pediatric bipolar disorder incidence trends and pharmacotherapy best
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A population and a disease state that some still think should not go together. The data suggests otherwise...TRANSCRIPT
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.
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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.
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