Title: The Diagnosis and Treatment of Pediatric Depression
1The 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
2Presentation Outline
- We will review the following
- Pediatric Depression Disease State
- Medication Treatment
- Tricyclic Antidepressants
- Serotonin Specific Reuptake Inhibitors
- Other antidepressants
- Augmenting medications ECT
- Psychotherapy Treatment
- Manualized therapies (CBT, IPT)
- Psychodynamic psychotherapy
- Current FDA Controversy
- Evidence based treatment recommendations
3Learning Objectives
- Participants will be able to
- Describe the primary differences between
pediatric and adult depression. - Identify evidence-based pharmacologic and
non-pharmacologic treatments for pediatric
depression. - Make rational treatment recommendations for
children and adolescents with depression.
4A Brief History of Depression in Children and
Adolescents
- 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 childrens immature superego would
not permit the development of depression - Research from Europe and NIMH funded American
studies in the 1970s increased the awareness
acceptance of childhood depression
5Psychoanalytic Perspective
- 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
6Epidemiology
- 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
- Gender ratio of 11 in childhood and 21 (female
to male) by adolescence - Lifetime prevalence of MDD among adolescents is
15 20 (similar to adults) 15.3 per NCS - Kashani Sherman, 1988 Fleming Offord, 1990
Lewinsohn et al, 1993 1994 Kessler Walters,
1998
7Epidemiology (2)
- Studies on Dysthymia suggest a wide range in
point prevalence children from 0.6 1.7 and
adolescents from 1.6 8.0 - 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)
8Epidemiology (3)
- Prevalence increases during adolescence, possibly
due to - 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
9Ordinary People
- 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 Conrads 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.
10Etiology Theories of Depression
- 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
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12Genetics (1)
- 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)
13Genetics (2)
- 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 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)
14More about Mothers
- 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)
15Even More about Mothers
- 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 STARD
trial which follows 151 mother/child pairs at 3
month intervals) - Remission of maternal depression after 3 months
of medication treatment was significantly
associated reductions in childrens 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 mothers
depression remitted vs. 12 of those whose
mothers 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
16And Fathers?
- Medical Expenditure Panel Survey data (N 22K US
children, ages 5 17) of both mothers and
fathers data generated by parents only. - 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 - Paternal MH problems are independently associated
with a 33 70 increased risk - Maternal MH problems are associated with a 50
-350 increased risk - Weitzman et al, 2011
17Serotonin Gene
- 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)
18Biogenic Amine Hypothesis
- 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.
19Neuroendocrine Markers
- 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
20Annie Hall
- Woody Allens 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
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22Clinical Presentation
- DSM-IV Criteria do not differ for children
adolescents - Generally, children show fewer neurovegetative
signs than adults - Irritability may substitute for depressed mood
23Diagnosis (1)
- 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
- Severity, psychosis, chronic, atypical,
postpartum, melancholic
24Diagnosis (2)
- Depressed Mood
- in children, can substitute irritable mood
- Anhaedonia (diminished interest pleasure)
- Significant decrease in weight (5)
- in children, failure to make expected weight
gains - 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
25Developmental Variants of MDD
- 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
- 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
26Clinical Variants of MDD
- Unipolar Depression
- Psychotic Depression
- Bipolar Depression
- Atypical Depression
- Seasonal Affective Disorder
- Subclinical or subsyndromal Depression
- Treatment-Resistant Depression
27Comorbidities
- 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
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29Thirteen
- 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
whats going on with his daughter.
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31Differential Diagnosis
- 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)
32Differential Diagnosis (2) Nonaffective
Psychiatric D/Os
- Anxiety Disorders
- ADHD
- Externalizing Disorders
- Learning Disorders
- SUDS
- Eating Disorders
- Personality Disorders
- Premenstrual Dysphoric Disorder
33Clinical Course
- 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
- 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
- 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
34Relapse
- 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 - Emslie et al, 1997 Kovacs, 1996 Lewinsohn et
al, 1994 Vostanis et al, 1996 Wood et al, 1996
35Recurrence
- 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 post-remission
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
- Emslie et al, 1997 Kovacs et al, 1996 1997
Lewinsohn et al, 1994
36Risk 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
- Geller Luby, 1997 Kovacs, 1996 Strober
Carlson, 1982
37Treatment
- 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
38Typical Exclusion Criteria for Pediatric
Depression Studies
- ADHD
- PTSD
- Bipolar Disorder
- Pervasive Developmental Disorders
- Mental Retardation
- Externalizing Disorders
- Psychosis
- Any recent medication treatment (within 2-4
weeks) - EtOH/drugs
- Eating Disorder
- Recent initiation of psychotherapy
- Potentially suicidal patients (attempts in past
year)
39Whats in a Study?
- The gold standard for any type of clinical
intervention study (medication, therapy,
community intervention, etc.) is that it be - Randomized
- Double-Blind
- Blinded to subject
- Blinded to treatment team
- Placebo Controlled
40Research Study Instruments
- 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
- Childrens Depression Rating Scale (most commonly
used) - Clinical Global Impression
- Childrens Global Assessment Scale
- Hamilton Depression Rating Scale
- Some of these are child self-administered
- Childrens Depression Inventory
- Beck Depression Inventory
41Placebo Effect
- 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
42Tricyclic Antidepressants (TCAs) History
- 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.
43Tricyclic Antidepressants
- The original antidepressants
- Examples
- 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
44TCA Mechanism of Action
45Tricyclic Antidepressants (2)
- 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) - 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
46Tricyclic 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
47Amines
- 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 nor-epinephrine 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.
48More About Amines
- 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.
- Desipramine (Secondary)
- Amitriptyline(Tertiary)
49Clinical Use
- Depression
- Anxiety (particularly serotonergic TCAs)
- ADHD
- Analgesia
- Migraine headache prevention
- Neuropathic pain (PNS)
- Enuresis
50TCA Side Effects
- Most common TCA side effects are related to
antimuscarinic (anticholinergic) activity,
including - 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.
51TCA Side Effects
52Safety Concerns with TCAs
- 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
53Monoamine Oxidase Inhibitors (MAOI)
- 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). - When applied transdermally the drug does not
enter the gastro-intestinal system as it does
when taken orally, thereby decreasing the dangers
of dietary interactions associated with MAOI
pills.
54MAOIs Continued
- Isocarboxazid (Marplan)
- Phenelzine (Nardil)
- Tranylcypromine (Parnate)
- Selegiline (Eldepryl Emsam)
55Clinical Use
- 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
56Side Effects
- 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.
Johns Wort). - MAOIs should not be combined with other
psychoactive substances (antidepressants, illicit
drugs, painkillers, stimulants, etc.) except
under expert care.
57Serotonin Specific Reuptake Inhibitors (SSRIs)
- The new antidepressants much safer and easier
to prescribe and tolerate - Examples
- 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
58Clinical Use
- Depression
- Anxiety
- OCD, Panic, Social, Generalized Anxiety
- Eating Disorders (especially Bulimia)
- Chronic Pain
- Premature Ejaculation
59Chemical Structure
- SSRIs may look different from one another, but
all of them block the reuptake of serotonin in
the synapse between two neurons
60SSRI Mechanism of Action
61Serotonin Specific Reuptake Inhibitors
- Numerous open label studies report a 70 90
response rate to SSRIs in adolescents - Ambrosini et al, 1999 Apter et al, 1994 Masi et
al, 1997 McConville et al, 1996 Rey-Sanchez
Gutierrez-Casares, 1997 Rodriguez-Ramos et al,
1996 Simeon et al, 1998 - 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 - 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
62SSRIs (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) - 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)
63SSRIs (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 gt50 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)
64SSRIs (4) Paroxetine (Paxil) cntd
- 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 (gt16). Generally tolerated well with a
greater incidence of suicidal behavior (4.4 vs.
2.1) in the paroxetine treated group, but not
statistically significant
65SSRIs (5) Paroxetine (Paxil) cntd
- Emslie et al (2006) completed a randomized,
multicenter, double-blind, 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.
66SSRIs (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)
67SSRIs (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)
68SSRIs (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 lt 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).
69SSRIs (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
70SSRIs (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 (n312)
- 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.
71Side 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)
72Bupropion (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
73Venlafaxine (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 lt 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
74Venlafaxine (Effexor) contd
- 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.
75Nefazodone (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 8-week open label fashion to explore
the pharmacokinetics of nefazodone - Statistically significant improvements were noted
on the CDRS-R, CGI, and CGAS - Pharmacokinetics were variable, but the
medication appeared safe
76Mirtazapine (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)
77Currently 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
78Antidepressant 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
DSM-III-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
79Electroconvulsive 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)
80ECT (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 (gt4 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
81Algorithm for Treatment of Depression in Children
and Adolescents
- Fluoxetine
- Alternate SSRI or SNRI
- TCA
- MAOI
- ECT
- May augment with lithium, T3, stimulant,
buspar, pindolol, antipsychotic, 2nd
antidepressant, benzodiazepine
82Psychotherapy Studies
- 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 als (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)
83Ordinary People
- Based on a novel by Judith Guest about an
affluent familys 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 Redfords Oscar winning directorial debut,
and Tim Huttons film debut in 1980 - After Tim Hutton, the younger son, tries to kill
himself, he is sent to a psychiatrist, Judd Hirsch
84(No Transcript)
85New 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
86Medication 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)
87TADS (2)
- Effect sizes at week 12 on the CDRS-R
- Combined 0.98 Fluoxetine 0.68 CBT -0.03
- Rates of Remission (lt28 on CDRS-R)
- 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
88TADS (3)
- 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 Impression-Improvement 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
89TADS (4)
- 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
90TORDIA
- 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
- Switch to a second SSRI (Paxil, Celexa, Prozac)
- Switch to a second SSRI CBT
- Switch to Effexor (150-225 mg)
- 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.
91TORDIA (2)
- 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 self-reported depressive symptoms and
SI than those assigned to venlafaxine (pgt0.3) - 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
92ADAPT
- 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
93CBT 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 Childrens 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
94Black Box Warning
95Recent 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
96Recent 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 als
two studies - Black Box Warning to apply to all antidepressants
97FDA 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 providers
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/defau
lt.htm
98How 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
99The 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.
100The 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
101Antidepressant 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