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Commentary: Clinical perspective on pediatric depression
With “black box” warnings expected, prescribing antidepressants to children and adolescents is changing. In the past year, information from previously unpublished studies has shown the drugs’ risks to be greater and benefits less in pediatric patients than doctors had believed.
As this article went to press, the FDA said it would adopt tougher labeling for antidepressants, as recommended by its Psychopharmacologic Drugs and Pediatric advisory committees. The advisors voted 15 to 8 at a Sept. 14 hearing in favor of a “black box” for all antidepressants, warning of increased risk of suicidality in pediatric patients.
We reported on the FDA’s Feb. 2 public hearing on increased risk of suicidality with antidepressants (CURRENT PSYCHIATRY, March 2004).1 This commentary provides a follow-up perspective on:
- the Columbia group’s report on classifying suicidality in SSRI clinical trial data
- how undisclosed clinical trial data tipped the SSRI risk-benefit balance in pediatric patients
- new data on using SSRIs plus psychotherapy for depressed adolescents.
WHAT THE COLUMBIA GROUP FOUND
In March, the FDA requested a warning label on SSRIs and related antidepressants that all patients be “monitored closely for worsening depression or the emergence of suicidality.” The advisory’s text and supporting information is available on the FDA’s Web site.2
The FDA also contracted with Columbia University to classify SSRI clinical trial events—first analyzed by FDA senior epidemiologist Dr. Andrew D. Mosholder—that might represent suicidality. Dr. Mosholder had reviewed pharmaceutical industry data from 22 placebo-controlled trials involving 4,250 pediatric patients and found that youths given antidepressants were nearly twice as likely to become suicidal as those given placebo (Box 1). Suicidality has historically been attributed to depressive illness rather than antidepressant use. Therefore, FDA officials cancelled Dr. Mosholder’s scheduled testimony at the Feb. 2 hearing—a decision that triggered congressional investigations—to allow for further analysis.
Nearly 2 years ago, FDA senior epidemiologist Dr. Andrew Mosholder requested that paroxetine’s manufacturer analyze suicidal behaviors in its pediatric clinical trial database. In July 2003, the same analysis was requested for eight other antidepressants (bupropion, mirtazapine, fluoxetine, nefazodone, fluvoxamine, sertraline, citalopram, venlafaxine).
The pharmaceutical manufacturers subsequently analyzed data from 22 short-term, placebo-controlled trials involving 4,250 youths—2,298 treated with antidepressants and 1,952 given placebo. Dr. Mosholder reviewed the analyses in September 2003 and found that youths taking antidepressants were nearly twice as likely to become suicidal as those taking placebo. Statistically, the risk of suicide-related events was significantly higher with venlafaxine and paroxetine than with placebo, and data for citalopram approached statistical significance on one measure.
Relative risks for suicide-related events were 0.9 with fluoxetine and 0.5 with mirtazapine, suggesting a possible protective effect (although mirtazapine’s analysis was based on a very small number of events). For all other drugs, relative-risk estimates were >1 or undefined because of lack of events. This association between suicide-related events and active drug treatment was observed only in major depressive disorder treatment trials.
The analyses had limitations; the trials reflected short-term antidepressant use, and each sponsor analyzed its data separately. Based on the evidence, Dr. Mosholder recommended that the FDA discourage use of antidepressants other than fluoxetine in children.
As of Aug. 21, the Columbia group had analyzed data from 25 studies and reviewed 423 adverse events that occurred during the trials’ randomized double-blind phase and/or within 30 days of the last dose of randomized treatment.3 These events included intentional self-injury, suicidal ideation, suicide attempts, accidental injuries, and accidental overdose.
The preliminary evidence suggests that young antidepressant users were 1.8 times more likely to have suicidal thoughts or behaviors compared with patients given placebo4—the same conclusion Dr. Mosholder reached nearly 1 year earlier.
RISK VERSUS BENEFIT
Are SSRIs safe in children? In the United Kingdom, a review by the Medicines and Healthcare Products Regulatory Agency (MHRA) of data submitted by paroxetine’s manufacturer revealed an unfavorable risk-to-benefit ratio in children and adolescents. Review of other data on other antidepressants soon followed.
Last December, the MHRA’s Committee on Safety of Medicines and its Expert Working Group on SSRIs advised that the risks and benefits of treating major depressive disorder in patients younger than age 18 were unfavorable for sertraline, citalopram, paroxetine, and escitalopram, and could not be assessed for fluvoxamine.5 The MHRA warned British physicians against prescribing paroxetine to depressed patients younger than age 18 and ordered labeling changes for paroxetine contraindicating its use in pediatric major depression.
Fluoxetine is the only SSRI for which the committee considers the risk-benefit balance to be favorable. It cautions British physicians, however, that fluoxetine may benefit only an estimated 1 in 10 pediatric patients.5
Are SSRIs effective in children? To be labeled for treating depression in children and adolescents, an SSRI must have proven efficacy (statistically and clinically significant improvement) in two independently conducted, double-blind, placebo-controlled trials. Five trials have met this standard—fluoxetine (2),6,7 sertraline (1),8 paroxetine (1-adolescents only),9 and citalopram (1)10—and three trials have not—paroxetine (2) and citalopram (1).11 Thus, only fluoxetine is FDA-approved for treating depressed children and adolescents.
However, lacking two positive trials does not necessarily indicate that a medication is not effective, especially when only two trials were conducted.12 Also, unpublished data now becoming available show inconsistencies with the published data.13
PUBLISHED VS. UNPUBLISHED DATA
In a meta-analysis by Whittington et al,13 data from five published, randomized, controlled trials of SSRIs (fluoxetine, paroxetine, sertraline and venlafaxine) were compared with data from unpublished reports found in the United Kingdom’s Committee on Safety of Medicines’ review. In the unpublished data, for example, paroxetine had a significantly lower response rate and more-pronounced placebo effect than the published data indicated.
As a result, these investigators concluded that the favorable risk-benefit profiles of paroxetine, sertraline, and venlafaxine for children and adolescents should be switched to unfavorable. They recommended against using these three antidepressants in youth because of possible increased risk of suicidal ideation and serious adverse events—findings that corresponded to the MHRA’s 2003 decisions.
Tipping the balance? Discrepancies between published and unpublished data raise alarms about nonreporting of negative trials. Except for one paroxetine trial, one early fluoxetine trial, and one more-recent fluoxetine trial funded by the National Institute of Mental Health (NIMH),14 the FDA’s “pediatric rule” of 1997 has produced all emerging data on SSRIs in children and adolescents. This rule gives pharmaceutical companies an additional 6 months of patent protection (which translates to millions of dollars) for conducting minimal research to collect data on medications’ safety in pediatric populations.
The subsequent Pediatric Research Equity Act of 2003 (PREA) requires pharmaceutical companies to conduct pediatric studies as part of nearly every new drug application filed since Jan. 1, 1999. Unfortunately, PREA does not regulate the quality of that research nor require that negative studies be disclosed.
TADS: FLUOXETINE PLUS CBT
The recently reported Treatment for Adolescents with Depression Study (TADS)14—funded by the NIMH—showed the benefit of combining fluoxetine with cognitive-behavioral therapy (CBT) for depressed children and adolescents. In the 12-week, multi-site, double-blind, placebo-controlled trial, 439 adolescents ages 12 to 17 diagnosed with major depressive disorder received fluoxetine, 10 to 40 mg/d; CBT alone; CBT with fluoxetine, 10 to 40 mg/d; or placebo. Response rates were:
- fluoxetine alone, 61% (95% confidence interval [CI], 51-70%)
- CBT alone, 43% (95% CI, 34-52%)
- fluoxetine with CBT, 71% (95% CI, 62- 80%)
- placebo, 34.8% (95% CI, 26-44%).
The two treatments containing fluoxetine were statistically more effective than CBT alone or placebo, as measured by the Clinical Global Impression scale. Clinically significant suicidal thinking—in 29% of the adolescents at baseline—improved significantly in all treatment groups, with fluoxetine plus CBT showing the greatest reduction (P = 0.02). Seven of 439 patients (1.6%) attempted suicide; there were no completed suicides.
An association between SSRIs and suicidal ideation in children and adolescents was first reported in the early 1990s.15 In theory, agitation and nervousness that occur in some children treated with SSRIs might increase their risk of self-injury or of harming others. Agitation, hyperkinesia, mania, and hypomania tend to be more frequent among patients treated with SSRIs (including fluoxetine) than among those receiving placebo (1 to 6% vs 0 to 4%).16
Clinicians should watch carefully for activation during SSRI treatment. The following symptoms may occur in activation syndromes: anxiety, agitation, panic attacks, hostility, impulsivity, akathisia (severe restlessness), insomnia, hypomania, irritability, or mania.17
On the other hand, no evidence has shown that increased agitation with SSRIs is synonymous with suicidal behavior, and no suicides have occurred in more than 4,000 children and adolescents studied in SSRI clinical trials. In fact, increased SSRI prescribing for children ages 10 to 19 appears to parallel a significant decrease in suicide in this population. With each 1% increase in SSRI use among adolescents, the number of suicides has declined by 0.23 per 100,000 adolescents per year.18 continued
WHAT ARE CLINICIANS TO DO?
Depression is a known risk factor for suicidal ideation or behavior, and subjects with serious suicidal ideation or suicide attempts are always excluded from clinical trials of antidepressant therapy. Suicide is also relatively rare. Thus, a strong association between SSRI treatment and suicide is difficult to demonstrate. Dozens of controlled trials with thousands of pediatric subjects would be required to show definitively that suicide is associated with antidepressant use.
Recently, a panel of psychiatrists and primary care physicians discussed the FDA’s earlier advisory and its effect on depression treatment.15 Overall, the FDA findings seemed not to have convinced these clinicians of a link between suicide and SSRIs. They commented that:
- the FDA has not established a “firm causal connection” between suicide and SSRIs but uses the term “activation syndrome” (Box 2)15-18
- “activation” may give some depressed patients “the energy to carry out things they have been somewhat inhibited from doing”
- “antidepressant jitteriness syndrome” has been observed more frequently in patients diagnosed with panic disorder or somatizing anxiety than with major depressive disorder, and very little evidence exists to link this syndrome with suicide risk.
Recommendations. As this dialogue continues, how should clinicians care for pediatric patients with major depressive disorder? We suggest the following approach:
- For patients taking antidepressants, recommend that they not stop the medication abruptly, as this may result in severe withdrawal syndrome and increase the risk of depressive relapse. If you discontinue SSRI therapy, taper the dosage over 1 to 2 weeks while monitoring for risky and suicidal behavior.
- For patients newly diagnosed with severe depression, fluoxetine remains an option to use with caution. This includes making an accurate diagnosis, monitoring for suicidality, minimizing side effects, and preventing drug interactions.1
Children with depression often exhibit somatic symptoms such as abdominal pain, headaches, or irritability. Adolescents are more similar to adults, exhibiting sad mood, boredom, apathy, lack of energy, and vegetative signs. Girls and boys are equally at risk for depression until puberty, when prevalence rates for girls begin to rise above those for boys.
Up to 6% of teens meet criteria for major depressive disorder, and up to 25% are affected by it by late adolescence.19 Untreated pediatric depression is associated with substantial morbidity, reduced academic performance, substance abuse, interpersonal problems, social withdrawal, and a poor quality of life.20,21 Depression is a major risk factor for suicide, the third-leading cause of death among U.S. teenagers.
Because treating bipolar depression with antidepressants can cause switching to mania, rule out bipolar depression and mixed episodes before prescribing antidepressants. Bipolar illness may be characterized by marked irritability—also seen in depressed children and adolescents (Box 3).19,21
Informed consent. Inform the patient and parents of antidepressants’ labeling and side effects. Discuss the possibility of disinhibition and impulsivity during initial therapy, which may increase the risk of suicidal ideation or suicide attempts.
Dosing. Although SSRIs do not show a clear dose-response relationship, their side effects are considered dose-dependent.22 Therefore, start children on lower dosages than are used in adolescents and adults, and monitor very closely.
Nondrug intervention. CBT and other psychotherapies have shown short-term benefits for depressed children.23 Therefore, to improve SSRIs’ risk-benefit ratio, you may wish to reserve antidepressants for youths:
- with moderate to severe depression, recurrent depression, or a three-generation family history of depression
- who are unlikely to respond to psychotherapy alone, behavioral or environmental change, or general emotional support.
CONCLUSION
Deciding to start, continue, or discontinue SSRIs and other antidepressants in depressed children and adolescents is difficult for clinicians, patients, and their families. Despite data showing increased suicidal behavior in some pediatric patients, SSRIs—when used with caution—remain an important depression treatment in this population.
Related resources
Drug brand names
- Bupropion • Wellbutrin
- Citalopram • Celexa
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Mirtazapine • Remeron
- Nefazodone • Serzone
- Paroxetine • Paxil
- Sertraline • Zoloft
- Venlafaxine • Effexor
Disclosure
Dr. Elizabeth Weller receives research/grant support from Forest Pharmaceuticals, Organon, and Wyeth Pharmaceuticals and is a consultant to Johnson & Johnson, Novartis Pharmaceuticals Corp., AstraZeneca Pharmaceuticals, and Otsuka Pharmaceutical.
Joon Kang reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Ronald Weller receives research/grant support from Wyeth Pharmaceuticals, Organon, and Forest Pharmaceuticals.
1. Sood AB, Weller EB, Weller RA. SSRIs in children and adolescents: where do we stand? Current Psychiatry 2004;3(3):83-9.
2. Food and Drug Administration. Center for Drug Evaluation and Research. Antidepressant use in children, adolescents, and adults. Available at: http://www.fda.gov/cder/drug/antidepressants/default.htm. Accessed Sept. 2, 2004.
3. Department of Health and Human Services. Public Health Service. Report of the audit of the Columbia suicidality classification methodology [memorandum]. Aug. 16, 2004. Available at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-09-TAB07-Iyasu-Audit_report.htm. Accessed Sept. 2, 2004.
4. Neergaard L. Suicide risk may prompt antidepressant warnings. Associated Press Aug. 21, 2004. Available at: http://chron.com (search archive). Accessed Sept. 15, 2004.
5. Medicines and Healthcare Products Regulatory Agency (UK). Use of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents with major depressive disorder (MDD). Dec. 10, 2003. Available at: www.mhra.gov.uk/news/2003.htm#ssri. Accessed Sept. 2, 2004.
6. 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
7. 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(10):1205-15.
8. Wagner KD, Ambrosini P, Rynn M, et al. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA 2003;290(8):1033-41.
9. Keller MB, Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled study. J Am Acad Child Adolesc Psychiatry 2001;40:762-72.
10. Wagner KD, Robb AS, Findling RL, et al. A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. Am J Psychiatry 2004;161(6):1079-83.
11. Laughren T. Background comments for Feb. 2, 2004 meeting of Psychopharmacological Drugs Advisory Committee (PDAC) and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee (PedsAC). Available at: http://www.fda.gov/ohrms/dockets/ac/04/brief-ing/4006B1_03_Background Memo 01-05-04.doc. Accessed Sept. 15, 2004.
12. Emslie GJ. Making sense of the research puzzle. AACAP News 2004;35(2):
13. Whittington CJ, Kendall T, Fonagy P, et al. Selective serotonin reuptake inhibitors in childhood depression: Systematic review of published versus unpublished data. Lancet 2004;363:1341-5.Also available at: http://www.thelancet.com/journal/vol363/iss9418 (scroll to article title). Accessed Sept. 2, 2004.
14. Treatment for Adolescents with Depression Study (TADS) team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression, JAMA 2004;922(7):807-20.
15. Vorstman J, Lahuis B, Buitelaar JK. SSRIs associated with behavioral activation and suicidal ideation. J Am Acad Child Adol Psychiatry 2001;40:1364-5.
16. Food and Drug Administration. Psychopharmacologic Drugs Advisory Committee and the Anti-Infective Drugs Advisory Committee. Briefing information for public hearing Feb. 2, 2004. Available at: www.fda.gov/ohrms/dockets/ac/04/briefing/4006b1.htm. Accessed Sept. 2, 2004.
17. Culpepper L, Davidson JR, Dietrich AJ, et al. Suicidality as a possible side effect of antidepressant treatment. Primary Care Companion: J Clin Psychiatry 2004;6(2):79-86.
18. Olfson M, Gameroff MJ, Marcus SC, Waslic BD. Outpatient treatment of child and adolescent depression in the United States. Arch Gen Psychiatry 2003;60:1236-42.
19. Kressler RC, Avenevoli S, Merikangas KR. Mood disorders in children and adolescents: an epidemiological perspective. Biol Psychiatry 2001;49:1002-14.
20. Shaffer D, Fisher P, Dulcan MK, et al. The NIMH Diagnostic Interview Schedule for Children, Version 2.3 (DISC-2.3): description, acceptability, prevalence rates, and performance in the MECA Study. Methods for the Epidemiology of Child and Adolescent Mental Disorders Study. J Am Acad Child Adolesc Psychiatry 1996;35:865-77.
21. Harrington R, Bredenkamp D, Groothues C, et al. Adult outcomes of child and adolescent depression. III: Links with suicidal behaviors. J Child Psychol Psychiatry 1994;35:1309-19.
22. Preskorn SH. Outpatient management of depression: a guide for the practitioner(2nd ed). Caddo, OK: Professional Publications, 1999.
23. Lewinsohn PM, Clarke GN. Psychosocial treatments for adolescent depression. Clin Psychol Rev 1999;19:329-42.
With “black box” warnings expected, prescribing antidepressants to children and adolescents is changing. In the past year, information from previously unpublished studies has shown the drugs’ risks to be greater and benefits less in pediatric patients than doctors had believed.
As this article went to press, the FDA said it would adopt tougher labeling for antidepressants, as recommended by its Psychopharmacologic Drugs and Pediatric advisory committees. The advisors voted 15 to 8 at a Sept. 14 hearing in favor of a “black box” for all antidepressants, warning of increased risk of suicidality in pediatric patients.
We reported on the FDA’s Feb. 2 public hearing on increased risk of suicidality with antidepressants (CURRENT PSYCHIATRY, March 2004).1 This commentary provides a follow-up perspective on:
- the Columbia group’s report on classifying suicidality in SSRI clinical trial data
- how undisclosed clinical trial data tipped the SSRI risk-benefit balance in pediatric patients
- new data on using SSRIs plus psychotherapy for depressed adolescents.
WHAT THE COLUMBIA GROUP FOUND
In March, the FDA requested a warning label on SSRIs and related antidepressants that all patients be “monitored closely for worsening depression or the emergence of suicidality.” The advisory’s text and supporting information is available on the FDA’s Web site.2
The FDA also contracted with Columbia University to classify SSRI clinical trial events—first analyzed by FDA senior epidemiologist Dr. Andrew D. Mosholder—that might represent suicidality. Dr. Mosholder had reviewed pharmaceutical industry data from 22 placebo-controlled trials involving 4,250 pediatric patients and found that youths given antidepressants were nearly twice as likely to become suicidal as those given placebo (Box 1). Suicidality has historically been attributed to depressive illness rather than antidepressant use. Therefore, FDA officials cancelled Dr. Mosholder’s scheduled testimony at the Feb. 2 hearing—a decision that triggered congressional investigations—to allow for further analysis.
Nearly 2 years ago, FDA senior epidemiologist Dr. Andrew Mosholder requested that paroxetine’s manufacturer analyze suicidal behaviors in its pediatric clinical trial database. In July 2003, the same analysis was requested for eight other antidepressants (bupropion, mirtazapine, fluoxetine, nefazodone, fluvoxamine, sertraline, citalopram, venlafaxine).
The pharmaceutical manufacturers subsequently analyzed data from 22 short-term, placebo-controlled trials involving 4,250 youths—2,298 treated with antidepressants and 1,952 given placebo. Dr. Mosholder reviewed the analyses in September 2003 and found that youths taking antidepressants were nearly twice as likely to become suicidal as those taking placebo. Statistically, the risk of suicide-related events was significantly higher with venlafaxine and paroxetine than with placebo, and data for citalopram approached statistical significance on one measure.
Relative risks for suicide-related events were 0.9 with fluoxetine and 0.5 with mirtazapine, suggesting a possible protective effect (although mirtazapine’s analysis was based on a very small number of events). For all other drugs, relative-risk estimates were >1 or undefined because of lack of events. This association between suicide-related events and active drug treatment was observed only in major depressive disorder treatment trials.
The analyses had limitations; the trials reflected short-term antidepressant use, and each sponsor analyzed its data separately. Based on the evidence, Dr. Mosholder recommended that the FDA discourage use of antidepressants other than fluoxetine in children.
As of Aug. 21, the Columbia group had analyzed data from 25 studies and reviewed 423 adverse events that occurred during the trials’ randomized double-blind phase and/or within 30 days of the last dose of randomized treatment.3 These events included intentional self-injury, suicidal ideation, suicide attempts, accidental injuries, and accidental overdose.
The preliminary evidence suggests that young antidepressant users were 1.8 times more likely to have suicidal thoughts or behaviors compared with patients given placebo4—the same conclusion Dr. Mosholder reached nearly 1 year earlier.
RISK VERSUS BENEFIT
Are SSRIs safe in children? In the United Kingdom, a review by the Medicines and Healthcare Products Regulatory Agency (MHRA) of data submitted by paroxetine’s manufacturer revealed an unfavorable risk-to-benefit ratio in children and adolescents. Review of other data on other antidepressants soon followed.
Last December, the MHRA’s Committee on Safety of Medicines and its Expert Working Group on SSRIs advised that the risks and benefits of treating major depressive disorder in patients younger than age 18 were unfavorable for sertraline, citalopram, paroxetine, and escitalopram, and could not be assessed for fluvoxamine.5 The MHRA warned British physicians against prescribing paroxetine to depressed patients younger than age 18 and ordered labeling changes for paroxetine contraindicating its use in pediatric major depression.
Fluoxetine is the only SSRI for which the committee considers the risk-benefit balance to be favorable. It cautions British physicians, however, that fluoxetine may benefit only an estimated 1 in 10 pediatric patients.5
Are SSRIs effective in children? To be labeled for treating depression in children and adolescents, an SSRI must have proven efficacy (statistically and clinically significant improvement) in two independently conducted, double-blind, placebo-controlled trials. Five trials have met this standard—fluoxetine (2),6,7 sertraline (1),8 paroxetine (1-adolescents only),9 and citalopram (1)10—and three trials have not—paroxetine (2) and citalopram (1).11 Thus, only fluoxetine is FDA-approved for treating depressed children and adolescents.
However, lacking two positive trials does not necessarily indicate that a medication is not effective, especially when only two trials were conducted.12 Also, unpublished data now becoming available show inconsistencies with the published data.13
PUBLISHED VS. UNPUBLISHED DATA
In a meta-analysis by Whittington et al,13 data from five published, randomized, controlled trials of SSRIs (fluoxetine, paroxetine, sertraline and venlafaxine) were compared with data from unpublished reports found in the United Kingdom’s Committee on Safety of Medicines’ review. In the unpublished data, for example, paroxetine had a significantly lower response rate and more-pronounced placebo effect than the published data indicated.
As a result, these investigators concluded that the favorable risk-benefit profiles of paroxetine, sertraline, and venlafaxine for children and adolescents should be switched to unfavorable. They recommended against using these three antidepressants in youth because of possible increased risk of suicidal ideation and serious adverse events—findings that corresponded to the MHRA’s 2003 decisions.
Tipping the balance? Discrepancies between published and unpublished data raise alarms about nonreporting of negative trials. Except for one paroxetine trial, one early fluoxetine trial, and one more-recent fluoxetine trial funded by the National Institute of Mental Health (NIMH),14 the FDA’s “pediatric rule” of 1997 has produced all emerging data on SSRIs in children and adolescents. This rule gives pharmaceutical companies an additional 6 months of patent protection (which translates to millions of dollars) for conducting minimal research to collect data on medications’ safety in pediatric populations.
The subsequent Pediatric Research Equity Act of 2003 (PREA) requires pharmaceutical companies to conduct pediatric studies as part of nearly every new drug application filed since Jan. 1, 1999. Unfortunately, PREA does not regulate the quality of that research nor require that negative studies be disclosed.
TADS: FLUOXETINE PLUS CBT
The recently reported Treatment for Adolescents with Depression Study (TADS)14—funded by the NIMH—showed the benefit of combining fluoxetine with cognitive-behavioral therapy (CBT) for depressed children and adolescents. In the 12-week, multi-site, double-blind, placebo-controlled trial, 439 adolescents ages 12 to 17 diagnosed with major depressive disorder received fluoxetine, 10 to 40 mg/d; CBT alone; CBT with fluoxetine, 10 to 40 mg/d; or placebo. Response rates were:
- fluoxetine alone, 61% (95% confidence interval [CI], 51-70%)
- CBT alone, 43% (95% CI, 34-52%)
- fluoxetine with CBT, 71% (95% CI, 62- 80%)
- placebo, 34.8% (95% CI, 26-44%).
The two treatments containing fluoxetine were statistically more effective than CBT alone or placebo, as measured by the Clinical Global Impression scale. Clinically significant suicidal thinking—in 29% of the adolescents at baseline—improved significantly in all treatment groups, with fluoxetine plus CBT showing the greatest reduction (P = 0.02). Seven of 439 patients (1.6%) attempted suicide; there were no completed suicides.
An association between SSRIs and suicidal ideation in children and adolescents was first reported in the early 1990s.15 In theory, agitation and nervousness that occur in some children treated with SSRIs might increase their risk of self-injury or of harming others. Agitation, hyperkinesia, mania, and hypomania tend to be more frequent among patients treated with SSRIs (including fluoxetine) than among those receiving placebo (1 to 6% vs 0 to 4%).16
Clinicians should watch carefully for activation during SSRI treatment. The following symptoms may occur in activation syndromes: anxiety, agitation, panic attacks, hostility, impulsivity, akathisia (severe restlessness), insomnia, hypomania, irritability, or mania.17
On the other hand, no evidence has shown that increased agitation with SSRIs is synonymous with suicidal behavior, and no suicides have occurred in more than 4,000 children and adolescents studied in SSRI clinical trials. In fact, increased SSRI prescribing for children ages 10 to 19 appears to parallel a significant decrease in suicide in this population. With each 1% increase in SSRI use among adolescents, the number of suicides has declined by 0.23 per 100,000 adolescents per year.18 continued
WHAT ARE CLINICIANS TO DO?
Depression is a known risk factor for suicidal ideation or behavior, and subjects with serious suicidal ideation or suicide attempts are always excluded from clinical trials of antidepressant therapy. Suicide is also relatively rare. Thus, a strong association between SSRI treatment and suicide is difficult to demonstrate. Dozens of controlled trials with thousands of pediatric subjects would be required to show definitively that suicide is associated with antidepressant use.
Recently, a panel of psychiatrists and primary care physicians discussed the FDA’s earlier advisory and its effect on depression treatment.15 Overall, the FDA findings seemed not to have convinced these clinicians of a link between suicide and SSRIs. They commented that:
- the FDA has not established a “firm causal connection” between suicide and SSRIs but uses the term “activation syndrome” (Box 2)15-18
- “activation” may give some depressed patients “the energy to carry out things they have been somewhat inhibited from doing”
- “antidepressant jitteriness syndrome” has been observed more frequently in patients diagnosed with panic disorder or somatizing anxiety than with major depressive disorder, and very little evidence exists to link this syndrome with suicide risk.
Recommendations. As this dialogue continues, how should clinicians care for pediatric patients with major depressive disorder? We suggest the following approach:
- For patients taking antidepressants, recommend that they not stop the medication abruptly, as this may result in severe withdrawal syndrome and increase the risk of depressive relapse. If you discontinue SSRI therapy, taper the dosage over 1 to 2 weeks while monitoring for risky and suicidal behavior.
- For patients newly diagnosed with severe depression, fluoxetine remains an option to use with caution. This includes making an accurate diagnosis, monitoring for suicidality, minimizing side effects, and preventing drug interactions.1
Children with depression often exhibit somatic symptoms such as abdominal pain, headaches, or irritability. Adolescents are more similar to adults, exhibiting sad mood, boredom, apathy, lack of energy, and vegetative signs. Girls and boys are equally at risk for depression until puberty, when prevalence rates for girls begin to rise above those for boys.
Up to 6% of teens meet criteria for major depressive disorder, and up to 25% are affected by it by late adolescence.19 Untreated pediatric depression is associated with substantial morbidity, reduced academic performance, substance abuse, interpersonal problems, social withdrawal, and a poor quality of life.20,21 Depression is a major risk factor for suicide, the third-leading cause of death among U.S. teenagers.
Because treating bipolar depression with antidepressants can cause switching to mania, rule out bipolar depression and mixed episodes before prescribing antidepressants. Bipolar illness may be characterized by marked irritability—also seen in depressed children and adolescents (Box 3).19,21
Informed consent. Inform the patient and parents of antidepressants’ labeling and side effects. Discuss the possibility of disinhibition and impulsivity during initial therapy, which may increase the risk of suicidal ideation or suicide attempts.
Dosing. Although SSRIs do not show a clear dose-response relationship, their side effects are considered dose-dependent.22 Therefore, start children on lower dosages than are used in adolescents and adults, and monitor very closely.
Nondrug intervention. CBT and other psychotherapies have shown short-term benefits for depressed children.23 Therefore, to improve SSRIs’ risk-benefit ratio, you may wish to reserve antidepressants for youths:
- with moderate to severe depression, recurrent depression, or a three-generation family history of depression
- who are unlikely to respond to psychotherapy alone, behavioral or environmental change, or general emotional support.
CONCLUSION
Deciding to start, continue, or discontinue SSRIs and other antidepressants in depressed children and adolescents is difficult for clinicians, patients, and their families. Despite data showing increased suicidal behavior in some pediatric patients, SSRIs—when used with caution—remain an important depression treatment in this population.
Related resources
Drug brand names
- Bupropion • Wellbutrin
- Citalopram • Celexa
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Mirtazapine • Remeron
- Nefazodone • Serzone
- Paroxetine • Paxil
- Sertraline • Zoloft
- Venlafaxine • Effexor
Disclosure
Dr. Elizabeth Weller receives research/grant support from Forest Pharmaceuticals, Organon, and Wyeth Pharmaceuticals and is a consultant to Johnson & Johnson, Novartis Pharmaceuticals Corp., AstraZeneca Pharmaceuticals, and Otsuka Pharmaceutical.
Joon Kang reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Ronald Weller receives research/grant support from Wyeth Pharmaceuticals, Organon, and Forest Pharmaceuticals.
With “black box” warnings expected, prescribing antidepressants to children and adolescents is changing. In the past year, information from previously unpublished studies has shown the drugs’ risks to be greater and benefits less in pediatric patients than doctors had believed.
As this article went to press, the FDA said it would adopt tougher labeling for antidepressants, as recommended by its Psychopharmacologic Drugs and Pediatric advisory committees. The advisors voted 15 to 8 at a Sept. 14 hearing in favor of a “black box” for all antidepressants, warning of increased risk of suicidality in pediatric patients.
We reported on the FDA’s Feb. 2 public hearing on increased risk of suicidality with antidepressants (CURRENT PSYCHIATRY, March 2004).1 This commentary provides a follow-up perspective on:
- the Columbia group’s report on classifying suicidality in SSRI clinical trial data
- how undisclosed clinical trial data tipped the SSRI risk-benefit balance in pediatric patients
- new data on using SSRIs plus psychotherapy for depressed adolescents.
WHAT THE COLUMBIA GROUP FOUND
In March, the FDA requested a warning label on SSRIs and related antidepressants that all patients be “monitored closely for worsening depression or the emergence of suicidality.” The advisory’s text and supporting information is available on the FDA’s Web site.2
The FDA also contracted with Columbia University to classify SSRI clinical trial events—first analyzed by FDA senior epidemiologist Dr. Andrew D. Mosholder—that might represent suicidality. Dr. Mosholder had reviewed pharmaceutical industry data from 22 placebo-controlled trials involving 4,250 pediatric patients and found that youths given antidepressants were nearly twice as likely to become suicidal as those given placebo (Box 1). Suicidality has historically been attributed to depressive illness rather than antidepressant use. Therefore, FDA officials cancelled Dr. Mosholder’s scheduled testimony at the Feb. 2 hearing—a decision that triggered congressional investigations—to allow for further analysis.
Nearly 2 years ago, FDA senior epidemiologist Dr. Andrew Mosholder requested that paroxetine’s manufacturer analyze suicidal behaviors in its pediatric clinical trial database. In July 2003, the same analysis was requested for eight other antidepressants (bupropion, mirtazapine, fluoxetine, nefazodone, fluvoxamine, sertraline, citalopram, venlafaxine).
The pharmaceutical manufacturers subsequently analyzed data from 22 short-term, placebo-controlled trials involving 4,250 youths—2,298 treated with antidepressants and 1,952 given placebo. Dr. Mosholder reviewed the analyses in September 2003 and found that youths taking antidepressants were nearly twice as likely to become suicidal as those taking placebo. Statistically, the risk of suicide-related events was significantly higher with venlafaxine and paroxetine than with placebo, and data for citalopram approached statistical significance on one measure.
Relative risks for suicide-related events were 0.9 with fluoxetine and 0.5 with mirtazapine, suggesting a possible protective effect (although mirtazapine’s analysis was based on a very small number of events). For all other drugs, relative-risk estimates were >1 or undefined because of lack of events. This association between suicide-related events and active drug treatment was observed only in major depressive disorder treatment trials.
The analyses had limitations; the trials reflected short-term antidepressant use, and each sponsor analyzed its data separately. Based on the evidence, Dr. Mosholder recommended that the FDA discourage use of antidepressants other than fluoxetine in children.
As of Aug. 21, the Columbia group had analyzed data from 25 studies and reviewed 423 adverse events that occurred during the trials’ randomized double-blind phase and/or within 30 days of the last dose of randomized treatment.3 These events included intentional self-injury, suicidal ideation, suicide attempts, accidental injuries, and accidental overdose.
The preliminary evidence suggests that young antidepressant users were 1.8 times more likely to have suicidal thoughts or behaviors compared with patients given placebo4—the same conclusion Dr. Mosholder reached nearly 1 year earlier.
RISK VERSUS BENEFIT
Are SSRIs safe in children? In the United Kingdom, a review by the Medicines and Healthcare Products Regulatory Agency (MHRA) of data submitted by paroxetine’s manufacturer revealed an unfavorable risk-to-benefit ratio in children and adolescents. Review of other data on other antidepressants soon followed.
Last December, the MHRA’s Committee on Safety of Medicines and its Expert Working Group on SSRIs advised that the risks and benefits of treating major depressive disorder in patients younger than age 18 were unfavorable for sertraline, citalopram, paroxetine, and escitalopram, and could not be assessed for fluvoxamine.5 The MHRA warned British physicians against prescribing paroxetine to depressed patients younger than age 18 and ordered labeling changes for paroxetine contraindicating its use in pediatric major depression.
Fluoxetine is the only SSRI for which the committee considers the risk-benefit balance to be favorable. It cautions British physicians, however, that fluoxetine may benefit only an estimated 1 in 10 pediatric patients.5
Are SSRIs effective in children? To be labeled for treating depression in children and adolescents, an SSRI must have proven efficacy (statistically and clinically significant improvement) in two independently conducted, double-blind, placebo-controlled trials. Five trials have met this standard—fluoxetine (2),6,7 sertraline (1),8 paroxetine (1-adolescents only),9 and citalopram (1)10—and three trials have not—paroxetine (2) and citalopram (1).11 Thus, only fluoxetine is FDA-approved for treating depressed children and adolescents.
However, lacking two positive trials does not necessarily indicate that a medication is not effective, especially when only two trials were conducted.12 Also, unpublished data now becoming available show inconsistencies with the published data.13
PUBLISHED VS. UNPUBLISHED DATA
In a meta-analysis by Whittington et al,13 data from five published, randomized, controlled trials of SSRIs (fluoxetine, paroxetine, sertraline and venlafaxine) were compared with data from unpublished reports found in the United Kingdom’s Committee on Safety of Medicines’ review. In the unpublished data, for example, paroxetine had a significantly lower response rate and more-pronounced placebo effect than the published data indicated.
As a result, these investigators concluded that the favorable risk-benefit profiles of paroxetine, sertraline, and venlafaxine for children and adolescents should be switched to unfavorable. They recommended against using these three antidepressants in youth because of possible increased risk of suicidal ideation and serious adverse events—findings that corresponded to the MHRA’s 2003 decisions.
Tipping the balance? Discrepancies between published and unpublished data raise alarms about nonreporting of negative trials. Except for one paroxetine trial, one early fluoxetine trial, and one more-recent fluoxetine trial funded by the National Institute of Mental Health (NIMH),14 the FDA’s “pediatric rule” of 1997 has produced all emerging data on SSRIs in children and adolescents. This rule gives pharmaceutical companies an additional 6 months of patent protection (which translates to millions of dollars) for conducting minimal research to collect data on medications’ safety in pediatric populations.
The subsequent Pediatric Research Equity Act of 2003 (PREA) requires pharmaceutical companies to conduct pediatric studies as part of nearly every new drug application filed since Jan. 1, 1999. Unfortunately, PREA does not regulate the quality of that research nor require that negative studies be disclosed.
TADS: FLUOXETINE PLUS CBT
The recently reported Treatment for Adolescents with Depression Study (TADS)14—funded by the NIMH—showed the benefit of combining fluoxetine with cognitive-behavioral therapy (CBT) for depressed children and adolescents. In the 12-week, multi-site, double-blind, placebo-controlled trial, 439 adolescents ages 12 to 17 diagnosed with major depressive disorder received fluoxetine, 10 to 40 mg/d; CBT alone; CBT with fluoxetine, 10 to 40 mg/d; or placebo. Response rates were:
- fluoxetine alone, 61% (95% confidence interval [CI], 51-70%)
- CBT alone, 43% (95% CI, 34-52%)
- fluoxetine with CBT, 71% (95% CI, 62- 80%)
- placebo, 34.8% (95% CI, 26-44%).
The two treatments containing fluoxetine were statistically more effective than CBT alone or placebo, as measured by the Clinical Global Impression scale. Clinically significant suicidal thinking—in 29% of the adolescents at baseline—improved significantly in all treatment groups, with fluoxetine plus CBT showing the greatest reduction (P = 0.02). Seven of 439 patients (1.6%) attempted suicide; there were no completed suicides.
An association between SSRIs and suicidal ideation in children and adolescents was first reported in the early 1990s.15 In theory, agitation and nervousness that occur in some children treated with SSRIs might increase their risk of self-injury or of harming others. Agitation, hyperkinesia, mania, and hypomania tend to be more frequent among patients treated with SSRIs (including fluoxetine) than among those receiving placebo (1 to 6% vs 0 to 4%).16
Clinicians should watch carefully for activation during SSRI treatment. The following symptoms may occur in activation syndromes: anxiety, agitation, panic attacks, hostility, impulsivity, akathisia (severe restlessness), insomnia, hypomania, irritability, or mania.17
On the other hand, no evidence has shown that increased agitation with SSRIs is synonymous with suicidal behavior, and no suicides have occurred in more than 4,000 children and adolescents studied in SSRI clinical trials. In fact, increased SSRI prescribing for children ages 10 to 19 appears to parallel a significant decrease in suicide in this population. With each 1% increase in SSRI use among adolescents, the number of suicides has declined by 0.23 per 100,000 adolescents per year.18 continued
WHAT ARE CLINICIANS TO DO?
Depression is a known risk factor for suicidal ideation or behavior, and subjects with serious suicidal ideation or suicide attempts are always excluded from clinical trials of antidepressant therapy. Suicide is also relatively rare. Thus, a strong association between SSRI treatment and suicide is difficult to demonstrate. Dozens of controlled trials with thousands of pediatric subjects would be required to show definitively that suicide is associated with antidepressant use.
Recently, a panel of psychiatrists and primary care physicians discussed the FDA’s earlier advisory and its effect on depression treatment.15 Overall, the FDA findings seemed not to have convinced these clinicians of a link between suicide and SSRIs. They commented that:
- the FDA has not established a “firm causal connection” between suicide and SSRIs but uses the term “activation syndrome” (Box 2)15-18
- “activation” may give some depressed patients “the energy to carry out things they have been somewhat inhibited from doing”
- “antidepressant jitteriness syndrome” has been observed more frequently in patients diagnosed with panic disorder or somatizing anxiety than with major depressive disorder, and very little evidence exists to link this syndrome with suicide risk.
Recommendations. As this dialogue continues, how should clinicians care for pediatric patients with major depressive disorder? We suggest the following approach:
- For patients taking antidepressants, recommend that they not stop the medication abruptly, as this may result in severe withdrawal syndrome and increase the risk of depressive relapse. If you discontinue SSRI therapy, taper the dosage over 1 to 2 weeks while monitoring for risky and suicidal behavior.
- For patients newly diagnosed with severe depression, fluoxetine remains an option to use with caution. This includes making an accurate diagnosis, monitoring for suicidality, minimizing side effects, and preventing drug interactions.1
Children with depression often exhibit somatic symptoms such as abdominal pain, headaches, or irritability. Adolescents are more similar to adults, exhibiting sad mood, boredom, apathy, lack of energy, and vegetative signs. Girls and boys are equally at risk for depression until puberty, when prevalence rates for girls begin to rise above those for boys.
Up to 6% of teens meet criteria for major depressive disorder, and up to 25% are affected by it by late adolescence.19 Untreated pediatric depression is associated with substantial morbidity, reduced academic performance, substance abuse, interpersonal problems, social withdrawal, and a poor quality of life.20,21 Depression is a major risk factor for suicide, the third-leading cause of death among U.S. teenagers.
Because treating bipolar depression with antidepressants can cause switching to mania, rule out bipolar depression and mixed episodes before prescribing antidepressants. Bipolar illness may be characterized by marked irritability—also seen in depressed children and adolescents (Box 3).19,21
Informed consent. Inform the patient and parents of antidepressants’ labeling and side effects. Discuss the possibility of disinhibition and impulsivity during initial therapy, which may increase the risk of suicidal ideation or suicide attempts.
Dosing. Although SSRIs do not show a clear dose-response relationship, their side effects are considered dose-dependent.22 Therefore, start children on lower dosages than are used in adolescents and adults, and monitor very closely.
Nondrug intervention. CBT and other psychotherapies have shown short-term benefits for depressed children.23 Therefore, to improve SSRIs’ risk-benefit ratio, you may wish to reserve antidepressants for youths:
- with moderate to severe depression, recurrent depression, or a three-generation family history of depression
- who are unlikely to respond to psychotherapy alone, behavioral or environmental change, or general emotional support.
CONCLUSION
Deciding to start, continue, or discontinue SSRIs and other antidepressants in depressed children and adolescents is difficult for clinicians, patients, and their families. Despite data showing increased suicidal behavior in some pediatric patients, SSRIs—when used with caution—remain an important depression treatment in this population.
Related resources
Drug brand names
- Bupropion • Wellbutrin
- Citalopram • Celexa
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Mirtazapine • Remeron
- Nefazodone • Serzone
- Paroxetine • Paxil
- Sertraline • Zoloft
- Venlafaxine • Effexor
Disclosure
Dr. Elizabeth Weller receives research/grant support from Forest Pharmaceuticals, Organon, and Wyeth Pharmaceuticals and is a consultant to Johnson & Johnson, Novartis Pharmaceuticals Corp., AstraZeneca Pharmaceuticals, and Otsuka Pharmaceutical.
Joon Kang reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Ronald Weller receives research/grant support from Wyeth Pharmaceuticals, Organon, and Forest Pharmaceuticals.
1. Sood AB, Weller EB, Weller RA. SSRIs in children and adolescents: where do we stand? Current Psychiatry 2004;3(3):83-9.
2. Food and Drug Administration. Center for Drug Evaluation and Research. Antidepressant use in children, adolescents, and adults. Available at: http://www.fda.gov/cder/drug/antidepressants/default.htm. Accessed Sept. 2, 2004.
3. Department of Health and Human Services. Public Health Service. Report of the audit of the Columbia suicidality classification methodology [memorandum]. Aug. 16, 2004. Available at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-09-TAB07-Iyasu-Audit_report.htm. Accessed Sept. 2, 2004.
4. Neergaard L. Suicide risk may prompt antidepressant warnings. Associated Press Aug. 21, 2004. Available at: http://chron.com (search archive). Accessed Sept. 15, 2004.
5. Medicines and Healthcare Products Regulatory Agency (UK). Use of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents with major depressive disorder (MDD). Dec. 10, 2003. Available at: www.mhra.gov.uk/news/2003.htm#ssri. Accessed Sept. 2, 2004.
6. 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
7. 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(10):1205-15.
8. Wagner KD, Ambrosini P, Rynn M, et al. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA 2003;290(8):1033-41.
9. Keller MB, Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled study. J Am Acad Child Adolesc Psychiatry 2001;40:762-72.
10. Wagner KD, Robb AS, Findling RL, et al. A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. Am J Psychiatry 2004;161(6):1079-83.
11. Laughren T. Background comments for Feb. 2, 2004 meeting of Psychopharmacological Drugs Advisory Committee (PDAC) and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee (PedsAC). Available at: http://www.fda.gov/ohrms/dockets/ac/04/brief-ing/4006B1_03_Background Memo 01-05-04.doc. Accessed Sept. 15, 2004.
12. Emslie GJ. Making sense of the research puzzle. AACAP News 2004;35(2):
13. Whittington CJ, Kendall T, Fonagy P, et al. Selective serotonin reuptake inhibitors in childhood depression: Systematic review of published versus unpublished data. Lancet 2004;363:1341-5.Also available at: http://www.thelancet.com/journal/vol363/iss9418 (scroll to article title). Accessed Sept. 2, 2004.
14. Treatment for Adolescents with Depression Study (TADS) team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression, JAMA 2004;922(7):807-20.
15. Vorstman J, Lahuis B, Buitelaar JK. SSRIs associated with behavioral activation and suicidal ideation. J Am Acad Child Adol Psychiatry 2001;40:1364-5.
16. Food and Drug Administration. Psychopharmacologic Drugs Advisory Committee and the Anti-Infective Drugs Advisory Committee. Briefing information for public hearing Feb. 2, 2004. Available at: www.fda.gov/ohrms/dockets/ac/04/briefing/4006b1.htm. Accessed Sept. 2, 2004.
17. Culpepper L, Davidson JR, Dietrich AJ, et al. Suicidality as a possible side effect of antidepressant treatment. Primary Care Companion: J Clin Psychiatry 2004;6(2):79-86.
18. Olfson M, Gameroff MJ, Marcus SC, Waslic BD. Outpatient treatment of child and adolescent depression in the United States. Arch Gen Psychiatry 2003;60:1236-42.
19. Kressler RC, Avenevoli S, Merikangas KR. Mood disorders in children and adolescents: an epidemiological perspective. Biol Psychiatry 2001;49:1002-14.
20. Shaffer D, Fisher P, Dulcan MK, et al. The NIMH Diagnostic Interview Schedule for Children, Version 2.3 (DISC-2.3): description, acceptability, prevalence rates, and performance in the MECA Study. Methods for the Epidemiology of Child and Adolescent Mental Disorders Study. J Am Acad Child Adolesc Psychiatry 1996;35:865-77.
21. Harrington R, Bredenkamp D, Groothues C, et al. Adult outcomes of child and adolescent depression. III: Links with suicidal behaviors. J Child Psychol Psychiatry 1994;35:1309-19.
22. Preskorn SH. Outpatient management of depression: a guide for the practitioner(2nd ed). Caddo, OK: Professional Publications, 1999.
23. Lewinsohn PM, Clarke GN. Psychosocial treatments for adolescent depression. Clin Psychol Rev 1999;19:329-42.
1. Sood AB, Weller EB, Weller RA. SSRIs in children and adolescents: where do we stand? Current Psychiatry 2004;3(3):83-9.
2. Food and Drug Administration. Center for Drug Evaluation and Research. Antidepressant use in children, adolescents, and adults. Available at: http://www.fda.gov/cder/drug/antidepressants/default.htm. Accessed Sept. 2, 2004.
3. Department of Health and Human Services. Public Health Service. Report of the audit of the Columbia suicidality classification methodology [memorandum]. Aug. 16, 2004. Available at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-09-TAB07-Iyasu-Audit_report.htm. Accessed Sept. 2, 2004.
4. Neergaard L. Suicide risk may prompt antidepressant warnings. Associated Press Aug. 21, 2004. Available at: http://chron.com (search archive). Accessed Sept. 15, 2004.
5. Medicines and Healthcare Products Regulatory Agency (UK). Use of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents with major depressive disorder (MDD). Dec. 10, 2003. Available at: www.mhra.gov.uk/news/2003.htm#ssri. Accessed Sept. 2, 2004.
6. 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
7. 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(10):1205-15.
8. Wagner KD, Ambrosini P, Rynn M, et al. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA 2003;290(8):1033-41.
9. Keller MB, Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled study. J Am Acad Child Adolesc Psychiatry 2001;40:762-72.
10. Wagner KD, Robb AS, Findling RL, et al. A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. Am J Psychiatry 2004;161(6):1079-83.
11. Laughren T. Background comments for Feb. 2, 2004 meeting of Psychopharmacological Drugs Advisory Committee (PDAC) and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee (PedsAC). Available at: http://www.fda.gov/ohrms/dockets/ac/04/brief-ing/4006B1_03_Background Memo 01-05-04.doc. Accessed Sept. 15, 2004.
12. Emslie GJ. Making sense of the research puzzle. AACAP News 2004;35(2):
13. Whittington CJ, Kendall T, Fonagy P, et al. Selective serotonin reuptake inhibitors in childhood depression: Systematic review of published versus unpublished data. Lancet 2004;363:1341-5.Also available at: http://www.thelancet.com/journal/vol363/iss9418 (scroll to article title). Accessed Sept. 2, 2004.
14. Treatment for Adolescents with Depression Study (TADS) team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression, JAMA 2004;922(7):807-20.
15. Vorstman J, Lahuis B, Buitelaar JK. SSRIs associated with behavioral activation and suicidal ideation. J Am Acad Child Adol Psychiatry 2001;40:1364-5.
16. Food and Drug Administration. Psychopharmacologic Drugs Advisory Committee and the Anti-Infective Drugs Advisory Committee. Briefing information for public hearing Feb. 2, 2004. Available at: www.fda.gov/ohrms/dockets/ac/04/briefing/4006b1.htm. Accessed Sept. 2, 2004.
17. Culpepper L, Davidson JR, Dietrich AJ, et al. Suicidality as a possible side effect of antidepressant treatment. Primary Care Companion: J Clin Psychiatry 2004;6(2):79-86.
18. Olfson M, Gameroff MJ, Marcus SC, Waslic BD. Outpatient treatment of child and adolescent depression in the United States. Arch Gen Psychiatry 2003;60:1236-42.
19. Kressler RC, Avenevoli S, Merikangas KR. Mood disorders in children and adolescents: an epidemiological perspective. Biol Psychiatry 2001;49:1002-14.
20. Shaffer D, Fisher P, Dulcan MK, et al. The NIMH Diagnostic Interview Schedule for Children, Version 2.3 (DISC-2.3): description, acceptability, prevalence rates, and performance in the MECA Study. Methods for the Epidemiology of Child and Adolescent Mental Disorders Study. J Am Acad Child Adolesc Psychiatry 1996;35:865-77.
21. Harrington R, Bredenkamp D, Groothues C, et al. Adult outcomes of child and adolescent depression. III: Links with suicidal behaviors. J Child Psychol Psychiatry 1994;35:1309-19.
22. Preskorn SH. Outpatient management of depression: a guide for the practitioner(2nd ed). Caddo, OK: Professional Publications, 1999.
23. Lewinsohn PM, Clarke GN. Psychosocial treatments for adolescent depression. Clin Psychol Rev 1999;19:329-42.