Introduction to Depressive Disorders in Children and Adolescents

1. Introduction to Depressive Disorders in Children and Adolescents Stephen Grcevich, MD Clinical Associate Professor of Psychiatry, NEOMED Presented at Children’s Hospital Medical Center of Akron September 2020 sgrcevich@neomed.edu

2. Course Overview • Session One: Epidemiology, presentation throughout childhood/adolescence, clinical course, risk factors, etiology • Session Two: Evaluation – diagnostic criteria, differential diagnosis, comorbidity, use of rating scales • Session Three: Pharmacotherapy and other medical treatments • Session Four: Non- pharmacologic treatments

3. What do we know about pediatric depression? • Why do kids get depressed? • How many kids/families are affected? • Developmental impact on kids?

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 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

7. Question 4 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

8. 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

9. 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

10. Epidemiology • MDD prevalence: 2% children, 4%-8% adolescents • 3.2% in children ages 3- 17 from most recent NCHS* • Male/female ratio: • Childhood 1:1 • Adolescence 1:2 • Cumulative incidence by age 18 years: 20% • 5% to 10% of youth have subsyndromal symptoms of MDD • Persistent Depressive Disorder prevalence: 0.6%- 1.7% children, 1.6%-8% adolescents *Ghandour RM et al. J Pediatr. 2019 March;206:256–267.e3

11. 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

12. 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

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

14. 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 Birmaher B et al. Child Adolesc Psychiatr Clin N Am. 2002; 11: 619-637

15. 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

16. 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

17. 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

18. Predictors of Manic Switching on Antidepressants in Kids with ADHD Additive risk of switching: conduct disorder, school behavior problems, parental mood disorder Biederman J et al. J Affect Disord. 2009 Dec; 119(1-3): 16–21.

19. 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.

20. 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/n eurocognitive changes of adolescence

21. 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) • Increased growth of amygdala from early to mid-adolescence in females

22. 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)

23. 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

24. 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

25. Questions?

26. Depressive Disorders in Children and Adolescents: Issues in Evaluation and Diagnosis Stephen Grcevich, MD Clinical Assistant Professor of Psychiatry, NEOMED Presented at Akron Children’s Hospital September 10, 2020

27. 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?

28. 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?

29. 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

30. 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)

31. 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

32. 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

33. 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

34. 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?

35. 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://candapediatricmedical homes.wordpress.com/child- psychiatry-rating-scales-for- primary-care-physicians/

36. 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

37. 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.

38. Advantages, 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?

39. 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

40. Persistent Depressive Disorder (Dysthymia) DSM-5 Criteria: • Persistent, long-term change in mood, less intense but more chronic than MDD • Cause as much or more psychosocial impairment as 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 Kovacs M et al. Arch Gen Psychiatry. 1994; 51: 365-374

41. 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

42. 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

43. 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

44. 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)

45. 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 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

46. 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

47. 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

48. 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

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

50. 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.

51. 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

52. 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

53. 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

54. 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

55. 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)

56. 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

57. Answers • 1-A • 2-D • 3-E • 4-C

58. Biological Treatment of Depression in Children and Adolescents Stephen Grcevich, MD Clinical Assistant Professor of Psychiatry, NEOMED Presented at Akron Children’s Hospital September 17, 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 provided 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: In most randomized studies of youth with depression, SSRIs are significantly 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 limit the ability to generalize results of psychotherapy studies in depressed youth.

63. Question 4: Which of the following statements is true: • A: Effect sizes are significantly larger for interpersonal therapy (IPT) in depressed teens than cognitive behavioral therapy (CBT). • B: Psychotherapy effect sizes in depressed youth are moderate to robust. • C: Parent ratings suggested more positive response to treatment than self-ratings. • D: Greater effects were seen from psychotherapy on anxiety measures vs. depression ratings.

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 red

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: • 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. 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

69. 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

70. 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

71. Fluoxetine: Serotonin receptor binding by dose Meyer JH et al. Am J Psychiatry 2004; 161:826–835

72. Treatment of Adolescent Depression (TADS) Study • Multicenter controlled clinical trial • Ages 12-17 with MDD • Compared efficacy of fluoxetine, CBT, combination, & placebo in 36 weeks with one- year follow-up.

73. 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%

74. 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

75. TADS: Suicidal ideation in acute treatment March J et al. J Am Acad Child Adolesc Psychiatry, 2006;45(12):1393-1403

76. 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 one-year follow-up Brent D et al, JAMA, 2008;299(8):901-913

77. TORDIA Results: • Response to CBT+2nd antidepressant 54%, antidepressant alone 41% (significant) • 2nd SSRI and Venlafaxine equally effective • 2nd SSRI better tolerated than venlafaxine

78. Early response important in TORDIA:

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/anti depressants/default.htm

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

81. How safe, effective 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 • NNH/NNT

82. Calculating the NNT… Total number of patients treated Responders to active treatment minus 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. 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 Bridge JA et al, JAMA 2007; 297(15):1683-1696

84. 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 Bridge JA et al, JAMA 2007; 297(15):1683-1696

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

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

87. SSRI Withdrawal

88. SSRI Half-lives

89. EKG Monitoring and Citalopram

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

91. Duloxetine for MDD in children, adolescents:

92. Desvenlafaxine for adolescent depression Weihs KH et al. J Child Adolesc Psychopharmacol; 28(1)

93. Medication algorithm for MDD in children, adolescents:

94. Algorithm for treatment- resistant depression in youth Wagner KD. Presented at AACAP Annual Meeting, 2017

95. Ketamine for treatment- resistant adolescent depression • Open label study, N=13, six infusions (0.5 mg/kg) over two weeks • Five (38%) adolescents met criteria for clinical response. • Three - sustained remission at 6-week follow-up; relapse within 2 weeks for other two responders. • Infusions were generally well tolerated; • Dissociative symptoms and hemodynamic symptoms were transient. • Higher dose was a significant predictor of treatment response. Cullen KR et al. J Child Adolesc Psychopharmacol; 28(7):437-444

96. TMS in Adolescent Depression Croarkin PE, McMaster FP. Child Adolesc Psychiatr Clin N Am. 2019 January ; 28(1): 33–43

97. ECT for Depression: • No RCTs in adolescents • May be effective treatment for when more conservative treatments have failed. • 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 mandatory - patient’s consent or assent should be obtained. • Systematic pre-treatment, post- treatment evaluation, including symptom and cognitive assessment is recommended.

98. 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

99. Exercise for Adolescent Depression:

100. Omega-3s in prepubertal depression: Nemets H et al. Am J Psychiatry (2006) 163(6):1098–100.

101. Light therapy for adolescent depression:

102. Conclusions: • Pharmacotherapy is appropriate for moderate- severe MDD or kids with MDD + suicidal ideation/plan • Fluoxetine & escitalopram only FDA-approved medications for MDD in pediatric population • Venlafaxine 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

103. Psychotherapeutic Treatment of Depression in Children and Adolescents Stephen Grcevich, MD Clinical Assistant Professor of Psychiatry, NEOMED Presented at Akron Children’s Hospital September 17, 2020

104. 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.

105. CBT and IPT: Two evidence- based psychotherapies Pediatrics March 2018, 141 (3) e20174082

106. 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” Weisz JR et al. J Consult Clin Psychol. 1997;65:703-707.

107. 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” Weersing VR et al. J Clin Child Adolesc Psychol. 2017 ; 46(1): 11–43

108. 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 Weersing VR et al. J Clin Child Adolesc Psychol. 2017 ; 46(1): 11–43

109. CBT in adolescents with depression • 26 randomized trials with majority adolescent samples • Mean effect size = 0.34 • Findings replicated by independent investigators • Considered a “well- established” treatment • Treatment effect sizes 42 weeks post treatment are quite modest (0.21) Eckshtain D et al. J Am Acad Child Adolesc Psychiatry 2020;59(1):45–63.

110. 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 Weersing VR et al. J Clin Child Adolesc Psychol. 2017 ; 46(1): 11–43

111. Interpersonal Therapy (IPT) in adolescents with depression • Five studies of individual IPT – four positive, • Three of four studies of individual IPT positive including equivalence to another effective treatment (CBT) - “well-established treatment” • Larger effect sizes (0.78) for IPT than CBT (0.31) Eckshtain D et al. J Am Acad Child Adolesc Psychiatry 2020;59(1):45–63.

112. Psychotherapy effect sizes associated with informant, treatment modality, comparison group Eckshtain D et al. J Am Acad Child Adolesc Psychiatry 2020;59(1):45–63.

113. 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” Weersing VR et al. J Clin Child Adolesc Psychol. 2017 ; 46(1): 11–43

114. 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 Weersing VR et al. J Clin Child Adolesc Psychol. 2017 ; 46(1): 11–43

115. 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 Weersing VR et al. J Clin Child Adolesc Psychol. 2017 ; 46(1): 11–43

116. 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 Weersing VR et al. J Clin Child Adolesc Psychol. 2017 ; 46(1): 11–43

117. Positive Outcome Predictors 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); 1427-39

118. 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

119. July 2020 review: Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination • Fluoxetine + CBT > CBT alone, psychodynamic therapy but not more effective than fluoxetine alone • No pharmacotherapy alone was more effective than psychotherapy alone • Only fluoxetine plus CBT and fluoxetine > pill placebo or psychological controls • Only IPT more effective than all psychological controls • Most results rated as “low” to “very low” in terms of confidence of evidence • Fluoxetine (alone or in combination with CBT) best choice for acute treatment of moderate-severe depression in children, adolescents Lancet Psychiatry. 2020 Jul; 7(7): 581–601

120. Conclusions • CBT and IPT are both effective and well- established treatments in adolescents with depression. • Overall trend in more recent research – little change in effect sizes compared to earlier studies. • How much “evidence- based” psychotherapy is available in the surrounding community?

121. Answers • 1-E • 2-C • 3-A • 4-A

122. Stay in touch! Stephen Grcevich, MD Family Center by the Falls 8401 Chagrin Road, Suite 14B Chagrin Falls, OH 44023 Office: (440) 543-3400 E-mail: drgrcevich@fcbtf.com Twitter:@drgrcevich

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