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Treatment of Pediatric Bipolar Disorder
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
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.
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
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
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.
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
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
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/
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
Notas do Editor
Average duration of treatment=10.8 weeksThe Second-Generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SAIETY) study was conducted between December 2001 and September 2007 at tertiary-care, academic inpatient and outpatient clinics in Queens, New York. Participants included 272 antipsychotic-naive patients aged 4 to 19 years. A total of 130 participants (47.8%) had mood spectrum disorder, 82 patients (30.1%) had schizophrenia, and 60 participants (22.1%) had disruptive or aggressive behavior spectrum disorder"We always thought that most of the effect on glucose and lipid metabolism was really coming through the indirect effect of weight gain," Dr. Correll said. "So in other words, if you gain weight, with or without the medications, it affects both glucose and lipid metabolism. This appears to be true to some degree, but there also appears to be a weight-independent effect that some of these medications have more than others.”Furthermore, the study also showed that adverse changes reached statistical significance for olanzapine only for fasting glucose, insulin, and insulin resistance. Moreover, quetiapine showed significant worsening of total cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and ratio of triglycerides to HDL cholesterol. With risperidone, only triglycerides increased significantly. However, at least during the first 3 months of treatment, baseline-to-endpoint changes were not significant with aripiprazole or in the untreated comparison group
Olanzapine has been associated with lipid, cholesterol elevation in other studies (TEOSS)Aripiprazole-frequently associated with akathisiaRisk of dystonic reactions is age-related…the younger the child, the greater the vulnerability
We’re not sure what these kids have! SMD? Suspect they’ll go on to be ADHD/Depressed, ADHD/anxious
What are differences with SMD?The name SMD would subsequently be changed to TDD and the hyperarousal criterion dropped. So what did we learn from research on SMD? We learned that children with SMD are as severely impaired as those who suffer from classical (episodic) Bipolar Disorder. But there are important differences between those who met criteria for SMD and those who met criteria for Bipolar Disorder (BD). The groups differed in their outcome, gender ratio, and possibly family history. Let me focus on just a few of the most significant findings here: Children with SMD/chronic irritability were at risk for later anxiety and unipolar depressive disorders — they did not turn out to be risk of developing BD. That finding, which was replicated by several studies, suggests that diagnosing children with non-episodic chronic irritability as having Bipolar Disorder may not only be inaccurate as opposed to premature, it may lead to offering these children ineffective or possibly harmful treatments.In children and adults with classic (episodic) BD, the gender ratio is approximately even. That means that males and females are equally likely to have the disorder. In children with SMD, however, boys outnumbered girls by a ratio of about 3:1.SMD is a serious mood disorder and is as impairing as BD in the short-term and long-term.85% of children and teens diagnosed with SMD also met diagnostic criteria for ADHD and Oppositional Defiant Disorder (ODD). That is not surprising when you think about chronically irritable children look like and how disruptive their behavior can be. But SMD is more than just ADHD+ODD, as it involves mood. Furthermore, children with severe irritability frequently meet diagnostic criteria for an anxiety disorder and have a family history of depression.
AACAP resource document regarding APA’s proposed criteria for DSM-V