Learning Pediatric Depressive Disorders Goals/Objectives Public - PDF document

Pediatric Depressive Disorders Prevalence Treatment Resistant Depression in Youth • ~2% of children • ~4 to 8% of adolescents John V. Campo, M.D. • Cumulative incidence 10-20% age 18 • Gender ratio Nationwide Children’s Hospital and The Ohio State University � Equal before puberty � Females predominate after puberty Learning Pediatric Depressive Disorders Goals/Objectives Public Health Relevance • Often unrecognized • Familiarity with the prevalence and impact � By patients and families of depression in children and adolescents � By clinicians • Familiarity with psychoeducation and • Functional impairment evidence based treatments for pediatric depressive disorders � Interpersonal and social impairment • Develop a management approach for � Poor school attendance/performance pediatric depressive disorders that prove resistant to initial treatment • Risk of persistence/recurrence 1

Pediatric Depressive Pediatric Depressive Disorders Disorders Public Health Relevance (cont.) Common Presentations – Signs • Psychiatric Comorbidity � ~ 1/3 to 2/3 of patients • Declining school performance � Greater impairment and service use • Social withdrawal � Associated with treatment resistance • Temper outbursts/arguing • Physical Comorbidity • Alcohol/substance abuse � Functional somatic symptoms • School absenteeism � Minor physical illness • Functional somatic symptoms � Chronic physical illness Pediatric Depressive Disorders Major Depressive Disorder Public Health Relevance (cont.) (MDD) Features in Youth • Physical health risks � Suicide, violence, accidental injury • Clinical picture similar to adults • Median duration � Alcohol/drug/tobacco use � 7 - 9 months - clinical samples � Health risk behaviors/unhealthy lifestyle � 1 - 2 months - community samples � Exacerbation of existing physical � ~ 90% remit by 1 to 2 years disease • Recurrence ~ 70% within 5 years • Nonadherence • Physiologic effects on disease process 2

Major Depressive Disorder (MDD) Major Depressive Disorder (MDD) Features in Youth (cont.) Risk for Recurrence • Bipolar disorder in 10 to 20% • Greater initial severity • Predictors of bipolar disorder • Subsyndromal depression � Psychosis • Parent-child conflict � FH of bipolar disorder • Abuse history � Rapid onset/offset � Mania/hypomania with Rx Building Foundation for Major Depressive Disorder (MDD) Intervention Risk for Prolonged Episode Establishing Credibility • Greater initial severity • Clear and frank diagnosis • Psychiatric comorbidity � Reassurance and education � Dysthymic disorder � Address uncertainties • Treatment as a partnership � Other psychiatric disorder � Delineate responsibilities • Anxiety, ADHD, Substance abuse � Facilitate communication • Parental depression � Honest collaboration • Parent-child conflict • Instill hope and positive expectations 3

SSRIs Treatment of Pediatric Selective Serotonin Reuptake Depression Inhibitors What is known? � Citalopram (Celexa) • Psychotherapeutic treatment � Escitalopram (Lexapro) � Cognitive Behavioral Therapy � Fluoxetine (Prozac) � Interpersonal Therapy • FDA approved pediatric MDD, OCD � Fluvoxamine (Luvox) • Psychopharmacologic treatment � SSRIs • FDA approved pediatric OCD � Paroxetine (Paxil) • Combination treatment � Sertraline (Zoloft) � CBT + SSRI • FDA approved pediatric OCD Treatment SSRI Efficacy Major Depressive Disorder Self-Care (MDD) • Several positive RCTs � Best data for fluoxetine � Less data for other individual SSRIs • > 2 positive trials needed for FDA approval • Often 4-5 trials needed for adult Rx approval • High placebo response rates (33-59%) • SSRI continuation may ↓ depression relapse • Combination CBT + SSRI > SSRI alone 4

TADS SSRI Safety Treatment for Adolescents Practical Considerations w/ Depression Study • 12-week multisite study of youth aged 12 to 17 • Pharmacokinetic drug-drug interactions years with MDD (N=439) • Clinical Global Improvement � Cytochrome P-450 system � CBT + fluoxetine 71%* • Citalopram, escitalopram, sertraline least � Fluoxetine 61%* problematic � CBT 43% • Lack of long-term safety data � Placebo 35% • * significantly different from placebo • CBT did not differentiate from placebo • Suicidality ↓ from 29% to 10% by week 12 SSRI Safety SSRI Tolerability Practical Considerations Common AEs (Side Effects) • Usually mild and dose dependent � GI symptoms (e.g., nausea, diarrhea) • Relatively HIGH therapeutic index (TI) � Headache � Low short term toxicity � Anxiety, nervousness, panic • Risk of suicidality � Sleep disturbance • Risk of precipitating mania � Restlessness, irritability, and agitation � Sedation, fatigue • Pharmacodynamic interactions � Dizziness or lightheadedness � Serotonin syndrome, bruising/bleeding � Sexual dysfunction � Other (e.g., tremor, dry mouth, sweating) • No well demonstrated long-term AEs in youth 5

Reanalysis of FDA Data SSRI Safety Antidepressant Efficacy for Youth FDA “Black Box” Warning # of N = % % Risk P- NNT Dx • To all antidepressant medications in U.S. RCTs 5,310 Response Difference Value (95% � “ increase the risk of suicidal thinking and Drug vs. (95% CI) CI) behavior in children and adolescents…” Placebo • Based on FDA review of 24 RCTs (N ~ 4400) � SSRIs ( Citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) 3,430 11 (8-15) <.001 10 MDD 15 61 vs. 50 (7-15) � Non-SSRIs ( Bupropion, mirtazipine, nefazodone, venlafaxine) � 95 AEs reclassified from raw data OCD 6 718 52 vs. 32 20 (13-27) <.001 6 (4-8) • “Suicidality” = attempt, SI, preparatory acts Anxiety 6 1,162 69 vs. 39 37 (22-52) <.001 3 • Suicidality in ~ 4% drug vs. 2% placebo (2-5) � No completed suicides CI= Confidence Interval � Only significant for venlafaxine alone RCTs = Randomized Controlled Trials Bridge et al., JAMA 2007 SSRI Safety Reanalysis of FDA Data A Public Health Perspective Rate of Emergent Suicidality • Coincident ↓ pediatric suicide rates with ↑ Dx # of Emergent % Risk P- NNH N = SSRI prescribing since late 1990s RCTs Suicidality Difference Value 5,310 (%) (95% CI) � Similar findings in US and Europe Drug vs. Placebo � Geographic trends for ↓ suicide with ↑ Rx • Longer Rx may reduce suicide risk MDD 15 3,430 3 vs. 2 1(-0.1-2) NS 125 � Rx > 180 days vs. Rx < 55 days OCD 6 718 1 vs. 0.5 0.5(-1- 2) NS 200 • Studies of completed suicide Anxiety 6 1,162 1vs. 0.2 0.7(-.4-2) NS 143 � < 10% completed suicides who had been CI= Confidence Interval prescribed antidepressants + at autopsy NS = Not significant RCTs = Randomized Controlled Trials Bridge et al., JAMA 2007 6

TORDIA SSRI Dosing Treatment of Resistant Depression in Adolescents • “Start low and go slow” • 12-week multisite study of youth aged 12 to 18 years with MDD who failed to respond to SSRI � Starting dose over first 3 to 7 days (N=334) � If tolerated, increase to target dose • Clinical Response � Reevaluate dose within 2 –3 weeks � SSRI 47.0 % � Venlafaxine 48.2 % � No CBT 40.5 % � CBT 54.8 % SSRI Dosing TORDIA Treatment of Resistant Depression in Adolescents • Starting doses Target Max • Conclusion 10 mg citalopram 20 mg 40 mg 5 mg escitalopram 10 mg 20 mg � CBT + Medication change > Medication change alone 10 mg fluoxetine 20 mg 40 mg � Switch to another SSRI just as 50 mg fluvoxamine 100 mg 300 mg efficacious as switch to Venlafaxine 25 mg sertraline 50 mg 200 mg and with fewer adverse events 7

SSRI Failure for Depression Treatment-Refractory What to do with limited evidence? Depression • Encourage psychotherapy – especially CBT Lessons from • Medication option 1 – Switch to a different SSRI Sir Arthur Conan Doyle & Sherlock Holmes • Medication option 2 – Switch to a different agent Stephen F. Pariser, M.D. � Switch to different antidepressant class Professor OSU Department of Psychiatry Director Mood Disorders Clinic • Novel agents (bupropion) Associate Chairman, CME • SNRIs (venlafaxine, mirtazapine, duloxetine) Ohio State University • Older agents (TCAs, MAOIs) College of Medicine & Public Health Sir Arthur Conan Doyle SSRI Failure for Depression 1859-1930 What to do with limited evidence? Son of Charles Altamont Doyle, a civil servant • in the Edinburgh Office of Works, and Mary • Medication option 3 – Augmentation strategies (Foley) Doyle. His father suffered from epilepsy and alcoholism and died in an asylum � SSRI augmentation strategies in 1893-mother kept a boarding house • Bupropion Educated in Jesuit schools; later studied at • Edinburgh University, qualifying as a doctor in • Busiprone 1885. After graduation practiced medicine until 1891, when he became a full time writer • Lithium Based Sherlock Holmes* on Doctor Joseph • • Atypical antipsychotics (e.g., aripiprazole) Bell, a surgeon and teacher** http://www.sherlock-holmes.org.uk/The_Society/Arthur_Conan_Doyle/Arthur_Conan_Doyle.htm *As far as Holmes' name, his last name may have been based on American jurist and fellow doctor Oliver Wendell Holmes and his first name may have come from Alfred Sherlock, a prominent violinist of his time. **Dr. Bell had the uncanny ability to reveal a patient's symptoms, diagnose patients and report on their origins before they would speak a word to him about their afflictions 8