Background Package
from
Pfizer Inc
for
September 13-14, 2004
Psychopharmacological Drugs
Advisory Committee
of the
Food and Drug Administration
August 10, 2004
Major Depressive Disorder (MDD) in children and
adolescents is a critical public health issue for the youth of America. If left
untreated, MDD can result in a significant risk of suicidal behavior, and is
the third leading cause of death in the pediatric population. Epidemiological
studies strongly suggest that usage of SSRIs have resulted in a reduction of
the number of suicides in this vulnerable patient population. Moreover,
Pfizer’s analysis of the placebo-controlled Zoloft® (sertraline
hydrochloride) pediatric database (281 Zoloft treated subjects and 279 placebo
treated subjects) demonstrates no association between Zoloft usage and an
increased risk of suicide and/or suicide related behavior.
Major depressive disorder (MDD) occurs in children and adolescents as well
as adults. The annual prevalence of
depression is estimated to be 2-3% in children aged 8-12 years and slightly
higher (4-8%) in youth aged 11 ½ to 18 years (AACAP, 1998) as compared with rates of 6.6% in
adults aged 18 and older (Kessler,
2003).
In order to diagnose depression, the Diagnostic and Statistical Manual Version IV with revisions (DSM-IV TR) is used. The diagnostic criteria are similar in children and adolescents to those utilized to diagnose depression in adults, with the exception that DSM notes that children and adolescents may exhibit an irritable mood rather than a depressed mood. In all age groups, suicidal thinking or behavior can be one of the diagnostic criteria, characterized in DSM as “abnormal morbid thoughts of death (not just fear of dying) or suicide”.
Clinical and epidemiological studies in children and adolescents have shown that a typical episode of MDD lasts 2-9 months; with a probability of the disease returning of 40% within 2 years and 70% by 5 years, similar to the rates of recurrence that have been reported for adults (Birmaher, 1996). Children and adolescents who suffer from MDD may experience a drop in school performance, family tension/problems, and conflicts with friends.
It is common to see coexisting psychiatric disorders in depressed youth (40% to 90% of the time). The most frequent coexisting disorders are dysthymic disorder (sometimes referred to as minor depression in that these youth display a chronically depressed mood or irritability lasting at least 1 year but do not meet criterion for major depression) and anxiety disorders (both at 30% to 80%), disruptive behavior disorders (10% to 80%), and abuse of alcohol or illicit substances (20% to 30%) (AACAP, 1998).
MDD in the pediatric population is associated with significant risk of suicidal thinking, attempts and even completed suicide. Approximately half of teenagers with MDD attempt suicide at some time during their lives and among children with MDD, there is a 4- to 5-fold higher lifetime risk of suicide attempt, compared with healthy children without depression (Kovacs, 1993; Rao, 1993). Kovacs et al (1993) noted similar results in a study of outpatient youths with MDD. They noted that, at study entry, 66% of subjects acknowledged a history of suicidal ideation, and 9% had already made at least one suicide attempt. The rate of suicide attempts in this study reached 24% by age 17. Important comorbid risk factors for suicide attempts included conduct and/or substance-abuse disorders.
The American Academy of
Child and Adolescent Psychiatry recommends, for first-line acute treatment of
MDD in children and adolescents, psychotherapy, treatment with a selective
serotonin reuptake inhibitor (SSRI), or both combined, depending on the
patient, the patient’s circumstances, and the severity of disease (AACAP, 1998).
Psychotherapy may take the form of individual, group, or
family therapy; cognitive behavioral therapy, interpersonal-, problem-solving,
or play therapy. There are few
placebo-controlled studies with psychotherapy.
Cognitive-behavioral therapy has
been shown to work in small studies, but does not appear to be as effective for
more severe illness. Treatment studies comparing psychotherapy, medication or
their combination are needed and are beginning to be conducted, and presented.
Prior to the
widespread use of SSRIs, tricyclic antidepressants (TCAs) were the most
commonly used pharmacotherapy for MDD.
Although tricyclic antidepressants (TCAs) have been shown to effect some
improvement in small open studies in children, more rigorous placebo-controlled
studies failed to demonstrate that TCAs were more effective
than placebo for the treatment of MDD in children and adolescents. TCAs also pose certain safety risks in
children, specifically cardiac arrhythmias, and a potential lethality in
overdose. The high degree of acceptance of
SSRIs for the treatment of MDD in adults, together with their low incidence of
side effects, easy once-a-day administration, and safety when taken in overdose
made it natural that physicians, faced with the need to treat patients
suffering from MDD would prescribe these in younger patients also, even if
off-label. Fluoxetine is currently the
only SSRI is indicated for the treatment of depression in childhood. The Zoloft
label contains safety and efficacy information with respect to the use of
Zoloft in pediatric OCD (acute and long-term), and safety information derived
from the pediatric MDD program.
Several epidemiological studies address rates of suicide following the introduction of SSRIs in adults (Hall et al, 2003 [patients ranged in age upward from 15 years]; Isaacson et al, 2000) and adolescents (Olfson et al, 2003). In each of these studies, a negative correlation was noted between usage of SSRIs and suicide rates and the correlation coefficients noted by Hall et al were quite strong (men, r=-0.91, p<0.01; women, r=-0.76, p<0.05). Olfson et al specifically assessed the rates of suicide in adolescents in a large managed care database and found a risk reduction for suicide of 0.23/100,000 population per year with a 1% increase in antidepressant usage.
Figure 1 below shows the chronology of Zoloft regulatory approvals in the United States, from initial approval for adult Major Depressive Disorder (MDD) in late 1991 and launch in 1992, through the present.