To:		UNITED STATES FOOD AND DRUG ADMINISTRATION PSYCHOPHARMACOLOGICAL DRUGS ADVISORY COMMITTEE & PEDIATRIC SUBCOMMITTEE, ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE
Re:		PEDIATRIC SUICIDALITY & THE USE OF ANTIDEPRESSANTS
Date:		FEBRUARY 2, 2004

Oral Testimony

Mr. Chairman, I respectfully request that my entire remarks be entered in the record.

My name is Rachel Adler. I am a member of the Board of Directors of the The Balanced Mind Foundation (The Balanced Mind Foundation), a parent-led, not-for-profit organization that is the leading source of public information for Pediatric Bipolar Disorder.

Board members Sheila McDonald and Jon Adler, are here as well.

Bipolar Disorder may emerge with an episode of major depression, an illness which often includes suicidality, even in preschoolers. Children with depression are at high risk to switch to bipolar disorder.

We surveyed 17,000 members in January of this year and received a 15% response rate over a 5 day period. 89% of respondents report that their child has been treated with an antidepressant.

We have received some favorable comments, but, alarmingly, the results indicate that in some subgroups of children suicidal ideation and behavior may emerge for the first time (or worsen) when a child is given an antidepressant. Some of these children, perhaps, have a vulnerability to Bipolar Disorder.

For these reasons, The Balanced Mind Foundation urges the FDA to require manufacturers to add a black box warning on the labeling for antidepressants to alert clinicians and parents of the possible potential of antidepressants to trigger or worsen suicidality, as well as mania or rapid-cycling bipolar disorder, in some children.

The Balanced Mind Foundation opposes any ban on the off-label use of these or other psychiatric medications in children because many of our members report them to be necessary and even lifesaving for their children with mood disorders, especially when used in combination with a mood stabilizer.

The Balanced Mind Foundation also urges the pharmaceutical industry and the federal government to fund research to analyze what factors are shared by those children who according to parent reports, became suicidal shortly after taking an antidepressant.

Finally, The Balanced Mind Foundation calls upon the pharmaceutical industry and the NIH to make public all safety and efficacy data from unpublished studies in children.

Written Testimony

The The Balanced Mind Foundation is concerned about the possible potential of antidepressants to trigger or worsen suicidal ideation and attempts in depressed children with bipolar disorder. At the same time, many of our members have found these medications to be helpful for their children, when used cautiously after mania is controlled with a mood-stabilizer.

Over the four years since The Balanced Mind Foundation first launched its Web site, www.thebalancedmind.org, numerous parents have reported on our Message Boards the results of their children using of antidepressants. Some report that their children first became suicidal immediately or shortly after being prescribed an antidepressant, and that these alarming symptoms stopped only when the medication was stopped. Others report that their child’s prior existing depression with suicidal ideation quickly escalated into rapid cycling/mixed states (the state with highest risk of suicide for any patient with bipolar disorder) soon after their child began treatment with an antidepressant, and that these increased symptoms subsided when the antidepressant was stopped. Conversely, other parents report that their children had suicidal thoughts or actions before taking any antidepressant, or which developed during treatment for bipolar disorder, and that the suicidal ideation and behavior improved when an antidepressant was added to the child’s treatment plan.

There is no reason to doubt the veracity of any of these reports. The reports indicate that in some subgroup of children suicidal ideation and behavior may emerge for the first time (or worsen) when a child is given an antidepressant. In some of these children--perhaps those with a vulnerability to bipolar disorder, or a genetic subset of them—the antidepressant itself appears, to credible witnesses (i.e., the child’s parents), to cause or contribute to suicidality.

Until researchers discover how to predict which children may have this paradoxical, and traumatic, response to an antidepressant, The Balanced Mind Foundation urges the FDA to require manufacturers to add a black box warning on the labeling for antidepressants to alert clinicians and parents of the possible potential for such a response. Doctors must be instructed to discuss with parents - clearly, directly, and often - the potential for suicidality and paradoxical reactions, and must closely and actively monitor their patients for the emergence of these and other serious side effects.

 

About The Balanced Mind Foundation

The Balanced Mind Foundation (The Balanced Mind Foundation) is a parent-led, not-for-profit organization of families raising children and adolescents diagnosed with, or at risk for, bipolar disorder (formerly known as manic-depressive illness). The Balanced Mind Foundation’s current membership has grown since its founding in 1999 to nearly 17,000 families and over 400 medical professionals, mostly child psychiatrists. The Balanced Mind Foundation’s Web site, www.thebalancedmind.org, is the leading source of public information for pediatric bipolar disorder. Most of our members are college-educated married women, and 23% report holding advanced or professional degrees. Numerous The Balanced Mind Foundation-sponsored online support groups serve thousands of families and carry over one million e-mail messages per month.

 

About pediatric bipolar disorder

Bipolar disorder affects at least 1% of older adolescents and adults, and there is no evidence that the rate in children is any lower.[1] The illness can emerge in children as young as preschool age, and is the most heritable (85-89%) of any psychiatric illness.[2] Fifty-nine percent of adults with bipolar disorder surveyed by the National Depressive and Manic-Depressive Association in 1993 reported that symptoms of their illness appeared during or before adolescence.[3] The time between onset of symptoms and proper treatment is often 8-10 years, longer for early-onset cases. The lifetime mortality rate in patients with bipolar disorder from suicide alone may be as high as 18%.[4]

Just as juvenile-onset diabetes is more serious and difficult to treat than adult-onset diabetes, pediatric bipolar disorder is more impairing and difficult to treat than bipolar disorder that emerges later in life.[5] Children with this severe medical condition must endure multiple trials of drugs at different doses and in various combinations as their clinicians, lacking evidence-based guidelines for treatment, try to find an effective and tolerable medication regimen to promote recovery and prevent relapse. Children often must take two, three, or more medications with different mechanisms of action to target different symptoms. Most of these medications are used off-label because they have not yet been tested in children. Many children reach stability, but the relapse rate is high. Growth, weight changes, puberty and environmental stressors often destabilize the child, requiring hospitalization and redoubled efforts to find an effective treatment strategy. The Balanced Mind Foundation’s 2002 Membership Survey revealed that over 40 different drugs, primarily mood stabilizers, lithium, anticonvulsants, and atypical antipsychotics, but including anti-anxiety agents, antidepressants, and stimulants, are used alone and in various combinations (along with psychoeducation and family therapy) to treat children with pediatric bipolar disorder.[6]

Bipolar disorder may emerge with an episode of major depression, an illness which often includes suicidal thoughts and behaviors, even in preschoolers.[7] Clinicians lack data on how to distinguish between bipolar depression and unipolar depression, or how to predict which children with depression will develop bipolar disorder, although there are some theories under study.[8] Children with depression are at high risk to switch to bipolar disorder: in one study by Dr. Barbara Geller of 72 pre-pubertal children with depression, up to 48% developed mania (and thus, bipolar disorder) by age 20.[9] It is common for a patient with bipolar disorder to have manic symptoms or even meet diagnostic criteria for mania before the onset of depression, but clinicians often do not identify the manic symptoms (nor do the patients nor parents tend to seek treatment for them) and the patient may be misdiagnosed as having “only” depression rather than bipolar disorder, and treated with an antidepressant. The use of antidepressants is one of the risk factors associated with switching from depression into mania or a mixed state.[10]

It is clear, from listening to our members, that well-meaning doctors often fail to warn parents about the life-threatening nature of depression, so as not to frighten them. In many cases, parents report, the treating clinicians said nothing to warn them of the risk of suicide attempts emerging as a symptom of the depression itself. They had no idea that children could ever experience an urge to end their own lives or take action toward that goal. Doctors also fail to warn parents about rare but serious side effects of medications used in treatment. Parents are often unaware of the possible triggering of mixed states or rapid-cycling by antidepressants, in the event the child has a possible genetic vulnerability to bipolar illness. Many parents also report that the treating clinician did not ask about other family members with mood disorders to determine if the child might be at elevated risk for bipolar illness, nor do doctors often inquire as to any history of manic symptoms in their patient, the child, before prescribing an antidepressant.

 

The Balanced Mind Foundation Survey Results

In order to contribute to this important discussion, The Balanced Mind Foundation surveyed its members who are raising a child diagnosed with, or at risk for, bipolar disorder. We e-mailed a request directly to 16,705 members on January 19, 2004, and the surveys were completed online by January 24, 2004, by 2,534 respondents (a 15% response rate). We asked our members to respond with respect to the use of antidepressants, as well as any suicidality observed, in one of their children (many of our members have two or more children diagnosed with bipolar disorder).

Some selected results[11] are of interest:

1. 89% of respondents report that their child has been treated with antidepressants, with 39% of that group prescribed antidepressants before the age of 8.
2. 78% of respondents report that their child has been suicidal at some time in his or her life, with 43% of those children displaying suicidal ideation and acts before age 8.
3. 55% of respondents with children who had ever taken an antidepressant and also ever been suicidal report that their child first became suicidal before ever taking an antidepressant. 45% report that their child first became suicidal some time after first taking an antidepressant.
4. Of the respondents who report that their child first became suicidal after taking an antidepressant, the time from taking the first dose until suicidal talk or behavior first emerged was within 24 hours in 16 cases (1.4%), between 1-7 days in 127 cases (11%), between 8-30 days in 179 cases (15%), between one month and six months in 294 cases (25%), and more than six months in 280 cases (24%). In another 251 cases (21%), the parent did not know how long the interval was between the child’s first dose of an antidepressant and emergence of suicidality in the child.
5. In 529 reports in which a child became suicidal after taking an antidepressant, the respondents reported holding the opinion that the antidepressant contributed to or caused the child to become suicidal. Another 348 respondents reported the opinion that the antidepressant was not what made their child become suicidal, and 267 reported that they had no opinion as to whether the drug contributed to or caused the child to become suicidal.
6. Four parents report that their child committed suicide while taking or after taking an antidepressant. We do not yet have data on time separating these events.

Conclusions that might be drawn from these survey results are obviously limited by the lack of a control group, the complex treatment regimens that often include multiple medications, the complexity of bipolar illness in children, and the anecdotal nature of the reports. A more detailed analysis of the survey data may yield further useful information.

Any child’s death by suicide is horrible to contemplate. Likewise, a suicide attempt or even suicidal ideation that might possibly have been caused or contributed to by a medicine prescribed to help a child by their doctor, and administered by his or her own parents, is heartbreaking. This prospect evokes apprehension and unease among parents of children with depression and bipolar disorder, especially if preventive measures are not being taken.

Researchers may regard suicidal ideation and low-lethality attempts as unlikely to lead to completed suicide, and imply that ideation and low-lethality attempts (such as found more often in women and, by implication, children) are not relevant to the risk of suicide.[12] Parents disagree. We know that the shock and horror of finding one’s despondent young son deliberately lying under the wheels of the family car, or witnessing one’s young daughter lock herself in the bathroom, sobbing “I’m going to make myself dead,” have enormous impact on the child and the whole family. We also know that suicide attempts by children are vastly underreported (one New York county in the late 1990s found 39 children under age 10 hospitalized for suicidal ideation or suicide attempts in one 13-month period)[13] or reported as “accidents.”[14] While the reports made may only amount to a “weak signal” among reports of all the lives saved by antidepressants, it is precisely those weak, faint, cries to which The Balanced Mind Foundation calls attention today.[15]

Some The Balanced Mind Foundation members—529 of the 2,534 who responded to this survey, or 20%—are convinced that their own children became suicidal due to treatment with an antidepressant. The following are a sample of comments describing what happened:

 

1. [Antidepressant #1] was first prescribed, but it immediately made him “hyper.” [Antidepressant #2] was prescribed next, at a low dose. After six months my son became very agitated and the doctor increased the dose. The next day my son was in a total psychotic state, including hallucinations, severe suicidality, severe paranoia, and homicidality. He was only 6 at the time and these symptoms were all new, and all occurred immediately after the increase in the [antidepressant #2] dosage
2. After only days on [an antidepressant] my daughter acted out her thoughts for the first time. She went to the knife drawer in our kitchen, threatening both herself and me
3. Before the antidepressant, my child expressed some doubt as to the worth of life. After the antidepressant she became quite suicidal and was hospitalized. For months and months she would say many times a day that she wanted to die. There was no reason to go to school because she was going to buy a gun when she turned 18 and kill herself anyway.
4. He became suicidal before [antidepressant] but it worsened with [antidepressant]; plus he seemed to lack the lethargic feelings he normally has when depressed. In other words, he had the thoughts, feelings, intent, and enough energy to follow through.
5. Although she had talked about being better off dead before being put on antidepressants, the talk became more frequent and the attempts occurred after she started on antidepressants.
6. My son had talked about wanting to be dead, but had never taken any action on it. After being on antidepressants, the only way I can describe his behavior is that he was driven to try to kill himself. I had to stop work and be with him 24/7.
7. After 4 days of [antidepressant] we left for a family vacation. My son became very violent and suicidal. We live in WI and were in VA. After 2 weeks, 4 different hospitals in three different states, we arrived back in WI for an additional 10 days of hospitalization and he still remains unstable. All this from 6 days of [antidepressant].
8. He was on an antidepressant and had tried to run out into traffic to try and get hurt. Last year, at age 9 he was again prescribed an antidepressant that initially seemed to help but after 3 weeks on it he became suicidal and took a knife and started cutting himself.
9. He was violent and completely out of control. It was the most frightening thing we have ever experienced. My husband and I stayed up round the clock to watch him. He didn't sleep. We feared for him, for us and for his siblings.
10. With [the antidepressant], [she] was not talking about suicide anymore, she was drinking household poisons and bug spray to kill herself.

 

More research is clearly needed to establish whether the beliefs of so many intelligent and articulate parents that antidepressants triggered suicidal behavior in their individual children are valid even though evidence from controlled clinical trials shows no overall increase in risk in group data.

These comments are not intended to negate The Balanced Mind Foundation members’ appreciation of the large decline in the overall suicide rate in older adolescents that corresponds with the rise in the use of antidepressants.[16] We received many positive comments about antidepressants that have helped some children considerably. These life-saving medications must remain available for use by doctors treating children with depression and other conditions for which they may be helpful. Here are some examples of the positive statements The Balanced Mind Foundation receives:

1. One of his many fears was that he would want to hurt himself or kill himself and wouldn't be able to stop himself from acting. He was started on [antidepressant] in June 2002. He has been completely without suicidal ideation since October 2002!
2. And it has been essential . . . in dealing with the depression she experiences with bipolar disorder. She is currently taking 2 mood stabilizers . . . and has still benefited from an antidepressant. She was suicidal before taking the antidepressant.
3. In my opinion the antidepressant has been helpful. On a low dose . . . suicidal ideation seems to have stopped.

 

Conclusion

The Balanced Mind Foundation recommends that the FDA require antidepressant manufacturers to add a black box warning to their labeling, similar to the black box on the labeling for Accutane, informing clinicians and parents of a possible potential for the drug triggering or worsening suicidality, as well as mania or rapid-cycling bipolar disorder, in some children. Such a warning would alert clinicians and parents of the need to watch carefully for the emergence of these behaviors and take protective action immediately if the behaviors emerge. The Balanced Mind Foundation opposes any ban on the off-label use of these or other psychiatric medications in children, because many of our members report them to be necessary and even lifesaving for their children with mood disorders.

The Balanced Mind Foundation also urges the pharmaceutical industry and the federal government to fund research to analyze what factors are shared by those children who (according to parent reports) became suicidal shortly after taking an antidepressant. Such research should include an epidemiological survey of parents who have a child who has taken or is taking an antidepressant, with all the relevant information on dosing, medication combinations, and side effects. Also, “n of 1” studies could be used to learn how well antidepressants work in individual children when rigorous measures of symptom improvement, functioning and adverse events are employed under double blind conditions. Due to the heterogeneity of mood disorders, for which there may be different pathways and different symptom patterns among pediatric subgroups, large group trials are unlikely to distinguish between symptoms resulting from the illness and symptoms resulting from adverse reactions to the medications.

Finally, The Balanced Mind Foundation calls upon the pharmaceutical industry and the National Institutes of Health to make public all safety and efficacy data from unpublished studies in children.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Author: Martha Hellander, J.D. Executive Director, The Balanced Mind Foundation 820 Davis St., Suite 520 Evanston, IL 60201 847.492-8519/voice mhellander@thebalancedmind.org

Respectfully submitted, Rachel Adler Sheila McDonald Members , The Balanced Mind Foundation Board of Directors

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

References

[1]Lewinsohn PM, et al. (1995). Bipolar disorders in a community sample of older adolescents: prevalence, phenomenology, comorbidity, and course. J Am Acad Child Adolesc Psychiatry;34:454463.

[2] McGuffin P, et al (2003). The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Archives of General Psychiatry, Vol. 60 No. 5, May 2003.

[3] Anonymous, 1993. National survey of NDMDA members finds long delay in diagnosis of manic-depressive illness. Community Psychiatry 44, 800801.

[4] Lifetime suicide rate of 18% for bipolar disorder based on review of over 80 studies (Kay Jamison & Fred Goodwin, Manic-Depressive Illness, Oxford Univ. Press, 1990, and Kay Jamison, Night Falls Fast: Understanding Suicide, Knopf, 1999).

[5] Geller B, et al (2002). Two-year prospective follow-up of children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry. 159(6): 927-33.

[6] The Balanced Mind Foundation (2003), unpublished membership survey.

[7] Luby JL, et al. (2003). The clinical picture of depression in preschool children. J Am Acad Child Adolesc Psychiatry 42:340348

[8] Luby, J. and Mrakotsky, C. (2003). Depressed Preschoolers with Bipolar Family History: A Group at High Risk for Later Switching to Mania? Journal of Child and Adolescent Psychopharmacology, 13 (2): 187-197.

[9] Geller, B., et al (2001). Bipolar disorder at prospective follow-up of adults who had prepubertal major depressive disorder . Am J Psychiatry 158 (1):125-7.

[10] Wilens, T., et al. (2003). A Systematic Chart Review of the Nature of Psychiatric Adverse Events in Children and Adolescents Treated with Selective Serotonin Reuptake Inhibitors. Journal of Child and Adolescent Psychopharmacology. Vol. 13, No. 2, p. 143-152.

[11] The Balanced Mind Foundation (2004), unpublished survey.

[12] Executive Summary of Preliminary Report of the Task Force on SSRIs and Suicidal Behavior in Youth (January 21, 2004). American College of Neuropsychopharmacology, p. 7.

[13] Weaver, Teri. “Children's suicides catching experts by surprise.” Syracuse Post, July 23, 2002.

[14] Rosenthal P.A. and Rosenthal S., "Suicidal behavior by preschool children." Am J. Psychiatry 141 (4): 520-525 (1984).

[15] Executive Summary of Preliminary Report of the Task Force on SSRIs and Suicidal Behavior in Youth (January 21, 2004). American College of Neuropsychopharmacology: “In medicine, any report of an individual case, or a series of cases, represents a weak form of evidence.” p. 5.

[16] World Health Organization (WHO), 2003 (http://www.who.int/mental_health/prevention/suicide/country_reports/en/)