Transcript Antidepressant Use in Children and Adolescents

The Diagnosis and Treatment of
Pediatric Depression
Jess P. Shatkin, MD, MPH
Vice Chair for Education
NYU Child Study Center
New York University School of Medicine
Presentation Outline
We will review the following:
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Pediatric Depression Disease State
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Medication Treatment
1.
2.
3.
4.
Psychotherapy Treatment
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1.
2.
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Tricyclic Antidepressants
Serotonin Specific Reuptake Inhibitors
Other antidepressants
Augmenting medications & ECT
Manualized therapies (CBT, IPT)
Psychodynamic psychotherapy
Current FDA Controversy
Evidence based treatment recommendations
Learning Objectives
Participants will be able to:
1.
2.
3.
Describe the primary differences between pediatric
and adult depression.
Identify evidence-based pharmacologic and nonpharmacologic treatments for pediatric depression.
Make rational treatment recommendations for
children and adolescents with depression.
A Brief History of Depression in
Children and Adolescents
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Case reports on childhood depression date to the early 17th
century
Melancholia in children was first reported in the mid-19th
century
In general, however, the existence of depression prior to
1960 was seriously doubted because it was felt that
children’s immature superego would not permit the
development of depression
Research from Europe and NIMH funded American studies
in the 1970’s increased the awareness & acceptance of
childhood depression
Psychoanalytic Perspective
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Psychoanalytic theory posits that depression results
from an intrapsychic conflict between the ego and
a persecutory superego
Psychoanalysis held that the superego was
formalized only after resolution of the Oedipal
Conflict, which occurred by late adolescence
By this theory, then, children could not experience
intrapsychic conflict and, ergo, could not develop
mood disorders
Epidemiology
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Varying rates have been reported; no large, well accepted
epidemiologic studies
Generally accepted 1-year incidence is:
*Preschool age 1%
*School age 2%
*Adolescent age 4 - 8%
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Gender ratio of 1:1 in childhood and 2:1 (female to male)
by adolescence
Lifetime prevalence of MDD among adolescents is 15 –
20% (similar to adults); 15.3% per NCS
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Kashani & Sherman, 1988; Fleming & Offord, 1990; Lewinsohn et al, 1993 & 1994;
Kessler & Walters, 1998
Epidemiology (2)
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Studies on Dysthymia suggest a wide range in point
prevalence: children from 0.6 – 1.7%; and adolescents
from 1.6 – 8.0%
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Garrison et al, 1992; Kashani et al, 1987; Lewinsohn et al 1993 & 1994
Studies in specialized populations show increased
incidence, such as 40% among children on neurology
wards with unexplained headaches (Ling et al, 1970); 7% of
general pediatric inpatients (Kashani et al, 1981); 28% of
children in psychiatric clinics (Carlson & Cantwell, 1980);
59% of child psychiatry inpatients (Petti, 1978); and 27%
of adolescent inpatients (Robbins et al, 1982)
Epidemiology (3)
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Prevalence increases during adolescence, possibly
due to:
1.
2.
3.
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Biological factors (e.g., sexual maturation)
Environmental factors (e.g., increased social/academic
expectations, more chance of exposure to negative
events)
Psychological & cognitive factors (e.g., increased
autonomy and abstract thinking)
Since 1940, each successive generation has been at
higher risk for MDD
Ordinary People
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Conrad Jarrett is 16 and has survived a boating
accident in which his brother, Buck, died.
The book takes place as Conrad tries to readjust to
life back at home after a psychiatric hospitalization
for a suicide attempt.
He sees a psychiatrist, Dr. Berger, who tries to
address Conrad’s chief desire upon presenting
(e.g., he wants to be in control).
This scene takes place as Berger is asking Conrad
about quitting the swim team.
Etiology: Theories of Depression
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Psychodynamic: anger turned inward; severe superego
Attachment: insecure early attachment
Behavioral: inability to obtain reinforcement
Cognitive: depressive mindset
Self-Control: deficits in self-monitoring, self-evaluation,
and self-reinforcement
Interpersonal: characteristic to individual, roles and events
Socioenvironmental: stressful life circumstances
exacerbate vulnerabilities
Neurobiological: neurochemical, endocrine, and receptor
abnormalities
Genetics (1)
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Findings from twin studies suggest a moderate genetic
influence on depression in community samples with
heritability ranging from 35 – 75% across studies (Eley,
1999; Glowinski et al, 2003)
Twin/adoption studies have not been conducted, so the
extent to which clinical depression in children and
adolescents is genetically driven is not known
Still, children with a parent who suffered from depression
as a child are up to 14x more likely than controls to become
depressed prior to age 13 (Weissman et al, 1988)
Children of parents with depression have about 2-3x the
risk of having depression (Beardslee et al, 1998; Weissman
et al, 1997)
Genetics (2)
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Children of depressed parents have an earlier age of onset
for their depression by 3 years (Weissman et al, 1997)
The lifetime history of MDD in mothers of children with
MDD is also high, about 50 – 75% (Kovacs, 1997)
A family history of depression is more common in 1st
degree relatives of children with MDD than in children
without MDD (Wickramaratne et al, 2000)
Adults with one or two copies of the short allele of the 5HT Transporter gene have been shown to exhibit more
depressive symptoms, diagnosable depression, and
suicidality in relation to stressful life events (Caspi et al
2003)
More about Mothers
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A 20-year follow-up of offspring of depressed and
non-depressed parents found that the risks for
anxiety disorders, major depression, and substance
dependence were ~3x higher in the offspring of
depressed parents vs. non-depressed parents; social
impairment was also greater. The time of greatest
incidence was 15 – 20 y/o; higher rates of medical
problems and mortality in the offspring of
depressed parents were beginning to emerge as the
offspring enter middle age (Weissman et al, 2006)
Even More about Mothers
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Effective treatment of mothers with MDD is associated with a
reduction of anxiety, depressive, and disruptive disorders and
symptoms in their offspring (Weissman et al, 2006; STAR*D
trial which follows 151 mother/child pairs at 3 month
intervals)
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Remission of maternal depression after 3 months of medication
treatment was significantly associated reductions in children’s
diagnoses and symptoms; diagnoses dropped by 11% vs. an 8%
increase in diagnoses among those children whose mothers did not
respond to medication treatment
Of the children with MDE at baseline, remission occurred in 33% of
those whose mother’s depression remitted vs. 12% of those whose
mother’s depression did not remit
17% of children (without dx at baseline) whose mothers remained
depressed developed a psychiatric diagnosis at 3 month f/u vs. none
of those whose mothers responded to treatment
And Fathers?
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Medical Expenditure Panel Survey data (N = 22K US
children, ages 5 – 17) of both mothers and fathers;
data generated by parents only.
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Scales used: PHQ-2, SF-12, MCS, CIS, PCS
Risks of child emotional/behavioral problems are
much greater if mothers, rather than fathers, have such
problems:
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Paternal MH problems are independently associated with a 33 –
70% increased risk
Maternal MH problems are associated with a 50 -350% increased
risk
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Weitzman et al, 2011
Serotonin Gene
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Among those with pervasive suicidal thoughts
and intent, levels of the major serotonin
metabolite (5-HIAA) are lower in the
cerebrospinal fluid.
Adults with one or two copies of the short allele
of the 5-HT Transporter gene have been shown
to exhibit more depressive symptoms,
diagnosable depression, and suicidality in
relation to stressful life events (Caspi et al 2003)
Biogenic Amine Hypothesis
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The biogenic amine or catecholamine hypothesis suggests
that too much neurotransmitter causes mania and too little
causes depression.
Too simplistic, but supported by the observation that
medications that increase dopamine, norepinephrine, and
serotonin improve depression and worsen mania.
Many limitations to this hypothesis, including the fact that
L-dopa and tryptophan, direct precursors of amines, have
no effect on mood; and cocaine and amphetamines which
block amine reuptake do not generally improve depression.
Neuroendocrine Markers
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70% of adults do not show normal suppression
of cortisol secretion following administration of
dexamethasone (DST), suggesting an alteration
in stress response.
Blunting of normal growth hormone release in
response to insulin challenge.
Blunted production of thyroid stimulating
hormone in response to thyroid releasing
hormone
Annie Hall
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Woody Allen’s 1976 breakthrough film about
his relationships with women
Won the Academy Award for Best Picture
Early in the film he reflects upon his childhood
in Brooklyn, which is filled with exaggerations
of how he “remembers” his childhood
He also demonstrates the increased abstract
thinking which can sometimes overwhelm
children as they enter adolescence
Clinical Presentation
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DSM-IV Criteria do not differ for children &
adolescents
Generally, children show fewer neurovegetative
signs than adults
Irritability may substitute for depressed mood
Diagnosis (1)
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The DSM-IV requires 5 of 9 symptoms for the
diagnosis
At least two straight weeks in duration with symptoms
present pretty much every day or most of every day
Not better accounted for by another illness
MDE = Major Depressive Episode
MDD = Major Depressive Disorder (2 or more
episodes, lifetime)
Specifiers
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Severity, psychosis, chronic, atypical, postpartum,
melancholic
Diagnosis (2)
1)
Depressed Mood
*in children, can substitute “irritable” mood
2)
3)
Anhaedonia (diminished interest & pleasure)
Significant decrease in weight (5%)
*in children, failure to make expected weight gains
4)
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9)
Insomnia or hypersomnia
Psychomotor agitation or retardation
Fatigue or loss of energy
Feelings of worthlessness or excessive guilt
Diminished ability to think or concentrate or
indecisiveness
Recurrent thoughts of death or suicidal ideation
Developmental Variants of MDD
Children:
 More symptoms of anxiety
(e.g., phobias, separation
anxiety), somatic complaints,
and auditory hallucinations
 Depression is expressed as
temper tantrums & behavior
problems
 Fewer delusions and serious
suicide attempts
 By middle childhood,
preoccupations w/death,
lowered self-esteem, social
withdrawal/rejection, & poor
school performance
Adolescents:
 More cognitive components to
their depression than children
 Guilt and hopelessness become
apparent
 More sleep & appetite
disturbances, delusions, suicidal
ideation & attempts
 Compared to adults, still more
behavior problems and fewer
neurovegetative difficulties
Clinical Variants of MDD
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Unipolar Depression
Psychotic Depression
Bipolar Depression
Atypical Depression
Seasonal Affective Disorder
Subclinical or subsyndromal Depression
Treatment-Resistant Depression
Comorbidities
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Most children with MDD have a comorbid psychiatric diagnosis:
*40 – 90% have a second psychiatric disorder
*20 – 50% have two or more comorbid disorders
Dysthymia and Anxiety Disorders (30 – 80%); Disruptive Disorders
(10 – 80%); and Substance Use Disorders (20 – 30%)
MDD usually manifests after the onset of other psychiatric
disorders, except substance abuse
Conduct problems may develop secondary to depression and persist
after the depression is effectively treated
Separation anxiety is more common in children, whereas SUDS,
conduct disorder, social phobia, and GAD are more common in
adolescents
-Birmaher et al, 1996; Goodyer et al, 1997; Kovacs, 1996; Rohde et al, 1991; Biederman et al, 1995;
Weissman et al, 1997
Thirteen
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Tells the story of Tracy, who is a straight-laced, geeky, 13
y/o A student growing up in LA with her brother, Mason.
Her divorced mother is a recovering drug addict living with
her former cocaine addict boyfriend; her absent &
generally unsuccessful father is struggling with earning
enough money to support the kids and develop something
for himself.
She becomes friends with Evie, a cool kid, by acting out
and as teen stress mounts in her life, she begins to cut to
cope.
In this scene, her father, who has not been paying close
attention, struggles to figure out what’s going on with his
daughter.
Differential Diagnosis
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Adjustment Disorder with Depressed Mood
Bereavement
General Medical Conditions (e.g., hypothyroidism,
cancer, lupus, anemia, HIV, diabetes, epilepsy, etc.)
Chronic Fatigue Syndrome
Medication induced (stimulants, neuroleptics,
corticosteroids, contraceptives)
Differential Diagnosis (2):
Nonaffective Psychiatric D/O’s
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Anxiety Disorders
ADHD
Externalizing Disorders
Learning Disorders
SUDS
Eating Disorders
Personality Disorders
Premenstrual Dysphoric Disorder
Clinical Course
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Median duration: Clinically
referred: 7 – 9 months;
community: 1 – 2 months
Predictors of increased
duration: depression severity,
comorbidity, negative life
events, parental psychiatric
disorders, poor psychosocial
functioning
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90% of MDD episodes remit
w/in 1-2 years after onset
(where remission is 2 weeks –
2 months with only 1
clinically significant
symptom)
≈ 50% relapse
6 – 10% of MDD are
protracted
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Clarke et al, 1992; Goodyer et
al, 1997; Kovacs, 1996;
Lewinsohn et al, 1994 & 1997;
Reinecke et al, 1998; Sanford et
al, 1995; Warner et al, 1992
Relapse
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Relapse is an episode of MDD during a period of
remission
40 – 60% of youth with MDD experience relapse
after successful treatment of acute episode
(indicates the need for continual treatment)
Predictors of relapse: natural course of MDD, lack
of compliance, negative life events, rapid
decrease/discontinuation of therapeutic treatment
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Emslie et al, 1997; Kovacs, 1996; Lewinsohn et al, 1994; Vostanis et al, 1996;
Wood et al, 1996
Recurrence
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Recurrence is the emergence of
MDD symptoms during a
period of recovery
(asymptomatic period of more
than 2 months)
Clinical & community samples
show probability of recurrence
20 – 60% w/in 1-2 years postremission and 70% after 5
years
Predictors of Recurrence:
 Earlier age at onset
 Increased number of prior
episodes
 Severity of initial episode
 Psychosis
 Psychosocial stressors
 Dysthymia & other
comorbidities
 Treatment noncompliance
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Emslie et al, 1997; Kovacs et al,
1996 & 1997; Lewinsohn et al,
1994
Risk of Bipolar Disorder
20 – 40% of depressed children & adolescents develop
bipolar disorder within 5 years of index episode of MDD
Predictors of Bipolar I Disorder onset:
 Early onset MDD
 Psychomotor retardation
 Psychotic features
 Family history of bipolar disorder
 Family history of psychotic depression
 Heavy familial loading for mood disorders
 Pharmacologically induced (hypo)mania
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Geller & Luby, 1997; Kovacs, 1996; Strober & Carlson, 1982
Treatment
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Opinions vary as to whether one should start
with psychotherapy or medication or both
Psycho-education of patient, family, and
teachers is critical
Parental (and other family members’) mental
health issues should be addressed
Certainly, the least restrictive treatment and
setting should be a starting point
Typical Exclusion Criteria for
Pediatric Depression Studies
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ADHD
PTSD
Bipolar Disorder
Pervasive Developmental
Disorders
Mental Retardation
Externalizing Disorders
Psychosis
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Any recent medication
treatment (within 2-4
weeks)
EtOH/drugs
Eating Disorder
Recent initiation of
psychotherapy
Potentially suicidal
patients (attempts in past
year)
What’s in a Study?
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The “gold standard” for any type of clinical
intervention study (medication, therapy,
community intervention, etc.) is that it be:
Randomized
 Double-Blind
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Blinded to subject
 Blinded to treatment team
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Placebo Controlled
Research Study Instruments
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Kids are often not very good informants about their own mood
state
They often underestimate medication effects and side effects
As a result various rating scales and surveys have been designed
to assess their responses to treatment
Some of these are clinician administered:
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Children’s Depression Rating Scale (most commonly used)
Clinical Global Impression
Children’s Global Assessment Scale
Hamilton Depression Rating Scale
Some of these are child self-administered:
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Children’s Depression Inventory
Beck Depression Inventory
Placebo Effect
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Typically very high in most medications
Studies of antidepressants in both children and
adults reveal approximately a 30% placebo rate
Overall response rates to antidepressants are about
65% at highest; consequently, about half of that is
due to placebo
True antidepressant response rate is about 35%
Remember, the average length of a depressive
episode (not chronic) is 6 – 9 months with or
without treatment
Tricyclic Antidepressants (TCAs): History
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The TCA story begins with the synthesis of chlorpromazine in 1950
from synthetic antihistamines first produced in the 1940s.
Chlorpromazine was thought to be an antihistamine, but in 1952 it
was found to have profound psychiatric effects. By 1955
chlorpromazine was widely used and rapidly revolutionized the world
of inpatient psychiatry as the first effective antipsychotic.
Imipramine, the first TCA, is an analogue of chlorpromazine, which
was not designed for the treatment of depression but rather for
psychosis. The drug's tendency to induce manic effects (and generally
worsening psychosis in schizophrenics), however, was noted, and the
paradoxical observation of a sedative inducing mania lead to testing
with depressed patients. The first trial of imipramine took place in
1955, and the first report of its antidepressant effects was published in
1957.
Merck introduced the second member of the TCA family,
amitriptyline (Elavil), in 1961.
Tricyclic Antidepressants
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The “original” antidepressants
Examples:
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Desipramine
Amitriptylene
Imipramine
Clomipramine
Nortriptylene
Putative Mechanism of Action: Block the reuptake of
norepinephrine, dopamine, and serotonin by neuronal
presynaptic receptors
Unfortunately, while effective for adult depression, they
have shown little utility in the treatment of pediatric
depression
TCA Mechanism of Action
Tricyclic Antidepressants (2)
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Open trials of TCAs have found that 60 – 80% of
depressed children and 44 – 75% of depressed adolescents
respond positively
At least 11 randomized DBPC trials each demonstrated no
difference between placebo and active TCA treatment (5 in
adolescents, 6 in children)
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Dulcan et al, 1998; Ryan & Varma, 1998
One study (Preskorn, 1987; n = 22) of depressed children
(ages 6 – 14) treated with imipramine was positive
Meta-Analysis (Hazell et al, 1995) found no effect
Tricyclic Antidepressants (3)
Problems with child & adolescent TCA studies:
 Small sample sizes
 Diagnostic heterogeneity (e.g., mild, mod, severe
depression) & included patients with secondary depression
(higher placebo response)
 Studies of limited duration (6 – 8 weeks)
 Lower doses were used because of cardiac safety concerns
 Noradrenergic (secondary amines) TCAs were exclusively
used (receptors not fully developed in children); except
imipramine study
 High prevalence of comorbid conditions
 More adolescents transition into Bipolar D/O than adults
(and BP depression may be less responsive to TCAs)
 More efficient hepatic metabolism of drugs in children
Amines
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Tricyclics are sometimes classified as secondary or tertiary
amines. In general, the tertiary amines boost serotonin as
well as nor-epinephrine (adrenergic) and produce more
sedation, anticholinergic effects, and orthostatic
hypotension. The secondary amines act primarily on norepinephrine and tend to have a lower side-effect profile.
Tertiary amines include: Amitriptyline, imipramine,
trimipramine, doxepin, clomipramine, and lofepramine.
Secondary amines include: Nortriptyline, desipramine,
protriptyline, and amoxapine.
More About Amines
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Amines are organic
compounds whose
functional group contains a
nitrogen atom with a lone
pair of electrons.
A primary amine has one
of the 3 hydrogen atoms
replaced by a carbon
group.
A secondary amine has 2
hydrogen atoms replaced
by carbon groups.
A tertiary amine has 3
hydrogen atoms replaced
by carbon groups.
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Desipramine (Secondary)
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Amitriptyline(Tertiary)
Clinical Use
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Depression
Anxiety (particularly serotonergic TCAs)
ADHD
Analgesia
Migraine headache prevention
 Neuropathic pain (PNS)
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Enuresis
TCA Side Effects
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Most common TCA side effects are related to antimuscarinic
(anticholinergic) activity, including:
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Dry mouth (salivary secretion is affected)
Dry nose
Blurred vision (accommodation in the eye is affected)
Decreased gastro-intestinal motility and secretion (constipation)
Urinary retention or difficulty with urination
Hyperthermia
Tolerance to these adverse effects often develops if treatment is continued
Side effects may also be less troublesome if treatment is initiated with low
dose and then gradually increased, although this may delay the clinical
effect.
Other side effects may include drowsiness, anxiety, restlessness, cognitive
and memory difficulties, confusion, dizziness, akathisia, increased appetite
with weight gain, sweating, decrease in sexual ability and desire, muscle
twitches, weakness, nausea and vomiting, hypotension, tachycardia, and
rarely irregular heart rhythm.
TCA Side Effects
Safety Concerns with TCAs
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Concern related to at least 8 reported cases of
“sudden” death in children and adolescents using
TCAs for the treatment of depression
QT prolongation and subsequent torsade de
pointes is the suggested cause of death
Level of risk remains unclear
Monoamine Oxidase Inhibitors (MAOI)
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Monoamine oxidase inhibitors (MAOIs) are a class of
powerful antidepressants
They work by decreasing the function of monoamine
oxidase, an intracellular enzyme which metabolizes
neurotransmitters
Due to potentially lethal dietary and drug interactions,
MAOIs had been reserved as a last line of defense, used
only when other classes of antidepressant drugs have been
tried unsuccessfully.
Recently, however, a patch form of the drug selegiline
(Emsam) was developed (2006).
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When applied transdermally the drug does not enter the gastrointestinal system as it does when taken orally, thereby decreasing
the dangers of dietary interactions associated with MAOI pills.
MAOIs Continued
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Isocarboxazid (Marplan)
Phenelzine (Nardil)
Tranylcypromine (Parnate)
Selegiline (Eldepryl & Emsam)
Clinical Use
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In the past MAOIs were prescribed for those
resistant to TCA therapy, but newer MAOIs are
now sometimes used as first-line therapy.
Depression
Social Anxiety
Smoking Cessation
Atypical Depression
NO data in children & adolescents
Side Effects
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Hypertensive crisis (when foods containing tyramine are
consumed) or hyperserotonemia (if foods containing tryptophan
are consumed). MAO typically degrades these products.
Assumed that tyramine displaces norepinephrine from the storage
vesicles, which may trigger a cascade in which excessive amounts
of norepinephrine can lead to a hypertensive crisis.
Examples of foods and drinks with potentially high levels of
tyramine include fermented substances, such as red chianti and
other aged red wines and aged cheeses.
The most significant risk associated with the use of MAOIs is the
potential for interactions with over-the-counter and prescription
medicines, illicit drugs and certain supplements (e.g. St. John’s
Wort).
MAOIs should not be combined with other psychoactive
substances (antidepressants, illicit drugs, painkillers, stimulants,
etc.) except under expert care.
Serotonin Specific
Reuptake Inhibitors (SSRIs)
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The “new” antidepressants; much safer and easier to
prescribe and tolerate
Examples:
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Fluoxetine (Prozac®)
Sertraline (Zoloft®)
Paroxetine (Paxil®)
Citalopram (Celexa®)
Fluvoxamine (Luvox®)
Escitalopram (Lexapro®)
Putative Mechanism of Action: Block the reuptake of
serotonin by neuronal presynaptic receptors
Very useful for pediatric anxiety disorders; generally less
effective (but often useful) for pediatric depression
Clinical Use
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Depression
Anxiety
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OCD, Panic, Social, Generalized Anxiety
Eating Disorders (especially Bulimia)
Chronic Pain
Premature Ejaculation
Chemical Structure
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SSRIs may look different from one another, but
all of them block the reuptake of serotonin in
the synapse between two neurons
SSRI Mechanism of Action
Serotonin Specific
Reuptake Inhibitors
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Numerous open label studies report a 70 – 90% response
rate to SSRIs in adolescents
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Simeon et al (1990) performed the first randomized DBPC
study of SSRIs in 32 adolescents (13 – 18 y/o) using 60 mg
fluoxetine (Prozac®) vs. placebo
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Ambrosini et al, 1999; Apter et al, 1994; Masi et al, 1997; McConville et al, 1996; ReySanchez & Gutierrez-Casares, 1997; Rodriguez-Ramos et al, 1996; Simeon et al, 1998
Rating scales included Ham-D and CGI
Results did not reach clinical significance
One historical case-control study (Strober et al, 1999)
found fluoxetine superior to imipramine in a severely ill
inpatient adolescent population
SSRIs (2): Fluoxetine (Prozac®)
Two randomized DBPC studies by Emslie et al demonstrated the superiority of
fluoxetine (Prozac®) over placebo, leading to FDA approval of fluoxetine for the
treatment of pediatric depression (ages 7 – 17):
1.
2.
1997 Single Site Study (sponsored by NIMH)
*n = 90, 8-week study, nonpsychotic MDD, 20 mg of fluoxetine vs.
placebo; CDRS-R & CGI
56% (fluoxetine) vs. 33% (placebo) showed improvement on CGI;
significant differences in weekly CDRS-R also noted (fluoxetine vs.
placebo); no difference in complete symptom remission
2002 Multisite Study (sponsored by Eli Lilly)
*n = 219, 9-week study, nonpsychotic MDD, 20 mg of fluoxetine vs.
placebo; CDRS-R & CGI
52% (fluoxetine) vs. 37% (placebo) showed improvement on CGI;
greater mean improvement on fluoxetine by week #1 (and maintained
through study) on CDRS-R; remission rates 41% (fluoxetine) vs. 20%
(placebo)
SSRIs (3): Paroxetine (Paxil®)


One recognized favorable open label study (Rey-Sanchez &
Gutierrez-Casares, 1997)
Keller et al (2001) performed a multisite randomized DBPC
trial of paroxetine in 275 adolescents (12 – 18 y/o) vs.
imipramine vs. placebo (sponsored by GSK)

A priori primary outcomes (all not significant) included:



Ham-D score ≤8 or a >50% reduction
Statistically significant change in mean Ham-D score
Post hoc analysis of primary and secondary outcomes (statistically
significant) included:



Revised Ham-D outcome to ≤8 “only”
Depression item sub-scores on Ham-D and K-SADS-L
CGI (65.6% for paroxetine vs. 52.1% for imipramine and 48.3% for
placebo)
SSRIs (4): Paroxetine (Paxil®) cnt’d

Berard et al (2006) reported on a prospective international
multicenter, RDBPC trial of paroxetine for adolescents (13
– 18 y/o) with depression



Data collected from 286 adolescents in 10 countries (not USA)
Response rate (at least 50% reduction from baseline) for
paroxetine vs. placebo was not statistically significant for
Montgomery-Asberg Depression Rating Scale (MADRS) scale nor
K-SADS
CGI was statistically better for paroxetine than placebo (69% vs.
57%), a secondary endpoint, with older adolescents generally
doing better than younger (>16). Generally tolerated well with a
greater incidence of suicidal behavior (4.4% vs. 2.1%) in the
paroxetine treated group, but not statistically significant
SSRIs (5): Paroxetine (Paxil®) cnt’d

Emslie et al (2006) completed a randomized, multicenter, doubleblind, placebo-controlled trial of Paroxetine






206 patients, aged 7 to 17 years old with major depressive disorder,
received paroxetine (10-50 mg/day) or placebo for 8 weeks from 2000 to
2001
The primary efficacy measure was change from baseline in the Children's
Depression Rating Scale-Revised total score at week 8 (LOCF)
Safety was primarily assessed by spontaneous reporting of adverse events
104 patients received paroxetine vs 102 who received placebo
CDRS-R total score adjusted mean changes from baseline for patients
receiving paroxetine and placebo were -22.58 (SE 1.47) and -23.38
points (SE 1.60), respectively (0.80, 95% confidence interval -3.09 to
4.69, p = 0.684); thus, paroxetine was not shown to be more efficacious
than placebo
Side Effects included increased cough (5.9% versus 2.9%), dyspepsia
(5.9% versus 2.9%), vomiting (5.9% versus 2.0%), and dizziness (5.0%
versus 1.0%). The incidence of adverse events of suicidal behavior
and/or ideation while taking study medication (excluding taper) was
1.92% (2/104) for paroxetine versus 0.98% (1/102) for placebo.
SSRIs (6): Sertraline (Zoloft®)


One recognized favorable multicenter open label study
(Ambrosini et al, 1999)
Wagner et al (2003) reported on two multisite-international
separate controlled trials; data were aggregated (sponsored by
Pfizer)






N = 376; age range 6 – 17 years
Primary outcome measures were mean change from baseline in CDRS-R, and
CGI & CGAS
Changes in mean CDRS-R & CGI between drug & placebo were significant
Based on a 40% decrease in adjusted CDRS-R total score at study endpoint,
69% vs. 59% were responders
The treatment effect was only noted for adolescents (when broken down by age
groups)
When the trials are considered separately, no effect was noted, possibly due to
very high placebo rates (59% for CDRS, 53% for CGI)
SSRIs (7): Citalopram (Celexa®)


Chart review by Bostic et al (1997) at CMHC of 21
adolescents showed favorable results on CGI by 76% of
patients
Multisite DBPC study by Wagner et al (2004) randomly
assigned 178 children and adolescents (7 – 17 y/o) to 20 –
40 mg/d citalopram or placebo for 8 weeks



Primary outcome measure was CDRS-R; secondary measure
included CGI
Statistically significant improvement on the CDRS-R was noted
by week #1; by week #8 36% of citalopram-treated patients vs.
24% of placebo patients demonstrated a statistically significant
treatment response
CGI results were not significant (47% vs. 45%)
SSRIs (8): Citalopram (Celexa®)

Von Knorring et al (2006) reported on a randomized, double-blind, multisite
(Europe) placebo-controlled study of citalopram in adolescents with major
depressive disorder





244 adolescents, 13 to 18 years old, with major depression were randomized to
treatment with citalopram (n = 124) or placebo (n = 120)
No significant differences in improvement of scores from baseline to week 12 between
citalopram and placebo were found. The response rate was 59% to 61% in both
groups according to the K-SADS and Montgomery Asberg Depression Rating Scale
(MADRS)
Remission (MADRS score < or =12) was achieved by 51% of patients with citalopram
and 53% with placebo.
A post hoc analysis revealed that more than two thirds of all patients received
psychotherapy during this study. For those patients not receiving psychotherapy, there
was a higher percentage of Kiddie-SADS-P responders with citalopram (41%) versus
placebo (25%) and a significantly higher percentage of MADRS responders and
remitters with citalopram (52% and 45%, respectively) versus placebo (22% and 19%,
respectively).
Side effects were mild. Suicide attempts, including suicidal thoughts and tendencies,
were reported by 5 patients in the placebo group and by 14 patients in the citalopram
group (not significant) with no pattern with respect to duration of treatment, time of
onset, or dosage. In contrast, the suicidal ideation (Kiddie-SADS-P) single item
showed worsening more frequently in the placebo (18%) than in the citalopram group
(8%).
SSRIs (9): Escitalopram (Lexapro®)




A RDBPC trial by Wagner et al (2006) examined
efficacy of escitalopram in 131 children and
adolescents (6 – 17 y/o dosed flexibly 10 – 20
mg/d) vs. 133 treated with placebo
82% of patients completed treatment with no
major AEs (HA & GI pain more common in active
treatment group) and no induction of SI/SA
Active treatment did not statistically separate from
placebo at endpoint by CDRS-R with LOCF
Post-hoc analysis of adolescent completers (12 – 17
y/o) did statistically separate active drug from
placebo by CDRS-R
SSRIs (10): Escitalopram (Lexapro®)





8 week RDBPC trial of 10 – 20 mg escitalopram per day in
adolescents 12 – 17 y/o
155 active treatment, 157 on placebo (n=312)
Statistically significant separation between drug and
placebo at end of trial (LOCF, 83% completion rate) with
a 22.1 point reduction in CDRS-R on active treatment
versus 18.8 point reduction on placebo (p = 0.22), Effect
Size = 0.27 (Emslie et al, 2009)
16-week double-blind extension of Emslie study found
that statistical separation was maintained for escitalopram
treated group (Findling et al, 2008)
The FDA review concluded that maintenance efficacy
could be extrapolated from data in adults, although not
systemically evaluated in adolescents.
Side Effects

When present, most notable during the first 1-4 weeks while the body adapts to the drug
(with the exception of sexual side effects, which tend to occur later in treatment but often
improve with time). Almost all SSRIs are known to cause one or more of these symptoms:

















nausea, vomiting, diarrhea
drowsiness
headache
clenching of teeth
extremely vivid and strange dreams
dizziness
changes in appetite
weight loss/gain (measured by a change in bodyweight of 7 pounds)
decreased sexual interest and/or anorgasmia
increased feelings of depression and anxiety
tremors
Autonomic dysfunction including orthostatic hypotension or sweating
Akathisia
hyponatremia
liver or renal impairment
suicidal ideation
photosensitivity (increased risk of sunburn)
Bupropion (Wellbutrin®)




Daviss et al (2001) treated 24 adolescents (11 – 16
y/o) w/ADHD and either MDD or Dysthymia in
an open label fashion with buproprion SR
After a 1-2 week single-blind lead in, all subjects
were dosed with buproprion SR to a target dose of
3 mg/kg BID for up to 10 weeks
Clinician rating was the CGI
30% improvement during placebo lead in, followed
by an 88% improvement in clinician rated
depression by CGI
Venlafaxine (Effexor®)

Mandoki et al (1997) treated 33 children & adolescents in a
randomized DBPC fashion for 6-weeks (8-17 y/o) with MDD
with either venlafaxine plus CBT or placebo plus CBT. The
dose in the 8-12 year olds was 37.5 mg/d whereas in the 13-17
year olds was 75 mg/d


Rating scales included HAMD for those 12+ y/o and CDRS for
those < 12 y/o, parent ratings (CBCL) and patient ratings (CDI)
Improvement noted in many subjects, but results were not
statistically significant


The authors suggest that the negative findings are due to low dosages,
high rates of hepatic metabolism in pediatric populations, short duration
of treatment, and the fact that CBT may have distorted any medication
effect
CBT was beneficial regardless of active medication treatment
Venlafaxine (Effexor®) cont’d

Emslie et al (2007) reported on the use of Venlafaxine ER in two
multicenter, randomized, placebo-controlled trials in children and
adolescents, ages 7 – 17 years, with MDD conducted between
October 1997 and August 2001



Patients received venlafaxine ER (flexible dose, based on body weight;
intent to treat, n = 169) or placebo (intent to treat, n = 165) for up to 8
weeks. The primary measure was the change from baseline in the
CDRS-R at week 8
There were no statistically significant differences between venlafaxine
ER and placebo on the CDRS-R. A post hoc age subgroup analysis of
the pooled data showed greater improvement on the CDRS-R
w/venlafaxine ER than with placebo (-24.4 versus -19.9; p = .022)
among adolescents (ages 12-17), but not among children (ages 7-11).
The most common adverse events were anorexia and abdominal pain.
Hostility and suicide-related events were more common in venlafaxine
ER-treated participants than in placebo-treated participants. There were
no completed suicides.
Nefazodone (Serzone®)

Wilens et al (1997) reported on 7 cases of children &
adolescents (average age = 12 y/o) with depression (4 with
BP depression) who took nefazodone for an average of 13
(±8) weeks at dosages averaging 350 mg/d



56% of adolescents were “much” or “very much” improved on
CGI
2 of the 4 BP patients did well and 2 experienced mild manic
activation
Findling et al (2000) studied 23 youth (7 – 17 y/o) in a 8week open label fashion to explore the pharmacokinetics
of nefazodone


Statistically significant improvements were noted on the CDRSR, CGI, and CGAS
Pharmacokinetics were variable, but the medication appeared
“safe”
Mirtazapine (Remeron®)




One published study; a multicenter open label
study of mirtazapine in adolescents (12 – 18 y/o)
with MDD (Haapasalo-Pesu et al, 2004); n = 24
Rating scales included Ham-D, BDI, & CGI
Doses of mirtazapine varied from 30 – 45 mg/d
Statistically significant improvement noted on all
rating scales (Ham-D = 78%; CGI = 74%)
Currently FDA Approved
Antidepressants & Indications

Major Depressive Disorder
Fluoxetine (Prozac®) 8 – 17 y/o
 Escitalopram (Lexapro®) 12 – 17 y/o


Obsessive Compulsive Disorder
Fluoxetine (Prozac®) 7 – 17 y/o
 Sertraline (Zoloft®) 6 – 17 y/o
 Fluvoxamine (Luvox®) 8 – 17 y/o
 Clomipramine (Anafranil®) 11 – 17 y/o

Antidepressant Augmentation
Lithium:
 Strober et al (1992) examined the effect of LiCO3
augmentation (300 mg TID) on imipramine in 24
treatment refractory adolescent MDD (DSM-III or DSMIII-R) patients in a 3-week open label trial. Mild beneficial
effects noted
 Walter et al (1998) noted effective LiCO3 augmentation of
venlafaxine (Effexor XR®) in two adolescent cases
 Ryan et al (1988) found LiCO3 augmentation in
adolescents with a partial response to imipramine effective
in a chart review
Electroconvulsive Therapy


Case reports in children and adolescents dating to 1942; most cases
suffer from lack of diagnostic clarity, small samples, and
heterogeneous diagnoses
Since 1990 numerous studies (all retrospective) have reported
success with ECT in adolescents with a variety of psychiatric
disorders (but primarily unipolar or bipolar mood disorders)
 Response rates vary from 51 – 100% in these studies, with higher
response rates noted among those with mood disorders
(Ghaziuddin et al, 2004)
 Only one study (Kutcher & Robertson, 1995) compared treated
patients with those who refused treatment


Significant improvements noted among those who received ECT
Treated patients had shorter hospital stays (74 vs. 176 days)
ECT (2)

Use estimates vary worldwide
NIMH Study (Thompson & Blaine, 1987) revealed
about 1.5% of all ECT performed in 1980 in the USA
(or about 500 cases) were between 11 – 20 y/o
 No mandatory reporting system currently exists


Safety
Guttmacher & Cretella (1988) noted that ECT was
ineffective in 4 cases and that prolonged seizures (>4
minutes) were caused
 This finding has not been replicated; all other studies
have found ECT effective and with no greater side
effects than those routinely found in adult studies

Algorithm for Treatment of Depression
in Children and Adolescents
Fluoxetine*
2. Alternate SSRI or SNRI*
3. TCA*
4. MAOI
5. ECT
*May augment with: lithium, T3, stimulant,
buspar, pindolol, antipsychotic, 2nd
antidepressant, benzodiazepine
1.
Psychotherapy Studies



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

7 of 9 studies indicate that CBT is more efficacious than a wait-list
condition or than a non-CBT alternative psychotherapy (Curry, 2001)
Harrington et al’s (1998) systematic review of CBT in depressed
children & adolescents indicated a beneficial effect in 62% of treated
patients vs. 36% in placebo groups
CBT is associated with more rapid remission of symptoms than is
family or supportive therapy (Brent et al, 1997)
Long term follow-up indicates high rates of remission or recovery
among adolescents with MDD but no superiority of CBT over other
psychotherapies (Birmaher et al, 2000)
No single type of CBT has been shown to be more efficacious than any
other
IPT has been shown more efficacious than a wait-list condition or
minimal clinical management in two acute treatment studies (Mufson et
al, 1999; Rossello & Bernal, 1999)
Ordinary People



Based on a novel by Judith Guest about an affluent
family’s painful adjustment to tragedy, Mary Tyler
Moore and Donald Sutherland play a seemingly
happy couple who lose the older of their two sons
in a boating accident.
Robert Redford’s Oscar winning directorial debut,
and Tim Hutton’s film debut in 1980
After Tim Hutton, the younger son, tries to kill
himself, he is sent to a psychiatrist, Judd Hirsch
New Data

NIMH sponsored “Treatment of Adolescents with
Depression Study” (TADS)




Multicenter controlled clinical trial
12 – 17 y/o with MDD
Aims to compare the efficacy of fluoxetine, CBT, combination,
and placebo at 36 weeks with 1 year f/u
NIMH sponsored “Treatment of Resistant Depression in
Adolescents” (TORDIA)



Multicenter controlled clinical trial
12 – 17 y/o treatment resistant adolescents
Aims to compare the efficacy of fluoxetine, paroxetine, or
venlafaxine, either alone or in combination with CBT for 24
weeks with 1 year f/u
Medication + Therapy: The TADS Study






Multisite study of adolescents, aged 12 – 17 y/o; n = 439;
tested for short (12 weeks) and longer term (36 weeks)
effectiveness with durability (1 year naturalistic follow-up)
[March et al, 2004]
Participants were randomly assigned to fluoxetine alone (10
– 40 mg/d), CBT alone, fluoxetine with CBT, or placebo;
medications blinded, all CBT conditions unblinded
Rating scales included CDRS-R and CGI
Rates of response on the CDRS-R indicate that combined
treatment (fluoxetine + CBT) was statistically superior to
fluoxetine alone and CBT alone
Fluoxetine alone was superior to CBT alone, which did not
separate from placebo
Rates of response on CGI for fluoxetine + CBT (71%),
fluoxetine alone (61%), CBT alone (43%), and placebo
(35%)
TADS (2)

Effect sizes at week 12 on the CDRS-R:


Rates of Remission (<28 on CDRS-R):




Combined = 0.98; Fluoxetine = 0.68; CBT = -0.03
Total by week 12 = 23% (37% COMB, 23% FLX, 16% CBT, 17% PBO)
Total by week 36 = 60% (60% COMB, 55% FLX, 64% CBT)
By 36 week extension, CBT had “caught up” with fluoxetine
and response rates were 69% for fluoxetine and 65% for CBT
Combined CBT + fluoxetine reached maximum benefit at
week 18 (85% response rate), 3 months earlier than CBT or
fluoxetine alone (all Rx converged at week 36, with med +
CBT at 86%, med and CBT alone each at 81%)


Younger, less chronically depressed, higher functioning, less hopeless w/less SI,
fewer melancholic features and comorbid dx, and those with greater expectations
for improvement were more likely to benefit from treatment
24 suicide related events occurred in the 12 week study; only fluoxetine had more
suicide related events than placebo; 5 total attempts; no suicide completion
TADS (3)


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


Treatment consisted of 3 stages: (1) acute (12 weeks), (2) continuation (6 weeks
more to 18th week), and (3) maintenance (18 week to 36th week)
242 FLX, CBT, and COMB patients in their assigned treatment at the end of stage
1 were included in this study
Stage 2 treatment varied based on stage 1 response. Stage 3 consisted of 3 CBT
and/or pharmacotherapy sessions and, if applicable, continued medication
Sustained response was defined as 2 consecutive Clinical Global ImpressionImprovement ratings of 1 or 2 ("full response")
Among 95 patients (39.3%) who had not achieved sustained response by week 12
(29.1% COMB, 32.5% FLX, and 57.9% CBT), sustained response rates during
stages 2 and 3 were 80.0% COMB, 61.5% FLX, and 77.3% CBT (difference not
significant)
Among the remaining 147 patients (60.7%) who achieved sustained response by
week 12, CBT patients were more likely than FLX patients to maintain sustained
response through week 36 (96.9% vs 74.1%; P = .007; 88.5% of COMB patients
maintained sustained response through week 36)
Total rates of sustained response by week 36 were 88.4% COMB, 82.5% FLX, and
75.0% CBT
Thus, most adolescents with depression who had not achieved sustained response
during acute treatment did achieve that level of improvement during continuation
and maintenance therapies
 Rohde et al, 2008
TADS (4)



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
196 patients followed 5 years out
96% eventually recovered from the index episode of MDE
within 3.5 years
Nearly half (46%) of those who recovered from MDE
became depressed again within 5 years, regardless of the
initial treatment they received
Girls were more likely than boys to have a repeat episode
(58% versus 33%)
Those with an anxiety disorder were also more likely to
have a recurrence (62% versus 42%)

Curry et al, 2010
TORDIA






RCT of 334 patients 12 – 18 years with MDD who had not responded to
2 months of initial treatment with SSRI (CGI of 2 or less & 50%
decrease on CDRS)
12 weeks of:
1)
Switch to a second SSRI (Paxil, Celexa, Prozac)
2)
Switch to a second SSRI + CBT
3)
Switch to Effexor (150-225 mg)
4)
Switch to Effexor + CBT
CBT + a switch to either medication regimen showed a higher response
rate (55%) than med switch alone (41%)
No difference in response rate between a second SSRI and Effexor; more
SEfx with Effexor (BP, rash)
No differential effects on self harm or SI
Less severe depression, less family conflict, and absence of NS-SIB
predicted better treatment response. COMB treatment was more evident
among youths who had more comorbid disorders (esp ADHD and
anxiety disorders), no abuse history, and less hopelessness.
TORDIA (2)


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
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
Patients were reassessed 48 and 72 weeks from intake
Remission defined as ≥ 3 weeks with ≤ 1 clinically significant
symptom and no associated functional impairment and relapse as ≥
2 weeks with probable or definite depressive disorder
By 72 weeks, 61% had reached remission
The group assigned to an SSRI had a more rapid decline in selfreported depressive symptoms and SI than those assigned to
venlafaxine (p>0.3)
Those with more severe depression, greater dysfunction, and EtOH
or drug use at baseline were less likely to remit
Remitters diverged from nonremitters by 6 weeks of treatment
Of 130 in remission by week 24, 25% relapsed within the next year
Summary: Most achieved remission but more than 1/3 did not and
¼ of remitters experienced a relapse

Vitiello et al, 2010
ADAPT



Adolescent Depression Antidepressant and
Psychotherapy Trial
RDBPC trial of 208 adolescents, 11 – 17 y/o (74%
female), at six outpatient clinics in England
Fluoxetine + CBT or Fluoxetine alone
10 mg/d x 1 week, 20 mg/d x 5 weeks; if no response by
week 6, 40 mg/d; if no response by week 12, 60 mg/d
 CBT delivered for 12 weeks plus 1 session week 28


Groups did not differ at F/U at 12 and 28 weeks

Goodyer et al, 2007
CBT + Sertaline

Melvin et al (2006) evaluated the effects of CBT and
sertraline, alone and in combination, for 73 adolescents (12
– 18 years) in the Netherlands





Diagnoses included MDD, DD, or Dep NOS
Randomly assigned to one of 3 treatments (med, CBT, combined)
at 3 community clinics
Measures included the Reynolds Adolescent Depression Scale,
Revised Children’s Manifest Anxiety Scale, Suicidal Ideation
Questionnaire, self report and CGI
CBT demonstrated a superior acute treatment response to
sertraline at 12 weeks (OR = 6.86, CI 1.12 – 41.82), but all groups
showed improvement maintained at 6 months; of those w/MDD
71% achieved partial remission (CBT = 71%, Med = 33%, Comb
= 47%)
Medication doses were lower than in prior sertraline studies and a
slow titration schedule was utilized
Black Box Warning
Recent FDA
Antidepressant Controversy



9 drugs included in FDA review (fluoxetine, sertraline,
paroxetine, fluvoxamine, citalopram, bupropion,
venlafaxine, nefazodone, mirtazapine)
Approximately 4400 patients
25 placebo controlled studies (ranging from 4 – 16 weeks
in duration):





16 in MDD
4 in OCD
2 in GAD
1 in social anxiety disorder
2 in ADHD
Recent FDA
Antidepressant Controversy (2)





Pooled analyses of these studies found an excess of SI and
attempts noted in children and adolescents taking
antidepressants (roughly 4% in those taking medication vs.
2% in those taking placebo)
No suicides occurred in these trials
FDA could not rule out an increased risk of suicidality for
any of these medications
Data was adequate to establish effectiveness in MDD only
for fluoxetine based upon Emslie et al’s two studies
Black Box Warning to apply to all antidepressants
FDA Recommended Guidelines

“After starting an antidepressant, your child should
generally see his/her healthcare provider:
Once a week for the first 4 weeks
 Every 2 weeks for the next 4 weeks
 After taking the antidepressant for 12 weeks
 After 12 weeks, follow your healthcare provider’s
advice about how often to come back
 More often if problems or questions arise”



FDA Medication guide (rev 1/26/05)
http://www.fda.gov/cder/drug/antidepressants/default.htm
How Real is the Concern?


12.5% (11 of 88) adolescents enrolled in a 12-16 week
psychotherapy for depression trial (randomly assigned to
CBT, systemic behavioral family therapy, or nondirective
supportive therapy) reported suicidality at some point
during treatment (no meds used) even though they denied
suicidality on initial intake interview.
The detection of suicidality was improved by specific and
systemmatic assessment, whereas in prior clinical trials of
depression adverse events were reported by patients or
observed. Self-reported suicidality in the week prior to
intake predicted the onset of emergent suicidality to a
much greater extent than did interview-rated suicidality,
treatment assignment, cognitive distortions, and
depression severity.

Bridge et al 2005: Emergent Suicidality in a Clinical Psychotherapy Trial for Adolescent Depression
The Reality Is…
 The
vast majority of teen suicide
completers are not on an SSRI at
the time of the event
 The risk of suicide increases greatly
for those with chronic MDD, as
opposed to those suffering a single
MDE.
The FDA and Adult Suicide



The FDA has recently reported that
antidepressants double the risk of suicidal behavior
in young adults (18 – 25 years) from about 0.25%
among adults who took placebos to 0.5% among
adults who took an antidepressant
The analysis found no increased risk of completed
suicides in patients taking the medications
The risk appears to decline with age
Antidepressant Sales




Prescriptions for antidepressants have dropped by 20%
for those 18 y/o and younger since 2004 when FDA
initial warnings were published
After concerns were raised in the Netherlands about
the suicide risk, there was a 22 percent drop from 2003
to 2005 in antidepressant prescriptions for patients
under 18 years and a corresponding 50 percent increase
in suicides (the number of suicides increased from 34
to 51)
Sales of antidepressants among adults were down 14%
in 2005
Sales are climbing again in 2006
Antidepressant Sales & Suicide Rates




Recent data suggest that antidepressant sales of Prozac,
amongst others, may be tied to a decrease in overall suicide
rate
The U.S. suicide rate held fairly steady for 15 years from
1973 – 1988 at 12.2 – 13.7/100,000
Subsequent to the introduction of Prozac in 1988, the
suicide rate gradually declined to 10.4/100,000 in 2000.
This drop is associated with an increase in Prozac
prescriptions from 2.47 million in 1988 to 33.32 million in
2002.
Adopting this data, the decrease in suicides totals 33,600
(Licinio et al, 2006)
Uh Oh…





From 2003 to 2004, the suicide rate among Americans younger than
19 years rose 18 percent, the most dramatic one-year change since the
government started collecting suicide statistics in 1979. Between 2003
and 2005 the number of SSRI prescriptions for pediatric depression
(ages 5 – 18) dropped by more than 50%.
The rise followed a sharp decrease in the prescribing of SSRI
antidepressants after placement of the Black Box Warning.
The data suggest that for every 20 percent decline in antidepressant
use among patients of all ages in the United States, an additional 3,040
suicides per year would occur. About 32,000 Americans commit
suicide each year.
If the drugs were causing a high rate of suicide, then the reduction in
prescriptions should have caused a decrease in the suicide rate.
The study included the Netherlands, which had a 22 percent decrease
in antidepressant use among children between 2003 and 2005. The
suicide rate among youngsters there increased by 49 percent in that
period.

Gibbons, 2007
TADS Lessons About Suicide



Remember that 24 suicide related events occurred in the 12
week study; only fluoxetine had more suicide related events
than placebo; 5 total attempts; no suicide completion
Findings across 36 weeks demonstrates that patients
treated with FLX alone were twice as likely as patients
treated with combined FLX + CBT or CBT alone to show
both clinically significant SI (on patient report) and to
experience treatment emergent suicide events (on clinician
report): FLX 14.7%, COMB 8.4%, and CBT alone 6.3%
Thus: (1) There is no increased risk of a suicide event with
CBT; (2) there is a protective effect on suicidality from
adding CBT to medication
The Other Side of Summer


After a decade long decline in the suicide rate
among youths, 10 – 19 y/o, there was an 18%
increase in suicide rates in 2004, a trend that
persisted in 2005
This analysis shows 326 more deaths than
expected in 2004 and 292 more deaths than
expected in 2005

Bridge et al, 2008
Evidence Based Treatment
Recommendations:
Take Home Points



When treating pediatric depression, start with
either CBT and/or medication
If medication is employed, you should seriously
consider using fluoxetine first line
You need to develop a monitoring strategy to
comply with FDA guidelines