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The Diagnosis and Treatment of Pediatric Depression


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 – PowerPoint PPT presentation

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Title: The Diagnosis and Treatment of Pediatric Depression

The Diagnosis and Treatment of Pediatric
  • 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
  • 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

Learning 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
  • Make rational treatment recommendations for
    children and adolescents with depression.

A Brief History of Depression in Children and
  • 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

Psychoanalytic 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

  • 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,

Epidemiology (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,

Epidemiology (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

Ordinary 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.

Etiology Theories of Depression
  • Psychodynamic anger turned inward severe
  • 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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Genetics (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,
  • 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)
  • 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)

More 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)

Even 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

And 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

Serotonin 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)

Biogenic 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.

Neuroendocrine 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

Annie 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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Clinical Presentation
  • DSM-IV Criteria do not differ for children
  • Generally, children show fewer neurovegetative
    signs than adults
  • Irritability may substitute for depressed mood

Diagnosis (1)
  • The DSM-IV requires 5 of 9 symptoms for the
  • 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

Diagnosis (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
  • 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
  • Recurrent thoughts of death or suicidal ideation

Developmental 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

Clinical Variants of MDD
  • Unipolar Depression
  • Psychotic Depression
  • Bipolar Depression
  • Atypical Depression
  • Seasonal Affective Disorder
  • Subclinical or subsyndromal Depression
  • Treatment-Resistant Depression

  • 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

(No Transcript)
  • 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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Differential Diagnosis
  • Adjustment Disorder with Depressed Mood
  • Bereavement
  • General Medical Conditions (e.g., hypothyroidism,
    cancer, lupus, anemia, HIV, diabetes, epilepsy,
  • Chronic Fatigue Syndrome
  • Medication induced (stimulants, neuroleptics,
    corticosteroids, contraceptives)

Differential Diagnosis (2) Nonaffective
Psychiatric D/Os
  • Anxiety Disorders
  • ADHD
  • Externalizing Disorders
  • Learning Disorders
  • SUDS
  • Eating Disorders
  • Personality Disorders
  • Premenstrual Dysphoric Disorder

Clinical 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
  • 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

  • Relapse is an episode of MDD during a period of
  • 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

  • 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

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
  • Geller Luby, 1997 Kovacs, 1996 Strober
    Carlson, 1982

  • 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
  • ADHD
  • PTSD
  • Bipolar Disorder
  • Pervasive Developmental Disorders
  • Mental Retardation
  • Externalizing Disorders
  • Psychosis
  • Any recent medication treatment (within 2-4
  • EtOH/drugs
  • Eating Disorder
  • Recent initiation of psychotherapy
  • Potentially suicidal patients (attempts in past

Whats 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

Research 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
  • Some of these are clinician administered
  • Childrens Depression Rating Scale (most commonly
  • Clinical Global Impression
  • Childrens Global Assessment Scale
  • Hamilton Depression Rating Scale
  • Some of these are child self-administered
  • Childrens Depression Inventory
  • Beck Depression Inventory

Placebo 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

Tricyclic 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.

Tricyclic 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

TCA Mechanism of Action
Tricyclic 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
  • 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
  • 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

  • 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.

More 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)

Clinical Use
  • Depression
  • Anxiety (particularly serotonergic TCAs)
  • ADHD
  • Analgesia
  • Migraine headache prevention
  • Neuropathic pain (PNS)
  • Enuresis

TCA Side Effects
  • Most common TCA side effects are related to
    antimuscarinic (anticholinergic) activity,
  • Dry mouth (salivary secretion is affected)
  • Dry nose
  • Blurred vision (accommodation in the eye is
  • 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
  • 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)
  • 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
  • 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

MAOIs Continued
  • Isocarboxazid (Marplan)
  • Phenelzine (Nardil)
  • Tranylcypromine (Parnate)
  • Selegiline (Eldepryl Emsam)

Clinical 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

Side 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.

Serotonin 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

Clinical Use
  • Depression
  • Anxiety
  • OCD, Panic, Social, Generalized Anxiety
  • Eating Disorders (especially Bulimia)
  • Chronic Pain
  • Premature Ejaculation

Chemical Structure
  • 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
  • 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

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)
  • 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
  • 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)
  • Ham-D score 8 or a gt50 reduction
  • Statistically significant change in mean Ham-D
  • 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) cntd
  • Berard et al (2006) reported on a prospective
    international multicenter, RDBPC trial of
    paroxetine for adolescents (13 18 y/o) with
  • 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

SSRIs (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

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
  • 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
  • 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 lt or 12) was achieved by
    51 of patients with citalopram and 53 with
  • 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,
  • 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 (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,
  • The FDA review concluded that maintenance
    efficacy could be extrapolated from data in
    adults, although not systemically evaluated in

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 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

Venlafaxine (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.

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 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

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
  • 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
    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

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,
  • Only one study (Kutcher Robertson, 1995)
    compared treated patients with those who refused
  • 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 (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

Algorithm 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

Psychotherapy 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)

Ordinary 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

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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
  • 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
  • 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
  • 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

TADS (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

TADS (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

  • 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,
  • 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.

  • Patients were reassessed 48 and 72 weeks from
  • 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
  • Vitiello et al, 2010

  • 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 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

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
  • 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

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 providers
    advice about how often to come back
  • More often if problems or questions arise
  • FDA Medication guide (rev 1/26/05)
  • http//

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
  • Bridge et al 2005  Emergent Suicidality in a
    Clinical Psychotherapy Trial for Adolescent

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
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