Pediatric Bipolar Disorder and ASD

Transcription

1 Pediatric Bipolar Disorder and ASD Janet Wozniak, MD Associate Professor of Psychiatry Massachusetts General Hospital

2 Disclosures My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose: Royalties (Spouse): Cambridge University Press, UptoDate Consultation Fees (Spouse): Advance Medical, FlexPharma, Merck Research Support (Spouse): UCB Pharma, NeuroMetrix

3 Scope of the Problem: Population Studies of Bipolar Disorder and Related Disorders in Youth Not USA: 1.9%* USA: 1.7%* Benjet 2009 Mexico Lynch 2006 Ireland Canals 1997 Spain Kim-Cohen 2003 New Zealand Stringaris 2010 UK Holtzmann 2010 German Verhulst 1997 Dutch Costello 1996 USA Kessler 2009 USA Gould 1998 USA Andrade 2006 USA Kashani 1987 USA Lewinsohn 1995 USA Merikangas 2010 USA *from Van Meter et al., JCP, in press Percent with Disorder

4 SCOPE OF THE PROBLEM Merikangas, et al, National Comorbidity Survey Replication-Adolescent Supplement J Am Acad Child Adolesc Psychiatry Oct;49(10):980-9

5 Most bipolar adults in STEP-BD reported onset in childhood or adolescence > 18 years: 35% < 13 years 28% 65% of adults with onset < 18 Almost a third with onset < to 18 years 37% Perlis, Miyahara, Marangell, Wisniewski, Ostacher, DelBello, Bowden, Sachs, Nierenberg, Biol Psych 2004;55:

6 Bipolar adults with childhood and adolescent onset had more lifetime suicide attempts and violence N= Child Adolescent Adult Suicide Attempts Violence Psychotic Features Perlis, Miyahara, Marangell, Wisniewski, Ostacher, DelBello, Bowden, Sachs, Nierenberg, Biol Psych 2004;55:

7 Clinical Presentation

8 DSM Mania Diagnosis Period of abnormally and persistently elevated, expansive or irritable mood and increased energy or activity (DSM5 addition) lasting 1 week or requiring hospitalization 3 of the following criteria (4 if irritable) Grandiosity Less sleep Pressured speech Flight of ideas Distractibility Goal-directed activity Excessive pleasurable activity

9 The most severe types of emotional dysregulation comes when mania and depression co-occur in the mixed states of bipolar disorder Regular Kid! typical Melancholy: sad, no pleasure, down on self, suicidal, self-destructive Euphoric: Giddy, goofy, silly, high, on drugs, laughing fits Irritability of Depression: angry, grouchy, cranky, whiney, complaining, difficult to please, short-tempered Manic level SEVERE IRRITABILITY: swearing, disrespectful, threatening, wild, out of control with Explosions that are frequent, for minutes, destructive, aggressive

10 Euphoria and Irritability in BPD Probands Euphoric Irritable

11 A DAY IN THE LIFE OF A BIPOLAR CHILD IS A ROLLER COASTER OF MOODS 10 year old Laura was cranky and miserable all day refusing her mother s suggestions for fun activities. After a phone from a friend she was talking a mile a minute with excitement over a school party, exaggerating her popularity. She demanded her mother buy her a new cell phone to use to text about the party and, when her mother refused, required a physical hold for over 60 minutes after she exploded in anger. Before bed, she sobbed and sobbed and told her mother How can you love me? I cause you so much trouble. You should just kill me.

12 Are All Forms of Irritability the Same? Heterogeneity of Irritability

13 Increasing Severity Heterogeneity of Irritability in Children ADHD ODD MDD MANIA Months Mick et al, 2007

14 Juvenile Mania The type of irritability observed in manic children is very severe, persistent, and often violent. The outbursts often include threatening or attacking behavior towards others, including family members, other children, adults, and teachers. Biederman et al. J Am Acad Child Adolesc Psychiatry. 1996; 35(8):

15 Heterogeneity of Irritability Labile mood/hot temper: ODD Severe irritability: MDD Explosive/violent irritability: BPD Mick et al. Biological Psychiatry. 2005; 58:

16 16% of a children 6-12 years of age in a clinic sample (N=262) met full criteria for mania J Am Acad Child Adolesc Psychiatry Jul;34(7):867-76

17 2002 MGH Study of Pediatric BPD Diagnostic Overlap of BPD and ADHD [Second Cohort] ADHD N=450 BPD N=112 N=17 Biederman et al. J of Affective Disorders. 2004; S82:45-58.

18 MGH Study of Pediatric BPD BPD Illness Age of Onset 8 Years (mean) BPD 1st Cohort p=ns BPD 2nd Cohort Biederman et al. J of Affective Disorders. 2004; S82:45-58.

19 MGH Study of Pediatric BPD BPD Illness Duration 8 Years (mean) BPD 1st Cohort p=ns BPD 2nd Cohort Biederman et al. J of Affective Disorders. 2004; S82:45-58.

20 MGH Study of Pediatric BPD Comorbid Disorders by Bipolar Cohort P=NS Bipolar 1st Cohort P=NS P=NS Bipolar 2nd Cohort % P=NS P=NS 0 Major Depression Psychosis ADHD Oppositional Defiant Disorder Disorder Conduct Biederman et al. J of Affective Disorders. 2004; S82:45-58.

21 MGH Study of Pediatric BPD 30 Treatment History: Hospitalization % P=NS P<0.001 Bipolar 1st Cohort Bipolar 2nd Cohort ADHD 2nd Cohort 2 Biederman et al. J of Affective Disorders. 2004; S82:45-58.

22 Our earliest work on the combined condition of mania and autism was met with skepticism by the autism research community ACCOMPANYING EDITORIAL BY AUTISM EXPERT Peter Tanguay, MD I suggest that the authors have mistaken the manifestations of difficult temperament in young children with autism for mania Those of us who deal with children with PDD know that 10% to 20% of them also have a difficult temperament. J Am Acad Child Adolesc Psychiatry Nov;36(11):1552-9

23 J Autism Dev Disord (2010) 40: DOI /s ORI GI NA L PA PER The Heavy Burden of Psychiatric Comorbidity in Youth with Autism Spectrum Disorders: A Large Comparative Study of a Psychiatrically Referred Population Gagan Joshi Car ter Petty Janet Wozniak Aude Henin Ronna Fried Maribel Galdo Meghan Kotarski Sarah Walls Joseph Bieder man Published online: 23 March 2010 Ó Springer Science+Business Media, LLC 2010 Abstr act The objective of the study was to systematically examine patterns of psychiatric comorbidity in referred youth with autism spectrum disorders (ASD) including autistic disorder and pervasive developmental disorder not otherwise specified. Consecutively referred children and adolescents to a pediatric psychopharmacology program were assessed with structured diagnostic interview and measures of psychosocial functioning. Comparisons were made between those youth satisfying high levels of psychiatric comorbidity and dysfunction comparable to the referred population of youth without ASD. These findings emphasize the heavy burden of psychiatric comorbidity afflicting youth with ASD and may be important targets for intervention. Keywor ds Autism spectrum disorders Psychiatric comorbidity Children and adolescents

24 Diagnoses in Psychiatrically Referred Youth with and without ASD N=2323 Attention-deficit/Hyperactivity Oppositional Defiant Disorder Conduct Disorder Multiple ( 2) Anxiety Disorders *** Major Depressive Disorder Bipolar I Disorder Psychosis Substance Use Disorders Cigarette Smoking Percentage *** ASD NON-ASD Statistical Significance: *p 0.05, **p 0.01, ***p J Autism Dev Disord Nov;40(11):

25 Autism Complicates the Course of Bipolar Disorder 100 School Functioning 100 Hospitalization % A*** A*** A*** AB***C** A*** A*** A*** AB* B** Extra help Special class Repeated grade % AB*** A B * * * Controls ADHD BPD-I BPD-I+ASD Controls ADHD BPD-I BPD-I+ASD Statistical Significance: *p 0.05, **p 0.01, ***p A = vs. Control; B = vs. ADHD; C = vs. BPD J Clin Psychiatry 2013;74(6):

26 Symptoms of Mania in BPD Youth with and without Autism BPD-I+ASD BPD-I * % Elated Mood Irritable Mood Grandiosity Decreased Sleep Pressured Speech Flight of Ideas / Racing Thoughts Distractibility Poor Judgment Increase in Activity ***p Statistical Significance: *p 0.05, **p 0.01, ***p J Clin Psychiatry 2013;74(6):

27 Summary of Clinical Presentation Frequently irritable Frequently non-episodic Frequently chronic Frequently mixed Highly comorbid with ADHD, ODD, CD, anxiety and ASD

28 Is Pediatric BPD Familial?

29 Morbid Risk in Relatives Familial Risk of BP-I Disorder in First Degree Relatives * P <0.01 vs. ADHD and Controls BP-I ADHD Control Proband n= Relative n= * Wozniak et al. Psychol Medicne 2011

30 Bipolar Disorder in First-Degree Relatives A family history of bipolar disorder is present in bipolar youth with and without autism AB*** A**B*** % Controls (N=411) ADHD (N=511) BPD (N=336) BPD+ASD (N=137) Statistical Significance: *p 0.05, **p 0.01, ***p A = vs. Control; B = vs. ADHD J Clin Psychiatry 2013;74(6):

31 Does Pediatric BPD have a unique course?

32 Persistence of DSM-IV BP-I in youth at 4-year Follow-up Full BP-I disorder 73.1% Euthymic 6.4% Subthreshold BP-I disorder 6.4% Treated 9.0% Full or subthreshold MDD 5.1% Wozniak, Biederman et al. 2010

33 Does Pediatric BPD have a unique pharmacological response?

34 Academic Debate The unfortunate reality is that current medications help too few people to get better and very few people to get well. - Thomas Insel NIMH Director NEJM 362;20. May 20, 2010.

35 1989 to 2010: FDA-Approved Medications for PBD Lithium Risperidone Aripiprazole Olanzapine Quetiapine

36 Many FDA Approved Treatments for Children and Adolescents with Emotional Dysregulation Lithium: manic or mixed states, patients aged years Risperidone: manic or mixed states, age years Aripiprazole: manic or mixed states, age years Olanzapine: manic or mixed states, age years Quetiapine: monotherapy or adjunct to lithium or divalproex sodium, manic states, age years Saphris manic or mixed episodes assoc with BPD I, age Fluoxetine: depression and OCD age 8+ Escitalopram: depression age 12+ Sertraline,fluvoxamine, anfranil: pediatric OCD Aripiprazole: irritability associated with autistic disorder ages 6-17 Risperidone: irritability associated with autism ages 5-16

37 Liu et al. J Am Acad Child Adolesc Psychiatry 2011; 50(8):

38 Number of Studies Studies of Pediatric Mania Psychopharmacology Published Studies 28 Open Label 12 RCT 2704 Subjects participated across studies Year 3 8 Open Label RCT

39 YMRS Score Mean Change in YMRS from Baseline by Medication Class 0 Traditional Mood Stabilizers Other Anticonvulsants Atypical Antipsychotics Naturopathic Treatments

40 Bipolar Youth with Autism Included in Clinical Trials of SGAs for Bipolar Youth N=151 BPD-ASD 84% (N = 128) BPD+ASD 16% (N = 23) CNS Neurosci Ther Jan;18(1):28-33

41 Rating Scales in BPD Youth with and without Autism N= p < NS NS p= YMRS CDRS ADHD-RS BPRS BPD-PDD BPD+PDD CNS Neurosci Ther Jan;18(1):28-33

42 Anti-Manic Response of Bipolar Youth to SGA Monotherapy: No difference with and without ASD N= NS YMRS ( 30%) NS YMRS ( 50%) BPD-PDD BPD+PDD CNS Neurosci Ther Jan;18(1):28-33

43 N-ACETYLCYSTEINE

44 Funding/support: This study was supported by a generous philanthropic donation from Kent and Elizabeth Dauten (Chicago, Illinois). November 2015

45 HIGH EPA OMEGA-3 FATTY ACIDS AND INSOSITOL IN PEDIATRIC BPD STUDY: ANIDEPRESSANT RESPONSE Percent of Subjects 90 OR= OR= OR=2.50 OR=2.50 OR=1.88 OR=3.75 HAM-D SMD (Omega-3 FA vs. Inositol)=0.51 HAM-D SMD (Omega-3 FA + Inositol vs. Inositol)=0.56 CDRS SMD (Omega-3 FA + Inositol vs. Inositol)=0.59 OR= OR=2.00 OR= OR=1.00 OR=1.88 OR= OR=2.37 OR= CGI MDD Improvement 2 30% HAM-D Improvement 50% HAM-D Improvement 30% CDRS Improvement % CDRS Improvement Inositol (n=7) Omega-3 FA (n=7) Omega-3 FA + Inositol (n=10) Wozniak et al, JCP in press

46 Percent of Subjects HIGH EPA OMEGA-3 FATTY ACIDS AND INSOSITOL IN PEDIATRIC BPD STUDY: OTHER RESPONSES OR=5.83 OR=1.88 OR=3.11 OR=6.00 OR=2.50 BPRS SMD (Omega-3 FA vs. Inositol)=0.77 BPRS SMD (Omega-3 FA + Inositol vs. Inositol)=0.60 CGI Anxiety SMD (Omega-3 FA + Inositol vs. Inositol)=0.55 CGI ODD SMD (Omega-3 FA + Inositol vs. Omega-3 FA)= OR=2.40 OR=8.08 OR= OR=2.37 OR= OR=3.46 OR= CGI ADHD Improvement 2 CGI Anxiety Improvement 2 CGI ODD Improvement 2 30% BPRS Improvement Inositol (n=7) Omega-3 FA (n=7) Omega-3 FA + Inositol (n=10) Wozniak et al, JCP in press

47 PBD Mania Trials: Summary Significant increase in clinical trials of antimanic agents over the past 10 years Atypical antipsychotic agents outperform traditional mood stabilizers and other anticonvulsants

48 SUMMARY: Pediatric BP Disorder Severe and highly dysfunctional clinical presentation highly consistent with adult bipolar disorder Positive family history of BPD Selective treatment response to antimanic agents Compromised course and outcome

49 SUMMARY: BP and ASD A clinically significant subgroup of individuals with ASD suffer from BP disorder Symptom of mania and familiality of BP disorder are similar in BP youth with and without ASD No differences in anti-manic response or tolerability to SGAs in BP diosrder youth with or without ASD