Disclosures. Learning Objectives. Psychopharmacology of Pediatric Anxiety and Depression 5/4/2017

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1 Psychopharmacology of Pediatric Anxiety and Depression Susan Sharp, DO Clinical Assistant Professor of Child and Adolescent Psychiatry Kansas University Medical Center The Children's Mercy Hospital, 2017 Disclosures I have no relevant financial relationships with the manufacturer of any commercial product and/or provider of commercial services discussed in this CME activity. Learning Objectives Review the epidemiology of anxiety disorders and depression Discuss the differential diagnosis for these disorders Review the evidence base and key studies involving the pharmacologic treatment of anxiety and depression 1

2 Case: Haley CC: crying spells and fear 7-year-old female with extended crying spells nightly, dreading school, not eating at school, fearful of her parents leaving her, excessive worries and feeling in the spotlight, nausea when nervous PMH: normal developmental history, history of ear infections as toddler Case cont.: Haley Family History: Mother is a worrier. Social History: Lives with parents and younger sister. Parents own a business. Attends 1 st grade, on track or ahead. Diagnosis: Separation Anxiety Disorder and Generalized Anxiety Disorder Treatment: Zoloft 12.5 mg, titrated gradually to 37.5 mg and therapy. Non-OCD Anxiety Disorders Epidemiology 5% of children and adolescents meet criteria for an anxiety disorder during given period of time. Anxiety disorders more common in females in general population. 1.5 to 2 times as many females as males. In treatment-seeking samples, more equal distribution. IACAPAP Textbook of Child and Adolescent Mental Health 2

3 Non-OCD Anxiety Disorders Age of Onset Separation anxiety disorder (SAD) early to mid childhood (7-8 years) Generalized Anxiety Disorder (GAD) late childhood (around years) Social Phobia (SoP)- early anxiety (around years) IACAPAP Textbook of Child and Adolescent Mental Health Anxiety Disorders Differential Diagnosis Drug withdrawal or intoxication Medication induced Asthma Gastritis Diabetes Primary insomnia Thyroid disorder ODD, ADHD Non-OCD Anxiety Disorders Treatment Child and Adolescent Multimodal Study (CAMS) (Walkup et al, 2008) Separation anxiety disorder, Social Phobia, Generalized Anxiety Disorder N=488, ages week acute trial, 4 arms=cbt, Sertraline (SRT), Combination (Comb), Placebo (PBO) SAD=Separation Anxiety Disorder, SoP=Social Phobia, GAD= Generalized Anxiety Disorder 3

4 Non-OCD Anxiety Disorders Treatment CAMS Results Comb > CBT=SRT> PBO 81% 60% 55% 24% Non-OCD Anxiety Disorders Treatment Meta-Analysis: Antidepressants in Pediatric Anxiety (Strawn et al, 2015) 9 studies involving 6 antidepressants (venlafaxine, sertraline, paroxetine, fluvoxamine, fluoxetine, duloxetine) Moderate Effect size (0.62) Effexor, cymbalta lower effect size than SSRIs Side effect of activation Non-OCD Anxiety Disorders Treatment Pediatric GAD: Duloxetine FDA approved. Strawn et al, 2015 RCT N=272, patients 7-17 yo with moderately severe GAD, 10 week trial. PARS outcome measure Duloxetine outperformed placebo 59% versus 42% 4

5 Case: Daniel CC: rituals taking up so much time 12-year-old male with history of fears of contamination and germs, nightly rituals, and rituals surrounding shower time. He also worried some and was perfectionistic. PMH: normal developmental and medical history unremarkable Case continued: Daniel FH: Mother some anxiety, not treated. SH: Lives with parents, older brother, and younger sister. 7 th grader, excellent grades. No substance abuse Diagnosis: OCD, some GAD symptoms Treatment: Prozac 40 mg and therapy OCD Epidemiology Prevalence 0.6-1% Age of onset Bimodal onset: late onset years, early onset 6-15 years. Boys earlier age of onset and more likely to have family member with Tourette s Disorder or OCD. Gender distribution more equal in adolescence. Child and Adolescent Psychiatry, Lewis 5

6 OCD: Treatment FDA approved medicines Prozac (ages 7-17) Zoloft (ages 6-17) Luvox (ages 8-17) Clomipramine (10 and older) OCD: Treatment The Pediatric OCD Treatment Study (POTS) randomized controlled trial (POTS study team, 2004) N=112, ages week study, 4 arms=cbt, sertraline, combination, Placebo Outcome measure CY-BOCS OCD: Treatment POTS Trial Results Comb, CBT, and SRT all outperformed placebo reducing CY-BOCS. Remission: Comb 53.6%, CBT 39.3%, SRT 21.4%, PBO 3.6%. Conclusion: Children and adolescents with OCD should begin treatment with CBT alone or with CBT plus an SSRI. 6

7 OCD: Treatment Meta-Analysis Differential efficacy of CBT and pharmacologic treatments for pediatric OCD. Sanchez-Meca et al, studies, 24 independent comparisons (10 pharmacologic, 11 CBT, 3 combined OCD: Treatment Meta-analysis CBT, pharmacologic treatments for pediatric OCD Results All interventions were efficacious in reducing OCD symptoms. Effect sizes: 1.23 for CBT, for medicine, for mixed treatments, Within pharm treatment clomipramine 1.305, SSRIs OCD: Treatment Augmentation strategies Add clomipramine to SSRI with careful monitoring, ideally choose SSRI with fewer P450 interactions Effexor or Cymbalta Atypical antipsychotics 7

8 Case: Abigail CC: I ve been depressed." HPI: 17-year-old female with several year history of depression. Insomnia, low appetite and energy, grades dropping, decreased ADLs, passive suicidal thoughts. Worries a lot. Zoloft made anxiety worse; Lexapro no benefit. PMH: Normal developmental history, medical history unremarkable Case continued: Abigail FH: Maternal GM with bipolar disorder, maternal great aunt with depression SH: parents divorced when she was 6, blended families on both sides, no substance abuse, no romantic relationships. Junior HS, grades As,Cs Diagnosis: Major Depression, GAD Treatment: Cross taper to Prozac. Cognitive behavioral therapy. Depression Epidemiology: 1-2% of children and 5% of adolescents suffer from clinically significant depression at any one time. Lifetime prevalence is higher. By age 16, 12% girls and 7% boys have had depression. IACAPAP Textbook of Child and Adolescent Mental Health 8

9 Depression Earlier age of onset is associated with greater illness burden in adulthood. Ratio of depression in males and females is roughly equal in childhood, but becomes roughly twice as common in females versus males in adolescence. IACAPAP Textbook of Child and Adolescent Mental Health Depression Differential Diagnosis Medications: Singulair, isotretinoin, corticosteroids, stimulants Substances of abuse- amphetamines, cocaine, MJ, solvents Infections- mononucleosis, influenza Epilepsy, traumatic brain injury Thyroid disorder Bipolar, DMDD, ADHD, ODD, adjustment disorder Depression- Treatment FDA approved medicines Prozac (ages 8-17) Lexapro (ages 12-17) 9

10 Depression: Treatment Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. (March et al, 2004.) N=439, ages week study, 4 arms=cbt, Prozac, combined, PBO Outcome measure Child Depression Rating Scalerevised, CGI Depression: Treatment TADS Results Comb> Prozac > CBT > PBO 73% 62% 48% 35% Comb and Prozac were statistically superior to CBT and PBO. Improvement in suicidality was greatest for patients receiving combination therapy. Depression: Treatment Treatment of SSRI-Resistant Depression in Adolescents Trial (TORDIA) (Brent et al, 2008) N=334, ages 12-18, non responders to two month initial treatment with an SSRI 12-week trial of: 1) Switch to second different SSRI 2) Switch to different SSRI plus CBT 3) Switch to Effexor 4) Switch to Effexor plus CBT 10

11 Depression: Treatment TORDIA trial Outcome measure CGI improvement score and decrease in CDRS-R by 50% Results CBT plus switch to either medication showed a higher response rate than a medication switch alone, but there was no difference in response rate between Effexor and a second SSRI. Depression: Treatment Texas Children s Medication Algorithm Project- Hughes et al 2007 Consensus guidelines for medication treatment for major depressive disorder 1)Monotherapy SSRI 2)Switch alternate SSRI 3)Augment (Lithium, Wellbutrin, Remeron) if partial response, or switch to alternate class (SNRI, Wellbutrin, Remeron) if no response References Walkup et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 2008; 359: Strawn, et al. Efficacy and tolerability of antidepressants in pediatric anxiety disorders: a systematic review and metaanalysis. Dep and Anx 2015;32: Strawn, et al. A randomized, placebo-controlled study of duloxetine for the treatment of children and adolescents with generalized anxiety disorder. J Am Acad Child Adoesc Psychiatry 2015 Apr; 54(4):

12 References Pediatric OCD Treatment Study Team. Cognitive behavior therapy, sertraline, and their combination with children and adolescents with obsessive compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA. 2004; 292: Sanchez-Meca et al. Differential efficacy of cognitive-behavioral therapy and pharmacological treatments for pediatric obsessive-compulsive disorder: a meta-analysis. J Anxiety Disord Jan;28(1): March et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. JAMA 2004 Aug 18;292(7): References Brent et al. Switching to Another SSRI or to Venlafaxine with or without Cognitive behavioral therapy for adolescents with SSRI-resistant depression. The TORDIA randomized controlled trial. JAMA. 2008;299: IACAPAP Textbook of Child and Adolescent Mental Health Lewis s Child and Adolescent Psychiatry: A Comprehensive Textbook, Lewis, References Hughes et al. Texas children s medication algorithm project: update from Texas consensus conference panel on medication treatment of childhood major depressive disorder. J Am Acad Child Adoesc Psychiatry 2007 June; 46(6): Strawn et al. Primary pediatric care psychopharmacology: focus on medications for ADHD, depression, and anxiety. Curr Prob Pediatr Adolesc Heath Care Jan 2017; 47(1):