Seeley JR. Natural course of adolescent major depressive disorder: I. Continuity into young adulthood. J Am Acad Child Adolesc Psychiatry. 1999;38(1);56-63.
6. Zisook S, Lesser I, Stewart JW, et al. Effect of age at onset on the course of major depressive disorder. Am J Psychiatry. 2007;164(10):1539-46.
7. Karlsson L, Kiviruusu O, Miettunen J, et al. One-year course and predictors of outcome of adolescent depression: a case-control study in Finland. J Clin Psychiatry. 2008:69(5):844-53.
8. Zisook S, Rush AJ, Albala A, et al. Factors that differentiate early vs. later onset of major depression disorder. Psychiatry Res. 2004;129(2):127-40.
9. Cicchetti D, Toth SL. The development of depression in children and adolescents. Am Psychol. 1998;53(2): 221-41.
10. Brown, G. W., and Harris, T. Social origins of depression: A study of psychiatric disorder in women. London: Tavistock Publications,1978.
11. Spear LP. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev. 2000;24(4):417-63.
12. Davey CG, Yucel M, Allen NB. The emergence of depression in adolescence: development of the prefrontal cortex and the representation of reward. Neurosci Biobehav Rev. 2008;32(1):1-19.
13. Nelson EE, Leibenluft E, McClure EB, Pine DS. The social re-orientation of adolescence: a neuroscience perspective on the process and its relation to psychopathology. Psychol Med. 2005;35(2):163-74.
14. Forbes EE, Dahl RE. Neural systems of positive affect: relevance to understanding child and adolescent depression? Dev Psychopathol. 2005;17(3): 827-50.
15. Casey BJ, Jones RM, Hare TA. The adolescent brain. Ann N Y Acad Sci. 2008;1124:111-26.
16. U.S. Food and Drug Administration. FDA Public Health Advisory. Available at: www.fda.gov/CDER/Drug/antidepressants/SSRIPHA200410.htm. Accessed February 17, 2009.
17. Kurian BT, Ray WA, Arbogast PG, Fuchs DC, Dudley JA, Cooper WO. Effect of regulatory warnings on antidepressant prescribing for children and adolescents. Arch Pediatr Adolesc Med. 2007;161(7):690-6.
18. Libby AM, Brent DA, Morrato EH, Orton HD, Allen R, Valuck RJ. Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs. Am J Psychiatry. 2007;164(6): 884-91.
19. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant prescription rates and rate of early adolescent suicide. Am J Psychiatry. 2006;163(11):1898-904.
20. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164(9):1356-63.
21. Giedd JN, Blumenthal J, Jeffries NO, et al. Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci. 1999;2(10):861-3.
22. Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA. Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science. 2004;306(5697): 879-81.
23. Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RC, Paul IA. Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry. Neuropsychopharmacology. 2006;31(1): 47-57.
24. Maciag D, Coppinger D, Paul IA. Evidence that the deficit in sexual behavior in adult rats neonatally exposed to citalopram is a consequence of 5-HT1 receptor stimulation during development. Brain Res. 2006;1125(1):171-5.
25. LaRoche RB, Morgan RE. Adolescent fluoxetine exposure produces enduring, sex-specific alterations of visual discrimination and attention in rats. Neurotoxicol Teratol. 2007;29(1):96-107.
26. Costei AM, Kozer E, Ho T, Ito S, Koren G. Perinatal outcome following third trimester exposure to paroxetine. Arch Pediatr Adolesc Med. 2002;156(11): 1129-32.
27. Nulman I, Rovet J, Stewart DE, et al. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry. 2002;159(11):1889-95.
28. Casper RC, Fleisher BE, Lee-Ancajas JC, et al. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr. 2003;142(4):402-8.
29. Schmidt MV, Sterlemann V, Ganea K, et al. Persistent neuroendocrine and behavioral effects of a novel, etiologically relevant mouse paradigm for chronic social stress during adolescence. Psychoneuroendocrinology. 2007;32(5):417-29.
30. Maletic V, Robinson M, Oakes T, Iyengar S, Ball SG, Russell J. Neurobiology of depression: an integrated view of key findings. Int J Clin Pract. 2007;61(12):2030-40.
31. Mueller TI, Leon AC, Keller MB, et al. Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. Am J Psychiatry. 1999;156(7):1000-6.
32. Post RM, Putnam F, Contel NR, Goldman B. Electroconvulsive seizures inhibit amygdala kindling: implications for mechanisms of action in affective illness. Epilepsia. 1984;25(2):234-9.
33. Altamura AC, Dell’osso B, Vismara S, Mundo E. May duration of untreated illness influence the long-term course of major depressive disorder? Eur Psychiatry. 2008;23(2):92-6.
34. Compton SN, March JS, Brent D, Albano AM 5th, Weersing R, Curry J. Cognitive-behavioral psychotherapy for anxiety and depressive disorders in children and adolescents: an evidence-based medicine review. J Am Acad Child Adolesc Psychiatry. 2004:43(2):930-59.
35. David-Ferdon C, Kaslow NJ. Evidence-based psychosocial treatments for child and adolescent depression. J Clin Child Adolesc Psychol. 2008:37(1):62-104.
36. Birmaher B, Brent D, AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(11):1503-26.
37. Hazell P, O’Connell D, Heathcote D, Henry D. Tricyclic drugs for depression in children and adolescents. Cochrane Database Syst Rev. 2002;(2): CD002317.
38. 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(11):1031-7.
39. Emslie GJ, Heiligenstein JH, Wagner KD, et al. Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry. 2002;41(11):1205-15.
40. Hetrick S, Merry S, McKenzie J, Sindahl P, Proctor M. Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004851.
41. Bridge JA, Iyengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA. 2007; 297(15):1683-96.
42. March J, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA. 2004; 292(7):807-20.
43. Brent D, 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(8):901-13.
44. Goodyer IM, Dubicka B, Wilkinson P, et al. A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial. Health Technol Assess. 2008;12(14):iii-iv,ix-60.