Samaritan Behavioral Health

FDA Black Box Warning on the Use of Antidepressants for Pediatric Patients

American Academy of Child and Adolescent Psychiatry

Supplementary Talking Points for Child and Adolescent Phychiatrists

October 31, 2004

In making a decision affecting the health of our children who have psychiatric disorders, the FDA, of necessity, had to accept the very limit of available data, and in some aspects had to extrapolate entirely beyond available information.

The FDA’s public health program on antidepressant medication use in children and adolescents now requires that pharmaceutical manufacturers place a black box in each antidepressant’s package insert. The warning is about increased suicidal thinking and suicidal behavior that can occur in children and adolescents during the early phases of treatment.

Drug Name

Suicidality in Children and Adolescents

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of [Drug Name] or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. [Drug Name] is not approved for use in pediatric patients except for patients with [Any approved pediatric claims here]. (See Warnings and Precautions: Pediatric Use)

Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of nine antidepressant drugs (SSRIs and others) in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 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 on drug was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.

The FDA advisory panels, which met in September 2004, became concerned that physicians’ variable prescribing practices for these antidepressant medications might increase any potential problem. It should be noted that the data on which the concern was based was derived from clinical trials where clinical standards were optimal. There is no evidentiary basis for believing that current practices are contributing to any significant public health problem. To the contrary, the increase in SSRI prescriptions has been correlated with a decrease in the youth suicide rate, and consecutive autopsies have failed to demonstrate the presence of a significant number of suicides with evidence of SSRI exposure.

The FDA followed several of the AACAP recommendations in the language and intent of the black box warning. These included the decision to require that a medication guide (Medguide) be distributed with each supply of antidepressant medication. This guide lays out specific warning signs of antidepressant side effects in lay language for parents.

The FDA black box noted the serious impairments of untreated depression as well as the newly discovered low risk of suicidal thoughts. It also called for more research on the long-term effectiveness of antidepressants. It is important to note that the FDA did not assert that the use of these medications in children and adolescents with depression was contraindicated, so physicians can continue to prescribe them.

What new research data actually support the FDA’s decision to use a black box warning?

Pooled analyses of short-term (4 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 over 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. It should be noted that only 78 of the 4,400 patients experienced suicidal thinking or suicidal behavior, and no suicides occurred in these trials. The average risk of such events on a drug was 4 percent, twice the placebo risk of 2 percent.

What unintended effects on practice might occur following the FDA’s issuing a black box?

Probably this warning will discourage the capricious prescribing of these drugs, eliminate direct-to-consumer advertising, and stop physicians from distributing drug samples. The warning may also keep depressed patients from seeking treatment. The black box warning also may cause physicians to avoid treating depressed children and adolescents because of fear of potential lawsuits. The Work Group on Research recommends that professional organizations support their members with open, strong statements about the value of this treatment.

How frequently do the research data suggest I would encounter this risk in my practice if I treat children and adolescents with antidepressants?

The FDA research has shown that there is a small increase in risk of suicidal ideation or suicidal behavior in children and adolescents treated with antidepressants. This effect represents a 2 % increase over that created by the use of a placebo. That means that if you institute medication treatment in 200 new patients, you will see approximately 8 child and adolescent patients with increased suicidal ideation or suicidal behavior. Four of those patients will have experienced these increased symptoms as part of their depression, while the remaining four may have increased ideation or suicidal behavior related to antidepressant treatment. It should be noted that both suicidal ideation and suicide attempts are very common in adolescence and do not have the same prognostic significance for completed suicide as those behaviors in later life. Thus, the annual prevalence of attempts in the U.S. is about 10 times greater than the prevalence of depression. Based on the most recent data, there are 370 attempts for every suicide among teen males and around 3,600 attempts among teen females each year for every suicidal death.

What do the research data suggest about the efficacy of antidepressants for treating depression in children and adolescents?

New research, such as the Treatment for Adolescents with Depression Study (TADS), confirms that using cognitive behavioral therapy (CBT) – a type of psychotherapy that focuses on managing negative emotions and thoughts – and fluoxetine (Prozac) results in successful treatment of moderate-to-severe adolescent depression. Seventy-one percent of the patients responded positively to the combination treatment of fluoxetine and therapy, which is a rate double the 35 percent response rate for patients on placebo. Over 60 percent of those assigned to fluoxetine alone were found to be responders by the end of the 12-week trial.

This means that on average each practitioner would need to treat just three patients to see a strong response to fluoxetine. This is in contrast to the need to treat over 50 patients in order to see evidence of the medication causing suicidal ideation or suicidal behavior. The Work Group on Research finds this risk-benefit ratio for the treatment of pediatric depression acceptable for child and adolescent patients.

How does the AACAP Work Group on Research recommend that I treat my child and adolescent patients with depression?

The Work Group continues to advise the child and adolescent psychiatrists in the AACAP to continue to treat with psychotherapy or antidepressants or the combination based on the available research evidence. The research evidence available to the FDA shows that fluoxetine, now the only SSRI antidepressant available as a lower-cost generic, has shown efficacy in the treatment of children and adolescents with depression and with OCD. Because of the data available, the Work Group recommends that fluoxetine alone, CBT alone or fluoxetine plus CBT be considered as first line treatment approaches for depressed pediatric patients. The Work Group also recommends that patients be monitored with the frequency of visits suggested by the FDA; although, there are no specific research data to support the frequency of face-to-face contacts.

What if I receive a referral for a child or adolescent who has failed on fluoxetine? Can I still treat with an alternative antidepressant?

The FDA did not contraindicate the use of any of the other SSRI antidepressants. Although there were some differences in the degree of risk among the nine antidepressants evaluated, the agency did not find compelling evidence to contraindicate any of the drugs with a higher than usual risk for the suicidal ideation or suicidal behavior, or, conversely, to not apply the black box warning to any antidepressant with a low risk rate. For that reason, the Work Group on Research would recommend considering any of the other SSRIs that the practitioner has had success with in other pediatric patients with depression.

What should I do if my child or adolescent depressed patient shows increased suicidal ideation or increased rates of suicidal behavior?

The Work Group reminds practitioners that they should take all steps necessary to protect the well being of their patients. In patients whose depression is persistently worse, or who are experiencing emergent suicidality, consideration should be given to changing the therapeutic regimen, including reducing the dose of the antidepressant, and possibly discontinuing the medication. Drug discontinuation should be considered if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Any discontinuation should be done carefully to prevent adverse events that may occur after abrupt antidepressant discontinuation. Doses should be tapered rather than an abrupt stoppage, particularly if the medication is an SSRI other than fluoxetine.

In the new FDA labeling, which recommendations lack research support and may not protect my patients from these side effects?

The new FDA labeling in the warnings and precaution section contain a number of suggestions that have yet to be supported by an adequate amount of research. For that reason, the AACAP Work Group on Research does not consider the factors listed below should be given more weight than other clinical issues in making treatment decisions.

Family history of bipolar disorder is not a reliable warning sign a patient will experience these side effects. The FDA recommends that bipolar disorder be ruled out before treating children and adolescents with antidepressants. Although this warning is called a precaution, it is not a contraindication. The FDA suggested labeling language states, “It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.” Although the label states that “such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression,” these factors were not shown to be predictive of increases in suicidal ideation or suicidal behavior in the FDA reviews. While the Work Group on Research agrees that a thorough evaluation should be done on each patient, the value of this data in guiding the decision of whether or not to treat with SSRIs is not established, and we do not believe such a history should preclude use of these agents beyond the caution of a “switch” from depression to mania or hypomania.

If there is a positive family history of bipolar disorder, a careful diagnostic assessment should be done to consider the possibility that the patient is not in the depressed phase of a bipolar illness. The risk of giving antidepressants to someone in the depressed phase of bipolar illness or a mixed episode is that the medication may switch the patient into a manic state, at least according to experience with adult bipolar patients. There are no definitive databased strategies for how best to treat depressed patients at genetic risk for bipolar disorder, including those patients who are at increased risk for developing bipolar disorder in the future.

Suicidal ideation or suicidal behavior does not always follow other SSRI side effects. The FDA label strongly hints that standard SSRI side effects may be precursors of suicidal ideation or suicidal behavior, and advises clinicians and parents to monitor for them without evidence that they are precursors for increased suicidal ideation or suicidal behavior. The new labeling states that “anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric.” These should be tracked, even though “a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established.” The Work Group on Research, while supporting the FDA’s concern over these side effects, does not agree that there are adequate data yet to support the FDA’s “concern that such symptoms may represent precursors to emerging suicidality.” The Work Group on Research does urge a discussion with patients and parents about the effects and side effects of SSRI medication and the natural or expected course of major depression. This will prepare them for managing the depressive thoughts that may persist after other symptoms resolve. It will also help them manage any symptoms of akathisia, insomnia, or other antidepressant side effects that may occur.

The effectiveness of a weekly monitoring program with face-to-face visits has yet to be proven. The FDA recommends a specific monitoring frequency for physicians when starting SSRI therapy. The FDA recommends that observation for clinical worsening, suicidality, or unusual changes in behavior during the initial few months of anti- depressant drug therapy “ideally would include at least weekly face-to-face contact with patients or their family members or caregivers during the first four weeks of treatment, then biweekly visits for the next eight weeks, then as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.” The AACAP Work Group on Research does not know of evidence that this frequency of visits is any better than phone contact with the family on a weekly basis with biweekly face-to-face visits during the first month of treatment.

The optimal frequency of visits is an empiric question worthy of testing. Until those research findings become available, practitioners should attempt to follow the FDA frequency of monitoring guidelines.

The FDA did not recommend a standardized rating form or side effect questionnaire for the practitioner to follow that would include the important concerns. The AACAP Work Group on Research is aware that two NIMH research projects now include forms with standard questions about important side effects that can be administered on a weekly basis. Forms such as these could prove to be effective in clinical care.

What is the downside of not using antidepressant medications to treat my child and adolescent patients with depression?

The NIMH TADS did not find an advantage of cognitive behavioral therapy (CBT) alone over placebo in the short term. However, CBT has been shown to be effective in other treatment studies of depression in children and adolescents. For that reason, effective treatment may include CBT or other evidence-based psychotherapies alone or with the antidepressant fluoxetine as a first-line treatment for depression. In particular, psychosocial treatment has been shown to have a protective effect against suicidal behavior or ideation when combined with antidepressant medication.

Why should childhood depression be treated with medications that carry any risk at all?

The AACAP Work Group on Research strongly supports the treatment of children and
adolescents with depression despite risks. Pediatric depression is a real illness, with neurobiological underpinnings. Effective treatments for this disorder are available. Although antidepressant treatment carries risks, untreated depression has potentially greater risks, and treatment is effective, especially when started early. Depression is a serious illness, sometimes episodic and often chronic, when it occurs in childhood. In addition to the human suffering that occurs because of the depression, the symptoms can and do interfere with academic learning, peer relationships, and family interactions, often derailing normal development.

Follow-up studies have shown a higher than normal rate of serious mental disorder in adult life and shortened mortality in those with childhood- or adolescent-onset depression. There are about 1.7 million suicide attempts per year and about 60 percent of those have a depressive or anxiety diagnosis. Because of the severity of the disorder, the Work Group on Research supports treatments that have been shown to be effective in easing the depression and allowing normal development. The 2004 NIMH TADS study has confirmed that the SSRI fluoxetine, alone or in conjunction with CBT psychotherapy, is an effective treatment for youth-onset depression.

What other steps is AACAP taking to support its members?

The AACAP plans to expedite the update on the practice parameter for depression and to distribute it in 2005. AACAP will also revise relevant Facts for Families to provide practitioners with suitable materials to hand out in the office. AACAP members are contributing to other projects to be included in a practice toolkit, including this letter, a model parental consent form, and a rating form to track the adverse events in antidepressants, such as increased suicidal ideation and suicidal behavior. The sample letter to parents or guardians that is enclosed will also be part of the toolkit.


Sample Letter to Families:
Explaining the FDA warnings about antidepressants

October 2004

Dear Parent/Guardian,

You may have heard media reports on concerns about prescribing antidepressant medication for children and adolescents. The reports describe the meeting at the Food and Drug Administration (FDA) in September 2004 to review the studies of children and adolescents taking antidepressants. The agency reviewed studies of depression and anxiety disorders, and an advisory committee discussed the effectiveness of these medications, as well as the concerns about increased risk of suicidal behavior in children and adolescents while taking the medications. This letter will explain some of the information and answer questions that you may have.

What did the FDA Advisory Committee determine?

After two days of hearings, the advisory committee determined that there is some increased risk of suicidal behavior for some children or adolescents taking antidepressants. About 3-4% of children or adolescents with depression who took an antidepressant had some type of suicidal behavior (such as a suicide attempt or suicidal thoughts), while 1-2% of those taking placebo (inactive pill) did. Therefore, there was almost a 2-fold increase in suicidal behavior in youth taking an antidepressant to treat their depression. There were NO completed suicides in any of these studies, which included over 4,000 children and adolescents. For those with an anxiety disorder, there was no difference in suicidal behavior in those being treated with antidepressants as compared to placebo.

The FDA advisory committee recommended that a stricter warning label be placed on all antidepressants. The type of warning label they recommended is called a “black box,” which means any doctor prescribing one of these medications has to clearly warn patients and their families about the risks associated with the medication. In this instance, the black box warns that there is a chance of increased risk of suicidal thoughts and behaviors in youth taking these medications. Although there were some minor differences between the various medications evaluated, the advisory committee decided that the same warnings should be given for all antidepressants.

How does this affect your child

If your child is already being treated with one of these medications and is doing well, then your child should continue on the treatment. In most cases, these increased risks occur during the first weeks of treatment. If your child has recently started one of these medications or is about to start, then you and your doctor will need to closely monitor him/her for any changes in behavior.

Suicidal thoughts are a symptom of depression. Additionally, depression is one of the largest risk factors for suicide. It is difficult to interpret whether suicidal thoughts and behaviors in depressed individuals are due to the illness itself or the medication. It can be either of these. In some people, antidepressant medications may increase these types of thoughts, so this warrants close monitoring for all patients.

It is important to note that, in the studies, 9% of adolescents in the general population make a suicide attempt, 3-4% had some suicidal behavior.

What should you do?

First, be upfront and honest with your child about these risks. Second, talk to your child or adolescent about whether they are having any suicidal thoughts, and let them know they should come to you if they start having such thoughts. Third, you, your child, and your child’s doctor should develop a safety plan for your child. This can include identifying an adult your child can call if he/she is thinking about suicide. Finally, you and your doctor should closely monitor your child for the first weeks of treatment. All child and adolescent patients beginning medication should be seen weekly for the first month, every other week for the second month, and at least once a month for the third month by the treating psychiatrist to closely monitor depressive symptoms and any problems. It is important that you do not change the dose of your medication without first discussing the change with your doctor.

What should I look for?

Be on the look out for certain behaviors that appear for the first time, seem worse, or worry your child or adolescent or you. These include new or more thoughts of suicide, trying to commit suicide, new or worse depression, new or worse anxiety, or feeling very agitated or restless. If these appear, a medical professional should be contacted right away.

If you have any questions about this information, ask your doctor, who will answer all other questions you or your child have.

We hope that this information answers your questions.


(name of doctor)