Download SSRI`s and the Black Box Warning: Patient Advocacy or Alarmist

SSRI’s and the Black Box
Warning:
Patient Advocacy or Alarmist
Propaganda?
Master’s Project Presentation
Lucas Kennedy
April 3, 2008
Adolescent Depression:
the basics
• Major Depressive Disorder is defined by
the DSM as follows:
“Either depressed /irritable mood or loss of pleasure
along with at least three other symptoms present over
the same 2 – week period”
Prevalence
• Depression is estimated to occur in 2% of all children
(under 12 years old) and 4 – 8% of adolescents (those
12 – 18).
• 20% of all American adolescents will experience a bout
of certified clinical depression by 18 and about 65% will
experience more fleeting episodes.
• 20-40% of adolescents diagnosed with MDD will
subsequently receive a bipolar diagnosis while 75% will
later be diagnosed with an anxiety disorder.
Suicide Statistics
• About 50% of adolescents diagnosed with MDD will
experience a suicide attempt.
• This same group is four to five times more likely to
attempt suicide at some point in their lives than
teenagers who are not depressed.
• Approximately 90% of persons who commit suicide have
been found to suffer from bipolar disorder, major
depression or some other psychiatric disorder upon
psychological autopsy.
Trends in Treatment
Number of office visits where
children and adolescents
reported depression
1995-96
2002-03
1.44 million
3.22 million
Percentage prescribed
antidepressants
47%
52%
Percentage of patients who
were prescribed SSRI’s
76%
81%
83%
68%
Proportion of patients who
received psychotherapy of
mental health counseling
A History of Controversy
• December of 2003: National Institute for Health and Clinical
Excellence (NICE) in Great Britain declared all SSRI’s but fluoxetine
to be not only ineffective but actually increase chances of suicide
related events one to three fold, effectively banning their use in
those under 18 years of age.
• October of 2004: The FDA announces a “black box warning”
associated with the use of all antidepressants in patients under the
age of 18 as a caution to both patients and practitioners about the
hazards of prescribing antidepressants in youth.
Australia, New Zealand and Canada soon followed suit with restrictions
of varying degrees on antidepressant usage in children and
adolescents.
The FDA’s Numbers
• The “black box warning” instituted by the FDA was
based upon a meta-analysis of 24 placebo controlled
randomized trials involving 4400 youth with OCD, MDD
and other psychiatric disorders.
• Studies on nine separate medications, including SSRI’s
and some other drug classes, were included in the metaanalysis.
• The FDA found that the risk of suicidal thinking or
behavior amongst patients receiving active drug was 4%
while those receiving placebo had a risk of only 2%.
Further Studies
• JAMA completed another meta-analysis in April of 2007 of 13
studies involving pediatric depression which included a total of 2910
patients.
• These studies involved both SSRI’s and second generation
antidepressants such as nefazodone and mirtazepine.
• They found that the rate of suicidality in active treatment groups was
3% while the rate in those receiving placebo was 2%.
• The calculated risk difference resulted in a NNH of 112.
• The pooled risk difference between the groups was 1% with a 95%
C.I. of -0.1% to 2%. As a result, JAMA found the risk of increased
suicidal ideation to be statistically insignificant.
The Power of Anecdotal Evidence
• Not a single completed suicide has been reported during
clinical trials of any antidepressant currently being used
in the treatment of youth MDD.
Let me repeat…………….
• Not a single completed suicide has been reported during
clinical trials of any antidepressant currently being used
in the treatment of youth MDD.
Part of the Problem
• The field of research involving antidepressant usage in youth is
relatively young itself: The very first randomized controlled trial
specifically designed to measure the efficacy of antidepressants in
children was conducted in 1997.
• As a result, we do not have a large body of work to draw from as
practitioners to assess risk or efficacy of pharmaceutical
antidepressants in children and adolescents.
• This also leaves open the possibility that some of the more severe
or rare side effects may not be observed until these drug therapies
have been used in much larger segments of the population (i.e.
hundreds of thousands or millions)
Part of the Problem
• None of the trials used by the FDA, JAMA or any other organization
were originally designed to measure suicidal behavior or tendencies.
• All of these studies were designed to assess efficacy of
antidepressants in relieving depressive symptoms.
• Information on suicidality included in the FDA report, and all
subsequent meta-analyses, was based on retrospectively assessed
definitions applied to information gleaned from adverse event logs
and psychological questionnaires.
• Richmond made note of this in a 2005 review: “these trials were not
designed to detect a difference in suicidality, leading to
heterogeneity in the manner in which adverse events data were
collected.”
Part of the Problem
Another valid concern is the lack of any defining characteristics
for many of the phrases that get tossed about concerning
suicidal behavior.
“In the American studies, the concept of suicidality was no more clearly
demarcated than what constituted a child. Terms used to define
suicidality included – though not in any uniform way across studies –
behavioral activation (itself a vague concept), disinhibition, impulsivity
emotional lability, self-inflicted harm, suicide ideation, suicide attempts
and completed suicide. In one study, a child who slapped herself was
considered to be suicidal, as was another child, who in a fit of anger
banged his head into a wall. An event involving a child frustrated
by his school performance who stabbed himself in the neck with a
pencil was labeled merely an accident.” John Bostwick: Mayo Clinic
Part of the Problem
What is the relative danger of suicidality?
Vitiello and Swede noted: “suicidal ideation is not an
accurate predictor of suicide since most persons with
such ideation do not attempt to die by suicide.”
Part of the Problem
• Selection of subjects for inclusion in studies of pharmaceutical
treatment of youth depression up until this point has been highly
exclusionary.
• The vast majority of researchers have disqualified any patients
found to have drug or alcohol dependency or co-morbid
psychological diagnoses such as bipolar disorder or schizophrenia.
• Most importantly, patients who are actively suicidal have been
completely excluded from most of the studies.
Gibbons et al noted: “by design, the randomized controlled trials
analyzed by the FDA systematically excluded patients who were
actively suicidal, and thus the FDA lacks data on those who are at
highest risk for suicide.”
How Did This Happen?
Time Magazine published an article in February of 2004 titled:
Prescription for Suicide? At the beginning of the article the
following narrative was included:
Kara Jaye-Anne Otter, 12, had been on the antidepressant Paxil for
seven months when she committed suicide. “I was told the worst side
effects would be flulike symptoms,” recalls her mother, Shannon Baker.
“But after three weeks she had begun to cop an attitude. Her grades
started falling. Then she didn’t care what she looked like, and she
was fighting with everybody.” Baker says her daughter developed
rashes and dark circles under her eyes and had trouble sleeping. Then,
on June 3, 2001, Kara pinned a note to her chest reading, “By the time
you find me I’ll be dead. I love you with all my heart. Don’t worry, Jesus
is with me.” She hooked a bungee cord onto a plate hanger on the wall,
wrapped the cord around her neck and pulled against it until she passed
out. Within minutes she was dead. (Lemonick, 2004)
How Did This Happen?
The article does go on to present a simplified but accurate
summation of the controversy over prescription of SSRI’s in
youth including arguments by physicians who support the
continued use of these medications in the treatment of
depression, however, the damage has been done.
Most people reading this article are not going to come away with
the message that many practitioners still believe that SSRI’s
are an important pharmaceutical option for depressed youth.
The majority of the people who read this article are going to
remember the vivid description of Kara Jaye-Anne Otter’s
suicide, and furthermore that this tragic sequence of events
was triggered by an antidepressant.
MOVIE TIME!!!!!
MOVIE TIME!!!!!
MOVIE TIME!!!!!
MOVIE TIME!!!!!
Pitfalls to Practice
• The Pediatric Advisory Committee along with the FDA
have crafted the following recommended monitoring
program in the event that antidepressants are prescribed
in youth: “weekly visits for the 1st month of treatment,
bimonthly during the 2nd month and once every 12 weeks
for the remainder of the dosing period.”
• Many parents may be unable or unwilling to bring their
children in for follow up on such a frequent basis.
Pitfalls to Practice
• A great majority of primary care providers in underserved areas may
not have access to specialized psychiatric treatment for their
pediatric patients and will be forced to care for these complex cases
with extremely limited resources.
• Many of these practitioners will be forced to prescribe SSRI’s “off
label” for fear that not prescribing may increase the risk of suicide in
their patient.
• Through initiating a “black box warning” and not an outright ban on
all antidepressants in youth the FDA has placed many practitioners
between a rock and a hard place, effectively washing their hands of
the matter.
What’s the Solution?
• While we as practitioners may or may not agree that
recent headlines concerning SSRI’s and their connection
to self harm in youth are overblown, we must still err on
the side of caution.
• Because most of the studies on youth depression have
excluded individuals with many predisposing factors that
could increase risk of suicide, we must be hypervigilant
with usage of antidepressants in those particular patients
who suffer from comorbid psychiatric of medical
conditions.
What’s the Solution?
• Parents and guardians must be warned of the possibility for
increased suicidal behavior in youth during the first few weeks of
treatment with antidepressant medications.
• Practitioners should consider the competency of their patient’s
parent or guardian particularly regarding the probable level of
vigilance they may have regarding a child’s changing psychological
symptoms.
• We must weigh the severity of a patient’s depression and it’s
likelihood to cause them physical harm against the possibility that
his or her caretaker may not remain observant enough to assess an
increase in the youth’s suicidal behavior due to institution of
antidepressant treatment.
What’s the Outcome?
• If we as health care workers can become more vigilant in
our treatment of depressed youth while not being gun
shy in prescribing antidepressants in appropriate
situations, I think mental health care in the United States
will improve drastically.
• If, however, all these black box warnings and alarmist
decrees scare us away from appropriate pharmaceutical
interventions for fear of increased liability, the most
vulnerable of our mentally ill youth will undoubtedly
suffer the most.
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BIBLIOGRAPHY
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