Lecture offered to Child and Adolescent Psychiatry Fellows, Akron Children's Hospital/ Northeast Ohio Medical University August 8, 2013

1. Stephen Grcevich, MD
Department of Psychiatry
Northeast Ohio Medical University
Presented at Children’s Hospital Medical Center of Akron
August 8, 2013
Treatment of Pediatric Bipolar Disorder
E-mail: drgrcevich@fcbtf.com Phone: (440) 543-3400
Twitter: @drgrcevich

2. Educational objectives:
 Identify critical questions challenging our
assumptions regarding treatment of bipolar
disorder in kids
 Review key literature evaluating effective
pharmacotherapy of pediatric bipolar disorder
 Examine available data on non-pharmacologic
treatments in kids with bipolar disorder
 Explore available research on treatment of
Disruptive Mood Dysregulation Disorder…and
speculate on potential treatment approaches

3. Pharmaceutical Industry
Consulting:
None since 2009
Grant/Research Support
Child and Adolescent Psychiatry
Trials (CAPTN) Network-ASK,
PARCA, NOTA studies funded
through NIMH, SPRITES-Pfizer
through Duke Clinical Research
Institute
Speakers’ Bureaus None since 2006
Other Financial/Material Support Web MD/Medscape (2008-12)
Major Shareholder None
Stephen Grcevich, MD: disclosures:Disclosures:

4. The greatest controversy in our field?
 40X increase in outpatient visits for pediatric bipolar
disorder between 1994-95 and 2002-03 (6X increase
in prevalence of bipolar diagnosis)
 The majority of kids receiving the diagnosis don’t
meet traditional DSM-IV criteria for the disorder
 Average number of psychotropic medications: 3.4
 Average number of medication trials: 6.3 (+/- 3.7)
 Medications approved for pediatric bipolar disorder
associated with rapid, large increases in weight, lipid,
cholesterol elevation, Type 2 diabetes
Moreno C, Laje G, Blanco C, et al. Arch. Gen. Psychiatry 64, 1032–1039 (2007).

5. AACAP Practice Parameters for Assessment and
Treatment of Bipolar Disorder (2007)
 Pharmacotherapy is the primary treatment in
well-defined DSM-IV Bipolar I disorder
 A comprehensive treatment plan, combining
medications with psychotherapeutic
interventions is needed to address the
symptomatology and confounding
psychosocial factors found in children and
adolescents with bipolar disorder
J . Am. Acad. Child Adolesc. Psychiatry, 46:1, January 2007

6. True or False…
 The majority of teens admitted to the hospital
for the first time for bipolar disorder achieve
functional recovery within the first twelve
months following their hospitalization.

7. The answer is…FALSE
 41% of teens exhibit functional recovery within a year
after initial hospitalization for bipolar disorder
 54% experience a syndromic recurrence within twelve
months (86% experience syndromic remission)
 66% are prescribed SGAs, 56% lithium and/or
divalproex, 24% antidepressants, 27% stimulants one
year later
 35% are adherent to medication (>75% of prescribed
doses, 42% “partially adherent (25-75% of doses), 23%
non-adherent
 Boys twice as likely as girls to achieve symptomatic
recovery
Delbello MP et al. Am J Psychiatry 2007 Apr; 164(4):582-90

8. FDA-approved medications for youth with
Bipolar Disorder
 Risperidone: Bipolar mania (10-17)
 Aripiprazole: Bipolar mania (10-17)
 Quetiapine: Bipolar mania (10-17)
 Olanzapine: (labeling-consider other drugs first)
Bipolar mania (13-17)
 Lithium Carbonate: Bipolar mania (12-17)…
”grandfathered” indication
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Pedi
atricAdvisoryCommittee/UCM193200.pdf

9. Second generation antipsychotics in
pediatric bipolar disorder:
 As of February, 2012: 11 RCTs published –all in 2007
or later
 Aside from TEAM, RCTs evaluated kids age 10 and
older
 Response rates in acute RCTs 45-89%, remission
achieved in 25-72%
 Treatment-refractory nature of patients enrolled at
academic medical centers attenuated magnitude of
AEs
 Little data examining long-term course on SGAs,
efficacy in preventing relapse
Hamrin V, Ienacco J. Expert Rev Neurother. 2010;10(7):1053-1088.

10. Second-generation antipsychotics in acute mania:

11. Treatment of Early-Age Mania (TEAM) study:
 Randomized, 8 week multicenter study of 279
patients ages 6-15 with Bipolar I Disorder
 Patients received lithium, divalproex sodium,
risperidone
 Mean lithium level 1.09 (0.34) mEq/L
 Mean divalproex sodium level: 113.6 (23.0) ug/ml
 Mean titrated risperidone dose 2.57 (1.21) mg/day
Geller et al. Arch Gen Psychiatry 2012 May;69(5):515-28

12. TEAM Study…results:
Geller et al. Arch Gen Psychiatry 2012 May;69(5):515-28

13. Treatment of Early-Age Mania (TEAM) study:
 Risperidone was more efficacious than lithium
or divalproex sodium for the initial treatment of
childhood mania
 Discontinuation rate higher for lithium than for
risperidone
 Increased weight gain, body mass index, and
prolactin level occurred with risperidone vs
lithium and divalproex sodium
 Thyrotropin level increased in subjects taking
lithium
Geller et al. Arch Gen Psychiatry 2012 May;69(5):515-28

14. Risperidone vs. Divalproex

15. Divalproex vs. Quetiapine

16. Lithium in pediatric bipolar disorder:
 One acute RCT: Li>PBO (46% response rate
vs. 8%) …Geller et al., 1998-in JAACAP
 Didn’t appear to prevent relapse
 Negative RCT in SMD
 No significant difference in relapse rates in
controlled discontinuation trial vs. placebo
(Kafantaris et al., 2004)
 Narrow therapeutic window, toxicity in
overdose concerns in adolescents
Hamrin V, Ienacco J. Expert Rev Neurother. 2010;10(7):1053-1088

17. Anticonvulsants in pediatric bipolar disorder:
 Divalproex sodium: open-label studies have
demonstrated response rates of 56-92%, but
two RCTs have failed to demonstrate efficacy
 Lamotrigine: Three open-label studies suggest
50-60% remission rates, helpful with bipolar
depression results confounded by adjunct
meds, RCT underway
 Topiramate, oxcarbazepine: Negative RCTs
Hamrin V, Ienacco J. Expert Rev Neurother. 2010;10(7):1053-1088

18. Findling’s lithium/divalproex randomized
discontinuation study

19. Comorbidity and pediatric bipolar disorder:
 ADHD: 90% in children with bipolar disorder,
60% in teens with bipolar disorder, 13% in
adults with bipolar disorder
 Prevalence of anxiety disorders: 56-76%
 Increased substance abuse risk-greater risk in
adolescent-onset vs. childhood onset BPD
 4X greater risk of post-traumatic stress
disorder
Joshi G, Wilens T. Child Adolesc Psychiatric Clin N Am 18 (2009) 291–319

20. How does comorbidity impact bipolar treatment?
 Risperidone>divalproex for kids with comorbid
disruptive behavior disorders (DBD)
 Patients without DBDs responded equally well
to risperidone and divalproex
 Kids with high levels of aggression have lower
levels of global functioning at treatment
completion
 TEAM Study: risperidone/lithium response
ratios…2.1 for patients with ADHD (1.0 without),
2.3 for non-obese patients (1.1 obese)
West AE et al. J Child Adolesc Psychopharmacol 2011 Dec;21(6):545-53

21. Other studies…
 Paliperidone-open-label study (N=15),
significant improvement in YMRS, severity of
ADHD, psychotic sx.
 Quetiapine-open label monotherapy in
preschoolers (n=30), school age (N=19)
children…response in preschoolers similar to
school-age children
 Open-label uridine-(N=7) reported to be helpful
in adolescents with depression, bipolar disorder
Joshi G et al. Psychopharmacology 2013 Jun;227(3):449-58
Joshi G et al. J Affect Disord 2012 Feb;136(3):1143-53
Kondo DG et al. J Child Adolesc Psychopharmacol 2011;21(2):171-75

22. ECT in adolescent mania?
 AACAP Practice Parameters refer to use in
treatment refractory adults, pregnancy, catatonia,
NMS
 “ECT should only be considered for adolescents
with well-characterized bipolar I disorder who have
severe episodes of mania or depression and are
nonresponsive (or unable to take) standard
medication therapies.”
 One series of 11 patients: One year follow-up-no
difference vs. non-ECT control group, two single
case reports
Taleb O et al. Eur Psychiatry. 2002 Jul;17(4):206-12.

23. True or false…
 Aripiprazole is not associated with significant
weight gain when used as monotherapy in
youth with bipolar disorder (and other
conditions) who are naïve to pharmacotherapy.

24. The answer is…FALSE
Correll, CU et al., JAMA. 2009;302:1765–1773.

25. Metabolic effects of second-generation
antipsychotics in pediatric patients:
Agent: Metabolic Effects:
Olanzapine fasting glucose
triglycerides
insulin
insulin resistance
Quetiapine total cholesterol
triglycerides
HDL cholesterol
triglyceride:HDL ratio
Risperidone triglycerides
Aripiprazole No significant metabolic effects
Correll, CU et al., JAMA. 2009;302:1765–1773.

26. Mood Stabilizer Side Effects
 Lithium: toxicity, potential lethality in overdose,
gastroenteritis (compounded by NSAIDs),
renal, thyroid toxicity, acne, weight gain,
tremor, polyuria
 Divalproex: PCOS, weight gain, hair loss,
tremor
 Lamotrigine: rare cases of Stevens-Johnson
(need slow titration)
David Axelson, MD, AACAP Board Review Course, 2012

27. Psychotherapy and psychosocial treatment:
 Multifamily educational groups: attenuated severity of
child’s mood symptoms (Fristad et al., 2009)
 IFP (Individual/family psychoeducation) 1 RCT (N=20)
improved children’s mood symptoms
 FFT (Family focused therapy) psychoeducation,
communication enhancement training, and problem solving
skills training-two year RCT indicated improvement in
depressive sx. with bipolar disorder
 DBT: One open label trial (N=10)
 CFF-CBT: Open-label trial (N=34) with three year follow-up
showed benefits of treatment were maintained
West A, Pavuluri M. Child Adolesc Psychiatric Clin N Am 18 (2009) 471–482

28. Why is psychotherapy important?
Axelson, DA. 2012 AACAP Board Review Course, Pittsburgh, PA

29. Multifamily psychoeducation:

30. Targeting expressed emotion?

31. So…how do we treat?
 Most treatment guidelines/practice parameters
are hopelessly outdated, including AACAP
practice parameters
 Consensus guidelines developed prior to FDA
indications for SGA, vast preponderance of
existing research
 Were study patients truly “bipolar”…or would
they be better characterized as DMDD?
Kowatch RA et al. J Am Acad Child Adolesc Psychiatry 2005; 44(3);213-35

32. What are clinicians doing in the community?

33. Overview of the literature:
 Do a very good evaluation to establish the
diagnosis first!
 SGAs represent first-line pharmacotherapy…
aripiprazole probably has fewest metabolic
effects
 Treat mania first in patients with multiple
comorbidities…consider treating ADHD, anxiety,
depression once mood stabilization addressed
 Is there a role for mood stabilizers in kids
without comorbid DBDs?

34. More treatment thoughts…
 I’d consider alternate FDA-approved SGA if patient
fails to respond to antipsychotic monotherapy
 Very little data on combinations of SGAs and mood
stabilizers
 CFF-CBT may be very helpful in maintaining
adherence, preventing relapse
 CBT, school based accommodations, intervention
helpful for comorbidities
 Side effects MATTER! Prescriptions don’t help
when kids refuse medication

35. What about DMDD?
There’s a large group of kids who demonstrate:
 Irritability as their predominant mood state
 Problems with emotional self-regulation often
resulting in aggression
 Problems with attention, concentration,
academic performance
 “At-risk” behaviors…self-injury, substance
use, suicidal threats

36. Kids with DMDD:
 Characterized by severe recurrent temper outbursts in response to
common stressors
 Temper outbursts are manifest verbally and/or behaviorally, such as in the
form of verbal rages, or physical aggression towards people or property
 The reaction is grossly out of proportion in intensity or duration to the
situation or provocation
 Responses inconsistent with developmental level
 Temper outbursts occur, on average, three or more times per week.
 Mood between temper outbursts is persistently negative (irritable, angry,
and/or sad).
 Negative mood is observable by others (e.g., parents, teachers, peers).
DSM-5, American Psychiatric Association, 2013

37. AACAP concerns about DMDD
 Diagnosis imprecise
 Syndrome based on work in patients described as
“SMD”
 Invites criticism for “pathologizing” temper tantrums
 Proposed criteria are almost certainly premature
 Research hasn’t clarified boundaries between
DMDD, ADHD, Oppositional Defiant Disorder and
developmentally acceptable behavior
 More information needed on how the phenotype
changes over the lifespan
American Academy of Child and Adolescent Psychiatry, March 30, 2010

38. What do kids with DMDD look like?
 Most have ADHD (86.3%) and ODD (84.2%)
 60% at NIMH were diagnosed in community with
bipolar disorder
 They have a higher than expected prevalence of
lifetime anxiety disorders (58.2%) and lifetime
major depression (16.4%)
 Seven times more likely to be depressed at age
18
 Chronic irritability in adolescence predicts MDD,
GAD and dysthymia at age 33
Leibenluft E. Am J Psychiatry 2011; 168(2):129-42

39. What I’ve observed…
 They have difficulty with transitions…”cognitive rigidity”
 They tend to “ruminate”…indecisive, think too much about
things, perseverate
 They may experience some improvement in some settings
from ADHD medication, but become more irritable, have
more meltdowns at home on medication
 They do better when they’re busy…inactivity increases
irritability
 They’re prone to behavioral activation on SSRIs that is often
mistaken for mania, hypomania

40. How I’m treating DMDD…
 Conservative use of ADHD medication…limited as much as
possible to school day
 Meltdowns related to perseverative frustration with inability to
achieve desired outcomes may respond to SSRIs,
clomipramine
 Behavioral activation from SSRIs appears dose-
dependent…titrate weekly in small increments
 Lots of CBT! Kids need strategies to help manage
perseverative thinking
 Aggressively dosing accommodations, school-based
interventions
 SGAs as last resort for severe aggression (risperidone)

41. Resources:
 AACAP Bipolar Disorder Resource Center
http://www.aacap.org/cs/BipolarDisorder.ResourceCenter
 Child and Adolescent Bipolar Foundation
http://www.bpkids.org/
 TEAM Study:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581342/
 Leibenluft paper on Severe Mood
Dysregulation
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396206/

42. Questions?

43. Stay in Touch!
Family Center by the Falls: http://www.fcbtf.com
Phone: (440) 543-3400
E-mail: drgrcevich@fcbtf.com
https://www.facebook.com/StephenGrcevichMD
@drgrcevich