Pediatric Bipolar Pediatric Bipolar DisorderDisorder

Incidence Trends And Incidence Trends And Pharmacotherapy Best Pharmacotherapy Best

PracticesPracticesClinical Insight Regarding A Clinical Insight Regarding A

Misunderstood Mental Illness in the Misunderstood Mental Illness in the Pediatric PopulationPediatric Population

John W. Probst, MPHJohn W. Probst, MPH

44thth Year Pharm.D. Student Year Pharm.D. Student

USC School of PharmacyUSC School of Pharmacy

March 25, 2009March 25, 2009

AgendaAgenda

Provide presentation objectivesProvide presentation objectives

Epidemiological backgroundEpidemiological background

Researched pharmacotherapy Researched pharmacotherapy

treatmentstreatments

Clinical treatment best practicesClinical treatment best practices

Summary and Q & ASummary and Q & A

ObjectivesObjectives Provide epidemiological background Provide epidemiological background

regarding the incidence of pediatric bipolar regarding the incidence of pediatric bipolar disorder (BD) disorder (BD)

Discuss findings in the literature that support Discuss findings in the literature that support various psychotropic treatment approachesvarious psychotropic treatment approaches

Synthesize pharmacotherapy research Synthesize pharmacotherapy research findings and clinical practice as to which findings and clinical practice as to which treatment approach works best for this treatment approach works best for this patient populationpatient population

Epidemiological Epidemiological Background Background

Statistical OverviewStatistical Overview Historical studies show BD prevalence to be Historical studies show BD prevalence to be

only 0.1-1.0% in pediatric populationonly 0.1-1.0% in pediatric population Incidence rates in the past 10 years have:Incidence rates in the past 10 years have:

Doubled in outpatient clinical settings (up to 6%)Doubled in outpatient clinical settings (up to 6%) Quadrupled in community hospitals (up to 40%)Quadrupled in community hospitals (up to 40%)

Number of psychiatric office visits for youth Number of psychiatric office visits for youth with BD has with BD has 40x in past decade 40x in past decade

Adult BD retrospective: 60% had onset of Adult BD retrospective: 60% had onset of sxs <20 yo, while 10% had onset of sxs <10 sxs <20 yo, while 10% had onset of sxs <10 yoyo

Diagnostic ClarityDiagnostic Clarity Allows for a clearer Allows for a clearer

understanding of BD understanding of BD s/sxs in young peoples/sxs in young people

Different and better Different and better defined, age-specific defined, age-specific diagnostic criteriadiagnostic criteria

Clinicians can Clinicians can diagnose and treat diagnose and treat with more confidencewith more confidence

Operation “Correct Operation “Correct Diagnosis”Diagnosis”

Alarming Alarming in diagnoses has caused concern: in diagnoses has caused concern: Is the differential diagnosis accurate?Is the differential diagnosis accurate? Have comorbid mental/behavioral disorders been Have comorbid mental/behavioral disorders been

accounted for and also fully characterized?accounted for and also fully characterized? Is the most appropriate pharmacotherapy Is the most appropriate pharmacotherapy

approach being employed to treat the patient, approach being employed to treat the patient, not just sxs?not just sxs?

Number of guided research/studies have Number of guided research/studies have risen dramatically, as reflected by an risen dramatically, as reflected by an in in interest within medical community re: BD in interest within medical community re: BD in youthyouth

Comorbid ConfoundersComorbid Confounders Mental/behavioral D/O Mental/behavioral D/O

can complicate the dx can complicate the dx (e.g. autism, ODD, (e.g. autism, ODD, etc.)etc.)

Research continues to Research continues to elucidate differences elucidate differences between BD & ADHDbetween BD & ADHD

Other disorders are Other disorders are relatively common in relatively common in children with BDchildren with BD

Era of Assessment Era of Assessment ToolsTools

Currently, ten (10) publications are available Currently, ten (10) publications are available that are commonly used when assessing that are commonly used when assessing pediatric BDpediatric BD Only two (2) publications were specifically designed Only two (2) publications were specifically designed

to assess BD in a pediatric population. Tools used:to assess BD in a pediatric population. Tools used: K-SADSK-SADS = Schedule for Affective Disorders and = Schedule for Affective Disorders and

Schizophrenia for School-Age ChildrenSchizophrenia for School-Age Children MRSMRS = Mania Rating Scale = Mania Rating Scale CMRSCMRS = Child Mania Rating Scale= Child Mania Rating Scale

Most important epidemiological development Most important epidemiological development for this disease and population (i.e. real dx for this disease and population (i.e. real dx basis)basis)

Key Population Key Population FindingsFindings

Smoking and/or substance use is positively Smoking and/or substance use is positively correlated to pediatric BD (no causation correlated to pediatric BD (no causation proved)proved)

Young people with BD are more likely to be Young people with BD are more likely to be overweight or obese than the adults with BDoverweight or obese than the adults with BD

Monotherapy for pediatric BD patients is Monotherapy for pediatric BD patients is rarely effective when comorbid conditions existrarely effective when comorbid conditions exist

More youth suffer from mixed episodes and More youth suffer from mixed episodes and cyclothymia, making BD dx and tx difficultcyclothymia, making BD dx and tx difficult

Risk of suicide and/or violence is very highRisk of suicide and/or violence is very high

Researched Researched Pharmacotherapy Pharmacotherapy

TreatmentsTreatments

Medication Usage Medication Usage BreakdownBreakdown

PURSUIPURSUIT of T of

EFFICACEFFICACYY

Historical Drugs of Historical Drugs of ChoiceChoice

Lithium carbonateLithium carbonate – only FDA approved – only FDA approved medication to treat BD in kids >13 yomedication to treat BD in kids >13 yo

Divalproex and quetiapineDivalproex and quetiapine popular combo treatment approach for poor & popular combo treatment approach for poor &

non-responders to lithium (other atypicals used non-responders to lithium (other atypicals used too)too)

commonly used for acute tx of mania/mixed commonly used for acute tx of mania/mixed episodesepisodes

Third line and beyondThird line and beyond – Stimulants, SSRIs, – Stimulants, SSRIs, other antidepressants (including TCAs), FGAs, other antidepressants (including TCAs), FGAs, SGAs, lamotrigine, CBZ and even BZDsSGAs, lamotrigine, CBZ and even BZDs

TRIAL and

ERROR

Drugs of Study - Drugs of Study - GabapentinGabapentin

Dose studied = 900-2400mg/dayDose studied = 900-2400mg/day Best results for “rapid cyclers” & refractory ptsBest results for “rapid cyclers” & refractory pts Patients responded well as evident by improved Patients responded well as evident by improved

mood, appetite and only moderate weight gainmood, appetite and only moderate weight gain 1 pt d/c drug experienced irritability and strong 1 pt d/c drug experienced irritability and strong

mood swings (was concurrently on stimulant)mood swings (was concurrently on stimulant) Touted for safe, easily tolerated, low DDIs Touted for safe, easily tolerated, low DDIs

profile, while showing strong efficacyprofile, while showing strong efficacy

Drugs of Study - Drugs of Study - TopiramateTopiramate

Few studies in pediatrics due to poor Few studies in pediatrics due to poor results in adult population (i.e. sampling bias)results in adult population (i.e. sampling bias)

Young Mania Rating Scale (YMRS) assessment Young Mania Rating Scale (YMRS) assessment tool used – helped show greatest baseline tool used – helped show greatest baseline ΔΔ

Studied as acute treatment only – no quality Studied as acute treatment only – no quality data re: long-term maintenance tx was founddata re: long-term maintenance tx was found

Main drawback for most studies is small Main drawback for most studies is small sample size – achieving statistical significance sample size – achieving statistical significance is hardis hard

Drugs of Study - Drugs of Study - CombosCombos

““Best” results are with lithium, divalproex and Best” results are with lithium, divalproex and an adjunct of choice (e.g. stimulant, SGA, etc.)an adjunct of choice (e.g. stimulant, SGA, etc.)

Another successful “cocktail” was risperidone Another successful “cocktail” was risperidone + either lithium or divalproex – especially BD I+ either lithium or divalproex – especially BD I

Many studies show improved mood when BOTH Many studies show improved mood when BOTH lithium and divalproex were on boardlithium and divalproex were on board

Body of research continues to show that mono-Body of research continues to show that mono-therapy for pediatric BD patients does not worktherapy for pediatric BD patients does not work

Tx Research Tx Research ShortcomingsShortcomings

Insufficient and limited Insufficient and limited data – information gapsdata – information gaps

Studies have been small, Studies have been small, inadequately designed & inadequately designed & aren’t always longitudinalaren’t always longitudinal

Very little data focusing Very little data focusing on maintenance on maintenance treatmenttreatment

Maintenance medication Maintenance medication compliance and refining compliance and refining of regimens are poorly of regimens are poorly researched topics researched topics

Pharmacotherapy Pharmacotherapy ChallengesChallenges

Tailor treatment Tailor treatment regimens for acute and regimens for acute and especially chronic BD in especially chronic BD in pediatricspediatrics

Determine best therapy Determine best therapy for mania & depressionfor mania & depression

Provide tx algorithms for Provide tx algorithms for providers dealing with providers dealing with complicated patientscomplicated patients

Coordinate drug therapy Coordinate drug therapy with CBT programs - key with CBT programs - key for maint/euthymiafor maint/euthymia

Clinical Clinical Treatment Treatment

Best PracticesBest Practices

Today’s Working Today’s Working StandardStandard

Treatment is largely determined by phenotypeTreatment is largely determined by phenotype Varies by country based on diagnostic criteriaVaries by country based on diagnostic criteria Becoming increasingly dependent on assessment Becoming increasingly dependent on assessment

toolstools CBCL-BDCBCL-BD = Child Behavior Checklist for BD = Child Behavior Checklist for BD YMRSYMRS = Young Mania Rating Scale = Young Mania Rating Scale

Clinicians are beginning to categorize pediatric Clinicians are beginning to categorize pediatric BD as either “narrow” or “broad” to guide tx(s)BD as either “narrow” or “broad” to guide tx(s)

Acute mania = mood stabilizer and/or SGAAcute mania = mood stabilizer and/or SGA Lithium is favored in children; divalproex in teensLithium is favored in children; divalproex in teens Stimulants and other adjuncts are tolerated wellStimulants and other adjuncts are tolerated well

The Role of The Role of PsychotherapyPsychotherapy

Best when entire family is Best when entire family is involved upon diagnosisinvolved upon diagnosis

Current approaches include:Current approaches include: FFTFFT = family focused treatment = family focused treatment IFTIFT = individual family treatment = individual family treatment MFPGMFPG = multifamily = multifamily

psychoeducation groupspsychoeducation groups CBT is a mainstay treatment CBT is a mainstay treatment

and data shows great benefit and data shows great benefit in controlling sxs of mania in controlling sxs of mania and depression long termand depression long term

One Regimen Fits All?One Regimen Fits All? Further delineation and customization of Further delineation and customization of

diagnosis and treatment – why not cookie diagnosis and treatment – why not cookie cutter?cutter? Providers can establish a meaningful prognosisProviders can establish a meaningful prognosis Interventions made at subsyndromal or early stagesInterventions made at subsyndromal or early stages

Genetic and neuroimaging methodologies Genetic and neuroimaging methodologies are starting to reveal a potentially wide are starting to reveal a potentially wide array of etiologies (i.e. BD “spectrum”) array of etiologies (i.e. BD “spectrum”)

Questions re: who should receive monotherapy Questions re: who should receive monotherapy vs. combo, and when to modify therapy, still vs. combo, and when to modify therapy, still remainremain

Focus on Prognosis Focus on Prognosis GoalsGoals

Quality of life and long term health are starting Quality of life and long term health are starting to become as important as controlling acute sxsto become as important as controlling acute sxs Determine role/extent of SGAs in weight gain, etc.Determine role/extent of SGAs in weight gain, etc. Emphasis on managing other comorbid conditions to Emphasis on managing other comorbid conditions to

maximize drug efficacy and improve pt outlookmaximize drug efficacy and improve pt outlook Determine longitudinal course of BD in order to Determine longitudinal course of BD in order to

guide patient through transition to adulthoodguide patient through transition to adulthood Stress appropriate medication utilization, while Stress appropriate medication utilization, while

minimizing cost burden & ADRs - not so in past minimizing cost burden & ADRs - not so in past

SummarySummary

Much More to Learn…Much More to Learn… As understanding increases about the pediatric As understanding increases about the pediatric

BD population, better diagnostic tools and BD population, better diagnostic tools and treatment approaches are being developedtreatment approaches are being developed

Drug therapy for pediatric BD is starting to be Drug therapy for pediatric BD is starting to be directed by better “trials”, hence fewer “errors”directed by better “trials”, hence fewer “errors”

Customizing pharamcotherapy is still a work in Customizing pharamcotherapy is still a work in progress for: progress for: 1)1) acute vs. chronic; acute vs. chronic; 2)2) mania/mixed vs. depression; and mania/mixed vs. depression; and 3)3) comorbid vs. comorbid vs. lone disorder lone disorder

Proper tx is critical for long-term Proper tx is critical for long-term QOL!! QOL!!

Medication BreakdownMedication Breakdown Current DOCCurrent DOC

Divalproex (maniaDivalproex (mania**)) Lamotrigine (depressionLamotrigine (depression**)) SGAsSGAs

RisperidoneRisperidone QuetiapineQuetiapine Ziprasidone/AripiprazoleZiprasidone/Aripiprazole Clozapine/Olanzapine - REFClozapine/Olanzapine - REF

TopiramateTopiramate GabapentinGabapentin CarbamazepineCarbamazepine

Others still in useOthers still in use

Lithium (depressionLithium (depression**))

OxcarbazepineOxcarbazepine

Stimulants (SR is Stimulants (SR is

best)best)

FGAsFGAs

AntidepressantsAntidepressants

TrazadoneTrazadone

based on based on efficacy in efficacy in adults - new adults - new studies support studies support use in youthuse in youth

* * general general consensus/some dataconsensus/some data

Any Questions?Any Questions?

ReferencesReferences1.1. Castilla-Puentes R. Castilla-Puentes R. Multiple episodes in children and adolescents Multiple episodes in children and adolescents

with bipolar disorder: comorbidity, hospitalization, and treatment with bipolar disorder: comorbidity, hospitalization, and treatment (data from a cohort of 8,129 patients of a national managed care (data from a cohort of 8,129 patients of a national managed care database). database). International Journal of Psychiatry in MedicineInternational Journal of Psychiatry in Medicine. 2008. . 2008. 38(1):61-70.38(1):61-70.

2.2. Demeter CA, et al. Current research in child and adolescent bipolar Demeter CA, et al. Current research in child and adolescent bipolar disorder. disorder. Dialogues in Clinical NeuroscienceDialogues in Clinical Neuroscience. 2008. 10(2):215-28.. 2008. 10(2):215-28.

3.3. Goldstein BI, et al. Preliminary findings regarding overweight and Goldstein BI, et al. Preliminary findings regarding overweight and obesity in pediatric bipolar disorder. obesity in pediatric bipolar disorder. Journal of Clinical PsychiatryJournal of Clinical Psychiatry. . Dec 2008. 69(12):1953-9.Dec 2008. 69(12):1953-9.

4.4. Goldstein BI, et al. Significance of cigarette smoking among youths Goldstein BI, et al. Significance of cigarette smoking among youths with bipolar disorder. with bipolar disorder. American Journal on AddictionsAmerican Journal on Addictions. Sep-Oct . Sep-Oct 2008. 17(5):364-71.2008. 17(5):364-71.

5.5. Hamrin V, Pachler M. Pediatric Bipolar Disorder: Evidence-Based Hamrin V, Pachler M. Pediatric Bipolar Disorder: Evidence-Based Psychopharmacological Treatments. Psychopharmacological Treatments. Journal of Child and Journal of Child and Adolescent Psychiatric Nursing. Adolescent Psychiatric Nursing. Feb 2007. 20:1; Psychology Feb 2007. 20:1; Psychology Module p.40.Module p.40.

6.6. Holtmann M, et al. Rapid increase in rates of bipolar diagnosis in Holtmann M, et al. Rapid increase in rates of bipolar diagnosis in youth: "true" bipolarity or misdiagnosed severe disruptive behavior youth: "true" bipolarity or misdiagnosed severe disruptive behavior disorders? disorders? Archives of General PsychiatryArchives of General Psychiatry. Apr 2008. 65(4):477.. Apr 2008. 65(4):477.

ReferencesReferences7.7. Leibenluft E, Rich BA. Pediatric Bipolar Disorder. Leibenluft E, Rich BA. Pediatric Bipolar Disorder. Annual Review of Annual Review of

Clinical Psychology. Clinical Psychology. 2008. 4:163–87.2008. 4:163–87.

8.8. Masi G, et al. Comorbidity of conduct disorder and bipolar disorder Masi G, et al. Comorbidity of conduct disorder and bipolar disorder in clinically referred children and adolescents. in clinically referred children and adolescents. Journal of Child & Journal of Child & Adolescent PsychopharmacologyAdolescent Psychopharmacology. Jun 2008. 18(3):271-9.. Jun 2008. 18(3):271-9.

9.9. Miklowitz DJ, et al. Family-focused treatment for adolescents with Miklowitz DJ, et al. Family-focused treatment for adolescents with bipolar disorder: results of a 2-year randomized trial. Sep 2008. bipolar disorder: results of a 2-year randomized trial. Sep 2008. Archives of General PsychiatryArchives of General Psychiatry. 65(9):1053-61.. 65(9):1053-61.

10.10. Munesue T, et al. High prevalence of bipolar disorder comorbidity Munesue T, et al. High prevalence of bipolar disorder comorbidity in adolescents and young adults with high-functioning autism in adolescents and young adults with high-functioning autism spectrum disorder: a preliminary study of 44 outpatients. spectrum disorder: a preliminary study of 44 outpatients. Journal of Journal of Affective DisordersAffective Disorders. Dec 2008. 111(2-3):170-5.. Dec 2008. 111(2-3):170-5.

11.11. Pavuluri MN, Naylor MW. Multi-Modal Integrated Treatment for Pavuluri MN, Naylor MW. Multi-Modal Integrated Treatment for Youth With Bipolar Disorder. Youth With Bipolar Disorder. Psychiatric TimesPsychiatric Times. May 2005. 22 (6).. May 2005. 22 (6).

12.12. Pavuluri MN, et al. Pediatric Bipolar Disorder: A Review of the Past Pavuluri MN, et al. Pediatric Bipolar Disorder: A Review of the Past 10 Years. 10 Years. Journal of American Academy of Child and Adolescent Journal of American Academy of Child and Adolescent PsychiatryPsychiatry. 2005. 44(9):846-871.. 2005. 44(9):846-871.

ReferencesReferences13.13. Ryback RS, et al. Letters to Editor – Gabapentin in Bipolar Ryback RS, et al. Letters to Editor – Gabapentin in Bipolar

Disorder. Disorder. Journal of Neuropsychiatry & Clinical Journal of Neuropsychiatry & Clinical NeurosciencesNeurosciences. 9 (2): 301.. 9 (2): 301.

14.14. Singh, T. Pediatric Bipolar Disorder: Diagnostic Challenges Singh, T. Pediatric Bipolar Disorder: Diagnostic Challenges in Identifying Symptoms and Course of Illness. in Identifying Symptoms and Course of Illness. PsychiatryMMC.com.PsychiatryMMC.com. Jun 2008. Jun 2008.

15.15. Wilens TE, et al. Further evidence of an association between Wilens TE, et al. Further evidence of an association between adolescent bipolar disorder with smoking and substance use adolescent bipolar disorder with smoking and substance use disorders: a controlled study. disorders: a controlled study. Drug & Alcohol DependenceDrug & Alcohol Dependence. . Jun 2008. 95(3):188-98.Jun 2008. 95(3):188-98.