CLINICAL REVIEWS
Recognizing and treating depression
in children and adolescents
I
n March 2004, the Food and Drug
Administration (FDA) issued a
public health advisory cautioning
physicians, their patients, and their
patients’ families to closely monitor
both adults and children with de-
pression for the emergence of suicidal
behavior after beginning antidepres-
sant therapy.1 In October 2004, FDA
required manufacturers of antide-
pressants to add a black-box warning
to the labeling of antidepressants re-
garding an increased risk for new-
onset suicidal behavior in children
and adolescents taking antidepres-
sants.2 This advisory was based on
the results of 24 placebo-controlled
trials of 4400 children and adoles-
cents, which found that antidepres-
sant use was associated with an
approximate 4% frequency of new-
onset suicidal behavior compared
with a rate of approximately 2% with
placebo.2 None of the children in the
clinical trials completed suicide. The
FDA advisory committee recom-
mended that antidepressants not be
contraindicated in children and ado-
lescents because access to them is
necessary for those who benefit from
the drugs.2
The use of antidepressants in
youth has received greater scrutiny
since FDA issued that warning.3,4
Prescriptions written for antidepres-
sants for children age 10–18 years de-
JULIE A. DOPHEIDE, PHARM.D., BCPP, is Associate Professor of Clini-
cal Pharmacy, Psychiatry and the Behavioral Sciences, Schools of
Pharmacy and Medicine, University of Southern California, 1985
Zonal Avenue, Los Angeles, CA 90089 (dopheide@usc.edu).
Recognizing and treating depression
JULIE A. DOPHEIDE
Purpose. The clinical presentation and
neurobiology of depression in youth and its
appropriate treatment, as well as strate-
gies for improving therapeutic benefit and
preventing adverse outcomes, including
suicide, are reviewed.
Summary. Functionally impairing depres-
sion occurs in 2–10% of children and ado-
lescents. A diagnosis of depression should
be considered when a physically healthy
child exhibits depressed mood or anhe-
donia, multiple somatic complaints, or be-
havioral changes, such as bullying, aggres-
sion, and social withdrawal. Risk factors for
depression include childhood trauma, ge-
netic susceptibility, and environmental
stressors. Antidepressants and cognitive
behavioral therapy are the most effective
treatments for adolescents with depres-
sion. Youth are at risk for the same adverse
effects as adults but have an increased risk
of behavioral activation, or switch, to mania
and suicidal thoughts and behaviors early
in treatment. Compared with other antide-
pressants, fluoxetine has the most evi-
dence for safety and efficacy, particularly in
creased by 10–16% in 2004, com-
pared with a 50% increase between
1998 and 2002. 3,4 An increased
awareness of teen suicide and the
need for parent and family education
about treatment options for depres-
sion have resulted from FDA’s warn-
ing. However, clinicians express con-
cern that the black-box warning on
antidepressant labeling will lead to
Copyright © 2006, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/06/0201-0233$06.00.
DOI 10.2146/ajhp050264
Am J Health-Syst Pharm—Vol 63 Feb 1, 2006
adolescents 12 years or older. There is very
little evidence for the effectiveness of any
antidepressant in children 11 years and
younger. Youth receiving antidepressants
should be monitored closely for new-onset
or worsening suicidality, particularly during
the first two weeks after starting medica-
tion, and for three months of therapy. Be-
havioral activation, aggression, worsening
depression, anxiety, insomnia, or impulsivity
can herald a switch to mania or suicidality.
Conclusion. Depression in youth is com-
mon and treatable and responds best to
multimodal treatment combining patient
and family education, cognitive behavioral
therapy, and antidepressant medication.
The potential benefits of antidepressants
outweigh the risks for adolescents. Family
and psychotherapeutic interventions are
most effective for prepubertal children.
Index terms: Adolescents; Antidepres-
sants; Cognitive therapy; Depression; Diag-
nosis; Fluoxetine; Patient information; Pedi-
atrics; Suicides; Toxicity
Am J Health-Syst Pharm. 2006; 63:233-43
increased rates of youth suicide due
to decreased use of antidepressants
to effectively manage depression.5,6
Strong support for the effectiveness
of fluoxetine in treating adolescent
depression exists in the literature.7,8
Cognitive behavioral therapy (CBT)
also has proven efficacy for the treat-
ment of depression in children and
adolescents.9
233
 CLINICAL REVIEWS Recognizing and treating depression
Although effective treatments for
depression in youth are well estab-
lished, community care for depres-
sion in children and adolescents is
lacking, with serious gaps in access to
care and a lack of ongoing treat-
ment.10,11 This article reviews the
clinical presentation of depression in
youth, neurobiological and environ-
mental risk factors associated with
depression in youth, pharmacologic
and nonpharmacologic treatment
options, and recommendations for
clinical monitoring and patient and
family education.
Epidemiology and clinical course
An increasing body of knowledge
confirms that depression is a com-
mon and persistent illness in youth,
affecting 0.3% of preschoolers, 2% of
elementary school-age children, and
5–10% of adolescents.12,13 The rates
of prepubertal depression are similar
for boys and girls; however, depres-
sion rates double in females after pu-
berty.12,13 Hormonal and environ-
mental influences are thought to
contribute to the increased frequency
of depression in female adolescents.14
Rates of depression increase dramat-
ically as children move into adoles-
cence.14 Comorbidities such as sub-
stance abuse and anxiety disorders
increase the risk of depression by
two- to threefold.13,14 An estimated
10–20% of adolescents have had at
least one major depressive episode by
age 18 years.13,14 One study of 9863
students age 10–16 years found that
29% of American Indian youth ex-
hibited symptoms of depression,
compared with 22% of Hispanic,
18% of Caucasian, 17% of Asian-
American, and 15% of African-
American youth.14
Untreated, a depressive episode
can last seven to nine months, and
approximately 50% of patients will
relapse within five years of their
first episode.12,15 Depression compro-
mises the developmental process,
with associated difficulties with con-
centration and motivation,15 leading
234 Am J Health-Syst Pharm—Vol 63 Feb 1, 2006
to poor academic performance, years) talk about running away from
impaired social functioning, poor home; display boredom, low self-
self-esteem, and a higher risk of esteem, guilt, or hopelessness; and
suicide.5,12,14 have a fear of death. Compared with
Clinical presentation. Major de- adolescents with depression, chil-
pressive disorder has been validated dren with depression are less likely to
in children as young as 3 years (Table suffer from delusions or make seri-
1). 16-18 For example, preschoolers ous attempts to commit suicide.18
may persistently show suicidal or Depressed adolescents (age 12–17
self-destructive themes in play, or years) display more sleep and appe-
parents and caregivers may notice tite disturbances and are prone to
that a physically healthy child is un- reckless behavior, delusions, suicidal
interested in play.16 Depression in ideation and acts, and impairment of
children 8 years or younger may not overall functioning. 18 Depressed
be recognized because this age group teenagers have more behavior distur-
is less likely to verbalize the emotion- bances and fewer neurovegetative
al symptoms of depression and more symptoms (e.g., low energy, psycho-
likely to display symptoms of anxiety motor slowing) than do adults with
(e.g., phobias, separation anxiety), depression.12,18
somatic complaints (e.g., “my tum- When a child or adolescent displays
my hurts,” “I don’t feel good”), and new-onset depressive symptoms with
auditory hallucinations. 17,18 De- or without psychosis, bipolar disor-
pressed children are irritable, have der should be seriously considered as
temper tantrums, and display other a possible diagnosis.19,20 Risk factors
problem behavior (e.g., shouting, for bipolar disorder include a family
lack of interest in playing with history of the illness, a history of
friends).18 Older children (age 9–12 antidepressant-induced mania, and
Table 1.
Comparison of Clinical Presentation of Major Depressive Illness by
Age8,12,16-18
Age (yr) Frequency (%) Clinical Presentation
≥19 17 Depressed mood or anhedonia and at least four of the
nine following symptoms that last at least 2 wk with
functional impairment: (1) sleep and appetite changes,
(2) psychomotor changes (slowing or agitation), (3)
hopelessness, (4) worthlessness, (5) diminished energy,
(6) poor concentration, (7) tearfulness, (8) suicidal
thoughts, and (9) suicide plan
12–18 5–10 Same as adult criteria except more impulsivity,
irritability, and behavioral changes; more reckless
behavior; poor school performance; more sleep and
appetite disturbances than displayed by younger
children; suicidal thoughts and attempts similar to
those in adults; genetic link to depression stronger;
chronic course more likely
9–12 3–5 Same as adult criteria except more complaints of
boredom, low self-esteem, guilt, hopelessness,
wanting to run away from home, and fear of death
6–8 2–4 Same as adult criteria except for difficulty verbalizing
feelings; more somatic complaints (e.g., “my tummy
hurts, ” “I don’t feel good”); outbursts of crying,
shouting; unexplained irritability; anhedonia observed
by others
3–5 0.3–0.5 Same as 6–8 yr olds, except symptoms not necessarily
present over an entire 2-wk period; markedly
diminished interest in play; feelings of worthlessness
or suicidal, self-destructive themes persistently evident
in play
 CLINICAL REVIEWS
psychomotor retardation associated
with the depressive symptoms.19,20 It
is important to screen for bipolar
disorder in these patients because
treatment with antidepressants is
more likely to trigger mania in these
individuals, thereby increasing the
number or severity of suicidal behav-
iors.20-22 If a diagnosis of bipolar dis-
order is confirmed, a mood stabilizer
(e.g., lithium, valproate) should be
initiated before adding an antide-
pressant to treat persistent depressive
symptoms.22
Regardless of the presence of bi-
polar disorder, children and adoles-
cents have a greater risk of develop-
ing antidepressant-induced manic
conversion compared with adults.21,22
A longitudinal study of 87,920 pa-
tients taking antidepressants for any
reason found that 4,786 patients
(5.4%) age 5–29 years developed
manic conversion.21 Prepubertal or
peripubertal children age 10–14
years had twice the risk of manic
conversion, approximately 10%.21 In
pediatric psychiatry clinics in the late
1980s and early 1990s, the rate of
antidepressant-induced behavioral
activation, hypomania, or mania was
approximately 20–50%.23 The higher
rate was likely due to the inclusion
of youth with bipolar disorder and
the relatively higher starting dosages
of antidepressants in older clinical
trials.22,23 “
Comorbidities. A depressed
youth with no other psychiatric diag-
nosis is a rarity. Common comorbid
conditions include attention-deficit/
hyperactivity disorder (ADHD), op-
positional defiant disorder (ODD),
substance abuse, posttraumatic stress
disorder (PTSD), dissociative states,
and trauma-related hallucinations.12
The presence of multiple comorbid
conditions and psychosocial stres-
sors increases the severity and chro-
nicity of the depressive episode.12,14
In addition, combinations of medi-
cations can increase the risk of
adverse drug reactions and drug in-
teractions.23,24 An evaluation of treat-
Recognizing and treating depression
ments for depression in the commu-
nity found that 44% of children
prescribed antidepressants were
taking a concomitant psychotropic
medication.10
Etiology and risk factors
Youth involved in behaviors such
as bullying and substance abuse and
those with frequent somatic com-
plaints have higher rates of depres-
sive symptoms compared with those
not exhibiting such behaviors.14 High
familial loading for a mood disorder
(i.e., at least one first-degree and at
least one second-degree relative has a
mood disorder), a mother’s lifetime
anxiety disorder, and a behavioral
disorder in the child increases the
risk of developing a depressive disor-
der by threefold.25 Other risk factors
for developing depression include
genetic predisposition and psychoso-
cial stressors, such as maternal men-
tal illness, lack of paternal communi-
cation, unsafe living conditions,
physical or sexual abuse, and paren-
tal loss through death or divorce.12,14
A longitudinal study conducted in
New Zealand followed 1265 children
from birth to age 21 and monitored
factors associated with increased
rates of depression and suicidal be-
havior.26 As expected, those exposed
to sexual abuse, physical abuse, inter-
parental violence, parental criminali-
ty, and parental use of illicit drugs
had higher rates of depression and
suicidal thoughts and behavior.26
Factors associated with resiliency to
depression and suicidal behaviors
were intact family support systems,
positive peer affiliations, and high
self-esteem.26
Neurobiology of depression.
Magnetic resonance imaging studies
have shown measurable brain chang-
es in children and adolescents with
depression compared with nonde-
pressed control subjects. The left sub-
genual prefrontal cortex volume was
reduced in young women with ado-
lescent-onset major depression com-
pared with healthy controls.27 Ante-
Am J Health-Syst Pharm—Vol 63 Feb 1, 2006
rior cingulate cortex glutamatergic
concentrations were significantly
lower in children with depression
compared with age-matched con-
trols.28 Blunted growth-hormone se-
cretion is associated with an in-
creased risk of depression in youth.29
Smaller hippocampal volume was
found in depressed women with a
history of severe and prolonged
abuse in childhood but not in de-
pressed women who had not experi-
enced similar abuse.30 Another study
found smaller amygdala volumes
in 20 children and adolescents with
major depression compared with
24 healthy controls; hippocampus
volumes did not differ between
groups.31 There is increasing evi-
dence of a link among early child-
hood trauma, depressive illness, and
morphological brain changes, fur-
ther substantiating the biological ba-
sis of depression in youth.28,30
Neurogenetic studies provide ad-
ditional evidence for the biological
basis of depression. Caspi et al.32
found that a functional polymor-
phism in the promoter region of the
serotonin transporter (5-HTT) gene
moderates the influence of stressful
life events on the development of de-
pression. They assessed 1037 chil-
dren (52% male) for depression and
life stressors at ages 3, 5, 7, 9, 11, 13,
15, 18, 21, and 26 years. These chil-
dren were divided into three groups
on the basis of their serotonin-linked
promoter region (5-HTTLPR) geno-
type: those with two copies of the S
allele phenotype (S/S homozygotes)
(n = 147), those with one copy of the
S allele (S/L heterozygotes) (n = 435),
and those with two copies of the L
allele (L/L homozygotes) (n = 265).
The impact of life events on the self-
reports of depressive symptoms was
significantly stronger among individ-
uals carrying an S allele than among
L/L homozygotes (p = 0.02).32
Further analysis showed that
stressful life events predicted suicidal
ideation or attempt among individu-
als carrying an S allele but not among
235
 CLINICAL REVIEWS Recognizing and treating depression
L/L homozygotes.32 A separate case–
control and family-based study lends
support to these earlier findings.33
Sixty-eight depressed children and
68 age-matched controls found an
excess of the S/S genotype (p =
0.025) and of the S allele (p = 0.021)
among the children with depressive
illness.33 It seems that depressed and
suicidal children are more likely to
receive the S allele of the 5-HTTLPR,
and this may predispose them to de-
veloping depression in association
with stressful life events. Polymor-
phisms in the 5-HTT protein can
affect the use of serotonin by the
neuron.32 Serotonin dysregulation is
implicated in the pathophysiology of
depression in youth, and most effec-
tive antidepressants modulate sero-
tonin neurotransmission.8,12,23
Suicidality. Suicidal thinking and
attempts are common in youth with
or without depression, with 19% of
15–19-year olds thinking about sui-
cide and 9% attempting suicide each
year.34 If depressed, 35–50% will at-
tempt suicide, and 2–8% will com-
plete suicide over a decade.6,34 Longi-
tudinal studies have found that
increased rates of suicidal behaviors
in youth are associated with a family
history of suicide, childhood sexual
abuse, personality factors (e.g., high
rates of anxiety and novelty seeking),
negative peer affiliations, lack of
school success, and untreated behav-
ioral disorders and depression.26,35
Increased suicidality may also be re-
lated to developmental factors, such
as the lack of coping mechanisms or
“black-and-white” thinking, where
youth see themselves and their life as
“all good” or “all bad.” When things
seem “all bad,” youth turn to suicide
because they are unable to conceptu-
alize other options to end their emo-
tional suffering.9,26 Cognitive restruc-
turing and behavioral interventions
toward the development of coping
skills and alternatives to suicide are
two goals of CBT. CBT is considered
a first-line treatment for depression
in nonpsychotic youth.9,26,36
236 Am J Health-Syst Pharm—Vol 63 Feb 1, 2006
Completed suicide in youth is
considered rare, with an overall 12-
month incidence of 0.008% in youth
age 15–19 years.34 Suicide comple-
tion rates in youth actually decreased
from 1995 to 2005.5,34 Reasons cited
for this reduction include decreased
access to firearms and increased rec-
ognition and treatment of depres-
sion.5 One study examined regional
antidepressant use and national
suicide mortality files of children and
adolescents in 1990 and compared
them with similar data collected
in 2000.37 The study showed that
for every 1% increase in selective
serotonin-reuptake inhibitor (SSRI)
use in 10–19-year olds, there was a
decrease of 0.23 completed suicide
per 100,000 youth. This study of real-
world antidepressant use in youth
showed that antidepressants offer a
protective effect against suicide com-
pletion. This finding conflicts with
placebo-controlled clinical trials
studying antidepressants in youth,
which found increased suicidality
early in treatment.2,37
Another study analyzed the rela-
tionship between antidepressant
pharmacy prescription volumes and
U.S. suicide rates in all age groups
between 1996 and 1998.38 The annual
suicide rate in those three years
was 12.32 suicides per 100,000
people.38 Investigators found that
prescriptions for SSRIs and other
new-generation antidepressants
(nefazodone, mirtazapine, bupropi-
on, and venlafaxine) were associated
with a 33% lower suicide rate, or 8.2
suicides per 100,000 people, versus
those not receiving antidepressants
and those prescribed tricyclic antide-
pressants.38 A high number of pre-
scriptions for tricyclic antidepres-
sants in a county was associated with
increased suicide rates, although
counties with high rates of tricyclic
antidepressant prescribing had fewer
antidepressant prescriptions.38 These
findings were consistent in children,
adults, and the elderly. Similar to
previous studies’ findings on risk fac-
tors of suicide completion, male
sex was associated with higher sui-
cide completion rates. 34 Black fe-
males were the least likely to com-
plete suicide.38
In the United States, females re-
ceive more prescriptions for antide-
pressants compared with males, but
males have significantly higher sui-
cide completion rates.39 This sex dif-
ference applies to all ages, including
children. 5,34 According to several
studies, most suicides and serious
nonfatal suicide attempts are com-
mitted by individuals with major de-
pression that was untreated at the
time of death.39,40
Treatment
Effective, first-line treatment op-
tions for depression in youth include
CBT, interpersonal psychotherapy,
antidepressants, psychosocial inter-
vention, or a combination of non-
drug and pharmacologic options.8,9,41
In preschoolers and children under
eight years of age, therapeutic inter-
ventions are primarily psychosocial,
beginning with family counseling
and environmental modifications.41-43
Psychosocial interventions are par-
ticularly helpful in very young chil-
dren when it is clear that depressive
symptoms are a reaction to a child’s
environment.41,43 Examples of useful
psychosocial interventions include
treatment and support for depressed
or overwhelmed parents.43 Antide-
pressants, CBT, and interpersonal
psychotherapy have not demonstrat-
ed effectiveness in preschoolers or
children under eight years of age.7-9,12
Older children and adolescents
have a wider range of effective treat-
ment options, including CBT and
antidepressants.8,9
The effectiveness of CBT versus
antidepressants has not been ade-
quately assessed in children and ado-
lescents, although one study com-
pared placebo with fluoxetine and
CBT, fluoxetine alone, and CBT
alone in depressed adolescents. 8
Combination CBT and fluoxetine
 CLINICAL REVIEWS
produced the best therapeutic out-
come, and all treatments were more
effective compared to placebo.
Nonpharmacologic interven-
tions. CBT is considered the first-
line treatment for children and
adolescents with depression, with ef-
ficacy rates of 60–70%.9,42 CBT is
superior to interpersonal psycho-
therapy and other nonspecific psy-
chotherapeutic interventions, such
as supportive, psychodynamic, and
family therapy, in relieving symp-
toms of nonpsychotic major depres-
sion.9,36 CBT teaches patients to iden-
tify and counteract distortions in the
way they view themselves and their
circumstances.9,12 Interpersonal psy-
chotherapy focuses on problem areas
of grief, interpersonal roles, transi-
tions, and disputes. Interpersonal
psychotherapy may be as effective as
antidepressants for the treatment of
mild to moderate depression in
youth.44 Therapists qualified to pro-
vide interpersonal psychotherapy
and CBT range from well-supervised
novice social workers and occupa-
tional therapists to experienced child
psychologists and psychiatrists.9,44
One study found that younger
children and adolescents (10–14
years old) with less severe depressive
symptoms and less psychosocial im-
pairment may be more responsive to
psychotherapeutic interventions
compared with older adolescents
with more severe symptomatology.42
Another study showed that adoles-
cents age 13–17 years with major de-
pression and conduct disorder re-
sponded to CBT.36 Most studies of
CBT have been conducted with chil-
dren age 9 years or older, as younger
children may not have the verbal and
cognitive processing skills to benefit
from CBT.9
SSRIs. A summary of published
controlled trials of SSRIs for the
treatment of major depression in
youth is provided in Table 2. The
place in therapy, initial pediatric dos-
ages, and special considerations for
using antidepressants with the most
Recognizing and treating depression
well-established efficacy in the treat- Scale (CDRS)–revised (p = 0.001).8
ment of major depressive disorder in Fluoxetine plus CBT was superior to
youth are summarized in Table 3. fluoxetine alone (p = 0.02) and CBT
Fluoxetine. Fluoxetine is the only alone (p = 0.01). Statistical analysis
antidepressant with FDA-approved revealed that patients’ response to
labeling for the treatment of depres- fluoxetine alone did not differ signif-
sion in children age 8 years or older. icantly from CBT plus fluoxetine, al-
The approval was based on two though both were superior to CBT
placebo-controlled trials. The first and placebo.
study found that fluoxetine 10–40 Fluoxetine 10–40 mg/day was ad-
mg daily had significantly greater ef- ministered, with doses adjusted by a
ficacy (56%) than placebo (33%) in blinded clinician based on response
children age 8–18 years for eight to during six follow-up visits over 6
nine weeks (p = 0.02).7 In the second weeks.8 The mean highest dosage of
study, the efficacy rates were 41% for fluoxetine in each group ranged from
children receiving fluoxetine and 28.4 mg daily in the CBT plus fluox-
20% for those receiving placebo (p < etine group to 34.1 mg daily in the
0.01).45 These studies included chil- placebo group. Fifteen sessions of
dren with comorbid ADHD, ODD, CBT were administered over 12
and bipolar II disorder. They did not weeks. Adverse events were consid-
stratify results by patient age. Head- ered mild, with 10% of patients in all
ache was the only nonsolicited ad- treatment groups except CBT alone
verse event reported significantly reporting headache. Insomnia oc-
more often in fluoxetine-treated pa- curred in five CBT plus fluoxetine-
tients versus those receiving placebo. treated patients, three patients re-
In the Treatment of Adolescents ceiving fluoxetine alone, and one
with Depression Study (TADS), 439 patient in the placebo group. Upper
adolescents age 12–17 years were di- abdominal pain was reported in
vided into four treatment groups: six patients receiving fluoxetine
CBT, fluoxetine, CBT plus fluoxe- alone and two in the placebo group.
tine, and placebo.8 After 12 weeks of One patient receiving CBT plus flu-
treatment, combination CBT and oxetine and two patients receiving
fluoxetine was superior to placebo fluoxetine alone experienced irrita-
on the Children’s Depression Rating bility and hypomania.
Table 2.
Published Trials of SSRIs Versus Placebo for the Treatment of Major
Depression in Youth7,45-48,a
% Pts. Improved or Points
Duration Age No. Pts. on CDRS (Drug vs. Placebo)
Drug (wk) (yr) (Drug/Placebo) CDRS CGI
Fluoxetine 8 8–18 48/48 –16.2 vs. –6.7 56 vs. 33
(p = 0.002) (p = 0.02)
Fluoxetine 9 8–17 209/210 65 vs. 53 52 vs. 37
NS (p = 0.03)
Sertraline 10 6–11 86/91 –24 vs. –22 NS
12–17 103/96 –21.5 vs. –18.2 (p = 0.01)
Paroxetine 8 12–18 93/87 69 vs. 59 65 vs. 48
HAMD (p = 0.02)
Imipramine 8 12–18 95/87 NS 52 vs. 48
NS
Citalopram 8 7–17 89/85 36 vs. 24 47 vs. 45
(p < 0.05) NS
aSSRIs = selective serotonin-reuptake inhibitors, CDRS = Children’s Depression Rating Scale, CGI = Clinical
Global Impressions, NS = not significant, HAMD = Hamilton Depression Rating Scale.
Am J Health-Syst Pharm—Vol 63 Feb 1, 2006 237
 CLINICAL REVIEWS Recognizing and treating depression

Table 3. to the higher prescribing rate for ser-

Antidepressants with Well-Established Efficacy for the Treatment traline relative to other SSRIs.1
of Major Depressive Disorder in Youth8,23,24,46,48,51,52 The evidence for sertraline’s effec-
Place Initial Dosage Special Considerations tiveness in treating depression in
Drug in Therapy (Dosage Range) and Drug Interactions youth is not robust. Pooled data
Fluoxetine First linea ≤11 yr, 5 mg/day; ≥12 yr, Well studied in OCD and bulimia; from two studies comparing sertra-
10 mg/day (10–40 mg/ can increase plasma levels of line 50–200 mg daily for 10 weeks
day) macrolides, atomoxetine, versus placebo in depressed children
amphetamine, bupropion,
phenytoin, antipsychotics, and teens show a 69% response rate
zolpidem, and eszopiclone for sertraline versus 59% for those
Sertraline First lineb ≤11 yr, 12.5 mg/day; ≥12 Effective for OCD and other receiving placebo.46 After further ex-
yr, 25 mg/day (25–200 anxiety disorders; can increase
mg/day) plasma levels of macrolides, amination of the individual patient
atomoxetine, amphetamine, groups, patients age 6–11 years re-
bupropion, phenytoin, ceiving sertraline (n = 86) did not
antipsychotics, zolpidem, and
eszopiclone differ from those receiving placebo
Citalopram Second linec ≤11 yr, 10 mg/day; ≥12 Lower risk of drug interactions (n = 91) in their clinical outcome.
yr, 20 mg/day (20–60 compared with fluoxetine, but Adolescents age 12–17 years (n =
mg/day) drug interactions still possible;
least potent SSRI, so higher end 103) demonstrated a significant im-
of dosing range may be needed provement in depressive symptoms
Bupropion Second lined ≤11 yr, 37.5 mg IR b.i.d.; Can increase levels of versus the placebo group (n = 96), as
≥12 yr, 100 mg ER/day atomoxetine, amphetamine,
(100–400 mg/day) and risperidone measured by the CDRS (p = 0.01). Ad-
aFor children and adolescents with major depressive disorder or if obsessive-compulsive disorder (OCD) or verse effects from sertraline treatment
bulimia is present. that were more frequent than with pla-
bFor adolescents with major depressive disorder or if OCD, posttraumatic stress disorder, or generalized
anxiety disorder is present.
cebo were insomnia, anorexia, diar-
cFirst-line treatment if drug interactions with fluoxetine must be avoided; less evidence for efficacy. SSRI = rhea, vomiting, agitation, and urinary
selective serotonin-reuptake inhibitor.
dFor patients with comorbid attention-deficit/hyperactivity disorder or substance abuse problems or who incontinence, the last of which was
want to stop smoking. IR = immediate release, ER = extended release. more frequent in children age 11 years
or younger. Suicide was attempted by
two patients in the sertraline group
and two in the placebo group.46
Suicidal thoughts occurred in on the CDRS. However, the results Paroxetine. Paroxetine was the
29% of all TADS participants at base- lacked generalizability to those with second most commonly prescribed
line but improved in all treatment multiple episodes of depression: 86% SSRI in 2002, despite only one pub-
groups.8 Patients receiving fluoxetine of study participants were experienc- lished trial describing its efficacy on
plus CBT demonstrated the greatest ing their first episode of depression. the secondary outcome measure, the
decrease in suicidal thinking (p = Because patients’ mean age was 14.6 Clinical Global Impressions (CGI)
0.02). Seven patients (1.6%) at- years, results cannot be generalized scale.1 There was no difference be-
tempted suicide (four CBT plus to children under 12 years of age. tween paroxetine and placebo in the
fluoxetine treated, two fluoxetine Sertraline. Before FDA issued improvement of depression on the
treated, one CBT treated, and zero in warnings about increased suicidality primary outcome measure, the
the placebo group), with no com- associated with SSRIs, sertraline was Hamilton Depression Rating Scale
pleted suicides. Patients with known the most commonly prescribed anti- (HAMD). This eight-week trial com-
risk factors for suicide completion depressant in youth.1 In 2002, 10.8 pared the effect of paroxetine (n =
(bipolar disorder, history of sub- million prescriptions for sertraline 93) to imipramine (n = 87) and pla-
stance abuse, psychotic illness, or a were dispensed to children and teens cebo (n = 95) in adolescents age
suicide attempt within the past six for various diagnoses, including 12–18 years.47 Exclusion criteria in-
months) were excluded from the depression and anxiety disorders. cluded the presence of bipolar illness,
study.8 The results of TADS are gen- Sertraline’s FDA-approved labeling schizoaffective disorder, alcohol or
eralizable to adolescents treated in for the treatment of obsessive- substance use, PTSD, and current
the community. Half of patients en- compulsive disorder (OCD) in chil- suicidal ideation or plans.47
rolled in TADS had at least one dren age six years or older, coupled Ten patients treated with paroxe-
comorbid diagnosis, and their mean with the drug’s lower risk of drug in- tine developed adverse psychiatric
illness severity ranged from moder- teractions compared with fluoxetine events, including worsening depres-
ate to moderately severe as measured and fluvoxamine, likely contributed sion (n = 2), emotional lability with

238 Am J Health-Syst Pharm—Vol 63 Feb 1, 2006

 CLINICAL REVIEWS
suicidal ideation or gestures (n = 5),
conduct problems or hostility (n =
2), and euphoria (n = 1).47 Five pa-
tients in the imipramine group de-
veloped the following serious adverse
events: maculopapular rash (n = 1),
hostility (n = 1), dyspnea or chest
pain (n = 1), emotional lability (n =
1), and visual hallucinations or ab-
normal dreams (n = 1). An analysis
conducted by FDA showed that pa-
tients taking paroxetine had a higher
risk of developing new-onset or in-
creased suicidal behavior compared
with those receiving other SSRIs.
This prompted FDA to issue a warn-
ing in June 2003.1 Due to a lack of es-
tablished superiority over placebo in
treating depression and an increased
risk for causing suicidal behaviors
when compared with other SSRIs,
paroxetine should not be used for the
treatment of pediatric depression.
Citalopram. Citalopram has not
been shown to be clearly effective in
treating depression in children and
adolescents, although one controlled
trial found it to have significant effi-
cacy over placebo. 48 Ninety-three
children age 7–17 years with major
depression were treated with citalo-
pram and 85 received placebo over
eight weeks at 21 different academic
sites, including hospitals and clin-
ics.48 The youth had to meet criteria
for major depression as defined by a
score of ≥40 on the CDRS. The pri-
mary response criterion was a score
of <28 on the CDRS at the end of the
eight-week trial.48 Of the citalopram-
treated patients, 36% met the re-
sponse criterion, compared with
24% in the placebo group.48 There
was no significant difference between
citalopram (47% of responders) and
placebo (45% of responders) on the
CGI. The mean effective dosage of
citalopram was 25 mg daily.48 Citalo-
pram was considered well tolerated,
with abdominal pain, nausea, and
rhinitis occurring in over 10% of
citalopram-treated patients.48 Two
patients in the placebo group discon-
tinued study participation due to
Recognizing and treating depression
lack of response, and two patients in
the citalopram group withdrew from
the study due to agitation.
In another study, 25 clinically-
referred children age 7–18 years par-
ticipated in a 12-week trial of citalo-
pram to treat recurrent abdominal
pain associated with depressive and
anxiety symptoms. 49 Twenty-one
children (84%) were considered re-
sponders, with CGI scores of ≤2.49
More studies are needed to deter-
mine the role of citalopram in treat-
ing depression in pediatric patients.
It is an attractive agent, given its low-
er risk of drug interactions compared
with fluoxetine, fluvoxamine, and
paroxetine. Currently, escitalopram,
the S isomer of citalopram, is being
investigated for the treatment of pe-
diatric depression.
Fluvoxamine. Fluvoxamine has
not been studied for the treatment of
depression in youth, although clini-
cal trials show a positive response
for the treatment of anxiety disor-
ders, such as generalized anxiety dis-
orders, social anxiety disorder, sepa-
ration anxiety, and OCD in children
and teens. Fluvoxamine has FDA-
approved labeling for use in children
eight years or older with OCD.50 It
has also been effective in decreasing
binging and purging, anxiety, and
depressive symptoms associated with
bulimia in adolescents.50 Fluvoxa-
mine’s adverse effects are similar to
those of fluoxetine, except that it is
generally better tolerated when taken
at bedtime.23,51 Fluoxetine causes less
insomnia when taken in the morn-
ing.23,45 Fluvoxamine is a potent in-
hibitor of the cytochrome P-450
isoenzymes 1A2 and 3A4 and can
raise blood levels of drugs that rely
on these isoenzymes for metabolism
(e.g., caffeine, macrolide antibiotics,
some antipsychotics).23,50
Dual-reuptake inhibitors. Bupro-
pion. No published controlled clini-
cal trials have established the efficacy
of bupropion for children and ado-
lescents with depressive illness, but
two trials have demonstrated its effi-
Am J Health-Syst Pharm—Vol 63 Feb 1, 2006
cacy and safety for adolescents with
conduct disorder, substance abuse,
and ADHD with or without comor-
bid depressive illness.45,51,52 Bupropi-
on is contraindicated in patients with
concomitant seizure disorders or eat-
ing disorders because it poses an un-
acceptable risk of seizures.53 It has
been suggested as an option for treat-
ing refractory depression when two
SSRIs trials have failed.54
Venlafaxine. Venlafaxine current-
ly has no literature support for ef-
ficacy in pediatric depression. 51,55
One placebo-controlled trial of
immediate-release venlafaxine was
conducted in 33 outpatients age 8–17
years with major depression.55 Chil-
dren in both groups were rated week-
ly using the Child Behavior Check-
list, CDRS, HAMD, and Children’s
Depression Inventory and received
psychotherapy, primarily CBT. Each
weekly session consisted of 45 min-
utes of individual and 15 minutes of
collateral therapy. Depressive symp-
toms improved significantly over six
weeks on all rating scales, but there
was no significant difference between
venlafaxine and placebo groups.
Dosages of venlafaxine were 37.5 mg
daily in children 8–12 years old and
75 mg daily in older adolescents. Low
dosages and a short duration of treat-
ment may have contributed to a lack
of detectable drug effect with ven-
lafaxine. Mania occurred in one
venlafaxine-treated patient, com-
pared with none in the placebo
group. Significant nausea was report-
ed in 7 of 16 venlafaxine-treated pa-
tients, compared with 1 patient in
the placebo group. It is unknown if
extended-release venlafaxine would
have resulted in less nausea. Adoles-
cents treated with venlafaxine had
significantly increased appetite. Im-
provement in depressive symptoms
was likely related to weekly therapy
and contact with a clinician. Similar
to paroxetine, FDA has found a rela-
tively greater risk of new-onset sui-
cidality with venlafaxine relative to
other antidepressants.1 In the ab-
239
 CLINICAL REVIEWS Recognizing and treating depression
sence of demonstrated efficacy and
concerns over new-onset suicidality,
venlafaxine should be reserved for
those who do not respond to fluoxet-
ine or sertraline.54
Nefazodone, trazodone, and mir-
tazapine. No controlled clinical trials
have established efficacy for nefa-
zodone and trazodone in children
and adolescents with depressive ill-
ness. An open-label trial has de-
scribed nefazodone’s efficacy in
treating depression and sleep distur-
bances.56 Nefazodone carries a warn-
ing of hepatotoxicity and is seldom
prescribed.57 No controlled clinical
trials have demonstrated mirtaza-
pine’s efficacy in treating depression
in children and adolescents. One
open-label pilot study in 23 adoles-
cents (age 12–18 years) with major
depression found a positive response
at an average mirtazapine dosage of
32.9 mg daily.58 The most common
treatment-emergent adverse effects
were tiredness, increased appetite,
and dizziness.
Tricyclic antidepressants. Con-
trolled clinical trials have shown no
significant difference between tricy-
clic antidepressants and placebo in
the treatment of depression in chil-
dren and adolescents.12,57 The limita-
tions of tricyclic antidepressant trials
include small sample size, possible
subtherapeutic dosages, and high
response rates to placebo.12,51 The
cardiovascular toxicity of tricyclic
antidepressants is well established.59
Increases in pulse and diastolic blood
pressure and prolongation of the
P-R, QRS, and Q-T intervals are well
documented in pediatric patients re-
ceiving tricyclic antidepressants.59,60
Therefore, the risks of tricyclic an-
tidepressants outweigh potential
benefits for most children with de-
pression.12,60 When these drugs are
administered to youth with a comor-
bid condition like ADHD or enure-
sis, electrocardiograms and vital-sign
monitoring are mandatory at base-
line, after each dosage increase, and
biannually thereafter.12,59
240 Am J Health-Syst Pharm—Vol 63 Feb 1, 2006
Status of depression treatment in
youth. The literature points to sub-
optimal treatment of depression in
youth. Analysis of health service use
data over four years (1996–99) in pa-
tients age 6–18 years showed that
only 1% received treatment for de-
pression, despite an estimated 2–8%
rate of depression.10 The majority
(79%) of treated children received
one or more psychotherapy sessions,
and 56.9% received medication.10
Those treated with medication were
more likely to suffer from anhedonia,
live in large urban communities,
have parents who graduated from
high school, and have health insur-
ance. Nearly half (47%) of children
and adolescents received combined
treatment with medication and
at least one psychotherapy session.
The study found that continuing care
was lacking. For example, 33.5% of
patients had only one or two psycho-
therapy sessions. For those who re-
ceived more, the mean number dur-
ing a one-year period was 7.7 visits.10
Cumulative evidence on CBT and
interpersonal psychotherapy shows
that 8–16 weekly sessions are recom-
mended for an optimal outcome.9,61
Of those who were prescribed medi-
cation, 15–18-year old patients were
more likely to receive medications
than were younger children.10 The
duration of medication treatment
and the number of medication
follow-up visits were not reported.
A study examining the quality of
care for Medicaid-covered youth in
1998 found that 42.1% of 507 youth
with new episodes of depression re-
ceived an antidepressant.11 Of these
youth, only 28% had three or more
follow-up visits in the next three
months, despite guidelines that rec-
ommend weekly to biweekly follow-
up visits in the first six to eight weeks
after starting pharmacotherapy. 1
Twenty-nine percent had no further
follow-up visits.11 Lack of follow-up
has been reported to lead to lack of
adherence and lack of antidepressant
effectiveness.11
Monitoring and counseling
Follow-up appointments. Both
the safety and effectiveness of antide-
pressants can be enhanced through
regular monitoring and counseling
by a clinician.12,58 In response to the
black-box warning of increased sui-
cidality with antidepressants in
youth, FDA has issued guidelines for
monitoring.1 These guidelines rec-
ommend weekly face-to-face contact
with the clinician for the first 4 weeks
after starting an antidepressant, with
contact every other week for the next
4 weeks, another contact with the cli-
nician after 12 weeks, and as clinical-
ly indicated beyond 12 weeks.1 The
risk of new-onset suicidal behavior is
greatest in the first 2 weeks of treat-
ment. The risk steadily decreases
thereafter, with no increased risk af-
ter 12 weeks of continuous treat-
ment.62 A medication guide should
accompany all antidepressant pre-
scriptions for any indication in
youth, including major depression,
anxiety disorders (OCD, PTSD, gen-
eralized anxiety disorder), and eating
disorders.1
The medication guide alerts fami-
lies and caregivers of the following
regarding antidepressant use:
1. There is a risk of suicidal thoughts or
actions,
2. Close monitoring and contact with
the clinician can prevent suicidal
thoughts or actions in your child,
3. Behavioral changes or any increase in
suicidal thoughts, attempts, worsen-
ing depression, worsening anxiety,
panic attacks, agitation, restlessness,
aggression, anger, violence, impulsiv-
ity, and moodiness can indicate a
greater risk for suicide, and
4. There are benefits and risks associat-
ed with antidepressant use, and these
must be discussed on a case-by-case
basis with families and clinicians.1
Additional clinician-provided
counseling. Along with counseling
patients and their families or care-
givers about the risk of suicidality,
 CLINICAL REVIEWS
the clinician should spend time dis-
cussing depression as a chronic bio-
logical illness that is responsive to
treatment.5,6 The onset of therapeutic
benefit of medication or nonphar-
macologic treatment can take two
to four weeks.7,8,51 The dosage of anti-
depressant may need to be increased
to the maximum tolerated dose for
eight weeks before an adequate
trial is achieved.12,54 Slow dosage ad-
justment, with increases no more
than every two to four weeks, can
minimize the risk of behavioral acti-
vation, hypomania, and other ad-
verse effects.22,23 Once remission is
achieved, patients should continue
therapy for at least 6–12 months.51
Maintenance therapy may be needed
to prevent relapse.12 An antidepres-
sant should not be discontinued
abruptly (unless mania is the reason
for discontinuation), as antidepres-
sant withdrawal symptoms can be se-
vere. 22,23 For example, withdrawal
symptoms from abrupt discontinua-
tion of an SSRI or venlafaxine can
include tearfulness, anxiety, insom-
nia, nausea, paresthesias, and night-
mares. 23,45 Withdrawal symptoms
from tricyclic antidepressants include
nausea, vomiting, and diarrhea.51,63
Adverse effects. As a class, all
SSRIs have a similar adverse-effect
profile. Common adverse effects ex-
perienced in 10% or more of indi-
viduals who take SSRIs include
nausea, diarrhea, restlessness, in-
somnia, headache, and sexual dys-
function.7,12,23 Uncommon-to-rare
adverse effects include extrapyrami-
dal effects (dystonia, pseudoparkin-
sonism, tardive dyskinesia). 23 In-
creased bleeding has been reported
in children age 8–15 years who de-
veloped bruising or epistaxis one
week to three months after starting
SSRI treatment.64 Children and ado-
lescents are susceptible to the same
adverse effects that adults experi-
ence, and all of the adverse effects
listed above have been reported in
children and adolescents who take
SSRIs.
Recognizing and treating depression
Bupropion can cause similar ad-
verse effects to those of SSRIs (nau-
sea and insomnia) but is not associ-
ated with sexual dysfunction. Parents
should be counseled on the risk of
seizures with bupropion, particularly
when bupropion is combined with
alcohol or stimulants like amphet-
amine or cocaine. Venlafaxine’s ad-
verse effects are also similar to those
of SSRIs (nausea, insomnia or som-
nolence, sexual dysfunction), but
venlafaxine carries an added dose-
related risk of elevated blood pres-
sure.65 Compared with adults, youth
who take antidepressants have an in-
creased risk of behavioral activation,
hypomania or mania, and new-onset
suicidal thoughts and behaviors.1,21,23
Clinicians should also counsel pa-
tients and their families or caregivers
on the following points:
1. Multimodal treatment, including a
combination of psychosocial inter-
ventions, family therapy, individual
CBT for the child, and antidepressant
medication, is most effective for
treating depression.
2. Fluoxetine should be considered the
first-line antidepressant because its
efficacy is clearly established and it
carries a low risk of new-onset suicid-
al behaviors.
3. For any youth, the risk of increased
suicidal behavior with any antide-
pressant is highest during the first
weeks to months of treatment or if
the dosage is increased or decreased.
4. Children or adolescents who develop
anxiety, agitation, panic attacks, in-
somnia, irritability, hostility, impul-
sivity, severe restlessness, hypomania,
or mania during antidepressant ther-
apy may be at increased risk of wors-
ening depression or suicidality.
5. Children and adolescents have a great-
er risk of “switching” to hypomania or
mania when taking antidepressant
therapy; if this occurs, they should
seek help immediately.1,2,5,6,8,12,23,51,62
Conclusion
Depression in children and ado-
Am J Health-Syst Pharm—Vol 63 Feb 1, 2006
lescents is common. Multimodal
treatment includes patient and fami-
ly education, CBT, and antidepres-
sant medication. The potential bene-
fits of some antidepressant agents
outweigh the risks of treatment in
adolescents; family and psychothera-
peutic interventions are recom-
mended for pre-pubertal children.
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