Research on Child and Adolescent Mental Health

Bornstein, Zborowski, Fisher & Greenberg, 1994),
the benign side-effect profile, and low lethality in
overdose. While a double-blind, placebo-controlled
study of 40 adolescents with major depression did
not find any significant differences between placebo
and fluoxetine (Simeon, Dinicola, Ferguson &
Copping, 1990), more recent studies with much
larger samples and lower overall placebo responses
have suggested response rates comparable to those
reported in adults. Several open studies have
reported 70 to 90 percent response rates to
fluoxetine or sertraline for treatment of adolescents
with major depression (DeVane and Sallee, 1996).
An 8-week double blind study of treatment of
depression in a large sample of youth showed that
both children and adolescents responded
significantly better to fluoxetine than to placebo
(56% vs. 33%) (Emslie et al., 1997). In addition, a
multicenter, double-blind, placebo-controlled study
examined the efficacy of paroxetine and
imipramine in 275 adolescents with unipolar
depression (Keller, Ryan, Birmaher et al., 1998).
Youth treated with paroxetine had a statistically
greater improvement over those treated with
placebo in global functioning and depression scores
at the end of study, and there was a remission of
depressive symptoms.
Better study paradigms, including augmentation
strategies, multiple medication strategies to
manage comorbid disorders, and the use of
algorithmic treatments, are needed to help guide
clinical practice. It is interesting that from 1996 to
1997, children between the ages of 6 and 18
received 792,000 prescriptions for SSRI’s to treat
depression (Hoar, 1998). This pattern is based on
relatively few studies, with relatively modest
effects, as noted above. For this reason, a multi-site
study was completed to develop an algorithm for
treating major depression, based on consensus
among academic clinicians, researchers, practicing
clinicians, administrators, consumers, and families.
The process initially addressed strategies of
treatment and tactics to implement the strategies,
including medication augmentation and medication
combinations (Hughes et al., 1999).
In sum, most clinical trials of antidepressants
conducted to date have been based on open studies
and/or relatively small sample sizes, with
conclusions about their safety, efficacy, and
effectiveness based on group-means comparisons.
From a clinical utility perspective, separate and
distinct algorithms for management of the same
illness or disorder may be necessary for different
patient populations or different types of treatment
environments. In addition, unique developmental
characteristics, the presence of comorbid
symptoms, and the role for nonmedication
alternatives need to be considered. For example, a
study in adults found that treatment with
combined medication (nefazodone) and
psychotherapy (cognitive behavioral analysis
system) was more efficacious than treatment alone
for chronic major depression, suggesting that
combined treatments are superior (Keller et al.,
2000).
The mechanisms by which antidepressants work to
address depressive symptoms are not well
understood. While both noradrenergic and
serotonergic neurotransmitter systems have been
implicated in the etiology of major depression, their
role must be understood in the developmental
context of how these systems mature during
childhood and adolescence. For example, lack of
response to tricyclic antidepressants in younger
cohorts could be secondary to later maturation of
noradrenergic brain substrates (Murrin, Gibbens &
Ferrer, 1985). Dopamine beta-hydroxylase, the
enzyme involved in the conversion of dopamine to
noradrenaline, increases in activity from birth to
about age 8 (Weinshilboum, 1983). Such
developmental differences are key in understanding
the molecular effects of antidepressants. Animal
studies have begun to characterize the subcellular
actions of antidepressant treatments such as
activation of the cyclic adenosine monophosphate
(cAMP), which in turn leads to regulation of specific
target genes (e.g., increased expression of brain-
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