The Diagnosis and Treatment of Pediatric Depression

1
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

2
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

3
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
  depression.
• Make rational treatment recommendations for
  children and adolescents with depression.

4
A 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

5
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

6
Epidemiology

• 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

7
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,
  1982)

8
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

9
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.

10
Etiology 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

11
(No Transcript)
12
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,
  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)

13
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)

14
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)

15
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

16
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

17
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)

18
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.

19
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

20
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

21
(No Transcript)
22
Clinical Presentation

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

23
Diagnosis (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

24
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
  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

25
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

26
Clinical Variants of MDD

• Unipolar Depression
• Psychotic Depression
• Bipolar Depression
• Atypical Depression
• Seasonal Affective Disorder
• Subclinical or subsyndromal Depression
• Treatment-Resistant Depression

27
Comorbidities

• 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

28
(No Transcript)
29
Thirteen

• 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.

30
(No Transcript)
31
Differential 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)

32
Differential Diagnosis (2) Nonaffective
Psychiatric D/Os

• Anxiety Disorders
• ADHD
• Externalizing Disorders
• Learning Disorders
• SUDS
• Eating Disorders
• Personality Disorders
• Premenstrual Dysphoric Disorder

33
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
  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

34
Relapse

• 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

35
Recurrence

• 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

36
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

37
Treatment

• 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

38
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
  weeks)
• EtOH/drugs
• Eating Disorder
• Recent initiation of psychotherapy
• Potentially suicidal patients (attempts in past
  year)

39
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

40
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
  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

41
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

42
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.

43
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

44
TCA Mechanism of Action
45
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
  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

46
Tricyclic Antidepressants (3)

• Problems with child adolescent TCA studies
• Small sample sizes
• Diagnostic heterogeneity (e.g., mild, mod, severe
  depression) included patients with secondary
  depression (higher placebo response)
• Studies of limited duration (6 8 weeks)
• Lower doses were used because of cardiac safety
  concerns
• Noradrenergic (secondary amines) TCAs were
  exclusively used (receptors not fully developed
  in children) except imipramine study
• High prevalence of comorbid conditions
• More adolescents transition into Bipolar D/O than
  adults (and BP depression may be less responsive
  to TCAs)
• More efficient hepatic metabolism of drugs in
  children

47
Amines

• 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.

48
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)

49
Clinical Use

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

50
TCA 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.

51
TCA Side Effects
52
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

53
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
  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.

54
MAOIs Continued

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

55
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

56
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.

57
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

58
Clinical Use

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

59
Chemical Structure

• SSRIs may look different from one another, but
  all of them block the reuptake of serotonin in
  the synapse between two neurons

60
SSRI Mechanism of Action
61
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

62
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
  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)

63
SSRIs (3) Paroxetine (Paxil)

• One recognized favorable open label study
  (Rey-Sanchez Gutierrez-Casares, 1997)
• Keller et al (2001) performed a multisite
  randomized DBPC trial of paroxetine in 275
  adolescents (12 18 y/o) vs. imipramine vs.
  placebo (sponsored by GSK)
• A priori primary outcomes (all not significant)
  included
• Ham-D score 8 or a 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)

64
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
  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

65
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
  placebo.

66
SSRIs (6) Sertraline (Zoloft)

• One recognized favorable multicenter open label
  study (Ambrosini et al, 1999)
• Wagner et al (2003) reported on two
  multisite-international separate controlled
  trials data were aggregated (sponsored by
  Pfizer)
• N 376 age range 6 17 years
• Primary outcome measures were mean change from
  baseline in CDRS-R, and CGI CGAS
• Changes in mean CDRS-R CGI between drug
  placebo were significant
• Based on a 40 decrease in adjusted CDRS-R total
  score at study endpoint, 69 vs. 59 were
  responders
• The treatment effect was only noted for
  adolescents (when broken down by age groups)
• When the trials are considered separately, no
  effect was noted, possibly due to very high
  placebo rates (59 for CDRS, 53 for CGI)

67
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)

68
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
  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).

69
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

70
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,
  2008)
• The FDA review concluded that maintenance
  efficacy could be extrapolated from data in
  adults, although not systemically evaluated in
  adolescents.

71
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)

72
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

73
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

74
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.

75
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

76
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)

77
Currently FDA Approved Antidepressants
Indications

• Major Depressive Disorder
• Fluoxetine (Prozac) 8 17 y/o
• Escitalopram (Lexapro) 12 17 y/o
• Obsessive Compulsive Disorder
• Fluoxetine (Prozac) 7 17 y/o
• Sertraline (Zoloft) 6 17 y/o
• Fluvoxamine (Luvox) 8 17 y/o
• Clomipramine (Anafranil) 11 17 y/o

78
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

79
Electroconvulsive Therapy

• Case reports in children and adolescents dating
  to 1942 most cases suffer from lack of
  diagnostic clarity, small samples, and
  heterogeneous diagnoses
• Since 1990 numerous studies (all retrospective)
  have reported success with ECT in adolescents
  with a variety of psychiatric disorders (but
  primarily unipolar or bipolar mood disorders)
• Response rates vary from 51 100 in these
  studies, with higher response rates noted among
  those with mood disorders (Ghaziuddin et al,
  2004)
• Only one study (Kutcher Robertson, 1995)
  compared treated patients with those who refused
  treatment
• Significant improvements noted among those who
  received ECT
• Treated patients had shorter hospital stays (74
  vs. 176 days)

80
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

81
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

82
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)

83
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

84
(No Transcript)
85
New Data

• NIMH sponsored Treatment of Adolescents with
  Depression Study (TADS)
• Multicenter controlled clinical trial
• 12 17 y/o with MDD
• Aims to compare the efficacy of fluoxetine, CBT,
  combination, and placebo at 36 weeks with 1 year
  f/u
• NIMH sponsored Treatment of Resistant Depression
  in Adolescents (TORDIA)
• Multicenter controlled clinical trial
• 12 17 y/o treatment resistant adolescents
• Aims to compare the efficacy of fluoxetine,
  paroxetine, or venlafaxine, either alone or in
  combination with CBT for 24 weeks with 1 year f/u

86
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)

87
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
  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

88
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

89
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

90
TORDIA

• RCT of 334 patients 12 18 years with MDD who
  had not responded to 2 months of initial
  treatment with SSRI (CGI of 2 or less 50
  decrease on CDRS)
• 12 weeks of
• 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.

91
TORDIA (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

92
ADAPT

• Adolescent Depression Antidepressant and
  Psychotherapy Trial
• RDBPC trial of 208 adolescents, 11 17 y/o (74
  female), at six outpatient clinics in England
• Fluoxetine CBT or Fluoxetine alone
• 10 mg/d x 1 week, 20 mg/d x 5 weeks if no
  response by week 6, 40 mg/d if no response by
  week 12, 60 mg/d
• CBT delivered for 12 weeks plus 1 session week 28
• Groups did not differ at F/U at 12 and 28 weeks
• Goodyer et al, 2007

93
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

94
Black Box Warning
95
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

96
Recent FDA Antidepressant Controversy (2)

• Pooled analyses of these studies found an excess
  of SI and attempts noted in children and
  adolescents taking antidepressants (roughly 4 in
  those taking medication vs. 2 in those taking
  placebo)
• No suicides occurred in these trials
• FDA could not rule out an increased risk of
  suicidality for any of these medications
• Data was adequate to establish effectiveness in
  MDD only for fluoxetine based upon Emslie et als
  two studies
• Black Box Warning to apply to all antidepressants

97
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//www.fda.gov/cder/drug/antidepressants/defau
  lt.htm

98
How Real is the Concern?

• 12.5 (11 of 88) adolescents enrolled in a 12-16
  week psychotherapy for depression trial (randomly
  assigned to CBT, systemic behavioral family
  therapy, or nondirective supportive therapy)
  reported suicidality at some point during
  treatment (no meds used) even though they denied
  suicidality on initial intake interview. 
• The detection of suicidality was improved by
  specific and systemmatic assessment, whereas in
  prior clinical trials of depression adverse
  events were reported by patients or observed. 
  Self-reported suicidality in the week prior to
  intake predicted the onset of emergent
  suicidality to a much greater extent than did
  interview-rated suicidality, treatment
  assignment, cognitive distortions, and depression
  severity.
• Bridge et al 2005  Emergent Suicidality in a
  Clinical Psychotherapy Trial for Adolescent
  Depression

99
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.

100
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

101
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