treatment of pediatric bipolar disorder
DESCRIPTION
Lecture offered to Child and Adolescent Psychiatry Fellows, Akron Children's Hospital/ Northeast Ohio Medical University August 8, 2013TRANSCRIPT
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: [email protected] Phone: (440) 543-3400 Twitter: @drgrcevich
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
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:
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).
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
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.
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 recoveryDelbello MP et al. Am J Psychiatry 2007 Apr; 164(4):582-90
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/PediatricAdvisoryCommittee/UCM193200.pdf
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.
Second-generation antipsychotics in acute mania:
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
TEAM Study…results:
Geller et al. Arch Gen Psychiatry 2012 May;69(5):515-28
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 lithiumGeller et al. Arch Gen Psychiatry 2012 May;69(5):515-28
Risperidone vs. Divalproex
Divalproex vs. Quetiapine
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
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
Findling’s lithium/divalproex randomized discontinuation study
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
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
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):449-58Joshi G et al. J Affect Disord 2012 Feb;136(3):1143-53Kondo DG et al. J Child Adolesc Psychopharmacol 2011;21(2):171-75
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.
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.
The answer is…FALSE
Correll, CU et al., JAMA. 2009;302:1765–1773.
Metabolic effects of second-generation antipsychotics in pediatric patients:
Agent: Metabolic Effects:
Olanzapine fasting glucosetriglyceridesinsulininsulin resistance
Quetiapine total cholesteroltriglyceridesHDL cholesteroltriglyceride:HDL ratio
Risperidone triglyceridesAripiprazole No significant metabolic effects
Correll, CU et al., JAMA. 2009;302:1765–1773.
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
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
Why is psychotherapy important?
Axelson, DA. 2012 AACAP Board Review Course, Pittsburgh, PA
Multifamily psychoeducation:
Targeting expressed emotion?
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
What are clinicians doing in the community?
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?
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
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
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
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
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
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
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)
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/
Questions?
Stay in Touch!
Family Center by the Falls: http://www.fcbtf.com
Phone: (440) 543-3400
E-mail: [email protected]
https://www.facebook.com/StephenGrcevichMD
@drgrcevich