Bipolar Disorder in Youth Janet Wozniak, M.D. Associate Professor of Psychiatry Director, Pediatric Bipolar Disorder Research Program Harvard Medical School Massachusetts General Hospital
Pediatric-Onset Bipolar Disorder National Trends in the Outpatient Treatment of Children and Adolescents with Antipsychotic Drugs Olfson et al. Arch Gen Psychiatry. 2006;63:679-685. Conclusions: There has been a sharp national increase in antipsychotic treatment among children and adolescents in office-based medical practice. Second-generation antipsychotics are being widely prescribed, and emerging empirical evidence provides a base of support that is limited to short-term safety and efficacy.
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
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: Fluoxetine: depression and OCD age 8+ Escitalopram: depression age 12+ Sertraline,fluvoxamine, anfranil: pediatric OCD
Treatment Approaches Pharmacological Non-Pharmacological Individual Dialectical Behavioral Therapy Cognitive Behavioral Therapy Interpersonal Social Rhythms Therapy Parent Guidance Specialized Schools/ Residentials Inpatient Hospitalizations Special Education/Therapeutic Schools Wilderness Programs
Why Treat? Treatment Risk versus Benefit includes the risk of not treating with attendant: Suicide attempts and completed suicide Substance Abuse and Addiction Reckless Behavior with Arrest and other consequences
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
Why Treat? Early-Onset Bipolar Disorder and Treatment Delay Are Risk Factors for Poor Outcome in Adulthood Post et al 2010 Methods N=529 bipolar oupatients mean age 42 years Prospective Life Charting for 4 years Results: 50% had illness onset in childhood or adolescence versus adult onset Delay to first treatment correlated inversely with age of onset of illness J Clin Psychiatry 2010;71(7):864-872
Why Treat? Early-Onset Bipolar Disorder and Treatment Delay Are Risk Factors for Poor Outcome in Adulthood RESULTS: In year 1, the early onset cases had: greater severity of depression and mania, greater number of episodes and more days depressed, more days of ultradian cycling, fewer days euthymic. After 4 years, the early onset cases still had: greater severity and duration of depression fewer days euthymic. Delay to first treatment was associated with: more time depressed greater severity of depression greater number of episodes more days of ultradian cycling fewer days euthymic J Clin Psychiatry 2010;71(7):864-872
Can we wait? Post, Leverich, et al. 2010.
20 Year Literature Review PubMed search 1989-2010 Pediatric Bipolar Disorder Mania Children Pharmacotherapy Clinical trials published in English Open label and Randomized Control Trials Excluded chart reviews and case reports J Am Acad Child Adolesc Psychiatry, 2011;50(8):749-762.
Number of Studies Studies of Pediatric Mania Psychopharmacology 1989-2010 40 Published Studies 28 Open Label 12 RCT 2704 Subjects participated across studies Year
Number of Studies by Anti-Manic Medication Class Traditional Mood Stabilizers: lithium, divalproex, and carbamazepine Other Anticonvulsants: topiramate, oxcarbazepine, lamotrigine Atypical Antipsychotics: aripirazole, olanzapine, quetiapine, risperidone, ziprasidone
Number of Subjects Participating in Pediatric Anti-Manic Trials Naturopathic Treatments n= 71 Atypical Antipsychotics n=1474 Traditional Mood Stabilizers n= 915 Other Anticonvulsants n=244
Antiepileptics Traditional Mood Stabilizers Atypical Antipsychotics Response Rates to Monotherapy aripiprazole olanzapine quetiapine risperidone ziprasidone Overall lithium 33% 38% 45% 51% 49% 52% 53% 61% 62% 66% 66% 73% 75% carbamazepine divalproex overall lamotrigine 41% 43% 40% 40% 41% 54% oxcarbazepine topiramate overall 32% 35% 39% 42% 43% 0% 10% 20% 30% 40% 50% 60% 70% 80%
Mania Response Rates by Medication Class Mean Response Rate
YMRS Score Mean Change in YMRS from Baseline by Medication Class Traditional Mood Stabilizers Other Anticonvulsants Atypical Antipsychotics Naturopathic Treatments 0-2 -4-6 -8-5.6-10 -12-10.99-11.03-14 -16-18 -16.8
Clinical Trials: Combination Treatment Only 1 RCT of acute mania treatment in bipolar I adolescents Response Rate 87% Divalproex + Quetiapine 53% Divalproex + Placebo
PBD Mania Trials: Summary Significant increase in clinical trials of anti-manic agents over the past 10 years Atypical antipsychotic agents outperform traditional mood stabilizers and other anticonvulsants Limited evidence to support combination pharmacotherapy
How the Literature Review Findings Match Expert Practice Prescribing practices at Massachusetts General Hospital Joseph Biederman, MD Timothy Wilens, MD Janet Wozniak, MD J Child and Adolesc Psychopharmacology, 2009;19(5):529-538.
Methods Retrospective, unblinded chart review Identified active pediatric patients (age 4-19yo) diagnosed with bipolar disorder or bipolar spectrum disorder Generated an alphabetical patient list for each clinician Collected data for the first ten to twenty patients on the list No exclusion criteria
Treatment of Patients Diagnosed with PBD 68% treated for comorbid diagnosis Mean number of total psychotropic medications per patient = 3.0±1.6
Treatment Specifically Targeting Pediatric Mania or Mixed State Mean number of anti-manic agents per patient = 1.4±0.77
Response to Treatment Diagnosis Mean Pretreatment CGI-S Mean CGI-I CGI-I 2 Mania 5.4±0.6 2.0±0.8 80% Mixed state 5.7±0.7 2.3±0.7 57% Overall 5.2±0.8 2.2±0.7 66%
Summary of Expert Prescribing Practice Most patients require combination treatment SGA s were the most commonly prescribed class for both monotherapy and combination therapy SGA clinical response rate was similar to RCT s Potter et al. 2009
Literature vs. Expert Practice in the Treatment of Mania Evidence supports SGA monotherapy in PBD 66% response rate in 8 RCT s 66% of experts use SGA s for monotherapy Combination therapy requires further research Only 1 RCT Experts frequently prescribe combination pharmacotherapy
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 Weight gain and metabolic risks associated with antipsychotic medications in children and adolescents Correll et al JChildAdolescPsychopharm 2011 Dec;21(6):517-35 N=34 studies olanzapine 3.8 to 16.2 kg (n=353) clozapine 0.9-9.5 kg (n=97) risperidone 1.9-7.2 kg (n=571) quetiapine 2.3-6.1 kg (n=133) aripiprazole 0-4.4 kg (n=451)
Change from Baseline (kg) Weight Gain in 8-week Open Label Trials of Second Generation Antipsychotic Monotherapy in 116 Children with Bipolar Disorder 06 05 04 03 aripiprazole quetiapine risperidone ziprasidone olanzapine 02 01 00 0 1 2 3 4 5 6 7 8 Biederman et al (2007), AACAP; Boston
Treatment algorithm (Kowatch 2005) Stage I monotherapy +/- augmentation Stage 2 switch monotherapy agent Stage 3 combo mood stabilizer + SGA Or switch monotherapy Stage 4 Combination 1 mood stabilizer + SGA 2 mood stabilizers + SGA Stage 5 alternate monotherapy Stage 6 ECT vs. Clozapine
Comorbid disorders Depression Lithium, Lamotrigine, or bupropion Avoid SSRI s ADHD Stimulant after mood stabilized ODD / Conduct disorder SGA s PDD irritability SGA s (risperidone) 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)
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 autism comorbid with Pediatric BPD SGA secondary analysis of SGA trials demonstrated improvement of bipolar disorder in the autism subjects (Joshi, et al )
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 extended-release 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
Funding/support: This study was supported by a generous philanthropic donation from Kent and Elizabeth Dauten (Chicago, Illinois). November 2015
ANTI-MANIC RESPONSE TO TREATMENT The combined treatment of omega-3s and inositol outperformed either treatment used alone for mania Wozniak, J Clinical Psychiatry
ANTI-DEPRESSANT RESPONSE TO TREATMENT The combined treatment with both omega-3s and inositol outperformed eithe agent used alone in bipolar spectrum youth Wozniak, J Clinical Psychiatry
Natural Help for Depression and Mania? N-Acetyl Cysteine (NAC) is a precursor to glutathione, a potent anti-oxidant (we can t absorb glutathione, so best to ingest the precursor which crosses into the brain and gets converted). Destroys free radicals which lead to cell destruction. NAC is an altered form of the amino acid cysteine. Cysteine is found in high protein foods.
Source: https://fundraise.massgeneral.org/nac-study
Future Research Questions Studies of young children < 12 years old and preschoolers Combination pharmacotherapy trials Pharmacotherapy of comorbid disorders ADHD Depression OCD Psychosocial treatment Natural treatments including meditation