In these lectures presented by Dr. Stephen Grcevich to child and adolescent psychiatry trainees at Akron Children's Hospital in January 2021, the following objectives were addressed: Identify critical questions challenging our assumptions regarding treatment of bipolar disorder in kids. Explore diagnostic challenges associated with comorbidity with other common mental health conditions. Review key literature evaluating effective pharmacotherapy of pediatric bipolar disorder. Examine available data on non-pharmacologic treatments in kids with bipolar disorder.

1. Evaluation and
Treatment of
Bipolar and
Related Disorders
in Children and
Adolescents
Stephen Grcevich, MD
Family Center by the
Falls
Chagrin Falls OH
Clinical Associate
Professor of
Psychiatry, NEOMED
Presented at Akron
Children’s Hospital
January 7, 2021

2. Educational
objectives:
• Identify critical questions challenging
our assumptions regarding treatment of
bipolar disorder in kids
• Explore diagnostic challenges
associated with comorbidity with other
common mental health conditions
• Review key literature evaluating
effective pharmacotherapy of pediatric
bipolar disorder
• Examine available data on non-
pharmacologic treatments in kids with
bipolar disorder

3. Pharmaceutical Industry
Consulting:
Shire U.S.
Grant/Research Support
SPRITES-Pfizer through Duke
Clinical Research Institute
Speakers’ Bureaus None since 2006
Other Financial/Material Support None relevant
Major Shareholder None
Stephen Grcevich, MD: disclosures:
Disclosures:

4. The greatest controversy in our
field during the 2010s?
• 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. Diagnostic
trends
• Increased rates of
bipolar disorder in youth
plateaued around 2010.
• How psychiatrists
understood severe
irritability in kids
• Inclusion of DMDD in
the DSM in 2013, use of
disruptive behavior
disorder diagnoses are
possible explanations
Le J et al. J Affective Disorders 2020;264(1):242-248

6. Controversies
• Higher prevalence, earlier age of onset in U.S
vs Canada, Europe
• More psychiatric illness is present across 4
generations of family members in the U.S. versus
Europe
• Higher incidence of multiple traumatic events,
childhood adversity in U.S.
• 2/3 of U.S. patients with bipolar disorder
experience first mood episode by age 19 vs 1/3
in Europe
Post RM et al. Neuroscience and Biobehavioral Reviews 2017;74(A):204-213

7. Prevalence in
youth
• Prevalence of Bipolar I: 0.6%
• Prevalence of Bipolar
Spectrum Disorders: 3.9%
• Trend – lower rates in most
recent studies
Van Meter A, et al. J Clin Psychiatry 2019;80(3):18r12180

8. Findings from U.S. studies of
pediatric bipolar disorder
• 75% met criteria for BP I, 25% BP II
• 69% experienced first bipolar episode by age 18
• 31.1% - first episode prior to age 13
• 38.1% - first episode in adolescence (ages 13-18)
• Very high rates of comorbidity among parents with
bipolar disorder
• 74% of children of parents with bipolar disorder
received a psychiatric diagnosis
• 39% - anxiety disorders
• 32% - major depression
• 31% - ADHD
• 19% - substance use disorders
• 19% - bipolar disorder
Post RM et al. J. Affect. Disorders, 160 (2014), pp. 27-33

9. Criteria for Bipolar I:
• A distinct period of abnormally and persistently
elevated, expansive or irritable mood and abnormally
and persistently increased goal-directed activity or
energy, lasting at least one week and present most of
the day, nearly every day.
• Three or more of the following symptoms (four if mood
is only irritable)
• Inflated self esteem/grandiosity
• Decreased need for sleep
• More talkative/pressured speech
• Flight of ideas, subjective experience of racing thoughts
• Increased distractibility
• Increased goal-directed activity
• Activities with painful/harmful consequences
DSM-5, American Psychiatric Press, 2013

10. Bipolar II Disorder
• Abnormally, persistently elevated, expansive or
irritable mood lasting at least four days.
• Meets full criteria for a past/present episode of
Major Depression
• Not severe enough to cause marked
impairment in social, educational functioning or
result in hospitalization
• No psychotic features (psychotic features =
mania)
• Not attributable to substance use, medication
DSM-5, American Psychiatric Press, 2013

11. Cyclothymic Disorder
• At least one year of hypomanic symptoms that
don’t meet criteria for a hypomanic episode,
depressive symptoms that don’t meet criteria
for major depression (two years in adults).
• Mood symptoms present at least half the time,
absent for no more than two months at a time.
• Never met full criteria for major depression,
bipolar I, bipolar II
DSM-5, American Psychiatric Press, 2013

12. Other Specified Bipolar and
Related Disorder
• Don’t meet full criteria for another bipolar
spectrum disorder
• Used when clinicians want to specify why
patient doesn’t meet full criteria
• Examples:
• Short duration hypomania with major depression
• Hypomanic episodes with insufficient symptoms
• Hypomania without prior major depression
• Short duration cyclothymia (<12 months in youth)
DSM-5, American Psychiatric Press, 2013

13. Diagnostic Specifiers
• Anxious distress
• Manic with mixed features
• Depressed with mixed features
• Rapid cycling
• Melancholic features
• Atypical features
• Psychotic features
• Catatonia
• Peripartum onset
• Seasonal pattern
• Partial/full remission
DSM-5, American Psychiatric Press, 2013

14. Comorbidity in pediatric
bipolar disorder
0
10
20
30
40
50
60
Anxiety ADHD DBD SUD
Prevalence
Anxiety ADHD DBD SUD
Frias A. et al. J. Affect. Disorders, 174 (2015), pp. 378-389

15. Differential diagnosis
• ADHD
• DMDD
• Behavioral activation (SSRIs)
• Depression
• Anxiety disorders
• Substance use
• Discordance between observers
Carlson, GA. World Psychiatry. 2012 Oct; 11(3): 146–152.

16. Distinguishing Bipolar
disorder from severe ADHD
• Episodic spikes in
distractibility
• Episodes of heightened
impulsivity
• Elevated self-esteem
• Flight of ideas
• Activities with harmful
consequences
• Decreased need for
sleep, terminal insomnia
• Pressured speech (more,
louder, faster)
• Consistent level of
distractibility
• Consistently impulsive
• Low self-esteem
• Tangential, circumstantial
• Impulsive
• Night owls (up late, sleep
late)
• Impulsive speech
(interrupt others)

17. 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.

18. Clinical course of bipolar
disorder
• 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

19. Rating Scales, Screening
Tools
• P-YMRS (Parent Version-Young Mania Rating
Scale)
• Adapted from adult YMRS in pediatric research
settings
• 11 question, 60-point scale
• Average scores: 25 for mania 20 for hypomania
• Scores >13 indicated a potential case of mania or
hypomania
• Scores > 21 suggest probable case
• Will identify most cases of bipolar, but with an
extremely high false positive rate.
Gracious B et al. J Am Acad Child Adolesc Psychiatry (2002) 41(11): 1350-1359.

20. Neuroimaging Findings
• Smaller amygdala volumes vs. controls
• amygdala volumes failed to show a normal increase
with aging
• Abnormal white matter microstructure in
superior frontal regions, inferior/ventral frontal
areas
• Orbitofrontal or anterior cingulate cortex
• Anterior regions of the corpus callosum
• Structural connectivity deficits between
prefrontal-subcortical areas
Pfeifer JC et al. J Am Acad Child Adolesc Psychiatry. 2008;47:1289‐1298.

21. Biomarkers
• Increased inflammatory and oxidative stress
markers
• Decreased neurotrophic markers, particularly
during acute mood episodes
• Peripheral biomarkers, particularly those that
fluctuate in relation to symptoms, have the
potential for clinical application such as in the
selection, prediction, and assessment of
treatments
• Elevated high-sensitivity c reactive protein (hsCRP)
• Decreased Brain-derived neurotrophic factor (BDNF),
interleukin 6 (IL-6)
Goldstein BI et al. Bipolar Disord. 2017 Nov; 19(7): 524–543.

22. 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

23. FDA-approved medications for
youth with Bipolar Disorder
• Risperidone: Bipolar mania (10-17)
• Aripiprazole: Bipolar mania (10-17)
• Quetiapine: Bipolar mania (10-17)
• Asenapine: Bipolar I disorder (10-17)
• Olanzapine: (labeling-consider other drugs first) Bipolar
mania (13-17)
• Lithium Carbonate:
• acute treatment of mania (7-17)
• ongoing maintenance treatment of bipolar disorder (7-17)
• Lurasidone: Approved for treatment of Major Depression
in patients with Bipolar Disorder (10-17) as monotherapy.
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Pedi
atricAdvisoryCommittee/UCM193200.pdf

24. 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.

25. Second-generation antipsychotics in acute
mania:

26. 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

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

28. 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

29. Risperidone vs. Divalproex

30. Divalproex vs. Quetiapine

31. Lithium in pediatric bipolar
disorder:
• Superior to placebo in 8 week RCT (47% vs.
21%) (Findling et al., 2015)
• Li>PBO (46% vs. 8%) Geller (JAACAP 1998)
• 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
Findling RL et al. Pediatrics. 2015 Nov;136(5):885-94.

32. More on the clinical course of
bipolar disorder (COBY I study)
• 2.5 years after onset of index episode 81.5%
recovered
• 1.5 years later 62.5% had syndromal recurrence,
especially depression
• 1/3 had single recurrence, 30% had two or more
• Initial episode polarity predicted that of other episodes
• Youth symptomatic 60% of follow up period
• 40% had symptoms for 75% of the time
• 16% of them had psychotic symptoms
Birmaher B et al. Am J Psychiatry 2009; 166:795–804

33. COBY I: Lithium vs. other
mood-stabilizing medications
• 413 youth, ages 7-17, 11-year longitudinal follow-
up
• Compared patients on lithium vs. other mood
stabilizers - mood symptoms, suicidality,
psychosocial function, hospitalization, aggression,
substance use
• 340 participants with 2638 6-month follow up
blocks: 886 on LI vs.1752 OMS
• Patients on Lithium:
• older, less lifetime anxiety, fewer on antidepressants
• had half as many suicide attempts and fewer depressive
episodes
• less psychosocial impairment, less aggression
Hafeman, DM et al. J Am Acad Child Adolesc Psychiatry 2020;59(10):1146–1155

34. 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: Possibly helpful as an adjunct to
conventional bipolar treatment in a subset of
older adolescents.
• Topiramate, oxcarbazepine: Negative RCTs
Hamrin V, Ienacco J. Expert Rev Neurother. 2010;10(7):1053-1088
Findling RL et al. J Am Acad Child Adolesc Psychiatry 2015;54(12):1020–1031.

35. Lithium/divalproex randomized
discontinuation study

36. 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

37. 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

38. 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

39. 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: no difference vs. non-
ECT control group at 12-month follow-up, two
single case reports
Taleb O et al. Eur Psychiatry. 2002 Jul;17(4):206-12.

40. 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.

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

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

43. 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

44. 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
• 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

45. DBT in adolescent bipolar
disorder
• When compared to “treatment as usual”
controls, teens receiving DBT
• Attended significantly more therapy
sessions
• Experienced significantly less symptoms of
depression
• 3X more likely to experience reduction in
suicidal ideation
Goldstein TR et al. J Child Adolesc Psychopharmacol. 2015;(25)2:140-49

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

47. Multifamily
psychoeducation:

48. Targeting expressed
emotion?

49. 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

50. What are clinicians doing in the
community?

51. Overview of the literature:
• Do a very good evaluation to establish the
diagnosis first!
• SGAs represent first-line pharmacotherapy…
aripiprazole 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?

52. 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

53. 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/