PSYCHOPHARMACOLOGIC APPROACHES TO DEPRESSION IN CHILDREN AND - PowerPoint PPT Presentation

PSYCHOPHARMACOLOGIC APPROACHES TO DEPRESSION IN CHILDREN AND ADOLESCENTS

Learning Objectives • Describe the evidence for selective serotonin reuptake inhibitors (SSRIs) in youth with depressive disorders • List predictors of treatment response in adolescents with SSRI-resistant major depressive disorder • List specific patient characteristics that may guide treatment selection in adolescents with major depressive disorder

Off-Label Medication Use Dr. Strawn does intend to discuss the use of off-label/unapproved use of drugs.

Clinical Aspects of Depression Vary Weight loss (increases with age) 1 Hypersomnia (increases with age) 2 Depressed mood, lack of concentration, insomnia, suicidal ideation Irritability 3 Increase in suicide attempts and Moodiness 3 suicide completion Loss of interest 3 Somatic complaints Delusions Age 4 Age 7 Puberty Preschool School-Age Adolescence Ryan et al. The Clinical Picture of Major Depression in Children & Adolescents. Arch Gen Psychiatry 1987;44:854-61; Luby et al. Modification of DSM-IV Criteria for Depression in Depressed Preschool Children. Am J Psychiatry 2003;160:1169-72; Lewinsohn et al. Major depression in community adolescents: age at onset, episode duration, and time to recurrence. J Am Acad Child Adolesc Psychiatry 1994;33:809-18.

EDSP: Incidence and Onset of Depression Beesdo et al. Incidence and risk patterns of anxiety and depressive disorders and categorization of generalized anxiety disorder. Arch Gen Psychiatry 2010;67:47-57.

Treatment of Depression in Youth • Multimodal treatment—psychotherapy and pharmacotherapy • Pharmacotherapies • Psychotherapies • SSRIs are 1 st line • cognitive behavioral, psychopharmacologic treatment • supportive, for children with depression • group, • SNRIs are also being used by • family therapy, many clinicians, but data are limited • social skills training, and • No positive trials for MAOIs • psychodynamic • No positive trials for TCAs Strawn and Walkup. The quest to identify the best treatment for pediatric depression. Lancet Psychiatry 2020 (in press); Birmahar et al. Practice Parameter for the Assessment and Treatment of Children and Adolescents with Depressive Disorders. J Am Acad. Child Adolesc Psychiatry 2007;46:1503-26.

Treatment of Adolescent Depression Study Placebo Depression Rating Scale Score CBT Alone 60 Adjusted Mean Children’s Fluoxetine alone • Fluoxetine + CBT > placebo, p=.001 Fluoxetine + CBT • Fluoxetine + CBT > fluoxetine, p=.02 • Fluoxetine > CBT alone, p=.01 45 • Response rates: • fluoxetine + CBT, 71%; • fluoxetine alone, 61%; • CBT alone, 43%; 30 6 • placebo, 35% 0 12 Treatment Week March et al. JAMA 2004;292:807-20; Emslie et al. J Am Acad Child Adolesc Psychiatry 2006;45:1440–55.

Symptomatic Improvement in MDD 4 Morbid Thoughts Anhedonia Mean Scale Score Observed Depression 3 Reported Depression 2 1 0 6 8 10 0 1 2 3 4 12 Fluoxetine Treatment Week Tao et al. J Child and Adolesc Psychopharmacology 2010.

Time Course of Response and Side Effects Receptor sensitivity Monoamine levels Weight gain (if applicable) activation Symptoms Duration of antidepressant treatment

SSRI Response: How long to wait? 0 Improvement in Depressive -0.1 Symptoms -0.2 -0.3 -0.4 -0.5 0 2 4 6 8 10 Week Varigonda et al. JAACAP 2015;54(7):557-64; Strawn et al. JAACAP 2018;57(4):235-44.

Titration Strategies Based on RCTs escitalopram sertraline fluoxetine Initial 5 mg 25 mg 5 mg Week 1 10 mg 50 mg 20 mg Week 2 10 mg 50 mg 20 mg Week 3 10 mg 100 mg 20 mg Week 4 10 mg 100 mg 20 mg Optional increases Week 5 15 mg 100 mg 40 mg Week 6 15 mg 150 mg 40 mg Week 7 20 mg 150 mg 40 mg Week 8 20 mg 150 mg 40 mg Week 9 20 mg 150 mg 40 mg Age 7–11 Week 10 20 mg 150 mg 40 mg

Titration Strategies Based on RCTs escitalopram sertraline fluoxetine Initial 5 mg 25 mg 10 mg Week 1 5 mg 50 mg 10 mg Week 2 10 mg 50 mg 20 mg Week 3 10 mg 50 mg 20 mg Week 4 15 mg 75 mg 20 mg Optional increases Week 5 15 mg 100 mg 20 mg Week 6 20 mg 100 mg 20 mg Week 7 20 mg 150 mg 40 mg Week 8 20 mg 150 mg 40 mg Week 9 20 mg 200 mg 60 mg Age 12–17 Week 10 20 mg 200 mg 60 mg

Rationale for Focus on Adolescents With Treatment-Resistant Depression (TRD) • Remission rate around 30% • TRD associated with increased morbidity and development of chronic depression • Identify the next, best steps for SSRI- resistant depression in adolescents Brent et al. Treatment of Resistant Depression In Adolescents. JAMA 2008;299(8):901-13. Strawn and Walkup. The quest to identify the best treatment for pediatric depression. Lancet Psychiatry 2020 (in press). Strawn et al. Treatment Resistant Depression in Adolescents: Clinical Features and Measurement of Treatment Resistance. J Child Adolesc.Psychopharm 2020 (in press).

Defining “Adequate” SSRI Treatment Fluoxetine 40 mg • > 8 weeks • Last 4+ weeks at equivalent of 40 mg of Fluoxetine 40 mg fluoxetine • May use 20 mg equivalent if unable to tolerate higher dose Fluoxetine 20 mg Brent D et al. JAMA 2008;299(8):901-13.

TORDIA Design SNRI Venlafaxine XR N= 334 Age: 12–18 years SNRI + CBT Dx: MDD + no Venlafaxine XR response to 2-month SSRI initial SSRI Non-responders SSRI + CBT (>2 mos of tx) Citalopram + CBT Paroxetine + CBT Primary Outcome: Fluoxetine + CBT CGI-I <2 + >50% decrease in CDRS-R SSRI and d CDRS-R. Citalopram Paroxetine Fluoxetine Wk Week Week -3 0 12 Brent D et al. JAMA 2008;299(8):901-13.

What did they find?

TORDIA: Primary Findings 5 Antidepressant without 6 Clinical Global Impression CBT SSRI 0 4 Antidepressant + CBT Venlafaxine Scale—Severity 5 CDRS Score 0 3 4 2 0 3 1 0 2 0 6 0 12 6 0 12 Treatment Week Treatment Week Brent D et al. JAMA 2008;299(8):901-13.

TORDIA: Primary Findings Improvement in Depressive Symptoms Mills, Croarkin Strawn. Under review 2020.

TORDIA: Primary Findings Improvement in Depressive Symptoms p =0.01 Mills, Croarkin Strawn. Under review 2020.

Anhedonia and Treatment Response • Only symptom that predicts lack of remission when controlling for others • Strongest predictor of fewer depression free days anhedonia • Treatment did not target positive affect (only 1.5 sessions of behavioral activation) • May need to more specifically target behavioral activation

Drug and Alcohol Use in TORDIA Substance Use Severity No response Response Time (weeks) Goldstein BI et al. J Am Acad Child Adolesc Psychiatry 2009;48(12):1182-92.

Plasma Concentration and Response P= .04 ≥ GM 80 P=.005 <GM 70 P=.07 60 50 40 30 20 10 0 VEN FLX/CIT FLX CIT PAR Sakolsky DJ et al. J Clin Psychopharmacol 2011;31(1):92-7.

Adolescent SSRI Exposure 14-year-old female 16-year-old female Ramsey et al. Gene-Based Dose Optimization in Children. Annu Rev Pharmacol Toxicol 2020;60:4.1–4.21.

Cytochrome P450 Enzymes and Pharmacokinetics in Adolescents Ramsey et al. Annu Rev Pharmacol Toxicol 2020;60:4.1–4.21.

Pediatric Escitalopram and CYP2C19 Phenotype Equivalent Poor metabolizer dose Intermediate metabolizer Normal metabolizer Poor 10 mg Rapid metabolizer metabolizer Ultrarapid metabolizer Intermediate 15 mg metabolizer Normal 20 mg metabolizer Rapid 25 mg metabolizer Ultrarapid 30 mg metabolizer Strawn, Poweleit, Ramsey. CYP2C19-guided escitalopram and sertraline dosing in pediatric patients: a pharmacokinetic modeling study. J Child Adol Psychop 2019;29(5):340-7.

Pediatric Sertraline and CYP2C19 Poor metabolizer Phenotype Equivalent Intermediate metabolizer dose Normal metabolizer Poor 50 mg Rapid metabolizer metabolizer Ultrarapid metabolizer Intermediate 125 mg metabolizer Normal 150 mg metabolizer Rapid 175 mg metabolizer Ultrarapid 225 mg metabolizer Strawn JR et al. J Child Adol Psychop 2019;29(5):340-7.

TORDIA: Self-Harm in High Ideators 12.0% p=0.02 Low High 10.0% p=0.75 8.0% 6.0% 4.0% 2.0% 0.0% SSRI VLX Adapted from G. Emslie. Annual Meeting of the American Academy of Child & Adolescent Psychiatry 2012.

TORDIA: Treatment and Suicidal Events Brent DA et al. Am J Psychiatry 2009;166:418–26.

TORDIA: Early Response 65 Non-Remitters 60 55 50 CDRS-R 45 40 35 30 25 20 0 6 12 24 Week Emslie GJ et al. Am J Psychiatry. 2010;167(7):782-91.

TORDIA: Early Response 65 Non-Remitters 60 Remitters 55 50 CDRS-R 45 40 35 30 25 20 0 6 12 24 Week Emslie GJ et al. Am J Psychiatry 2010;167(7):782-91.

TORDIA: Insomnia • Trazodone-treated patients, 6x < likely to respond than patients who did not receive any soporific ( p =0.001) Trazodone mCPP • Trazodone-treated patients 3x more likely to self-harm (OR=3, p =0.03) • No patient receiving trazodone + paroxetine or fluoxetine responded (0/13) • Patients treated with other soporifics responded similarly to those who received no sleep medication (60% vs. 50%) Shamseddeen W et al. J Child Adolesc Psychopharmacol 2012;22(1):29-36.