This is the slide set to the lectures I provided to the medical staff of Child and Adolescent Behavioral Health in Canton, OH during the Fall-Winter of 2018

1. Introduction to Depressive Disorders in Children and
Adolescents
Stephen Grcevich, MD
Clinical Associate Professor of Psychiatry, NEOMED
Presented at Child and Adolescent Behavioral Health
November 2018 – January 2019

2. Overview of the course…
• Epidemiology, presentation throughout
childhood/adolescence, clinical course, risk factors,
etiology
• Evaluation – diagnostic criteria, differential
diagnosis, comorbidity, use of rating scales
• Pharmacotherapy and other medical treatments
• Non-pharmacologic treatments

3. What do we know about
depression in children, teens?
• Why do kids get depressed?
• How many kids/families are affected?
• What’s the impact on kids developmentally?

4. Question 1
A prepubertal child with a diagnosis of MDD is
most likely to have which of the following
symptoms…
• A-auditory hallucinations
• B-paranoid delusions
• C-drug abuse
• D-rosy glow
• E-all of the above

5. Question 2
• A teenager with MDD is NOT likely to have
which of the following symptoms
• A-Hypersomnia
• B-Overeating
• C-Delusions
• D-Separation Anxiety Disorder
• E-Suicidal ideation

6. Question 3
Which of the following predicts recurrence of
MDD in youth?
• A-Later age at onset
• B-Decreased number of prior episodes
• C-Psychosis
• D-Intelligence
• E- All of the above

7. Question 4
Which of the following increases likelihood of
bipolar disorder in youth with MDD?
• A-Comorbid ADHD
• B- Psychomotor agitation
• C-Comorbid anxiety disorder
• D-Family history of non-psychotic depression
• E-Heavy familial loading for mood disorders

8. Question 5
Which statement best characterizes Persistent
Depressive Disorder in youth?
• A-Not associated with increased risk of MDD
• B-10% of youth with Dysthymia have MDD
• C-Dysthymia has mean episode of 3-4 years for
clinical & community samples
• D-First MDD episode usually occurs 10 years
after onset of Dysthymia,
• E-None of the above

9. Answers
• 1-A
• 2-D
• 3-C
• 4-E
• 5-C

10. What is depression?
• A condition resulting from disordered capacity for
emotional self-regulation
• Mediated by interconnections between prefrontal cortex
and limbic system
• Exaggerated activation of amygdala in adolescents in
response to emotional cues, under-recruitment of
prefrontal cortex
• Multiple neurotransmitter systems involved
• The role of serotonin in inhibiting and opposing the
effects of dopamine, especially in terms of impulsive and
aggressive behavior

11. MDD Diagnostic Criteria:
DSM-5
• At least 2 weeks of pervasive change in mood manifest
by either depressed or irritable mood and/or loss of
interest and pleasure.
• Other symptoms: changes in appetite, weight, sleep,
activity, concentration or indecisiveness, energy, self-
esteem (worthless, excessive guilt), motivation, recurrent
suicidal ideation or acts.
• Symptoms produce clinically significant distress or
impairment
• Symptoms not attributable to substance abuse,
medications, other psychiatric illness, medical illness

12. Epidemiology
• MDD prevalence: 2% children, 4%-8%
adolescents
• Male/female ratio:
• Childhood 1:1
• Adolescence 1:2
• Cumulative incidence by age 18 years: 20%
• Each successive generation at higher risk for
MDD since 1940
• Persistent Depressive Disorder prevalence: 0.6%-
1.7% children, 1.6%-8% adolescents

13. National Comorbidity Survey
• Nationwide study of 10K+ adolescents for MDD
• Lifetime prevalence: 11%, 12-month prevalence 7.5%
• “Severe MDD” (2-5X greater functional impairment) in
¼ of total MDD cases
• 60% receive treatment
• Most treatment isn’t diagnosis-specific
• Most treatment isn’t delivered by mental health
professionals
Avenovili et al. J Am Acad Child Adolesc Psychiatry 2015;52(1)37-44.e2

14. Developmental Variations of
Depression
CHILDREN:
• More symptoms of anxiety
(i.e. phobias, separation
anxiety), somatic
complaints, auditory
hallucinations
• Express irritability with
temper tantrums & behavior
problems
• Fewer delusions, serious
suicide attempts
• Prepubertal onset related to
conduct disorder, impulsive
aggression
ADOLESCENTS:
• More sleep and appetite
disturbances, delusions,
suicidal ideation & acts,
impairment of
functioning
• Compared to adults,
more behavioral
problems, fewer
neurovegetative
symptoms

15. How does the clinical presentation of
depression differ with age?
Goldman S. Child Adolesc Psychiatric Clin N Am 21 (2012) 217-235.

16. Clinical Course of Depression:
• Median Duration:
Clinically referred youth: 7-
9 months
Community youth: 1-2
months
• Predictors of longer
duration: depression
severity, comorbidity,
negative life events,
parental psychiatric
disorders, poor
psychosocial functioning
• Remission defined as a
period of 2 weeks to 2
months with 1 clinically
significant symptom
• Recovery defined as an
asymptomatic period
lasting at least two months
• 90% MDD episodes remit
1-2 years after onset
• 6%-10% MDD are
protracted

17. Relapse
• Relapse is an episode of MDD during period of
remission
• Predictors of relapse: Natural course of MDD, lack of
treatment adherence, negative life events, rapid
decrease or discontinuation of therapy
• 40%-60% youth with MDD relapse after successful
acute therapy
• Relapse may indicate a need for continuous treatment

18. Recurrence
• Defined as emergence of
MDD symptoms during
recovery (asymptomatic
period of more than 2
months)
• Probability of recurrence
• 20%-60% within 1-2
years of remission,
• 70% after 5 years
Predictors:
• Earlier age at onset
• Increased number of prior
episodes
• Severity of initial episode
• Psychosis
• Psychosocial stressors
• Dysthymia & other
comorbidity
• Lack of adherence to
therapy

19. Risk of Bipolar Disorder in Kids
with Major Depression
20%-40% MDD youth develop bipolar disorder in 5 years of onset of
MDD
Predictors of Bipolar I Disorder Onset:
• Early onset MDD
• Psychomotor retardation
• Psychosis
• Family history of psychotic depression
• Heavy familial loading for mood disorders
• Pharmacologically induced hypomania

20. Risk factors for depression
• Family history
• Prior experience of
depression
• Negative cognitive
style
• Bereavement
• Poverty
• Exposure to violence
• Life stressors
• Social isolation
Specific risk factors
Non-specific risk
factors
Beardslee WR et al. Child Adolesc Psychiatric Clin N Am 21 (2012) 261-278.

21. Sources of biological vulnerability
• Transporter genes (gene x environment pathway)
• HPA axis
• Affective and vagal tone
• Cerebral variations (form and development)
• Cognitive style
• Influence of hormones during puberty
• Neurophysiologic/neurocognitive changes of
adolescence

22. Neuroimaging Findings:
• Cortical thinning as possible endophenotype of early-onset
depression (Peterson & Weissman, 2011)
• Decreased hippocampal volume (Rao, 2009)
• Increased amygdala activation (Yang, 2010)
• Decreased regional cerebral blood flow…(Ho et al., 2013)

23. Neuroimaging findings in
females…
• Smaller nucleus accumbens volume
• Increased growth of amygdala from early to
mid-adolescence
Whittle S et al. Am J Psychiatry. 2014 May;171(5):564-71.

24. Genetic Factors
• Children with depressed parent 3x likely to
have lifetime episode of MDD (lifetime risk
15%-60%)
• Concordance rates of 40-65% in monozygotic
twins
• Prevalence of MDD in first-degree relative of
children with MDD is 30%-50% (parents of
MDD children also have anxiety, substance
abuse, personality disorders)

25. Epigenetic Factors
• Epigenetic changes in ID3, GRIN1, and TPPP genes in combination
with experiences of maltreatment may confer risk for depression in
children.
• ID3 involved in the stress response, GRIN1 involved in neural
plasticity, and TPPP involved in neural circuitry development.
• Short allele of serotonin transporter gene-linked polymorphism
region (5HTTLPR) associated with increased risk of depression only
if they experienced severe maltreatment in childhood
• Other candidate genes – Corticotrophin releasing hormone Type 1
receptor (CRHR1) and brain-derived neurotrophic factor gene
(BDNF)
• Epigenetic changes are frequently long lasting, but not necessarily
permanent
Weder et al. J Am Acad Child Adolesc Psychiatry 2014;53(4)417-24.e5

26. Summary of contributing factors to course
of childhood, adolescent depression
• 2-4X increased risk after puberty, especially in girls
• Poor school success, learning problems, comorbid psychiatric
disorders that interfere with learning
• Genetic & environmental factors
• Non-shared intrafamilial & extrafamilial environmental experiences (how
individual parents treat each child)
• Kids at high genetic risk more sensitive to adverse environmental effects
• Personality traits: judgmental, anger, low self-esteem, dependency
• Cognitive style & temperament: negative attributional styles
• Adverse childhood experiences (ACE)
• Recent adverse events
• Conflictual family relations
• Neglect, abuse

27. Questions?

28. Depressive Disorders in Children and Adolescents
Issues in Evaluation and Diagnosis
• Stephen Grcevich, MD
• Clinical Assistant Professor of Psychiatry, NEOMED
• Presented at Children’s Hospital Medical Center of Akron
• February, 2018

29. Topics to be covered today:
• Diagnostic criteria for depressive disorders seen in
children and teens
• Differential diagnosis of depression
• Common comorbidities associated with pediatric
depression
• Use of rating scales in assessment
• Depressive disorder modifiers in DSM-5
• DMDD as a depressive disorder?

30. How do you diagnose
depression?
• What signs, symptoms are you looking for in your
interviews with child/parent/caregiver?
• Do you use rating scales? If so, how much weight
do you place on the results?
• How do you differentiate depression from “normal”
response to living in dysfunctional environments?

31. MDD Diagnostic Criteria:
DSM-5
• At least 2 weeks of pervasive change in mood manifest
by either depressed or irritable mood and/or loss of
interest and pleasure.
• Other symptoms: changes in appetite, weight, sleep,
activity, concentration or indecisiveness, energy, self-
esteem (worthless, excessive guilt), motivation, recurrent
suicidal ideation or acts.
• Symptoms produce clinically significant distress or
impairment
• Symptoms not attributable to substance abuse,
medications, other psychiatric illness, medical illness

32. Differential Diagnosis of MDD
in Children, Teens
• Anxiety disorders, OCD
• DMDD
• Bipolar disorder
• Learning disabilities
• ADHD, disruptive behavior disorders
• Personality disorders (Borderline PD)
• Substance use disorders
• Adjustment disorder with depressed mood
• Medical causes (including medication)

33. Differential Diagnosis:
Complexities of General Medical
Conditions
• May be accompanied by symptoms of depression
• Impact course of depressive disorder
• MDD can be diagnosed if depressive symptoms
preceded or not solely due to medical illness or
medications to treat medical illness
• Incidence of MDD higher in certain medical illnesses
• Chronic illness may affect sleep, appetite, energy
• Guilt, worthlessness, hopelessness, suicidal ideation
usually not attributed to medical illness but suggest MDD

34. Medical conditions associated
with depressive symptoms
• Cancer, hypothyroidism, lupus, acquired
immunodeficiency syndrome, anemia, diabetes,
epilepsy
• Chronic Fatigue Syndrome: symptoms similar to
MDD but with more somatic symptoms, less
mood, cognitive, social symptoms
• Medication induced symptoms: stimulants,
neuroleptics, corticosteroids, contraceptives

35. Comorbidity
• Present in 40%-90% of youth with MDD; two or more
comorbid disorders present in 20%-50%
• Comorbidity in youth with MDD: Dysthymia or anxiety
disorders (30%-80%), disruptive disorders (10-80%),
substance abuse disorders (20%-30%)
• MDD onset after comorbid disorders, except for
substance abuse
• Conduct problems: May be a complication of MDD &
persist after MDD episode resolves
• Anxiety: Children manifest separation anxiety;
adolescents manifest social phobia, GAD, conduct
disorder, substance abuse

36. Diagnostic Complexities
• Overlap of mood disorder symptoms
• Symptoms overlap with comorbid disorders
• Developmental variations in symptom
manifestations
• Etiological variations of mood disorders involving
gene-environment interactions
• Spectrum or categorical disorders?
• Effects of medical conditions?

37. Rating Scales for Depression
• Children’s Depression Inventory (CDI 2)
• Beck Depression Inventory (BDI-II)
• Rating scales in public domain…
• Columbia Depression Scale
• PHQ-9 (teen version)
• Center for Epidemiological Studies Depression Scale
for Children (CES-DC)
Link for scales in public domain:
https://candapediatricmedicalhomes.wordpress.com/child-
psychiatry-rating-scales-for-primary-care-physicians/

38. Children’s Depression
Inventory
• Originally derived from BDI
• 27 item, self-report scale used in children ages 7-17
• Each item scored on 0-2 scale
• 20 - typical cutoff score for depression, scores of 36
or higher suggest severe depression
• Examines five factor areas…
• Negative Mood
• Interpersonal Problems
• Ineffectiveness
• Anhedonia
• Negative Self Esteem

39. Beck Depression Inventory
(BDI-II)
• 21 item, self-report scale
• Designed for individuals ages 13 and up
• Patient asked to evaluate symptoms over the
last two weeks
• Each item scored on a 0-3 scale
• 0–13: minimal depression
• 14–19: mild depression
• 20–28: moderate depression
• 29–63: severe depression.

40. Advantages and disadvantages
of rating scales…
• Advantages:
• May help guide treatment decision-making
• Provides a tool for measuring treatment response
• Kids may respond differently to questions presented
on rating scale vs. clinical interview
• Disadvantages:
• Should we assume kids understand the questions?
• Are we measuring distress (or something else) as
opposed to depression?
• Are we treating a score instead of the kid?

41. Distinguishing bereavement from
depression in the DSM-5
• Painful feelings often come in
waves, intermixed with
positive memories of the
deceased
• Self-esteem usually preserved
• A stressor that may precipitate
depression
• Mood and ideation is almost
constantly negative
• Corrosive feelings of
worthlessness, self-loathing
are common
• Should not be diagnosed in
the context of typical
bereavement
Grief Depression
American Psychiatric Association, 2013

42. Persistent Depressive Disorder
(Dysthymia) DSM-5 Criteria:
• Persistent, long-term change in mood, less
intense but more chronic than MDD
• Depressed mood on most days for most of the
day for at least 1 year (2 years in adults)
• At least 2 other symptoms: appetite, sleep, low
energy/fatigue, low self-esteem, poor
concentration or difficulty with decision-making,
hopelessness
• Person is not without symptoms for more than
2 months at a time and has not had MDD for
the first year of disturbance; never had manic
or hypomanic episode

43. Clinical Course: Relation of
Persistent Depressive Disorder
• Associated with increased risk of MDD
• 70% of youth with Persistent Depressive Disorder have
MDD
• Persistent Depressive Disorder has mean episode of
3-4 years for clinical & community samples
• First MDD episode usually occurs 2-3 years after onset
of Persistent Depressive Disorder, gateway to
recurrent MDD
• Risk for Persistent Depressive Disorder: chaotic
families, high family loading for mood disorders,
particularly Persistent Depressive Disorder

44. DSM-5 Depressive Disorder Modifiers
Suggest Need for Alternate Intervention
Strategies
• Anxious Distress
• Mixed features (mania, hypomania)
• Melancholic features
• Atypical features
• Psychotic features
• Catatonia
• Peripartum onset
• Seasonal pattern

45. Depressive disorder modifiers
in DSM-5: Anxious Distress
At least two of the following symptoms during the majority of
days of a major depressive or persistent depressive
episode)…
• Keyed up/tense,
• Unusually restless,
• Difficulty concentrating because of worry,
• Fear something awful may happen,
• Feeling the individual might lose control of himself, herself
Severity specified as mild (two symptoms) moderate (three
symptoms) moderate-severe (four or five symptoms) severe
(four of five symptoms PLUS motor agitation)

46. MDD with psychotic features
• MDD associated with mood congruent or incongruent
hallucinations and/or delusions (unlike adolescents, children
manifest mostly hallucinations)
• Occurs in up to 30% of those with MDD
Is associated with…
• more severe depression,
• greater long-term morbidity,
• resistance to antidepressant monotherapy,
• low placebo response,
• increased risk of bipolar disorder
• family history of bipolar and psychotic depression

47. Depressive disorder modifiers
in DSM-5: Mixed Features
At least three of the following manic/hypomanic symptoms during the
majority of days of a major depressive episode
• Elevated, expansive mood
• Inflated self-esteem, grandiosity
• More talkative than usual, pressure to keep talking
• Flight of ideas or subjective experience that thoughts are racing
• Increase in energy or goal-directed activity
• Increased, excessive involvement in activities with potential for painful
consequences
• Decreased need for sleep
Diagnosis should be Bipolar I or Bipolar II disorder for patients who meet
criteria for those conditions

48. Depressive disorder modifiers
in DSM-5: Melancholic Features
Loss of pleasure in all, or almost all activities, or lack of
reactivity to usually pleasurable stimuli, including three or
more of the following:
• Distinct quality of depressed mood characterized by
profound despondency, despair, moroseness, or “empty
mood”
• Depression worse in the morning
• Early AM awakening (at least two hours before usual time)
• Marked psychomotor agitation or retardation
• Significant anorexia or weight loss
• Excessive or inappropriate guilt

49. Depressive disorder modifiers
in DSM-5: Atypical Features
These features predominate during the majority of days of a
major depressive episode
• Mood reactivity (brightens in response to actual or potential
positive events and two or more of the following
• Significant weight gain or increase in appetite
• Hypersomnia
• Leaden paralysis (heavy, leaden feelings in arms, legs)
• Longstanding pattern of interpersonal rejection sensitivity
Criteria not met for melancholic features or catatonia within
that depressive episode

50. Depressive disorder modifiers
in DSM-5: Psychotic Features
Delusions and/or hallucinations are present
• Mood-congruent psychotic features
• Mood-incongruent psychotic features

51. Depressive disorder modifiers
in DSM-5: Seasonal pattern
This specifier applies to recurrent Major Depressive
Disorder…
• Regular temporal relationship between onset of MDD
episodes and time of year (Fall, Winter)
• Full remission (or switch to mania/hypomania) often occurs
in Spring
• Two MDD episodes in ;last two years with NO non-seasonal
episodes of MDD
• Seasonal episodes of MDD outnumber non-seasonal MDD
episodes throughout the patient’s lifetime.

52. What about Disruptive Mood
Dysregulation Disorder?
There’s a large group of kids who demonstrate…
• Irritability as their predominant mood state
• Problems with emotional self-regulation frequently
leading to aggression
• Difficulties with attention, concentration, academic
performance
• “At-risk” behaviors…self injury, substance use, suicidal
behaviors

53. DSM-5 criteria for Disruptive Mood
Dysregulation Disorder (DMDD):
• A. Severe, recurrent temper outbursts manifested verbally (rages) and/or behaviorally (physical
aggression to people, property) grossly out of proportion in intensity or duration to the
situation/provocation
• B. Temper outbursts inconsistent with developmental level
• C. Temper outbursts occur, on average, 3X or more/week
• D. Mood between outbursts persistently irritable or angry, observable to others
• E. Above four criteria present for 12+ months, with no more than three months symptom-free
• F. A and D criteria present in at least two of three settings (home, school, peers), severe in at least
one setting
• G. Initial diagnosis not made in children under 6 or over 18
• H. Age of onset prior to age 10
• I. No distinct period >1 day where criteria for mania, hypomania met
• J. Doesn’t occur exclusively during MDD episode, not better explained by another mental disorder
(ASD, PTSD, Separation Anxiety Disorder, Persistent Depressive Disorder)…can’t coexist with
ODD, Bipolar Disorder, Intermittent Explosive Disorder
• K. Not attributable to substance use, another medical, neurologic condition

54. What do kids with DMDD look like?
• Most have ADHD (86.3%) and ODD (84.2%)
• 60% at NIMH were diagnosed in community with bipolar
disorder
• They have a higher than expected prevalence of lifetime
anxiety disorders (58.2%) and lifetime major depression
(16.4%)
• Seven times more likely to be depressed at age 18
• Chronic irritability in adolescence predicts MDD, GAD
and dysthymia at age 33
Leibenluft E. Am J Psychiatry 2011; 168(2):129-42

55. What I’ve observed about kids
with DMDD…
• They have difficulty with transitions…”cognitive rigidity”
• They tend to “ruminate”…indecisive, think too much
about things, perseverate
• They may experience some improvement in some
settings from ADHD medication, but become more
irritable, have more meltdowns at home on medication
• They do better when they’re busy…inactivity increases
irritability
• They’re prone to behavioral activation on SSRIs that is
often mistaken for mania, hypomania

56. How I’m treating DMDD…
• Conservative use of ADHD medication…limited as much as
possible to school day
• Meltdowns related to perseverative frustration with inability
to achieve desired outcomes may respond to SSRIs,
clomipramine
• Behavioral activation from SSRIs appears dose-
dependent…titrate weekly in small increments
• Lots of CBT! Kids need strategies to help manage
perseverative thinking
• Aggressively dosing accommodations, school-based
interventions
• SGAs as last resort for severe aggression (risperidone)

57. Summary: MDD in Children &
Adolescents
• Diagnostic criteria similar for depression in children
and adults, although clinical presentation may differ
• Differential diagnosis is extensive and complex,
requiring careful evaluation
• Comorbidity is probably the norm as opposed to the
exception
• Rating scales may be useful tools in evaluation,
measuring response to treatment
• Kids who meet diagnostic criteria for DMDD at higher
risk of MDD as they progress into adulthood

58. Biological Treatment of Depression in Children and
Adolescents
Stephen Grcevich, MD
Clinical Assistant Professor of Psychiatry, NEOMED
Presented at Children’s Hospital Medical Center of Akron
September 27, 2018

59. What we’ll look at today…
• Examine the relevant literature evaluating the safety and
efficacy of antidepressants in children and teens.
• Provide an update on the risks of suicidal thoughts and
behavior in youth prescribed antidepressants
• Review the relative benefits and limitations of available
medications used to treat depression in kids
• Discuss other biological treatments for MDD in children and
teens

60. Question 1: Which of the following medications
are approved by the FDA for use in pediatric
depression?
• A: Paroxetine (Paxil)
• B: Venlafaxine XR (Effexor XR)
• C: Fluvoxamine (Luvox)
• D: Citalopram (Celexa)
• E. Escitalopram (Lexapro)

61. Question 2: Which of the following
statements about the TADS study is
true?
• A: CBT appeared to provide significant benefit to
depressed teens after twelve weeks compared to
placebo
• B: Teens treated with fluoxetine demonstrated an
increase in suicidal thoughts during the acute phase
of treatment
• C: Fluoxetine as a stand-alone treatment for
depression was more effective than CBT in acute
treatment
• D: There was no significant benefit from combining
CBT with fluoxetine in acute treatment

62. Question 3: Which of the
following statements is false:
• A: Most randomized studies of SSRIs in youth with depression
have demonstrated medication more effective than placebo
• B: SSRIs tend to demonstrate far more robust effect size for
treatment of anxiety in children and adolescents than for
depression
• C: The occurrence of increased suicidal thoughts in response to
treatment with SSRIs is greater in youth with depression than
anxiety
• D: Differences in delivery of cognitive-behavioral therapy in the
community may limit the ability to generalize results of treatment
in large scale studies of youth with depression or anxiety

63. Answers
• 1-E
• 2-C
• 3-A

64. MDD Diagnostic Criteria: DSM-5
• At least 2 weeks of pervasive change in mood manifest
by either depressed or irritable mood and/or loss of
interest and pleasure.
• Other symptoms: changes in appetite, weight, sleep,
activity, concentration or indecisiveness, energy, self-
esteem (worthless, excessive guilt), motivation, recurrent
suicidal ideation or acts.
• Symptoms produce clinically significant distress or
impairment
• Symptoms not attributable to substance abuse,
medications, other psychiatric illness, medical illness
American Psychiatric Association, 2013

65. Treatment options for
depression:
• Antidepressant medication
• Cognitive-Behavioral Therapy (CBT)
• Family Therapy
• Other therapies (interpersonal therapy, group therapy, supportive
psychotherapy)
(Evidence-based interventions in orange)
J Am Acad Child Adolesc Psychiatry, 2007; 46(11):1503-1526

66. Indications for Pharmacotherapy in
AACAP Practice Parameters for
Depression:
• Children, teens with moderate to severe
depression
• More severe episodes generally require
antidepressant treatment
• Medication may be administered alone until the
child is amenable to psychotherapy, or combined
with therapy from the beginning
• Youth who don’t respond to monotherapy
(medication or psychotherapy) require a
combination of medication and psychotherapy
J Am Acad Child Adolesc Psychiatry, 2007; 46(11):1503-1526

67. Metanalysis of Randomized
Trials of SSRIs:
• Effect size of SSRIs in MDD: 0.25
• Effect size in OCD: 0.48
• Effect size in non-OCD anxiety: 0.69
• Adolescents respond more robustly than school-age
children for both MDD and anxiety
• Better response to antidepressants in more severe illness
Bridge JA et al, JAMA 2007; 297(15):1683-1696

68. FDA approved medications for
MDD in children, adolescents…
• Fluoxetine for patients ages 8 and above
• Escitalopram for patients ages 12 and above
• Paroxetine not recommended for use in adolescent
patients
http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm413161.htm

69. Why does fluoxetine perform better
than other SSRIs in MDD?:
• Long half life makes inconsistent adherence less of
a concern
• Unique pharmacokinetic, pharmacodynamic
properties?
• Lower rates of discontinuation from withdrawal
symptoms
• Studies involved fewer sites, more experienced
investigators
Bridge JA et al, JAMA 2007; 297(15):1683-1696

70. The TADS (Treatment of
Adolescent Depression) Study
• NIMH sponsored “The Treatment of Adolescents with
Depression Study” (TADS):
• Multicenter controlled clinical trial
• 12-17 year olds with MDD
• Compared efficacy of fluoxetine, CBT, combination, &
placebo in 36 weeks with 1 year follow-up.
March J et al. J Am Acad Child Adolesc Psychiatry, 2006;45(12):1393-1403

71. TADS Study: Response
Rates
March J et al. J Am Acad Child Adolesc Psychiatry, 2006;45(12):1393-1403
Week FLX+CBT FLX CBT PBO
12 73% 62% 48% 35%
18 85% 69% 65%
36 86% 81% 81%

72. TADS Study: Full Remission (36 weeks)
Kennard B et al. (2006), J Am Acad Child Adolesc Psychiatry 45:1404-1411
0
5
10
15
20
25
30
35
40
COMB FLX CBT PBO
% Remission
% Remission

73. TADS: Suicidal ideation in acute
treatment

74. Serotonin transporter
binding:

75. Treatment Resistant Study
(TORDIA):
• NIMH funded multicenter study “Treatment of
Resistant Depression in Adolescents (TORDIA)
• Aims to benefit treatment-resistant adolescents, age
12-18 years old
• Compared fluoxetine, paroxetine, or venlafaxine,
either alone or in combination with CBT for 24 weeks
with 1 year follow-up
Brent D et al, JAMA, 2008;299(8):901-913

76. TORDIA Results:
• Response to CBT+2nd antidepressant 54%,
antidepressant alone 41% (significant)
• 2nd SSRI and Venlafaxine equally effective
• 2nd SSRI better tolerated than venlafaxine
Brent D et al, JAMA, 2008;299(8):901-913

77. Early response important in
TORDIA:

78. Effect Sizes for SSRIs…
SSRI Use Effect Size
Anxiety 0.69
OCD 0.48
Depression 0.25
Bridge JA et al, JAMA 2007; 297(15):1683-1696

79. The FDA and Antidepressants
for Kids:
• Boxed warning regarding increased risk of suicidality
issued 10/15/04
• Antidepressants were not contraindicated in children
and adolescents
• Website for more info:
www.fda.gov/cder/drug/antidepressants/default.htm

80. Suicide rates in U.S., 1970-2010

81. How effective (or safe) is the
drug I might prescribe?
• Number Needed to Treat (NNT)
• The average number of patients who need to be treated
for one of them to benefit compared with controls in a
clinical trial
• Number Needed to Harm (NNH)
• The average number of patients who need to be exposed
to a specific risk factor so that one patient is harmed who
wouldn’t have been harmed absent the risk factor
• Benefit Risk Ratio
• Number Needed to Harm/Number Needed to Treat

82. Calculating the NNT…
Total number of patients treated
Responders to active treatment – Placebo responders
The “perfect” drug would have an effect size of 1.0
Exercise: 100 high school students are enrolled in a
double-blind study in which they receive one week of
Vyvanse and one week of placebo pills. 75 respond to
Vyvanse, 25 to placebo. What’s the NNT?

83. Metanalysis of Randomized
Trials of SSRIs:
• Increased risk of SI/SA in MDD vs. PBO: 0.9%
• Increased risk of SI/SA in OCD vs. PBO: 0.7%
• Increased risk of SI/SA in anxiety vs. PBO: 0.5%
Bridge JA et al, JAMA 2007; 297(15):1683-1696

84. Do risks and benefits vary by the condition
being treated?
(Number Needed to Harm)
0
50
100
150
200
250
Depression Anxiety OCD
Risks and benefits of antidepressant therapy
Harm=New onset suicidal thinking, behavior
NNH

85. Risk/Benefit Ratio of SSRIs by
condition treated
0
5
10
15
20
25
30
35
40
Depression Anxiety OCD
Risks and benefits of antidepressant therapy
Harm=New onset suicidal thinking, behavior
NNT Risk/Benefit

86. Predictors of Suicidal Events
Grcevich SJ et al. Presented at American Academy of Child and Adolescent Psychiatry, October 2009

87. SSRI side effects:
• Nausea
• Weight gain
• Behavioral activation/disinhibition
• Restlessness
• Vivid dreams
• Increased clotting time
• Fatigue
• Sexual side effects

88. SSRI Withdrawal

89. SSRI Half-lives

90. EKG Monitoring and
Citalopram

91. Medication algorithm for MDD
in children, adolescents:

92. Duloxetine for MDD in
children, adolescents:

93. Treatment of MDD: Tricyclic
Antidepressants (TCA’s)
• TCA’s: imipramine, desipramine, amitriptyline,
nortriptyline, doxepin, clomipramine
• No RCTs have demonstrated efficacy vs.
placebo

94. Omega-3s in prepubertal
depression:

95. rTMS in adolescent
depression:

96. Light therapy for adolescent
depression:

97. Exercise for Adolescent
Depression:

98. ECT for Depression:
• No RCTs in adolescents
• May be effective treatment for adolescents with severe mood
disorders when more conservative treatments have been
unsuccessful.
• May be considered when there is a lack of response to two or more
trials of pharmacotherapy, when severity of symptoms precludes
waiting for a response to pharmacological treatment.
• Mood disorders in adults have a high rate of response to ECT (75%–
100%)
• Consent of legal guardian is mandatory, patient’s consent or assent
should be obtained.
• Systematic pre-treatment, post-treatment evaluation, including
symptom and cognitive assessment is recommended.
J. Am. Acad. Child Adolesc. Psychiatry, 2004;43(12):1521–1539.

99. Retrospective study of ECT:
• N=41 (mean age 17.0±1.8 years old)
• Mean duration of illness of 38.1 ± :26.9 months, 17.1% had prior ECT
• Psychotic symptoms (53.7%), depressed mood (43.9%), catatonia (17.1%),
suicidal behavior (17.1%), non-suicidal self-injury (7.3%), mania (2.4%)
• Mean of 9.6 ± 5.1 bi-frontal ECT treatments.
• Response rate: 70.0% in primary psychotic illness, 79.0% in youth with a
mood disorder.
• Higher response rate in depression vs. bipolar (92% vs. 44%, p=0.046).
• AE: Postictal agitation (12.5%), tachycardia (10%), headache, nausea (5%
each).
• “ECT was safe and efficacious, particularly in youth with unipolar
depression.”
Grudnikoff E. et al. 60th Annual Meeting of the American Academy of Child and
Adolescent Psychiatry, Orlando FL, October 2013

100. Conclusions:
• Pharmacotherapy is appropriate treatment option for
children, teens with moderate-severe MDD or kids with
MDD + suicidal ideation/plan
• Escitalopram has demonstrated efficacy in teens with
treatment-resistant MDD, but tolerated more poorly than
SSRIs
• Both SSRIs and CBT are associated with overall
decrease in suicidal ideation in teens with MDD
• While most kids with MDD improve in response to
treatment, full remission remains elusive, even with
medication + CBT

101. Psychosocial Treatment of Depression in Children
and Adolescents
Stephen Grcevich, MD
Clinical Assistant Professor of Psychiatry, NEOMED
Presented at Children’s Hospital Medical Center of Akron
September 27, 2018

102. What we’ll look at today…
• Examine the evidence base for psychosocial treatments of
depression in children and teens
• Discuss the limitations of the research literature on
psychotherapy for children and teens with depression
• Review the current knowledge regarding predictors and
modifiers of response to psychotherapy for teens with
depression.

103. CBT in children (under age 13)
with depression
• Seven controlled studies (patients compared to
waitlist or psychologically inert control)
• One study – positive findings in favor of CBT
• Four studies – generally positive, but more
equivocal findings
• Two negative studies
• “Possibly efficacious”

104. CBT modalities in children with
depression
• Three studies of individual CBT – “experimental
treatment”
• Four studies of group CBT – one of the four was
positive – “possibly efficacious”
• One positive study of CBT through
videoconferencing – “possibly efficacious”

105. Other psychosocial interventions
in children with depression
• One RCT compared individual psychodynamic
psychotherapy vs. family therapy
• Lots of missing data, difficult to ascertain effects
of natural remission
• Psychodynamic therapy marginally more
effective than family therapy
• Both individual psychodynamic and family
therapy considered “experimental” treatments for
children with depression

106. CBT in adolescents with
depression
• 27 randomized trials with control comparison
• CBT superior to control in 15/27 studies
• Findings replicated by independent investigators
• Considered a “well-established” treatment

107. CBT modalities in adolescents
with depression
• Fourteen studies of individual CBT – seven of
fourteen positive, including equivalence to
another effective treatment (IPT) - “well-
established treatment”
• Seven of twelve studies of group CBT positive –
“well-established treatment”
• One study of technology-assisted CBT failed to
demonstrate benefit compared to usual
treatment – “experimental”
• One of two trials of CBT bibliotherapy - positive

108. Interpersonal Therapy (IPT) in
adolescents with depression
• Six studies of IPT – five of six positive,
• Three of four studies of individual IPT positive
including equivalence to another effective
treatment (IPT) - “well-established treatment”
• Two positive studies of group IPT positive –
response in the third study was equal to “well-
established” treatments
• Group IPT – “probably efficacious”

109. Family Therapy in adolescents
with depression
• Five studies of family therapy – two positive, two
failed to separate from controls, inferior to CBT
in one study
• Difficult to interpret findings across studies
because of differences in modality used
• Family therapy – “possibly efficacious”

110. Predictors and moderators of psychotherapy
response in adolescents with depression
• Predictors – baseline characteristics of children,
teens and families associated with poor
response regardless of study conditions
• Moderators – baseline variables associated with
differential response to treatment modalities

111. Predictors of response to psychotherapy in
adolescents with depression
• Younger age of onset
• Shorter duration of
symptoms
• Better treatment
expectancy
• Readiness to change
• Poor global functioning
• Melancholic features
• Suicidality
• Non-suicidal self-harm
• Anxiety
• Cognitive distortions
• Hopelessness
• Family conflict
Positive Response Negative Response

112. Moderators of response to
psychotherapy in adolescents with
depression
• Higher severity of
symptoms
• Higher family income
(CBT)
• Comorbid anxiety
• Poor social functioning
(IPT)
• Increased family conflict
(IPT)
• Non-suicidal self-harm
• Comorbid substance
abuse
• Hopelessness
• Parental depression
Greater Response Lesser Response

113. Predictors of Outcomes in
TADS
• Younger age
• Less chronically depressed
• Higher functioning
• Less hopelessness
• Less suicidal
• Less melancholic
• Fewer comorbid diagnoses
• Greater expectations of improvement from treatment
Curry J et al. J Am Acad Child Adolesc Psychiatry, 2006;45(12):1427-1439

114. Modifiers of Outcomes in
TADS
• Combined treatment more effective than
medication in kids with moderate, but not severe
depression, kids with high levels of cognitive
distortions.
• CBT was equal to combined treatment in kids
from high income families
Curry J et al. J Am Acad Child Adolesc Psychiatry, 2006;45(12):1427-1439

115. Conclusions
• CBT and IPT are both effective and well-
established treatments in adolescents with
depression
• A paucity of research exists demonstrating
effectiveness of psychotherapy in children with
depression
• Overall trend in more recent research – more
modest benefits from treatment
• How much “evidence-based” psychotherapy is
available in the surrounding community?

116. Stay in Touch!
Family Center by the Falls: http://www.fcbtf.com
Phone: (440) 543-3400
E-mail: drgrcevich@fcbtf.com
https://www.facebook.com/StephenGrcevichMD
@drgrcevich