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May 2008 · Vol. 57, No. 5: 330-331
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CLINICAL INQUIRIES
Which drugs are most effective for moderate to severe depression in adolescents?Janelle Guirguis-Blake, MD;
Andrew Wright, MD;
University of Washington, Department of Family Medicine, Tacoma Family Medicine Residency Program (JGB), Rural Fellowship Program (AW), Tacoma, Wash Joanne Rich, MLISUniversity of Washington Health Sciences Libraries, Seattle
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Evidence-based answer
Fluoxetine is the only selective serotonin-reuptake inhibitor (SSRI) approved by the US Food and Drug Administration (FDA) to treat depression in children 8 years of age and older; it also has the most favorable benefit-to-risk profile compared with placebo in trials lasting up to 12 weeks (strength of recommendation [SOR]: A, meta-analysis). Fluoxetine combined with cognitive behavioral therapy (CBT) is superior to fluoxetine alone, CBT alone, or placebo (SOR: B, single well-done randomized controlled trial [RCT]). Further research is needed to address the long-term efficacy of fluoxetine treatment.
Tricyclic antidepressants, citalopram, escitalopram, venlafaxine, and sertraline are minimally effective in treating depression in adolescents (SOR: A, meta-analysis). Head-to-head trials are needed to compare the efficacy of antidepressants.
(For information on the safety of antidepressants in adolescents, see the Clinical Inquiry.)
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Clinical commentary Jason Crawford, MD, MPHUniversity of Nevada School of Medicine, Reno
Fluoxetine: A valuable tool
Two studies—the Treatment for Adolescents with Depression Study (TADS)1 and the recently published Adolescent Depression, Antidepressants, and Psychotherapy Trial (ADAPT)2—both based on validated survey tools available in primary care, clearly demonstrate the effectiveness of SSRIs—particularly fluoxetine—for alleviating depressive symptoms.
In my clinical practice, fluoxetine is a valuable tool to rapidly improve depression and common comorbid conditions such as bulimia nervosa, anorexia nervosa, binge-eating disorder not otherwise specified, panic disorder, and obsessive-compulsive disorder. The recent ADAPT trial provides further convincing and consistent data that SSRI therapy should be considered first-line therapy for adolescent depression.
Obviously, prudence mandates close follow-up of your teenage patients and thorough discussion of the risk of increased suicidality with both the patient and parent or guardian.
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 Evidence summary
Fifteen well-designed trials have examined the efficacy of antidepressants for treating major depressive disorder in youth. All reported the changes in total scores on standard depression scales: the Children’s Depression Rating Scale-Revised, Clinical Global Impressions, Hamilton Rating Scale for Depression, or Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children. The TABLE summarizes the findings for SSRIs and venlafaxine based on a meta-analysis of the 15 trials.3 (For more on the characteristics and efficacy of venlafaxine and SSRIs in young people, see TABLE W1, available online at www. jfponline.com.)
TABLEEfficacy of SSRIs and venlafaxine in young people
| DRUG |
ABSOLUTE RISK REDUCTION %* (95% CI) |
NNT (95% CI) |
| Citalopram/escitalopram† |
8 (1 to 16) |
13 (7 to 200) |
| Fluoxetine† ‡ |
20 (11 to 29) |
6 (4 to 10) |
| Sertraline§ |
10 (0 to 20) |
10 (6 to 500) |
| Paroxetine† |
5 (-3 to 13) |
NA |
| Venlafaxine‡ |
11 (1 to 21) |
10 (5 to 112) |
The best bet: Fluoxetine plus CBT
The landmark Treatment for Adolescents with Depression Study, which was included in the meta-analysis, comprised 4 treatment arms: fluoxetine alone, CBT alone, fluoxetine with CBT, and placebo. Only the combination therapy group showed a statistically significant improvement compared with placebo in the primary outcome (improved Children’s Depression Rating Scale-Revised). Improvement in the Clinical Global Impressions score, a subjective measure, was statistically significant in 71% of patients receiving combination therapy and 60.6% of those treated with fluoxetine compared with placebo (34.8%) or CBT alone (43.2%).1
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FAST TRACK
Consider SSRIs as first-line therapy for adolescent depression
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Two RCTs showed that sertraline was slightly, but statistically significantly, better than placebo when the 2 identically designed trials were combined.4 Pooled results of 3 RCTs demonstrated that paroxetine was no better than placebo.3 Two RCTs of citalopram and 1 RCT of escitalopram showed marginally significant benefit over placebo only when pooled.3 A post hoc subgroup analysis of 2 combined RCTs comparing extended-release venlafaxine with placebo showed modest, statistically significant improvement in depressive symptoms in adolescents, but not children.5 A 2007 Cochrane review supports the use of SSRIs to treat major depressive disorder in adolescents, reporting efficacy as 1.28 times that of placebo (95% confidence interval, 1.17-1.41).6
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FAST TRACK
Fluoxetine combined with cognitive behavioral therapy is superior to fluoxetine alone
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Quality of available clinical evidence is limited. Statistical significance was demonstrated in meta-analyses only when data from smaller trials were combined. Fluoxetine was the only antidepressant studied in nonindustry-sponsored trials for major depressive disorder in adolescents. Moreover, results are not often reported separately for children (5-12 years of age) and adolescents (12-18 years of age).
Side effects are an issue for tricyclics
A 2002 Cochrane meta-analysis reported marginal evidence to support using tricyclic antidepressants for treating adolescents. However, these drugs have significantly more side effects than placebo.7 No placebo-controlled RCTs of bupropion, duloxetine, mirtazapine, or St. John’s wort for treating major depressive disorder in adolescents were identified.
Recommendations
A 1998 practice parameter published by The American Academy of Child and Adolescent Psychiatry (AACAP) strongly favors psychotherapy alone or in combination with medication. The guideline recommends treatment throughout the acute and continuation phase of illness—at least 6 months—with possible active treatment during the maintenance phase (which begins after 6 months to 1 year without symptoms and may extend indefinitely). AACAP advocates using SSRIs as first-line therapy without endorsing a specific medication.8
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FAST TRACK
The Society for Adolescent Medicine notes that the evidence for SSRIs—particularly for fluoxetine—is compelling
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The Society for Adolescent Medicine supports pharmacotherapy for depressed adolescents, stating that “data supporting the effectiveness of selective serotoninreuptake inhibitors for adolescents with major depressive disorder, particularly for fluoxetine, is compelling.”9 Similarly, the American College of Neuropsychopharmacology notes that the risk-to-benefit ratio favors drug therapy for moderate to severe depression in adolescents and recommends fluoxetine as an effective treatment for major depression in youth; RCTs comparing other SSRIs with fluoxetine are needed to establish the efficacy of these drugs.10
- Treatment for Adolescents With Depression Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression. JAMA. 2004;292:807–820.
- 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: randomised controlled trial. Br Med J. 2007;335:142.
- 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;297:1683–169. (and Web-only content http://jama.ama-assn.org/cgi/content/full/297/15/1683, accessed June 13, 2007).
- Wagner KD,
Ambrosini P,
Rynn M, et al. Efficacy of setraline in the treatment of children and adolescents with major depressive disorder. JAMA. 2003;290:1033–1041.
- Emslie GJ,
Findling RL,
Yeung PP, et al. Venlafaxine ER for the treatment of pediatric subjects with depression: results of two placebo-controlled trials. J Am Acad Child Adolesc Psychiatry. 2007;46:479–488.
- Hetrick S,
Merry S,
McKenzie J, et al. Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents. Cochrane Database Syst Rev. 2007;(3): CD004851.
- Hazell P,
O’Connell D,
Heathcote D, et al. Tricyclic drugs for depression in children and adolescents. Cochrane Database Syst Rev. 2002;(2):CD002317.
- Birmaher B,
Brent DA,
Benson RS, et al. Summary of the practice parameters for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. 1998;37:1234–1238.
- Lock J,
Walker LR,
Rickert VI, et al. Suicidality in adolescents being treated with antidepressant medications and the black box label: position paper of the Society for Adolescent Medicine. J Adolesc Health. 2005;36:92–93.
- Mann JJ,
Graham E,
Baldessarini RJ, et al. ACNP Task Force report on SSRIs and suicidal behavior in youth. Neuropsychopharmacology. 2006;31:473–492.
The Journal of Family Practice ©2008 Quadrant HealthCom Inc.
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