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Introduction to Depressive Disorders in Children and
Adolescents
Stephen Grcevich, MD
Clinical Associate Professor of Psyc...
Overview of the course…
• Epidemiology, presentation throughout
childhood/adolescence, clinical course, risk factors,
etio...
What do we know about
depression in children, teens?
• Why do kids get depressed?
• How many kids/families are affected?
•...
Question 1
A prepubertal child with a diagnosis of MDD is
most likely to have which of the following
symptoms…
• A-auditor...
Question 2
• A teenager with MDD is NOT likely to have
which of the following symptoms
• A-Hypersomnia
• B-Overeating
• C-...
Question 3
Which of the following predicts recurrence of
MDD in youth?
• A-Later age at onset
• B-Decreased number of prio...
Question 4
Which of the following increases likelihood of
bipolar disorder in youth with MDD?
• A-Comorbid ADHD
• B- Psych...
Question 5
Which statement best characterizes Persistent
Depressive Disorder in youth?
• A-Not associated with increased r...
Answers
• 1-A
• 2-D
• 3-C
• 4-E
• 5-C
What is depression?
• A condition resulting from disordered capacity for
emotional self-regulation
• Mediated by interconn...
MDD Diagnostic Criteria:
DSM-5
• At least 2 weeks of pervasive change in mood manifest
by either depressed or irritable mo...
Epidemiology
• MDD prevalence: 2% children, 4%-8%
adolescents
• Male/female ratio:
• Childhood 1:1
• Adolescence 1:2
• Cum...
National Comorbidity Survey
• Nationwide study of 10K+ adolescents for MDD
• Lifetime prevalence: 11%, 12-month prevalence...
Developmental Variations of
Depression
CHILDREN:
• More symptoms of anxiety
(i.e. phobias, separation
anxiety), somatic
co...
How does the clinical presentation of
depression differ with age?
Goldman S. Child Adolesc Psychiatric Clin N Am 21 (2012)...
Clinical Course of Depression:
• Median Duration:
Clinically referred youth: 7-
9 months
Community youth: 1-2
months
• Pre...
Relapse
• Relapse is an episode of MDD during period of
remission
• Predictors of relapse: Natural course of MDD, lack of
...
Recurrence
• Defined as emergence of
MDD symptoms during
recovery (asymptomatic
period of more than 2
months)
• Probabilit...
Risk of Bipolar Disorder in Kids
with Major Depression
20%-40% MDD youth develop bipolar disorder in 5 years of onset of
M...
Risk factors for depression
• Family history
• Prior experience of
depression
• Negative cognitive
style
• Bereavement
• P...
Sources of biological vulnerability
• Transporter genes (gene x environment pathway)
• HPA axis
• Affective and vagal tone...
Neuroimaging Findings:
• Cortical thinning as possible endophenotype of early-onset
depression (Peterson & Weissman, 2011)...
Neuroimaging findings in
females…
• Smaller nucleus accumbens volume
• Increased growth of amygdala from early to
mid-adol...
Genetic Factors
• Children with depressed parent 3x likely to
have lifetime episode of MDD (lifetime risk
15%-60%)
• Conco...
Epigenetic Factors
• Epigenetic changes in ID3, GRIN1, and TPPP genes in combination
with experiences of maltreatment may ...
Summary of contributing factors to course
of childhood, adolescent depression
• 2-4X increased risk after puberty, especia...
Questions?
Depressive Disorders in Children and Adolescents
Issues in Evaluation and Diagnosis
• Stephen Grcevich, MD
• Clinical Assi...
Topics to be covered today:
• Diagnostic criteria for depressive disorders seen in
children and teens
• Differential diagn...
How do you diagnose
depression?
• What signs, symptoms are you looking for in your
interviews with child/parent/caregiver?...
MDD Diagnostic Criteria:
DSM-5
• At least 2 weeks of pervasive change in mood manifest
by either depressed or irritable mo...
Differential Diagnosis of MDD
in Children, Teens
• Anxiety disorders, OCD
• DMDD
• Bipolar disorder
• Learning disabilitie...
Differential Diagnosis:
Complexities of General Medical
Conditions
• May be accompanied by symptoms of depression
• Impact...
Medical conditions associated
with depressive symptoms
• Cancer, hypothyroidism, lupus, acquired
immunodeficiency syndrome...
Comorbidity
• Present in 40%-90% of youth with MDD; two or more
comorbid disorders present in 20%-50%
• Comorbidity in you...
Diagnostic Complexities
• Overlap of mood disorder symptoms
• Symptoms overlap with comorbid disorders
• Developmental var...
Rating Scales for Depression
• Children’s Depression Inventory (CDI 2)
• Beck Depression Inventory (BDI-II)
• Rating scale...
Children’s Depression
Inventory
• Originally derived from BDI
• 27 item, self-report scale used in children ages 7-17
• Ea...
Beck Depression Inventory
(BDI-II)
• 21 item, self-report scale
• Designed for individuals ages 13 and up
• Patient asked ...
Advantages and disadvantages
of rating scales…
• Advantages:
• May help guide treatment decision-making
• Provides a tool ...
Distinguishing bereavement from
depression in the DSM-5
• Painful feelings often come in
waves, intermixed with
positive m...
Persistent Depressive Disorder
(Dysthymia) DSM-5 Criteria:
• Persistent, long-term change in mood, less
intense but more c...
Clinical Course: Relation of
Persistent Depressive Disorder
• Associated with increased risk of MDD
• 70% of youth with Pe...
DSM-5 Depressive Disorder Modifiers
Suggest Need for Alternate Intervention
Strategies
• Anxious Distress
• Mixed features...
Depressive disorder modifiers
in DSM-5: Anxious Distress
At least two of the following symptoms during the majority of
day...
MDD with psychotic features
• MDD associated with mood congruent or incongruent
hallucinations and/or delusions (unlike ad...
Depressive disorder modifiers
in DSM-5: Mixed Features
At least three of the following manic/hypomanic symptoms during the...
Depressive disorder modifiers
in DSM-5: Melancholic Features
Loss of pleasure in all, or almost all activities, or lack of...
Depressive disorder modifiers
in DSM-5: Atypical Features
These features predominate during the majority of days of a
majo...
Depressive disorder modifiers
in DSM-5: Psychotic Features
Delusions and/or hallucinations are present
• Mood-congruent ps...
Depressive disorder modifiers
in DSM-5: Seasonal pattern
This specifier applies to recurrent Major Depressive
Disorder…
• ...
What about Disruptive Mood
Dysregulation Disorder?
There’s a large group of kids who demonstrate…
• Irritability as their ...
DSM-5 criteria for Disruptive Mood
Dysregulation Disorder (DMDD):
• A. Severe, recurrent temper outbursts manifested verba...
What do kids with DMDD look like?
• Most have ADHD (86.3%) and ODD (84.2%)
• 60% at NIMH were diagnosed in community with ...
What I’ve observed about kids
with DMDD…
• They have difficulty with transitions…”cognitive rigidity”
• They tend to “rumi...
How I’m treating DMDD…
• Conservative use of ADHD medication…limited as much as
possible to school day
• Meltdowns related...
Summary: MDD in Children &
Adolescents
• Diagnostic criteria similar for depression in children
and adults, although clini...
Biological Treatment of Depression in Children and
Adolescents
Stephen Grcevich, MD
Clinical Assistant Professor of Psychi...
What we’ll look at today…
• Examine the relevant literature evaluating the safety and
efficacy of antidepressants in child...
Question 1: Which of the following medications
are approved by the FDA for use in pediatric
depression?
• A: Paroxetine (P...
Question 2: Which of the following
statements about the TADS study is
true?
• A: CBT appeared to provide significant benef...
Question 3: Which of the
following statements is false:
• A: Most randomized studies of SSRIs in youth with depression
hav...
Answers
• 1-E
• 2-C
• 3-A
MDD Diagnostic Criteria: DSM-5
• At least 2 weeks of pervasive change in mood manifest
by either depressed or irritable mo...
Treatment options for
depression:
• Antidepressant medication
• Cognitive-Behavioral Therapy (CBT)
• Family Therapy
• Othe...
Indications for Pharmacotherapy in
AACAP Practice Parameters for
Depression:
• Children, teens with moderate to severe
dep...
Metanalysis of Randomized
Trials of SSRIs:
• Effect size of SSRIs in MDD: 0.25
• Effect size in OCD: 0.48
• Effect size in...
FDA approved medications for
MDD in children, adolescents…
• Fluoxetine for patients ages 8 and above
• Escitalopram for p...
Why does fluoxetine perform better
than other SSRIs in MDD?:
• Long half life makes inconsistent adherence less of
a conce...
The TADS (Treatment of
Adolescent Depression) Study
• NIMH sponsored “The Treatment of Adolescents with
Depression Study” ...
TADS Study: Response
Rates
March J et al. J Am Acad Child Adolesc Psychiatry, 2006;45(12):1393-1403
Week FLX+CBT FLX CBT P...
TADS Study: Full Remission (36 weeks)
Kennard B et al. (2006), J Am Acad Child Adolesc Psychiatry 45:1404-1411
0
5
10
15
2...
TADS: Suicidal ideation in acute
treatment
Serotonin transporter
binding:
Treatment Resistant Study
(TORDIA):
• NIMH funded multicenter study “Treatment of
Resistant Depression in Adolescents (TOR...
TORDIA Results:
• Response to CBT+2nd antidepressant 54%,
antidepressant alone 41% (significant)
• 2nd SSRI and Venlafaxin...
Early response important in
TORDIA:
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):168...
The FDA and Antidepressants
for Kids:
• Boxed warning regarding increased risk of suicidality
issued 10/15/04
• Antidepres...
Suicide rates in U.S., 1970-2010
How effective (or safe) is the
drug I might prescribe?
• Number Needed to Treat (NNT)
• The average number of patients who...
Calculating the NNT…
Total number of patients treated
Responders to active treatment – Placebo responders
The “perfect” dr...
Metanalysis of Randomized
Trials of SSRIs:
• Increased risk of SI/SA in MDD vs. PBO: 0.9%
• Increased risk of SI/SA in OCD...
Do risks and benefits vary by the condition
being treated?
(Number Needed to Harm)
0
50
100
150
200
250
Depression Anxiety...
Risk/Benefit Ratio of SSRIs by
condition treated
0
5
10
15
20
25
30
35
40
Depression Anxiety OCD
Risks and benefits of ant...
Predictors of Suicidal Events
Grcevich SJ et al. Presented at American Academy of Child and Adolescent Psychiatry, October...
SSRI side effects:
• Nausea
• Weight gain
• Behavioral activation/disinhibition
• Restlessness
• Vivid dreams
• Increased ...
SSRI Withdrawal
SSRI Half-lives
EKG Monitoring and
Citalopram
Medication algorithm for MDD
in children, adolescents:
Duloxetine for MDD in
children, adolescents:
Treatment of MDD: Tricyclic
Antidepressants (TCA’s)
• TCA’s: imipramine, desipramine, amitriptyline,
nortriptyline, doxepi...
Omega-3s in prepubertal
depression:
rTMS in adolescent
depression:
Light therapy for adolescent
depression:
Exercise for Adolescent
Depression:
ECT for Depression:
• No RCTs in adolescents
• May be effective treatment for adolescents with severe mood
disorders when ...
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% ...
Conclusions:
• Pharmacotherapy is appropriate treatment option for
children, teens with moderate-severe MDD or kids with
M...
Psychosocial Treatment of Depression in Children
and Adolescents
Stephen Grcevich, MD
Clinical Assistant Professor of Psyc...
What we’ll look at today…
• Examine the evidence base for psychosocial treatments of
depression in children and teens
• Di...
CBT in children (under age 13)
with depression
• Seven controlled studies (patients compared to
waitlist or psychologicall...
CBT modalities in children with
depression
• Three studies of individual CBT – “experimental
treatment”
• Four studies of ...
Other psychosocial interventions
in children with depression
• One RCT compared individual psychodynamic
psychotherapy vs....
CBT in adolescents with
depression
• 27 randomized trials with control comparison
• CBT superior to control in 15/27 studi...
CBT modalities in adolescents
with depression
• Fourteen studies of individual CBT – seven of
fourteen positive, including...
Interpersonal Therapy (IPT) in
adolescents with depression
• Six studies of IPT – five of six positive,
• Three of four st...
Family Therapy in adolescents
with depression
• Five studies of family therapy – two positive, two
failed to separate from...
Predictors and moderators of psychotherapy
response in adolescents with depression
• Predictors – baseline characteristics...
Predictors of response to psychotherapy in
adolescents with depression
• Younger age of onset
• Shorter duration of
sympto...
Moderators of response to
psychotherapy in adolescents with
depression
• Higher severity of
symptoms
• Higher family incom...
Predictors of Outcomes in
TADS
• Younger age
• Less chronically depressed
• Higher functioning
• Less hopelessness
• Less ...
Modifiers of Outcomes in
TADS
• Combined treatment more effective than
medication in kids with moderate, but not severe
de...
Conclusions
• CBT and IPT are both effective and well-
established treatments in adolescents with
depression
• A paucity o...
Stay in Touch!
Family Center by the Falls: http://www.fcbtf.com
Phone: (440) 543-3400
E-mail: drgrcevich@fcbtf.com
https:/...
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Introduction to Depressive Disorders in Children and Adolescents

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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

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Introduction to Depressive Disorders in Children and Adolescents

  1. 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. 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. 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. 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. 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. 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. 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. 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. 9. Answers • 1-A • 2-D • 3-C • 4-E • 5-C
  10. 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. 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. 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. 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. 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. 15. How does the clinical presentation of depression differ with age? Goldman S. Child Adolesc Psychiatric Clin N Am 21 (2012) 217-235.
  16. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 27. Questions?
  28. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 50. Depressive disorder modifiers in DSM-5: Psychotic Features Delusions and/or hallucinations are present • Mood-congruent psychotic features • Mood-incongruent psychotic features
  51. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 63. Answers • 1-E • 2-C • 3-A
  64. 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. 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. 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. 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. 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. 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. 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. 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. 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. 73. TADS: Suicidal ideation in acute treatment
  74. 74. Serotonin transporter binding:
  75. 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. 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. 77. Early response important in TORDIA:
  78. 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. 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. 80. Suicide rates in U.S., 1970-2010
  81. 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. 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. 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. 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. 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. 86. Predictors of Suicidal Events Grcevich SJ et al. Presented at American Academy of Child and Adolescent Psychiatry, October 2009
  87. 87. SSRI side effects: • Nausea • Weight gain • Behavioral activation/disinhibition • Restlessness • Vivid dreams • Increased clotting time • Fatigue • Sexual side effects
  88. 88. SSRI Withdrawal
  89. 89. SSRI Half-lives
  90. 90. EKG Monitoring and Citalopram
  91. 91. Medication algorithm for MDD in children, adolescents:
  92. 92. Duloxetine for MDD in children, adolescents:
  93. 93. Treatment of MDD: Tricyclic Antidepressants (TCA’s) • TCA’s: imipramine, desipramine, amitriptyline, nortriptyline, doxepin, clomipramine • No RCTs have demonstrated efficacy vs. placebo
  94. 94. Omega-3s in prepubertal depression:
  95. 95. rTMS in adolescent depression:
  96. 96. Light therapy for adolescent depression:
  97. 97. Exercise for Adolescent Depression:
  98. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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

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