Antidepressants and Youth: A Review for All Care Providers

from Practice Update, Winter 2005

By Kim Kelsay, MDCo-Director, Pediatric Day Treatment Program, National Jewish Medical and Research CenterAssistant Professor, Department of Psychiatry, University of Colorado Health Sciences CenterPresident, Colorado Child and Adolescent Psychiatry Society

Black Box Warning

On October 15, 2004, the U.S. Food and Drug Administration issued a letter to drug sponsors requiring a black box warning for the antidepressants listed in Table 1. This black box warning reads, "Pooled analysis of short-term (four to 16 weeks) placebo-controlled trials of nine antidepressant drugs (SSRIs and others) in children and adolescents with Major Depressive Disorder (MDD), Obsessive Compulsive Disorder (OCD), or other psychiatric disorders (a total of 24 trials involving more than 4,400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events was four percent, twice the placebo risk of two percent. No suicides occurred in these trials."

In addition to the black box warning, there is other material including statements about closely monitoring patients. “Ideally such observation would include, at least, weekly face-to-face contact with patients, their family members or caregivers during the first four weeks of treatment, then visits every other week for the next four weeks, then at 12 weeks and as clinically indicated beyond 12 weeks.” The FDA is also developing patient friendly medication guides outlining risks and warning signs of suicidality to be distributed by pharmacists, with each prescription or refill.

How will this impact the care of pediatric patients with depression, anxiety, or other mental health problems where a trial of an antidepressant may be indicated?

Perhaps understanding more about the process and evidence that led to this recommendation might help us determine how to approach the use of these medications in children.

Table 1

Background

In 2002, 2.7 million prescriptions for antidepressants were dispensed for children ages one to 11 years, and 8.1 million for adolescents ages 12-17 years. The following may have contributed to the number of prescriptions written. Both anxiety and depression were common. Anxiety disorders are the most common group of disorders in childhood and adolescence: prevalence ranges from 5 to 10 percent in the general population of children. The estimated prevalence of depressive disorders is 2 percent for primary school children, and 4 to 8 percent for adolescents. By age 18, 20 percent of the population will have experienced a depressive episode. Both anxiety and depression are associated with significant morbidity, and depression is a major risk factor for suicide. Strikingly, suicide is the third leading cause of death among adolescents ages 15-19 and fourth among youth ages 10-14. Until the development of SSRIs, many of the medications used to treat depression had not been shown to be effective in the pediatric population, and the tricyclic antidepressants have significant risks including prolongation of the QTC interval, sudden cardiac death, and the potential to be lethal in overdoses. Clinicians were hopeful when the SSRIs were approved for use in adults and later when Fluoxetine (MDD and OCD), Fluvoxamine (OCD), Setraline (OCD) and Anafranil (OCD) were labeled for use in children and appeared to have good benefit risk ratios.

How did the apparent change in the risk/benefit ratio of these antidepressants come to light? 

There has been a push to study medications in pediatric populations alongside adult populations, beginning in the late 1990s. In 1997, legislation allowed sponsors (or pharmaceutical companies) to extend exclusive marketing rights by studying medications in pediatric populations. This was followed by several legislative acts and regulations extending the incentive program and giving the FDA authority to require that studies of medications be performed in the pediatric population under certain conditions. Since 1997, there have been 290 requests issued by the FDA, and more than 200 studies have been reviewed for 100 medications. The importance of studying medications in children is underlined by the finding that one quarter of the above reviews resulted in changing the timing of the dose, the identification of a new adverse event, or a finding of an altogether lack of efficacy in the pediatric population.

The possible increased risk of suicidality was identified during a review to expand the indication for Paxil, submitted by Glaxo Smith Kline. In June 2003, the British regulatory agency issued a warning against the off label use of Paxil in children, and the FDA followed suit. The FDA requested more information from the makers of eight other antidepressants in response to problems with the classification of adverse events possibly leading to underestimates of the risk of suicidality. The resubmitted data appeared problematic, for example, an incident where a boy stabbed himself in the neck with a pencil during a test was classified as accidental. The FDA held a public forum in February 2004 and concluded that it needed more information, including an outside consultant to reclassify the adverse event data from the sponsors. Thus, the Columbia Classification Project was initiated.

Data Presented Leading To the Black Box Warning

Columbia University spearheaded the methodology and reclassification of the adverse event data by seven experts in suicide. The events from 23 trials were classified into suicidal events, non-suicidal events, or indeterminate events. The project was completed in August 2004, and the data was submitted to the Psychopharmacologic Drugs Advisory Committee (DDNP) for review. One month later, in September, the Pediatric Advisory Committee (PAC) and the DDNP held a joint meeting and included a public forum. The committees met over two days and were charged with making a recommendation to the FDA at the end of this time. The evidence presented at that meeting included the data from the classification project, the 12-week data from the Treatment of Adolescent Depression Study (TADS trial),1 a case control study, and presentations from professionals and the general public. Evidence not presented at this meeting, included other non-industry sponsored trials such as the Pediatric OCD Treatment Study (POTS),2 and epidemiologic data. Efficacy data (other than TADS) also was not discussed at this meeting.

The TADS study involved randomization of adolescents ages 12-17 years with Major Depressive Disorder into four treatment arms, Fluoxetine, Fluoxetine combined with cognitive behavioral therapy (CBT), CBT alone, and placebo. Fluoxetine and placebo were double blinded. At 12 weeks, the study has demonstrated efficacy of Fluoxetine (both alone and with CBT) in self /parent report ratings of depressive symptoms and clinician ratings of improvement. This study also found a high rate of suicidality at baseline of 29 percent, with improvement during treatment across all groups. The Fluoxetine and CBT group had the greatest rate of improvement in suicidality over time, suggesting a possible protective effect from CBT. Finally, there was no statistical difference in suicidality in the treatment arms receiving Fluoxetine than in the placebo arms, but there was an elevated risk of harm related events (including suicidal and non-suicidal acts or ideation of self or other harm) in the Fluoxetine treated groups (OR 2.19, 1.03-4.62 95 percent confidence interval).2

Data from the classification project involved 23 drug trials (four published) for indications including MDD, OCD and ADHD. The trials were completed between 1983 and 2004, and involved more than 4,400 subjects and nine medications. Although no single trial showed an elevated relative risk of suicidality, combined analysis of trials (including the TADS trial) showed an elevated risk for Paroxetine and Effexor, and overall combined analysis of all trials revealed a risk ratio of 1.95, and a risk difference of two percent. Using a numbers-needed-to-treat-in-order-to-harm (NNTH) analysis, one can estimate that on average a clinician will need to treat 50 patients to cause one patient increased suicidal ideation or behaviors. This is similar to the NNTH analysis from the TADS trial. Limitations of the analysis include different methodologies across trials, post-hoc analysis, and multiple outcomes.

The DDNP commented that studies have found associations between increased use of antidepressants and decreases in the suicide rate of children and adolescents but did not cite the following examples: the WHO found 33 percent reduction in suicide in 15 countries coincided with introduction of SSRIs and Olfson et al., found a one percent increase in antidepressant prescriptions for adolescents was associated with decrease in suicides by .23/100,000.3 Studies using patient-level controlled designs were presented at the meeting. For example, a British case control study of patients ages 10-69 years, who were prescribed antidepressants, matched patients who demonstrated suicidal behavior with those who did not. The study found a relative risk of four for non-lethal suicidal behavior for patients during the first nine days after filling a prescription versus more than 90 days after filling a prescription, and a relative risk of 38 for suicide in the first nine days versus 90 days or greater.4

At the end of the meeting, the committee voted unanimously that there was data from the 23 trials and TADS trial to support the conclusion that antidepressants increase the risk of suicidality in pediatric patients. The committee’s vote was split on support of a black box warning, 15 for and eight against. The committee discussed whether to single out a particular class of medications or single medication as being more or less safe, and agreed that variation of methodologies between studies and small sample sizes negated the possibility of drawing conclusions from studies that found no increased risk of suicidality. Another issue raised by various members of the committee was the need to balance warning patients and clinicians about these risks while not implicitly or explicitly prohibiting the use of these medications for pediatric patients.

The above meetings should be put in context of the mood on Capitol Hill. The Committee on Energy and Commerce, which has oversight of the FDA, and health issues had two meetings during September 2004, the first was to discuss disclosure issues of the pharmaceutical sponsored clinical trials of antidepressants in children, and the other was to discuss the FDA’s role in protecting public heath and the FDA’s review of safety and efficacy concerns in antidepressant use in children. Two committee members threatened to introduce legislation banning the prescription of antidepressants to patients under 18, “if the FDA didn’t act forcefully and swiftly to protect America ’s children.” Black box warnings are now required on all antidepressants.

How might this inform clinical practice? 

Unfortunately the data from the industry-sponsored trials does not help us predict which patients might be at increased risk to develop increased suicidality. However, a supportive, stable family might be better able to help clinicians monitor patients for changes in behavior, and pediatricians should consider referring depressed and anxious patients who do not have such support.

Suggestions For Primary Care Physicians Treating Anxiety and Depression In Pediatric Patients

1. Develop relationships with psychiatrists and therapists in the community to help with the following recommendations.
2. Assess any patient for suicidality prior to treatment. Refer patients that are actively suicidal, have unstable or chaotic families, have a family history of bipolar disorder, or who by history, or self report, present as agitated.
3. The practice parameter for treating suicidal youth put out by AACAP provides a overview of risk factors, and protective factors for suicide and suicidality, as well as measures to assess suicidality.

Anxiety

1. If a relative emergency exists, such as severe deterioration in level of function, or psychological symptoms leading to medical problems, consider starting medication while setting up a referral for CBT and child psychiatry.
2. If non-emergent, refer for CBT, and consider setting up psychiatry consultation for future.
3. If CBT does not provide enough relief, augment with Fluoxetine, Fluvoxamine, Sertraline, or Anafranil and set up psychiatry consultation.

Depression

1. If not suicidal, has stable family, and the patient is not agitated, refer for CBT, consider a trial of Fluoxetine and consider setting up psychiatry consultation for the future.
2. If response to CBT/Fluoxetine is inadequate, consider psychiatry consultation.

The family and patient of any patient started on medication should be given a review of the risks and benefits of medication, (consider a signed informed consent sheet), as well as, the schedule needed to monitor medication. Note that at this time, CBT is the therapy with the most data to support efficacy, however, other therapies may be indicated depending on the circumstances.

References

1. 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.

2. Cognitive-behavior therapy, Sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. Jama 2004;292(16):1969-76.

3. Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 2003;60(10):978-82.

4. Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. Jama 2004;292(3):338-43.

5. Summary of the practice parameters for the assessment and treatment of children and adolescents with suicidal behavior. J Am Acad Child Adolesc Psychiatry 2001;40(4):495-9.

References and Community Resources Provided To Help Clinicians Who Work With Children and Adolescents With Anxiety and Depression

Groups

The Children’s Hospital Department of Psychiatry and Behavioral Sciences has an outpatient psycho-therapy group, Socialization for Pre-Teen Boys and Girls for children in fourth, fifth and sixth grade. Socialization groups help children learn social skills such as cooperating with others, developing friendships and managing conflicts. Children improve their self confidence and self concept. They learn with peers and adult leaders in a fun setting.

Please note, an initial, one-time evaluation is required before joining a group session. Evaluations with Jeffrey Dolgan, PhD, will be scheduled at The Children’s Hospital’s main campus at 1056 E. 19th Avenue in Denver . The group meets weekly at Children’s Care Center – Littleton at Broadway and County Line Road .

The group meets for 90 minutes and group size is eight to nine children (fourth, fifth and sixth grades). The last 30 minutes is dedicated to parent discussion. Each group meets for 10 sessions.

CBT Anxiety Group: Taming the Worry Monster, 10-week groups for children (6-11 years) early and mid teens (12-14 years) or older adolescents (15 years and older) and their parents or caregivers. Contact Jane Robinson at National Jewish Medical and Research Center (303-398-1920). Most insurance accepted, self-pay is also an option.

Child and Adolescent Psychiatry

We at The Children’s Hospital understand how difficult it is to manage patient’s psychiatric needs with the shortage of child psychiatrists in town. We want to work with our primary care colleagues and have designed an evaluation and consultation clinic. Child Psychiatry faculty will evaluate and treat the patient on a short term basis until the treatment plan is clear, then refer back to the PCP with a diagnosis and treatment plan for continuing medication management. Faculty do not participate in managed care carve out plans for mental health insurance. Parents are asked to pay 80 percent of the fee up front (cash, check or charge). We then bill their insurance. If insurance pays more than 20 percent of the bill, parents will be reimbursed the remainder. Interested patients can call 720-777-6200 and indicate they would like a psychiatric assessment in the Child Psychiatry Faculty Clinic.

• Kim Kelsay, MD, of National Jewish Research and Medical Center , is available for medication consultations, as well as ongoing treatment. 303-398-1260
• University of Colorado Health Sciences Center, Child Psychiatry Training Clinic 303-724-1000
• Colorado Child and Adolescent Psychiatric Society 303-692-8783

Websites

• www.fda.gov/cder/drug/antidepressants/default.htm - This website links to all announcements put out by the FDA, as well as transcript and slides presented at the September 13 and 14 meetings.
• www.nimh.nih.gov/publicat/childqa.cfm - A helpful brochure about mental health in children, published by National Institute of Mental Health.
• www.aacap.org - The website of the American Academy of Child and Adolescent Psychiatry has many resources including facts for families, a sample letter for patients and talking points including treatment recommendations from the working group on research.