_of bipolar disorder child development center双相情感障碍影响儿童发展中心课件

ADHD: Diagnosis and Treatment of More Than One Disorder Steven R. Pliszka, MD Faculty Disclosure Steven R. Pliszka, MD, was a member of the Speakers Bureau for Shire US Inc. and Ortho-McNeil Pharmaceuticals, Inc. He has received grants/research support from Shire US Inc., Cephalon, Inc., McNeil, and Eli Lilly and Company, and is a consultant for Shire US Inc. He has received honoraria from Shire US Inc., McNeil and Cephalon, Inc. Topics To Be Covered ADHD “simplex” Adverse events of treatment (e.g., cardiovascular, psychiatric) ADHD with comorbidity ODD/CD Tics Aggression Bipolar Disorder CD = conduct disorder Adverse Events of Stimulants Update on the Controversy Estimated Reporting Rates (1992-2004): Pediatric Sudden Death (18 Years Old) Drug All Age Groups Pediatric Age Group 0-18 Years Total Prescriptions1Pediatric Exposure (p -y)2N3 Reporting Rate per 100,000 p-y Methylphenidate (Concerta, Ritalin) 110,734,0007,127,432110.2 Amphetamine (Adderall) and dextroamphetamine (Dexedrine) 70,699,0003,817,929130.3 Atomoxetine (Strattera)9,419,000601,24630.5 1IMS Health, National Prescription Audit Plus, January 1992 through December 2004. Data Extracted April 2005; 2Total person-years (p-y) times the percentage of drug appearances in the pediatric subgroup population (IMS Health, National Disease and Therapeutic Index, January 1993 to December 2004, Data Extracted June 2005); 3N = sudden death cases identified in FDA AERS database received from January 1992 through February 2005; Available at: /ohrms/dockets/AC/06/briefing/2006_42106_06_Gelperin.pdf. Accessed Jan. 29, 2007 Psychiatric Side Effects of Stimulants? Gelperin K (2006). Available at: /ohrms/dockets/ac/06/briefing/2006-4210B-Index/htm. Accessed Feb. 1, 2007 Drugs Type of trial No. of trials Duration of trials (range) Category of exposureN Patient- years Psychosis /mania events Suicidal events Aggression events Concerta DB46-28 dysPlacebo31710.20000 Drug DB32112.68000 OL71,000 participants Mean effect size of 0.78 Connor DF et al. (2002), J Am Acad Child Adolesc Psychiatry 41(3):253-261; Pappadopulos E et al. (2006), J Cdn Acad Child Adolesc Psychiatry 15(1):27-39 Psychopharmacology of ODD/CD ADHD children with ODD/CD respond to stimulants as well at those without ODD/CD No evidence that stimulants increase aggression at appropriate doses Relative to placebo, ADHD children on stimulants engage in less antisocial behavior ADHD-ODD/CD Issues With Stimulants Fear: stimulant therapy may lead to substance abuse Fact: untreated ADHD is a significant risk factor for substance abuse in adolescence Pharmacotherapy for ADHD may have protective effects Pharmacotherapy and Substance Abuse Pharmacotherapy and Substance Abuse: Adolescents With ADHD Ab = alcohol or drug abuse; Dep = dependence; Wilens TE et al. (2002), Annu Rev Med 53:113-131 Rate of SA (%) 0 5 10 15 20 25 30 35 40 45 EtOH Ab/DepDrug Ab/Dep UnmedicatedMedicated Treatment Plan for ADHD/ODD Optimize treatment of ADHD Stimulants, atomoxetine, bupropion (Wellbutrin) If good response of ADHD, add behavioral interventions If behavior interventions fail, consider guanfacine, clonidine (Catapres) Severe aggression, mood lability, consider mood stabilizers and SGAs Risperidone in Conduct Disorder: Study Design 6-week, double-blind, placebo- controlled study 110 children aged 5-12 with subaverage IQ (5-12 years) 0.02-0.06 mg/kg/day (0.98 mg/kg/day) mean dose Snyder R et al. (2002), J Am Acad Child Adolesc Psychiatry 41(9):1026-1036 Efficacy of Risperidone in Conduct Disorder: Change in Aggression Score Mean Reduction in Conduct Scores Snyder R et al. (2002), J Am Acad Child Adolesc Psychiatry 41(9):1026-1036 -18 -16 -14 -12 -10 -8 -6 -4 -2 0 BaselineWk. 1Wk. 2Wk. 3Wk. 4Wk. 5 Wk. 6 Placebo (N=57) Risperidone (N=52) Treatment Plan for ADHD/ODD Serotonin reuptake inhibitors (e.g., fluoxetine Prozac, paroxetine Paxil) not helpful for ADHD per se, rarely help ODD in absence of depression Rational and irrational polypharmacy CMAP Algorithm for Pharmacologic Management of ADHD and Aggression Pliszka SR et al. (2006), J Am Acad Child Adolesc Psychiatry 45(6):642-657 Tics and ADHD Many children with tics and ADHD can tolerate stimulants without an increase in tics Law and Schachar (1999): 12-month study, 91 children MPH treatment did not produce significantly more tics than placebo in children with or without mild-to-moderate pre-existing tic disorder Gadow et al. (1999): 24-month study, 34 children with ADHD and tic disorder or Tourettes syndrome Stimulant treatment was effective in controlling ADHD symptoms without adversely affecting tics Lipkin et al. (1994), in a review of 122 children treated with stimulant medication found 9% developed transient tics and 1% developed chronic tics Law SF, Schachar RJ (1999), J Am Acad Child Adolesc Psychiatry 38(8):944-951; Gadow KD et al. (1999), Arch Gen Psychiatry 56(4):330-336; Lipkin PH et al. (1994), Arch Pediatr Adolesc Med 148(8):859-861 Induction or Exacerbation of Tics Tics are usually transient; only very rarely do patients develop a chronic tic disorder When tics occur or increase Decrease dose Switch to another stimulant Adjunct agent to treat tics Try nonstimulant medication Controlled Trial of MPH and Clonidine Change in Y-GTSS Total Score Y-GTSS = Yale Global Tic Severity Scale; Tourette Syndromes Study Group (2002), Neurology 58(4):527-536 -14 -12 -10 -8 -6 -4 -2 0 Week 0Week 4Week 8 Week 12 Week 16 PLA MPH CLON MPH + CLON CMAP Algorithm for Pharmacologic Management of ADHD With Comorbid Tic Disorder Pliszka SR et al. (2006), J Am Acad Child Adolesc Psychiatry 45(6):642-657 Depressive Disorders Major depressive disorder Dysthymia Adjustment disorder with depressed mood Chronic dysphoria of adolescence (Non-DSM) Ethical aspects of diagnosisdo really help people by broadening or ignoring our diagnostic criteria? CDRS-R = Childrens Depression Rating Scale-Revised; Wagner KD et al. (2003), JAMA 290(8):1033-1041 Children and Adolescents With MDD: Score on the CDRS-R Adjusted Mean CDRS-R Score Visit Week Important Issues Only mildly depressed patients in trials Suicidal patients/inpatients excluded Drugs studied long after they have been on the market Enrollment pressures Treatment of Adolescent Depression Study (TADS) FLX + CBT: 71% response FLX alone: 61% CBT alone: 43% Placebo: 35% SI present in 29% at baseline, all groups improved significantly March J et al. (2004), JAMA 292(7):807-820 TADSSuicidal Ideation March J et al. (2004), JAMA 292(7):807-820 TADSHarm and Suicide Related Events March J et al. (2004), JAMA 292(7):807-820 Intent to Treat Cases 0 2 4 6 8 10 12 HarmSuicide Related SSRINo SSRI FDA Meta-Analysis Pooled all studies, published and unpublished Blinded reviewers at Columbia assessed each adverse event as to its self harm potential N 4,000 No suicides 4% SI on drug, 2% on placebo, statistically significant Hammad TA et al. (2006), Arch Gen Psychiatry 63(3):332-339 Relationship of Suicide and SSRI Prescription Rate Gibbons RD et al. (2006), Am J Psychiatry 163(11):1898-1904 Higher SSRI Prescription Rate 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 12345678910 Number of Suicides per 100,000 Trends in Completed Suicide Since Boxed Warning Hamilton BE et al. (2007), Pediatrics 119(2):345-360 Recent Meta Analysis Reviewed 27 studies of MDD, OCD and anxiety disorders in children and adolescents 15 MDD studies 6 OCD studies 6 anxiety studies Included studies not in FDA review Number of participants MDD: 3,430 OCD: 718 Anxiety: 1,162 Bridge JA et al. (2007), JAMA 297(15):1683-1696 Recent Meta Analysis (Cont.) DisorderTreatment Response (%) Placebo Response (%)p-Value MDD61500.001 OCD52320.001 Anxiety69390.001 Treatment SI (%)Placebo SI (%) MDD320.08 OCD100.57 Anxiety100.21 Bridge JA et al. (2007), JAMA 297(15):1683-1696 Clinical Guidelines Based on FDA meta-analysis, we tell families there is a 2-4% of SI vs. 1-2% on placebo; TADS study shows 60-70% chance of improvement of MDD Tell families to watch for and report increase in agitation or SI Use alternative SSRI (sertraline, citalopram) if fluoxetine fails, NRI after that1 1CMAP: Hughes et al. (in press), J Am Acad Child Adolesc Psychiatry Algorithm for ADHD and depression Issues in Pediatric Bipolar Disorder What is the prevalence of BD in childhood and adolescence? How should diagnostic criteria differ from adults, if at all? What is the role of the comorbidity of ADHD with pediatric BD? Aggression and BD Controversies in treatment Different Developmental Trajectories? 0 2 4 6 8 10 12 14 16 18 20 220 2 4 6 8 10 12 14 16 18 20 22 Mood StateMood State EuthymicEuthymic ManicManic DepressedDepressed Adult SubtypeAdult Subtype Adolescent SubtypeAdolescent Subtype BP II or IBP II or I BP NOS?BP NOS? ADHD RxADHD Rx ? ? Pediatric Euphoric BPsPediatric Euphoric BPs Age/YearsAge/Years Mood Stabilizers Classic mood stabilizers Lithium, divalproex, carbamazepinedespite use in adults, limited studies in children Negative studies Gabapentin (Neurontin) Tiagabine (Gabitril) Oxcarbazepine (Trileptal) Topiramate (Topamax) Lamotrigine (Lamictal)an emerging treatment Study Week Baseline % Positive Mean CGAS Score Urine Drug Assays Childrens Global Assessment Scale (CGAS) Scores Lithium vs. Placebo Efficacy for Acute Treatment of Adolescents With BD and Substance Dependency Geller B et al. (1998), J Am Acad Child Adolesc Psychiatry 37(2):171-178 35 45 55 65 123456 Lithium Placebo 0 20 40 60 3456 Lithium Placebo Lithium, Divalproex Sodium and Carbamazepine in the Treatment of Bipolar Disorder: Study Design 42 outpatient participants Mean age = 11.4 3.0 years 6-8 week monotherapy period Randomized to lithium, divalproex or carbamazepine Assessed weekly for 6-8 weeks Low dose chlorpromazine allowed as “rescue medication” Kowatch RA et al. (2000), J Am Acad Child Adolesc Psychiatry 39(6):713-720 Lithium, Divalproex Sodium and Carbamazepine in the Treatment of BD: Response Rates and Effect Size 1.0034Carbamazepine 1.0642Lithium 1.6346Valproate Effect Size ITT Response Rate (%)Medication p=0.66; p=0.66; KowatchKowatch RA et al. (2000), J RA et al. (2000), J Am Am AcadAcad Child Child AdolescAdolesc Psychiatry Psychiatry 39(6):713-720 39(6):713-720 Lithium, Divalproex Sodium and Carbamazepine in the Treatment of BD: Responders Pattern of Response Mean Y-MRS Score Week Kowatch RA et al. (2000), J Kowatch RA et al. (2000), J Am Am AcadAcad Child Child AdolescAdolesc Psychiatry Psychiatry 39(6):713-720 39(6):713-720 0 5 10 15 20 25 30 35 12345678 Carbamazepine Valproate Lithium Randomized Lithium in Adolescents With Bipolar Depression 27 adolescents (12-18 years old), BD-I current episode depressed 6-week open-label trial of lithium monotherapy, titrated to serum level of 1-1.2 mEq/L Response rate: 48% Remission rate: 30% Patel NC et al. (2006), J Am Acad Child Adolesc Psychiatry 45(3):289-297 Lithium (Li) and Risperidone (Risperdal) 38 children and adolescents, mean age 11.4, all with early onset BD, mixed or manic All participants received Li monotherapy first 17 responded to Li monotherapy, remaining 21 were augmented with risperidone, response rate rose to 85.7% Predictors of nonresponse to Li monotherapy: ADHD, severity, history of abuse, preschool age at start of treatment Pavuluri MN et al. (2006), J Child Adolesc Psychopharmacol 16(3):336-350 Divalproex Treatment for Youth With Explosive Temper and Mood Lability: A Double-Blind, Placebo-Controlled Crossover Design 20 outpatients Mean age = 13.8 80% male 90% special education Divalproex 6-week crossover trial Donovan SJ et al. (2000), Am J Psychiatry 157(5):818-820 Divalproex Treatment for Youth With Explosive Temper and Mood Lability: Response to Treatment 25280010Placebo 866780810Divalproex %NN%NNTreatment ImprovementImprovement Phase 2: Completed Treatment (N=15) Phase 1: Initial Treatment (N=20) Donovan SJ et al. (2000), Am J Psychiatry 157(5):818-820 Divalproex and Lithium for Pediatric Mania Kowatch et al. (2006), presented at AACAP meeting in Boston 150 patients aged 7-17 years randomized to divalproex, lithium or placebo for 8 weeks Divalproex superior to placebo, trend for lithium to be superior to placebo Depakote ER in pediatric mania Wagner et al. (2006), presented at AACAP meeting, Boston 150 adolescents (10-17 years) with mania randomzied to placebo or Depakote ER for 4 weeks, then enrolled in 6 month open label study Titrated to serum level of 80-125 g/mL No difference between Depakote ER and placebo in reducing symptoms of mania Valproate and Polycystic Ovary Disease (PCOS) 230 women with bipolar disorder ages 18-45 in the Systematic Treatment Enhancement of Bipolar Disorder (STEP-BD) study 86 valproate users, 144 non-valproate users On medication at least 3 months Median 12 months for valproate, 17 months for other mood stabilizers (non-antipsychotic) Joffe H et al. (2006), Biol Psychiatry 59(11):1078-1086 Valproate and PCOS (Cont.) p=0.002; Joffe H et al. (2006), Biol Psychiatry 59(11):1078-1086 0 2 4 6 8 10 12 Type of Mood Stabilizer Valproate Non-Valproate Rate of PCOS (%) Risk of Rash With Lamotrigine 1/10 rash; 3/1,000 serious rash; 1/100 pediatric patients1 Increased rash risk1, 2 Higher starting doses Faster initial titration Youth (age 18) Concurrent valproate (doubles lamotrigine levels) 1Package insert Lamotrigine (2006); Available at: . Accessed Jan. 26, 2007; 2Calabrese JR et al. (1999), J Clin Psychiatry 60(2):79-88 Case Studies With Lamotrigine 16-year-old girl with severe, melancholic depression; unresponsive to 2 SSRIs and bupropion, partial response to venlafaxine, full response to venlafaxine + lamotrigine 11-year-old male with severe euphoric manner, pressured speech, flight of ideas, clanging, severely motor driven, no response or adverse event to lithium, valproate, all SGAs Lamotrigine in Adolescents With Bipolar Depression 20 adolescents (mean age = 15.8), 7 boys, 13 girlsBD-I or -II in current depressive episode Lamotrigine started at 12.5-25 mg/day, mean final dose 131.6 mg/day, 7 participants on other medications 19 participants completed trial Response rate: 84%, remission rate: 63% Chang K et al. (2006), J Am Acad Child Adolesc Psychiatry 45(3):298-304 Other Anticonvulsants Gabapentin: no evidence for effectiveness as mood stabilizer in adults or children Topiramate: negative study in adults, trend toward efficacy in children and adolescents; no plan for development as mood stabilizercognitive side effects; substance abuse agent? Oxcarbazepine: no difference from placebo in child/adolescent mania trial1 A new antiepileptic does not a mood stabilizer make Wagner KD et al. (2006), Am J Psychiatry 163(7):1179-1186 SGA Antipsychotics Current agents Risperidone Olanzapine (Zyprexa) Quetiapine (Seroquel) Ziprasidone (Geodon) Aripiprazole (Abilify) Powerful Sometimes necessary Limit use because of . Sedation Weight gain Comparative Pharmacology of SGA Antipsychotics Ziprasidone Risperidone Olanzapine Quetiapine Clozapine 5-HT2A m1 H15-HT2C D2 1 H1 5-HT2A D2 5-HT2C 1 5-HT1D 5-HT2A D2 H1 1 5-HT2C m1 5-HT2C 1H1 5-HT2A D2 5-HT1A m1 1 H1 D2 5-HT2A 5-HT1A 5-HT2C 5-HT1A Olanzapine in pediatric mania Tohen et al. Am J Psychiatry 164: 1547 161 adolescents randomized to placebo or olanzapine Difference from placebo noted in week 1, very significant difference by week 3 Very serious weight gain and increase in serum lipids, glucose Quetiapine in pediatric mania Delbello et al. (AACAP, 2006) 277 randomized to quetiapine (400/600) or placebo for 3 weeks Difference from placebo at days 4 and 7 Sedation common (28-30%) 1.7 kg (3.7 lbs) weight gain Aripiprazole in pediatric mania N = 296 4 week study Remission rates Low EPS Little wt gain Chang et al, (2006) presented at AACAP Comparison of Divalproex + Quetiapine or Placebo in Children With BD 30 inpatients participants BD-I Mean age = 14 Randomized for 42 days DVPX + placebo DVPX + QUE Mean VPA level DVPX + placebo = 93 g/ml DVPX + QUE = 106 g/ml QUE titrated from 25 mg bid to 450 mg/day by day 7 Mean dose of QUE = 432 mg/day DelBello MP et al. (2002), J Am Acad Child Adolesc Psychiatry 41(10):1216-1223 Comparison of Divalproex + Quetiapine or Placebo in Children With BD Change in YMRS Score From Baseline to End p=0.006 p0.0001 Remission DelBello MP et al. (2002), J Am Acad Child Adolesc Psychiatry 41(10):1216-1223 0 5 10 15 20 25 30 35 DVPX + PboDVPX + QUE BaselineEndpoint Comparison of Quetiapine and Divalproex for Adolescent Mania 50 adolescents aged 12-18 with bipolar I disord