Treatment of Pediatric Bipolar Disorder


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

August 8, 2013

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  • 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
  • Treatment of Pediatric Bipolar Disorder

    1. 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: Phone: (440) 543-3400 Twitter: @drgrcevich
    2. 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. 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. 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. 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. 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. 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. 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 atricAdvisoryCommittee/UCM193200.pdf
    9. 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. 10. Second-generation antipsychotics in acute mania:
    11. 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. 12. TEAM Study…results: Geller et al. Arch Gen Psychiatry 2012 May;69(5):515-28
    13. 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. 14. Risperidone vs. Divalproex
    15. 15. Divalproex vs. Quetiapine
    16. 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. 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. 18. Findling’s lithium/divalproex randomized discontinuation study
    19. 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. 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. 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. 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. 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. 24. The answer is…FALSE Correll, CU et al., JAMA. 2009;302:1765–1773.
    25. 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. 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. 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. 28. Why is psychotherapy important? Axelson, DA. 2012 AACAP Board Review Course, Pittsburgh, PA
    29. 29. Multifamily psychoeducation:
    30. 30. Targeting expressed emotion?
    31. 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. 32. What are clinicians doing in the community?
    33. 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. 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. 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. 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. 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. 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. 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. 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. 41. Resources:  AACAP Bipolar Disorder Resource Center  Child and Adolescent Bipolar Foundation  TEAM Study:  Leibenluft paper on Severe Mood Dysregulation
    42. 42. Questions?
    43. 43. Stay in Touch! Family Center by the Falls: Phone: (440) 543-3400 E-mail: @drgrcevich