Child Onset Depression: Is It a Different Disorder?

1
Child Onset DepressionIs It a Different
Disorder?

• Neal Ryan

2
Conflict of Interest Statement

• No industry-funds in prior two years
• PI on the Pittsburgh site of the Keller et. al
  study of paroxetine funded by GSK
• PI on Pittsburgh site of Wyeth study of child
  depression
• Paid consultant (lifetime) to
• Abbott
• BMS
• GSK
• Johnson and Johnson
• Pfizer
• Wyeth

3
Joaquim Puig-Antich, 1944-1989
4
Joaquim Puig-Antich

• Born September 22, 1944, Barcelona Spain
• Died December 2, 1989
• Undergraduate 1953-1960, La Salle Bonanova,
  Barcelona
• Graduate 1961-1967, Facultad de Medicine,
  Universidad de Barcelona
• Post Graduate
• 1967 Clinique Rech., Montpellier, France,
  Resident in Neurosurgery
• 1970-1971 Sinai Hospital, Baltimore, Intern in
  Medicine
• 1971-1973, Beth Israel, New York, Resident in
  Psychiatry
• 1973-1975, Albert Einstein, New York, Child
  Psychiatry Fellow

5
Joaquim Puig-Antich

• Appointments
• 1975-1977 Albert Einstein, Assistant Professor
  of Psychiatry
• 1977-1983, Columbia, Assistant Professor of
  Clinical Psychiatry
• 1983-1984, Columbia, Associate Professor of
  Clinical Psychiatry
• 1984-1989, Pittsburgh, Professor of Psychiatry
• 1988-1989, Pittsburgh, Professor of Pediatrics

6
Additional Acknowledgements

• Ron Dahl
• David Axelson
• Boris Birmaher
• David Brent
• BJ Casey
• Cam Carter
• Mike De Bellis
• Erika Forbes

• Ahmad Hariri
• Joan Kaufman
• Chris Kye
• Cecile Ladouceur
• Chris May
• Jim Perel
• Scott Waterman
• Doug Williamson

7
Department of PsychiatryUniversity of Pittsburgh
Medical CenterWestern Psychiatric Institute and
Clinic
8
Child Depression

• Duration and Course
• Duration 3-9 months
• 6-10 last more than 2 years
• 70 recurrence in 5 years
• 20-40 become bipolar
• But 25 total adolescent prevalence of unipolar
  in epidemiologic studies versus 1-2 for bipolar
  disorders so numbers dont add up

9
Clinical Picture

• Clinical picture in child, adolescent and adult
  depression very similar
• Endogenicity/melancholic, suicide attempts,
  lethality of suicide attempts, and impairment of
  functioning increase with age
• Separation anxiety, phobias, somatic complains
  and comorbid behavioral problems decrease with age

10
Psychosocial Outcomes

• During depression and after recovery
• Worse functioning with friends and family
• Impaired performance in school
• Higher rate of pregnancy
• More smoking gateway
• Clear long-term persistence after successful
  treatment of depression

11
Increase in rate of depression, particularly
great in girls, correlated with puberty and not
age per se

• Point Prevalence
• 0.4 to 2.5 in children11 sex ratio
• 0.4 to 8.3 in adolescents21 female excess
• Lifetime prevalence in adolescence
• 15 - 25

12
What other disorders are like Major Depressive
Disorder

• Similar
• Complex genetic disorders, large environmental
  contribution, exacerbated by stress, treatment
  but no cure, the group that is responsible for
  most medical morbidity
• Hypertension
• Obesity, adult onset diabetes
• Alcohol Abuse
• Not similar
• Communicable diseases (avian flu)
• Single-gene disorders (ALS, sickle cell disease)
• Being struck by lightning

13
A Model for Genesis and Maintenance of Child
Depression
14
Child to Adult Depression

• Continuities
• Clinical picture
• Clinical course
• Responds to CBT and IPT in adolescents
• Responds to (at least some) SSRIs

• Discontinuities
• Probably unresponsive or minimally responsive to
  TCAs
• Some biological correlates of depression show
  maturational effects

15
Child Depression vs. Adolescent Depression vs.
Adult Depression

• Adolescent Depression is continuous with adult
  depression child depression shows less
  continuity but studies are very limited
• Perinatal insults, motor skill deficits, care
  taking instability and family-of-origin
  psychopathology increases hazard for child
  depression but not adult depression (Jaffee 2002)

16
Outcome of Child/Adolescent Depression

• More depression and anxiety
• probably a direct result of prior depression
  episode
• More nicotine dependence, alcohol abuse, suicide
  attempts, educational underachievement,
  unemployment and early parenthood
• possibly as a result of shared risk factors for
  depression and other adverse outcomes (Fergusson
  et al, 2002) though not all data supports this
  conclusion

17
Initiation of smoking
18
Substance abuse / dependence
19
Puberty
20
Puberty is starting earlier
21
Puberty and Brain Development

• Some brain changes precede pubertal increase in
  hormones and body changes
• Some brain changes appear to be the consequence
  of some pubertal processes
• Some adolescent brain maturation appears to be
  independent of pubertal processes
• Potential for creating internal dis-synchrony

Slide courtesy R. Dahl
22
Puberty and Motivation/Emotion

• Strongest links to pubertal changes per-se are in
  the domains of romantic motivation, sexual
  interest, emotional intensity, sleep/arousal
  regulation, appetite, and affective disorders
• A general increase in risk-taking,
  novelty-seeking, sensation-seeking
  (reward-seeking).
• Animal studies also show increase in
  novelty-taking (risk-taking?) in the
  peri-adolescent period (Spear 2000)

Slide courtesy R. Dahl
23
Puberty

• A number of developmental hormonal changes occur
  during the pubertal transition (reproductive
  hormones, adrenal androgens, growth hormones).
• Hormone levels fluctuate across hours and days.
• Increased stress exposure during adolescence also
  leads to hormonal (cortisol) and brain changes.
• There are complex interactions between
  reproductive hormones, stress-related hormones,
  and neural systems that regulate behavioral
  affect.
• There are profound individual differences in
  developmental trajectories in each of these
  systems.

Slide courtesy R. Dahl
24
Brain Development
25
Brain Development by Anatomic Region (145
Children Adolescents age 4-22 years of age who
underwent 243 MRI Scans) Giedd et al
Peak Cerebellum vs. Other Peaks lt.002,
lt.0001
26
Overview of Psychotherapy Studies in Child and
Adolescent Depression
27
Psychotherapy

• CBT
• CBT works better than wait-list and better than
  some other psychotherapies in child and
  adolescent major depression (Reinecke 1998,
  Harrington 1998 Brent 1997 Clarke 1999)
• IPT
• Works in depressed adolescents (Mufson, 1999)

28
TADS Results

• SSRICBT and SSRI better then placebo and better
  than CBT alone aggregating across measures
• CBT seemed to protect against suicidality while
  SSRI may increase it
• Combination better than SSRI alone but by small
  margin

29
A RCT of CBT to Prevent Adolescent Depression

• 13-18 yo adolescents who were at high risk for
  MDD because of family history (parental) for
  treated MDD current or in past year and who
  currently had subsyndromal depressive symptoms
• Randomized to usual care (N49) or 15 one-hour
  sessions of group CBT (N45)
• 26 month f/u
• 9.3 MDD in CBT group versus 28.8 in usual care
  by 14 months
• Preventive effect persisted but somewhat
  diminished at 18 and 24 months

30
Long Term Course and Maintenance

• Little evidence for long-term effect of
  short-term treatment
• CBT better than other therapy acutely but no
  difference in longitudinal course (Birmaher 2000)
• Modest evidence for long-term maintenance
• Fluoxetine better than placebo in preventing
  relapse over 1 year in fluoxetine responders, 34
  vs 60 relapse (Emslie 2001)
• However, overall there is little data

31
Pharmacotherapy of Child and Adolescent Depression
32
Pharmacotherapy

• In adults SSRIs SNRIs TCAs
• In children SSRIs gt TCAs

33
(No Transcript)
34
(No Transcript)
35
(No Transcript)
36
(No Transcript)
37
(No Transcript)
38
Summary

• Signal that SSRIs work
• But less than half of studies are positive
• This is like adult industry studies
• The more sites in the study, the smaller the
  effect size found (Brent et al., in press)
• Rushed studies probably decrease measured effect
  size
• However, even if this is true, you dont have any
  way to say how much this decrease is!

39
Summary

• Fluoxetine best replicated
• FDA does not feel that data available for other
  agents sufficient for indication
• Data not bad for citalopram and sertraline
• Data quite mixed for paroxetine

40
Putting Child and Adolescent Depression in its
place (compared to adult depression)
41
No difference in rates of adult MDD between MDD,
anxiety and control prepubs, but 59 of prepub
MDD had recurrence of depression. In those,
there was elevated rate of MDD in relatives.
42
(No Transcript)
43
(No Transcript)
44
(No Transcript)
45
(No Transcript)
46
(No Transcript)
47
(No Transcript)
48
(No Transcript)
49
(No Transcript)
50
(No Transcript)
51
Results

• More melancholic symptoms in depressed
  adolescents but otherwise children and
  adolescents have similar symptomatology,
  duration, and severity of the index episode
• Similar rates of recovery and recurrence
• Similar comorbid disorders
• Similar parental history of psychiatric disorders
• Index episode of both groups lasted on average 17
  months.
• 85 of children and and adolescent recovered
• 40 had at least one recurrence
• Guilt and female sex predicted longer episodes
• Prior history of MDD and father MDD predicted
  lower recovery and increased risk for recurrence

52
(No Transcript)
53
(No Transcript)
54
(No Transcript)
55

• trait-like marker for depression (or depression
  and anxiety
• stable through development and adulthood
• may be result of early life stressors (e.g.
  macaque variable foraging paradigm)

56
(No Transcript)
57
Results

• Increased activity in amygdala during
  presentation of fearful faces and a decrease in
  activation with repeated exposure to fearful
  faces
• Developmental differences in amygdala response to
  fearful and neutral faces
• Adults show increased amygdala activity for
  fearful faces
• Children show more amygdala activity in response
  to neutral faces
• Children may find neutral faces to be more
  ambiguous than adults do or even more ambiguous
  than fearful faces.

58
(No Transcript)
59
(No Transcript)
60
14 MDD and 17 control children 9-17 years Of 14
with MDD, 10 also had comorbid anxiety disorder
61
(No Transcript)
62
(No Transcript)
63
Reward Related Decision Making

• Anxiety disorders
• Increased response in cingulate and left caudate
  (reward related areas) during anticipation of
  reward and in caudate after receiving
  large-magnitude reward
• MDD
• Decreased response caudate after receiving a
  large-magnitude reward.

64
Thanks