Treatment of Bipolar Disorder in Youth Janet Wozniak, M.D. Associate Professor of Psychiatry Director, Pediatric Bipolar Disorder Research Program Harvard Medical School Massachusetts General Hospital
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National Trends in Visits with a Diagnosis of Bipolar Disorder as a Percentage of Total Office-Based Visits This increase highlights a need for clinical epidemiological reliability studies to determine the accuracy of clinical diagnoses Moreno et al., Arch Gen Psych, 2007
Disruptive Mood Dysregulation Disorder DMDD Criteria A. The disorder is characterized by severe recurrent temper outbursts that are grossly out of proportion in intensity or duration to the situation. 1. The temper outbursts are manifest verbally and/or behaviorally, such as in the form of verbal rages or physical aggression towards people or property. 2. The temper outbursts are inconsistent with developmental level. B. Frequency: The temper outbursts occur, on average, three or more times per week. C. Mood between temper outbursts: 1. Nearly every day, most of the day, the mood between temper outbursts is persistently irritable or angry. 2. The irritable or angry mood is observable by others (e.g., parents, teachers, peers). D. Duration: Criteria A-C have been present for 12 or more months. Throughout that time, the person has not had 3 or more consecutive months when they were without the symptoms of Criteria A-C. E. Criterion A or C is present in at least two settings (at home, at school, or with peers) and must be severe in at least in one setting. F. The diagnosis should not be made for the first time before age 6 or after age 18. G. The onset of Criteria A through E is before age 10 years.
The New Temper Tantrum Disorder Will the new diagnostic manual for psychiatrists go too far in labeling kids dysfunctional? By David Dobbs Posted Friday, Dec. 7, 2012, at 1:12 PM ET Published May 2013 American Psychiatric Association's Diagnostic Statistical Manual, Fifth Edition, or DSM-5
Bipolar I or II Disorder affected 2.9% of >10,000 adolescents, most with severe impairment
Merikangas, et al, National Comorbidity Survey Replication-Adolescent Supplement, 2010
SCOPE OF THE PROBLEM Meta-analysis of Epidemiologic Studies of Pediatric Bipolar Disorder Van Meter J Clin Psych 2011
Pediatric-Onset Bipolar Disorder Do children look different? Irritability and Fluctuating Mood States/Mixed States Less euphoria (or hard to detect?) AFFECTIVE STORMS SEVERELY Irritable: swearing, disrespectful, threatening, wild, out of control With Explosions: frequent, for 30-60+ minutes, destructive, aggressive Lower level Irritable: whiney, complaining, difficult to please, angry, grouchy, cranky, snappy Chronicity and?rapid Cycling Discrete episodes may be difficult to delineate Ultradian Cycling or changes in mood presentation/ polarity Developmental Distinctions in Symptoms What s grandiosity? What s hypersexuality? Spending?
Euphoria and Irritability in BPD Probands Euphoric N=5 Irritable N=23 N=38 Euphoric, Any = 28 Irritable, Any = 61 82% (23 of 28) of Euphoric subjects met for Irritability 38% (23 of 61) of Irritable subjects met for Euphoria
Kraepelin s Depressed, Mixed and Manic Across the Life span Kraepelin. Manic Depressive Insanity. 1921. Page 168 (Figure 45). Translated by RM Barclay. GM Robertson (ed). E & S Livingstone, Edinburgh.
Developmental Course in Bipolar Children: A disorder affecting preschoolers Children often ill for years by time of referral Mean Age at Onset 7 6 5 4 3 2 1 2.98 4.05 Bipolar Onset (4.55) 4.47 4.65 4.94 0 ADHD ANX ODD MDD CD
Mania Episodicity (N = 92) Youth are both episodic and chronic 100 90 % 80 70 60 50 40 12% Rapid Cycling > 4 episodes/yr 27% Ultra-Rapid 20 episodes/yr 1% Ultraradian 300 episodes/yr 7% Episodic, 12 m Presentation varies: mixed, manic, depressed Mood switches: irritable, euphoric, melancholy Comorbidity evident 30 20 41% Single, 12 m 10 5% Episodic, < 12 m 0 7% Single, < 12 m Chronic Episodic
Pediatric-Onset Bipolar Disorder: Why is it Underdiagnosed? The symptoms of ADHD and mania overlap and are difficult to disentangle Talkativeness, hyperactivity (physical agitation/energy), distractibility are symptoms of ADHD and mania ADHD is a common disorder of childhood (5-10%) and often includes emotional dysregulation
MGH Study of Pediatric BPD Comorbid Disorders by Bipolar Cohort, Clinic Samples Prior to 1995 and 1995-2002 P = NS P = NS Bipolar 1st Cohort Bipolar 2nd Cohort 100 90 P = NS 80 % 70 60 50 40 30 P = NS P = NS 20 10 0 Major Depression Psychosis ADHD Oppostional Defiant Disorder Conduct Disorder Psychiatric Diagnoses
Meta-Analysis of 5 Controlled Family Studies of Pediatric Bipolar Disorder These odds ratios indicate a risk of bipolar I disorder to relatives of bipolar I probands that is 4-14 times greater than the risk to relatives of nonbipolar probands NO EVIDENCE OF HETEROGENEITY IN MAGNITUDE OF FAMILIAL TRANSMISSION Wozniak J Clin Psych, 2012
Familial risk of bipolar I disorder in first-degree relatives of BP-I, ADHD and Control Probands Morbid risk in relatives * Proband n = 239 162 136 Relative n = 726 511 411 Wozniak J Clin Psych, 2012
Persistence: Most bipolar adults in STEP-BD (N=983) reported onset in childhood or adolescence About 65% of adults with onset < 18 Almost a third with onset <13 > 18 years: 35% < 13 years 28% 13 to 18 years 37% Perlis, Miyahara, Marangell, Wisniewski, Ostacher, DelBello, Bowden, Sachs, Nierenberg, Biol Psych 2004;55:875-881
Pediatric Bipolar Disorder Persistence Child Bipolar I Disorder Prospective Continuity With Adult Bipolar I Disorder; Characteristics of Second and Third Episodes; Predictors of 8- Year Outcome Conclusions: In grown-up subjects with child BP-I, the 44.4% frequency of manic episodes was 13 to 44 times higher than population prevalences, strongly supporting continuity. Geller, et al, Arch Gen Psychiatry, 2008;65(10):1125-1133
Persistence of Pediatric Bipolar Disorder Four-Year Longitudinal Course of Children and Adolescents With Bipolar Spectrum Disorders: The Course and Outcome of Bipolar Youth (COBY) Study N=214 Bipolar I and N=169 Bipolar II and NOS, followed for 4 years with the Longitudinal Interview Follow Up Evaluation Recurrences common Symptomatic on average for 60% of the follow-up period. 40% had symptoms during 75% of the followup period. 25% of BPD II and 38% of BPD NOS converted to BPI Birmaher, et al, Am J Psychiatry. 2009 Jul;166(7):795-804
Persistence of Pediatric Bipolar Disorder HIGH LEVEL OF PERSISTENCE OF PEDIATRIC BIPOLAR-I DISORDER FROM CHILDHOOD ONTO ADOLESCENT YEARS: A FOUR YEAR PROSPECTIVE 78 of 105 youth with Bipolar I disorder followed up after 3.6 years Baseline age 10.5 years, 76% male Age of onset bipolar disorder 4.9 years Duration of BPD at baseline 7.6 years Wozniak et al, J Psychiatr Res, 2011
Persistence of Bipolar Disorder in youth at 4-year Follow-up (N=78) Most continue with Bipolar I disorder 73.1% Better 6.4% Better, but Treated 9.0% Some symptoms of Mania 6.4% Not manic, but depressed 5.1% Only 5 (6.4%) subjects were better without treatment Wozniak et al, J Psychiatr Res, 2011
Off-Label Use All medications, described in this presentation constitute offlabel use in the USA with the exception of the following FDA approved medications: Fluoxetine: depression and OCD age 8+ Escitalopram: depression age 12+ Sertraline,fluvoxamine, anfranil: pediatric OCD
Off-Label Use All medications, described in this presentation constitute off-label use in the USA with the exception of the following FDA approved medications: Lithium: manic or mixed states, patients aged 13-17 years 2007 Risperidone: manic or mixed states, age 10-17 years 2008 Aripiprazole: manic or mixed states, age 10-17 years 2009 Olanzapine: manic or mixed states, age 13-17 years 2009 Quetiapine: monotherapy or adjunct to lithium or divalproex sodium, manic states, age 10-17 years 2015 Saphris manic or mixed episodes assoc with BPD I, age 10-17
Off-Label Use All medications, described in this presentation constitute off-label use in the USA with the exception of the following FDA approved medications: Aripiprazole: irritability associated with autistic disorder ages 6-17 Risperidone: irritability associated with autism ages 5-16
Treatment algorithm Stage I monotherapy +/- augmentation Stage 2 switch monotherapy agent Stage 3 combo mood stabilizer + SGA (Or switch monotherapy agent) Stage 4 Combination 1 mood stabilizer + SGA 2 mood stabilizers + SGA Stage 5 alternate monotherapy Stage 6 ECT vs. Clozapine Kowatch, JAACAP, 2005
Can we wait? Post, Leverich, et al. 2010.
Bipolar adults with childhood and adolescent onset had more lifetime suicide attempts and violence 80 70 N=983 60 50 40 30 Child Adolescent Adult 20 10 0 Suicide Attempts Violence Psychotic Features Perlis, Miyahara, Marangell, Wisniewski, Ostacher, DelBello, Bowden, Sachs, Nierenberg, Biol Psych 2004;55:875-881
Number of Subjects Participating in Pediatric Anti-Manic Trials J Am Acad Child Adolesc Psychiatry, 2011;50(8):749-762.
Mean Change in YMRS from Baseline by Medication Class Traditional Mood Stabilizers Other Anticonvulsants Atypical Antipsychotics Naturopathic Treatments 0-2 -4 YMRS Score -6-8 -10-12 -10.99-11.03-5.6-14 -16-18 -16.8
Weight Gain in 8-week Open Label Trials of Second Generation Antipsychotic Monotherapy in 116 Children with Bipolar Disorder 06 aripiprazole quetiapine Change from Baseline (kg) 05 risperidone ziprasidone 04 olanzapine 03 02 01 00 0 1 2 3 4 5 6 7 8 Biederman et al (2007), AACAP; Boston
Adverse Events Weight gain and metabolic risks associated with antipsychotic medications in children and adolescents N=34 studies olanzapine 3.8 to 16.2 kg clozapine 0.9-9.5 kg risperidone 1.9-7.2 kg quetiapine 2.3-6.1 kg aripiprazole 0-4.4 kg (n=353) (n=97) (n=571) (n=133) (n=451) Correll et al JChildAdolescPsychopharm 2011 Dec;21(6):517-35
Adverse Events One-year incidence rates of tardive dyskinesia in children and adolescents treated with second-generation antipsychotics: a systematic review Correll, et al JChildAdolescPsychopharm 2007;17(5):647-56 N=783 Results across 10 studies suggest relatively low 1-year TD rates in pediatric patients treated with SGAs. However, the available data base is limited by the small sample size of studies with SGAs other than risperidone and by the use of relatively low doses, which may have obscured a potentially greater risk for TD in children and adolescents treated with higher total SGA doses and for longer durations. Three new cases of TD emerged during long-term treatment with SGAs of up to 3 years, resulting in crude and annualized TD rates of 0.38%. In the two cases with information, TD resolved within weeks after antipsychotic discontinuation.
Adverse Events Pringsheim T, Lam D, Ching H, Patten S. Metabolic and neurological complications of second-generation antipsychotic use in children. Drug Saf. 34(8), 651 668 (2011).
Lithium, Divalproex Sodium, and Carbamazepine in Bipolar Disorder Kowatch et al. JAACAP 39, 713-720, 2000 Results The response rates were 53% for divalproex sodium 38% for lithium 38% for carbamazepine All 3 mood stabilizers were well tolerated with no serious adverse effects
Pediatric Bipolar Disorder: Progress in Treatments A prospective open-label trial of lamotrigine monotherapy in children and adolescents with bipolar disorder. J.CNS Neurosci Ther. 2010 A prospective open-label trial of extendedrelease carbamazepine monotherapy in children with bipolar disorder. JCAP 2010
This study was highly publicized in the major news media and suggest that 2 months of supplementation can have positive effects after one year on psychotic symptoms
Our own study shows that omega-3s can treat bipolar disorder in children This result is about 50% what we see with atypical antipsychotic medications, but without the serious or annoying side effects
Comorbid disorders Depression- after mania stabilized Lithium, Lamotrigine, or bupropion Avoid SSRI s ADHD Stimulant after mood stabilized Joshi G, Wilens TE. Child Adolesc Psych Clin N Am 18 (2009) Comorbidity in PBD 291-319.
Quetiapine not effective in Adolescent Bipolar Depression Mean (SD) change in CDRS-R scores from baseline to endpoint DelBello et al., 2009
Open Label Lamotrigine and Lithium Effective in Adolescent Bipolar Depression Chang et al JAmAcadChildAdolPsyc 2006 N=20 Adjunctive or monotherapy lamotrigine 63% responders (at least 50% decrease in CDRS) 84% much or very much improved CGI-I Patel et al JAmAcadChildAdolPsyc 2006 N=27 Monotherapy Lithium 48% responders (at least 50% decrease in CDRS)
Treatment of ADHD comorbid with Pediatric BPD Some SGA studies of bipolar disorder in youth also demonstrate improvement of ADHD (eg, paliperidone, joshi et al 2013; Aripiprazole, Tramontina 2007, 2009; Risperidone, Biederman 2008) One study correlated the improvement of ADHD with the improvement in mania In a chart review of risperidone, mania improved, but not ADHD (Frazier 1999) In studies of Equetro (Joshi 2010) and lamotrigine (Biederman, 2010), mania, depression and ADHD all improved
Treatment of ADHD comorbid with Pediatric BPD Improvement in ADHD shown in two add-on studies: Adderall v placebo, 4 week study, Scheffer 200 Methylphenidate v placebo, 4 week study, Findling 2007 However, methylphenidate v placebo in youth stabilized with Abilify showed no differences in improvement in ADHD. Zeni, 2009. Chart review of Strattera demonstrated improvement in ADHD symptoms in stabilized bipolar subjects, Chang 2005 8 wk open trial adjunct treatment in euthymic youth demonstrated improvement, Chang 2009
Treatment of ADHD comorbid with Pediatric BPD N=22,797 cases diagnosed with pediatric ADHD odds of developing BD were significantly and positively associated with: -- longer treatment with methylphenidate, mixed amphetamine salts, or atomoxetine being -- treatment with certain antidepressant medications, most notably fluoxetine, sertraline, bupropion, trazodone or venlafaxine Jerrell JM, J Clin Psychiatry.
Euthymic youths with bipolar disorder and ADHD may benefit from short-term concomitant treatment with methylphenidate A 4-week double-blind, placebo-controlled trial in youths ages 5 to 17 years with bipolar disorder and ADHD, were currently receiving a stable dose of at least one thymoleptic, and while euthymic continued to have clinically significant symptoms of ADHD. Patients received 1 week each of placebo, methylphenidate 5 mg twice daily, methylphenidate 10 mg twice daily, and methylphenidate 15 mg twice daily using a crossover design. Subjects were randomly assigned to receive one of six possible dosing orders. The primary outcome measure was the total score on the parent-completed ADHD RESULTS Lower scores during best dose treatment compared to the week of placebo treatment were found on the ADHD Rating Scale-IV (p <.05), suggesting a therapeutic benefit. A large effect size (Cohen's d = 0.90) was found for methylphenidate. Treatment was generally well tolerated. Rating Scale-IV. Findling et al., J. Am. Acad. Child Adolesc. Psychiatry, 2007;46(11):1445-1453.
Treatment of substance abuse comorbid with Pediatric BPD Lithium improved substance abuse, not bipolar, in comorbid pediatric subjects Geller, JAACAP, 1998
Treatment of autism comorbid with Pediatric BPD SGA secondary analysis of SGA trials demonstrated improvement of bipolar disorder in the autism subjects (Joshi, et al ) SGAs demonstrated improvement in ASD subjects (Hamrin, 2008; Atlas, 1995)
Pediatric Bipolar Disorder Treatment Summary Atypical antipsychotic agents outperform traditional mood stabilizers and other anticonvulsants Emerging evidence to support combination pharmacotherapy or natural treatments Highly comorbid, so combined therapies routine Depression difficult to treat
Future Research Questions Studies of young children < 12 years old and preschoolers Combination pharmacotherapy trials Pharmacotherapy of comorbid disorders ADHD Depression OCD Psychosocial treatment
Massachusetts General Hospital Department of Psychiatry Presents 39 th Annual Psychopharmacology Conference THURSDAY-SUNDAY, OCTOBER 22-25, 2015 THE WESTIN COPLEY PLACE BOSTON, MA MGHCME.ORG Psychopharmacology 39 th Annual Psychopharmacology Conference Friday, September Thursday 28 Sunday, October September 22 25, 30, 2015 2012 The Westin Copley Place