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

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: drgrcevich@fcbtf.com

https://www.facebook.com/StephenGrcevichMD

@drgrcevich