Depression in Childhood and Adolescence

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Depression in Childhood and Adolescence

• Alan Apter M.D
• Feinberg Child Study Center
• Schneider Childrens
• Medical Center

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DEPRESSION IS AN INTERNALIZING DISORDER

• DEPRESSION IS AN INTERNALIZING (VS EXTERNALIZING)
  DISORDER
• IS VERY MUCH UNDERDIAGNOSED
• THE DIAGNOSIS AND EARLY DETECTION OF
  INTERNALIZING DISORDERS IS A MAJOR PUBLIC HEALTH
  PROBLEM

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SYMPTOMS(1)

• Either depressed mood or loss of interest or
  pleasure
• In children or adolescents, an irritable mood may
  suffice for the depressed mood criterion

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SYMPTOMS(2)

• Significant weight loss or marked change in
  appetite may be substituted by a failure to make
  expected weight gains in children or adolescents

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Major Depression

• Sad mood, boredom, anhedonia, irritability
• Sleep changes
• Appetite changes
• Decreased concentration
• Decreased motivation
• Social withdrawal
• Guilt
• Suicidal ideation and behavior
• Functional impairment

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Related Forms of Depression

• Dysthymic Disorder
• Double Depression
• Psychotic Depression
• Bipolar Depression

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PROBLEMS

• NON-DEVELOPMENTAL PHENOTYPE
• NON SPECIFIC PHENOTYPE
• NEED FOR ENDOPHENOTYPE
• BIOLOGICAL
• COGNITIVE
• ENVIRONMENTAL

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Epidemiology
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Course

• Episode length 6-8 months
• Risk of recurrence in 2 years-40
• Risk of recurrence in 5 years-72
• Risk of second episode in adulthood-100

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Risk for Recurrence

• Subsyndromal depression
• Parent-child conflict
• Greater initial severity
• Abuse history

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Medical Treatments and Conditions

• Epilepsy
• Asthma
• Diabetes
• Thyroid disease
• Migraine
• Steroids
• Phenobarbital
• Cancer

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PSYCHIATRIC DIAGNOSES OF STUDY SAMPLE (n92)
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FLUVOXAMINE RESPONSE IN DEPRESSIVE AND ANXIOUS
PEDIATRIC ONCOLOGY PATIENTS(Gothelf et al., 2005)
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Selected Psychological Characteristics

• Autobiographical Memory
• Rumination/Distraction
• Attentional Bias

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Selected Psychological Characteristics

• Appraisal/Reappraisal
• Emotional Regulation
• Metacognition and Insight

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AUTOBIOGRAPHICAL MEMORY (Arieh, 2005)
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Cognitive Variables and Depression (Shorer 2005)
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Adverse Outcomes

• School dropout
• Substance and tobacco abuse
• Bipolar disorder
• Personality disorder
• Suicidal behavior

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Bipolar Disorder

• 10-20 of early-onset depression develop bipolar
  disorder
• Family loading for bipolar disorder and mood
  disorders
• Psychotic depression
• Hypersomnia/hyperphagia
• Hypomanic response to antidepressants

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Bipolar prevalence two examples

• Riverview Hospital Donovan et al 2003
• 2000 8/231 (4)
• 2001 28/211 (14)
• 2.5-fold increase
• Marketscan Martin Leslie 2003
• 1997 206/17,230 (1.2)
• 2000 474/26,006 (1.8)
• 56 increase

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Clinical Phenotypes of Juvenile ManiaLiebenluft,
Charney, Towbin Pine, AJP 2003

• Narrow
• Hallmark symptoms
• Full duration of episodes
• Intermediate
• Irritable (hypo)mania
• Short (lt3 days)
• Broad
• Mood and behavior disregulation

• Robbins Guze, circa 2003
• Clinical description
• Laboratory / Neurophysiology
• Delimitation
• Outcome studies
• Genetics and family aggregation
• Treatment response???

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Treatment

• Acute treatment-12 weeks
• Achievement of remission-12 weeks
• Continuation treatment-6 months
• Maintenance-for those with recurrent or chronic
  disorder

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Efficacious Treatments for Child and Adolescent
Depression
Type of Treatment Response Rate
Cognitive behavior therapy 54-60 Interpersonal
therapy 60-75 SSRIs 60 TCAs not
efficacious
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CBT Clinical Remission at End of Treatment
OVERALL p 0.05 CBT vs. SBFT p 0.03 CBT vs.
NST p 0.04
Clinical Remission absence of MDD and 3
consecutive BDI scores lt9 sustained through the
remaining sessions Abstracted from Brent et
al., 1997 A Clinical Psychotherapy Trial for
Adolescent Depression Comparing Cognitive,
Family, and Supportive Therapy, Arch. Gen.
Psychiatry 54877-885
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Poor Response to CBT (Brent et al., 1998)

• Poor functioning at intake
• Abuse
• Maternal depression
• Clinical referral vs. advertisement

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Failure to Achieve Remission as a Function of
Self-Reported Maternal Depression (BDI)
_
Brent et al. (1998)
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Overall and by treatment group MDD rate () at
the end of treatment
Suicidality and its relationship to treatment
outcome in depressed adolescents (28)
p.04
p.04
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Response to CBT and NST as Function of History of
Sexual Abuse
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IPT and CBT(Bronstein 2004)
IPT
CBT
Time-limited Focused therapy Present
experience Role of the therapist
interpersonal The interpersonal self Without
homework
Cognitive-Behavioral The cognitive self Home
work
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Dialectic Behavioral Therapy

• Specific for depression associated with
  Borderline Personality Disorder
• Heavily staff intensive
• Needs replication in adults and adolescents

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Pharmacotherapy

• SSRI treatment common
• Response rate around 50-60, often with
  incomplete remission
• Therefore around 50 of patients will need some
  second intervention

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Concerns about safety and efficacy of SSRIs

• The British Medicines and Healthcare Products
  Regulatory Agency (MHRA) issued a report on
  December 10, 2003 stating that the risk-benefit
  ratio for all antidepressants other than
  fluoxetine for adolescent depression was
  unfavorable. The FDA has issued a warning on
  March 22, 2004, but has not made as strong a
  statement, pending a review of the extant safety
  and efficacy data

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SSRI TREATMENT OF YOUTH MDD (Published Studies)
STUDY AGE N RESULTS Emslie (1997) 817 97 FLX gt
PLB Emslie (2002) 817 225 FLX gt PLB Keller
(2001) 1218 275 PRX gt PLB IMI Wagner
(2003) 617 376 SRT gt PLB Wagner
(2004) 717 174 CTL gt PLB
2004 August
RxS37
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SSRI TREATMENT OF YOUTH MDD (Unpublished
Industry Studies)
AGENT AGE N FINDINGS Citalopram 717 174 CTL gt
PLB Citalopram 1318 244 CTL
PLB Paroxetine 717 203 PRX PLB Paroxetine
1318 275 PRX PLB Sertraline (67) (188) SRT
PLB (p.08) Venlafaxine 617 141 VFX
PLB Venlafaxine 617 193 VFX PLB
Committee on Safety of Medicines 2003 (UK)
RxS39
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Medications for Depressed Children Just How
Effective?
NNT10 ES0.23
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David Rosenberg Wayne State
Mark Reineke U Chicago / Northwestern
Sanjeev Pathak Cincinnati
Norah Feeney Case Western
Anne Marie Albano NYU Bruce Waslick Columbia
Paul Rohde / Anne Simmons U Oregon
Elizabeth Weller Penn
John Walkup Hopkins
Charles Casat Carolinas Med Ctr
Chris Kratochvil Nebraska
Graham Emslie UT Southwestern
T A D S
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TREATMENT OF TEEN DEPRESSION (TADS) (n 439)
TREATMENT RECOVERED 95CI SUICIDAL
AES PLACEBO 34,
26-44 4 CBT 43 34-52 5
FXT 61 51-70
9 CBT FXT 71
62-80 6
TADS TEAM JAMA. 2004292807-820
RxS38
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Adverse Events(Kronenbrg 2005)
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Brent (JAMA 2007)

• 5,310 children and teenagers from 27 studies.
• 1/ 100 kids treated with antidepressants,
  experienced worsening suicidal feelings above
  what would have happened without drug treatment.
• In contrast, the FDA analysis found an added
  risk affecting about two in 100 patients.

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Venlafaxine ER Acad Child Adolesc Psychiatry.
2007

• No significant differences between venlafaxine ER
  and placebo
• Greater improvement on the Children's Depression
  Rating Scale-Revised with venlafaxine ER than
  with placebo (-24.4 versus -19.9 p .022) among
  adolescents (ages 12-17)
• not among children (ages 7-11).

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adverse events

• Anorexia and abdominal pain.
• Hostility and suicide-related events were more
  common in venlafaxine
• No completed suicides.

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Conversion-By Diagnosis
Severe Depression
Mild Depression
Anxiety
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Conversion-By Antidepressant Class
TCA
Other
SSRI
None
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Conversion-By Age Category
15-19
10-14
25-29
20-24
5-9
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By Age and Antidepressant Status
RR 5-14 2.9 (2.8,3.1) RR 15-29 1.4 (1.3, 1.5)
Exposed, 15-29
Exposed, 5-14
Unexposed, 15-29
Unexposed, 5-14
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PHARMACOGENETICS

• GENETIC STUDIES MAY
• ALSO ENABLE US TO
• PREDICT RESPONSE TO
• ANTIDEPRESSANT DRUGS

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Pharmacogenetic Data

• Response rate (CGI 2) for the different
  genotypes. P 0.048 at week 8

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Implications

• According to TADS, NNT / NNH ratio is 4
• Genotyping 5-HTT costs 1 and can be done in less
  than 24 hours.
• If carriers of the ss genotype are not expose
  to SSRI, the NNT / NNH equals 6

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Suicidality 5-HTR1Dß
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5-HTR1Dß

• 5-HTR1Dß gene knockout mice display increased
  aggressive response to intruders and impaired
  impulse control (Brunner 1999 Bouwknecht 2001)
• As yet no direct association to suicidality in
  humans (Stefulj, 2004)

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Implications

• The genetics of impulse control and aggression
  may be important in the understanding of
  SSRI-induced activation and suicidality
• Gene X Environment studies may be the future of
  these lines of investigation (Caspi, 2003)

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OMEGA 3(Nemets et al., 2005)

• Patients received 500mg or 1,000mg capsules
  depending on their ability to swallow a larger
  capsule
• Placebo for the 500mg capsule was olive oil
  (supplied by Ocean Nutrition, Canada) containing
  no omega-3 fatty acids

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OMEGA 3 in childhood depression

• p lt 0.001)

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For Prevention of Relapse

• Continuation treatment
• Treat residual depression
• CBT and MM helpful for treatment of residual
  depression and prevention of relapse
• Address family conflict
• Chronic depression treat with combination of CBT
  and medication

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MINDFULNESS BASED COGNITVE THERAPY

• Developed by Williams, Teasdale and Segal
• Useful in prevention of relapse in adults
• Works by decentering
• Can be used for large group therapy
• Needs therapists who are practicing meditators

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What is not Known

• Role of combination treatment
• Whether switch to another SSRI is equivalent to a
  switch out of class (e.g., venlafaxine)
• Role of augmentation
• Role of ECT/TMS

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Conclusions

• Depression in children is a common but
  under-diagnosed condition
• Depression in children is a chronic illness
• Depression in children is diagnosed by direct
  interviewing about symptoms
• Untreated this condition leads to considerable
  morbidity and some mortality

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New Horizons

• Major need to
• Prevent relapse
• Find treatments for resistant depression
• Specify treatments for specific endophenotypes