Pediatric Bipolar Disorder Incidence Trends And Pharmacotherapy Best

Pediatric Bipolar Disorder Incidence Trends And Pharmacotherapy Best Practices Clinical Insight Regarding A Misunderstood Mental Illness in the Pediatric Population John W. Probst, MPH 4 th Year Pharm.D. Student USC School of Pharmacy March 25, 2009

Agenda
Provide presentation objectives
Epidemiological background
Researched pharmacotherapy treatments
Clinical treatment best practices
Summary and Q & A

Objectives
Provide epidemiological background regarding the incidence of pediatric bipolar disorder (BD)
Discuss findings in the literature that support various psychotropic treatment approaches
Synthesize pharmacotherapy research findings and clinical practice as to which treatment approach works best for this patient population

Epidemiological Background

Statistical Overview
Historical studies show BD prevalence to be only 0.1-1.0% in pediatric population
Incidence rates in the past 10 years have:
Doubled in outpatient clinical settings (up to 6%)
Quadrupled in community hospitals (up to 40%)
Number of psychiatric office visits for youth with BD has  40x in past decade
Adult BD retrospective: 60% had onset of sxs <20 yo, while 10% had onset of sxs <10 yo

Diagnostic Clarity
Allows for a clearer understanding of BD s/sxs in young people
Different and better defined, age-specific diagnostic criteria
Clinicians can diagnose and treat with more confidence

Operation “Correct Diagnosis”
Alarming  in diagnoses has caused concern:
Is the differential diagnosis accurate?
Have comorbid mental/behavioral disorders been accounted for and also fully characterized?
Is the most appropriate pharmacotherapy approach being employed to treat the patient, not just sxs?
Number of guided research/studies have risen dramatically, as reflected by an  in interest within medical community re: BD in youth

Comorbid Confounders
Mental/behavioral D/O can complicate the dx (e.g. autism, ODD, etc.)
Research continues to elucidate differences between BD & ADHD
Other disorders are relatively common in children with BD

Era of Assessment Tools
Currently, ten (10) publications are available that are commonly used when assessing pediatric BD
Only two (2) publications were specifically designed to assess BD in a pediatric population. Tools used:
K-SADS = Schedule for Affective Disorders and Schizophrenia for School-Age Children
MRS = Mania Rating Scale
CMRS = Child Mania Rating Scale
Most important epidemiological development for this disease and population (i.e. real dx basis)

Key Population Findings
Smoking and/or substance use is positively correlated to pediatric BD (no causation proved)
Young people with BD are more likely to be overweight or obese than the adults with BD
Monotherapy for pediatric BD patients is rarely effective when comorbid conditions exist
More youth suffer from mixed episodes and cyclothymia, making BD dx and tx difficult
Risk of suicide and/or violence is very high

Researched Pharmacotherapy Treatments

Medication Usage Breakdown PURSUIT of EFFICACY

Historical Drugs of Choice
Lithium carbonate – only FDA approved medication to treat BD in kids >13 yo
Divalproex and quetiapine
popular combo treatment approach for poor & non-responders to lithium (other atypicals used too)
commonly used for acute tx of mania/mixed episodes
Third line and beyond – Stimulants, SSRIs, other antidepressants (including TCAs), FGAs, SGAs, lamotrigine, CBZ and even BZDs
TRIAL and ERROR

Drugs of Study - Gabapentin
Dose studied = 900-2400mg/day
Best results for “rapid cyclers” & refractory pts
Patients responded well as evident by improved mood, appetite and only moderate weight gain
1 pt d/c drug experienced irritability and strong mood swings (was concurrently on stimulant)
Touted for safe, easily tolerated, low DDIs profile, while showing strong efficacy

Drugs of Study - Topiramate
Few studies in pediatrics due to poor results in adult population (i.e. sampling bias)
Young Mania Rating Scale (YMRS) assessment tool used – helped show greatest baseline Δ
Studied as acute treatment only – no quality data re: long-term maintenance tx was found
Main drawback for most studies is small sample size – achieving statistical significance is hard

Drugs of Study - Combos
“Best” results are with lithium, divalproex and an adjunct of choice (e.g. stimulant, SGA, etc.)
Another successful “cocktail” was risperidone + either lithium or divalproex – especially BD I
Many studies show improved mood when BOTH lithium and divalproex were on board
Body of research continues to show that mono-therapy for pediatric BD patients does not work

Tx Research Shortcomings
Insufficient and limited data – information gaps
Studies have been small, inadequately designed & aren’t always longitudinal
Very little data focusing on maintenance treatment
Maintenance medication compliance and refining of regimens are poorly researched topics

Pharmacotherapy Challenges
Tailor treatment regimens for acute and especially chronic BD in pediatrics
Determine best therapy for mania & depression
Provide tx algorithms for providers dealing with complicated patients
Coordinate drug therapy with CBT programs - key for maint/euthymia

Clinical Treatment Best Practices

Today’s Working Standard
Treatment is largely determined by phenotype
Varies by country based on diagnostic criteria
Becoming increasingly dependent on assessment tools
CBCL-BD = Child Behavior Checklist for BD
YMRS = Young Mania Rating Scale
Clinicians are beginning to categorize pediatric BD as either “narrow” or “broad” to guide tx(s)
Acute mania = mood stabilizer and/or SGA
Lithium is favored in children; divalproex in teens
Stimulants and other adjuncts are tolerated well

The Role of Psychotherapy
Best when entire family is involved upon diagnosis
Current approaches include:
FFT = family focused treatment
IFT = individual family treatment
MFPG = multifamily psychoeducation groups
CBT is a mainstay treatment and data shows great benefit in controlling sxs of mania and depression long term

One Regimen Fits All?
Further delineation and customization of diagnosis and treatment – why not cookie cutter?
Providers can establish a meaningful prognosis
Interventions made at subsyndromal or early stages
Genetic and neuroimaging methodologies are starting to reveal a potentially wide array of etiologies (i.e. BD “spectrum”)
Questions re: who should receive monotherapy vs. combo, and when to modify therapy, still remain

Focus on Prognosis Goals
Quality of life and long term health are starting to become as important as controlling acute sxs
Determine role/extent of SGAs in weight gain, etc.
Emphasis on managing other comorbid conditions to maximize drug efficacy and improve pt outlook
Determine longitudinal course of BD in order to guide patient through transition to adulthood
Stress appropriate medication utilization, while minimizing cost burden & ADRs - not so in past

Summary

Much More to Learn…
As understanding increases about the pediatric BD population, better diagnostic tools and treatment approaches are being developed
Drug therapy for pediatric BD is starting to be directed by better “trials”, hence fewer “errors”
Customizing pharamcotherapy is still a work in progress for: 1) acute vs. chronic; 2) mania/mixed vs. depression; and 3) comorbid vs. lone disorder
Proper tx is critical for long-term  QOL!!

Medication Breakdown
Current DOC
Divalproex (mania * )
Lamotrigine (depression * )
SGAs
Risperidone
Quetiapine
Ziprasidone/Aripiprazole
Clozapine/Olanzapine - REF
Topiramate
Gabapentin
Carbamazepine
Others still in use
Lithium (depression * )
Oxcarbazepine
Stimulants (SR is best)
FGAs
Antidepressants
Trazadone
based on efficacy in adults - new studies support use in youth
* general consensus/some data

Any Questions?

References
Castilla-Puentes R. Multiple episodes in children and adolescents with bipolar disorder: comorbidity, hospitalization, and treatment (data from a cohort of 8,129 patients of a national managed care database). International Journal of Psychiatry in Medicine . 2008. 38(1):61-70.
Demeter CA, et al. Current research in child and adolescent bipolar disorder. Dialogues in Clinical Neuroscience . 2008. 10(2):215-28.
Goldstein BI, et al. Preliminary findings regarding overweight and obesity in pediatric bipolar disorder. Journal of Clinical Psychiatry . Dec 2008. 69(12):1953-9.
Goldstein BI, et al. Significance of cigarette smoking among youths with bipolar disorder. American Journal on Addictions . Sep-Oct 2008. 17(5):364-71.
Hamrin V, Pachler M. Pediatric Bipolar Disorder: Evidence-Based Psychopharmacological Treatments. Journal of Child and Adolescent Psychiatric Nursing. Feb 2007. 20:1; Psychology Module p.40.
Holtmann M, et al. Rapid increase in rates of bipolar diagnosis in youth: "true" bipolarity or misdiagnosed severe disruptive behavior disorders? Archives of General Psychiatry . Apr 2008. 65(4):477.

References
Leibenluft E, Rich BA. Pediatric Bipolar Disorder. Annual Review of Clinical Psychology. 2008. 4:163–87.
Masi G, et al. Comorbidity of conduct disorder and bipolar disorder in clinically referred children and adolescents. Journal of Child & Adolescent Psychopharmacology . Jun 2008. 18(3):271-9.
Miklowitz DJ, et al. Family-focused treatment for adolescents with bipolar disorder: results of a 2-year randomized trial. Sep 2008. Archives of General Psychiatry . 65(9):1053-61.
Munesue T, et al. High prevalence of bipolar disorder comorbidity in adolescents and young adults with high-functioning autism spectrum disorder: a preliminary study of 44 outpatients. Journal of Affective Disorders . Dec 2008. 111(2-3):170-5.
Pavuluri MN, Naylor MW. Multi-Modal Integrated Treatment for Youth With Bipolar Disorder. Psychiatric Times . May 2005. 22 (6).
Pavuluri MN, et al. Pediatric Bipolar Disorder: A Review of the Past 10 Years. Journal of American Academy of Child and Adolescent Psychiatry . 2005. 44(9):846-871.

References
Ryback RS, et al. Letters to Editor – Gabapentin in Bipolar Disorder. Journal of Neuropsychiatry & Clinical Neurosciences . 9 (2): 301.
Singh, T. Pediatric Bipolar Disorder: Diagnostic Challenges in Identifying Symptoms and Course of Illness. PsychiatryMMC.com. Jun 2008.
Wilens TE, et al. Further evidence of an association between adolescent bipolar disorder with smoking and substance use disorders: a controlled study. Drug & Alcohol Dependence . Jun 2008. 95(3):188-98.

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Pediatric Bipolar Disorder Incidence Trends And Pharmacotherapy Best

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