1. Treatment of Acute Mania in Pediatric Bipolar Disorder Assessing the Evidence Stewart S. Newman MD Senior Child Fellow

2. 2 Discussion Case 16 y/o WF with hx of bipolar disorder presents to the PES in the custody of AA police Reportedly was in a physical altercation with a fellow student at Pioneer HS Police indicate she was combative and belligerent towards them upon initial contact

3. 3 Discussion Case, cont’d Patient is followed by a Child Fellow in the Commonwealth outpatient clinic Previously treated with divalproex and risperidone in combination Records indicate she has missed her last three appointments, and her medication supply should have been exhausted two months ago

4. 4 Discussion Case, cont’d Per the outpatient treatment notes, the patient has been hospitalized once previously for suicidal ideation The patient has a history of intermittent cannabis and alcohol abuse There is a family history of bipolar disorder in a paternal grandfather

5. 5 Discussion Case, cont’d On initial assessment, she is hyperverbal, giddy and expansive, but can rapidly become angry and belligerent with staff She is unable to give an account of the altercation at school, simply stating “The bitch deserved it.”

6. 6 Discussion Case, cont’d Tells the evaluator repeatedly “You don’t want to do this, you know I’m too important to be put through this.” When stopped by the police officer from leaving PES, she begins to make sexualized comments towards him regarding being “handcuffed”

7. 7 Discussion Case, cont’d The patient becomes combative with staff members, tries to elope and Security responds to PES The patient is placed in the seclusion suite due to elopement risk She is refusing any medication to calm her or organize her thoughts

8. 8 “The Question” “What evidence do we have to guide the treatment of acute mania in pediatric bipolar disorder?”

9. 9 Levels of Evidence Level A: systematic review of RCTs with narrow confidence intervals Level B: systematic review of cohort studies with homogeneity, individual cohort study, or low quality RCT outcomes studies Level C: systematic review of case-control studies, individual case control studies, case series, and expert opinions with explicit critical appraisal Adapted from the US Preventive Services Task Force 1996

10. 10 Searching the Literature Online resources only Searches on Medline, EMBase, Cochrane, Up To Date, MD Consult, AACAP Website Used keyword searches: Pediatric bipolar disorder Pediatric mania Acute mania treatment

11. 11 Selected Articles M. N. Pavuluri et. al. “A Pharmacotherapy Algorithm for Stabilization and Maintenance of Pediatric Bipolar Disorder” JAACAP 43:7, July 2004 M. Bourin, O. Lambert and B. Guitton “Treatment of Acute Mania- from clinical trials to recommendations for clinical practice” Human Psychopharmacology 20, 2005 J. McClellan and J. Werry “AACAP Practice Parameters for the Assessment and Treatment of Children and Adolescents with Bipolar Disorder” JAACAP 1997

12. 12 Pavuluri et. al. 2004 Developed and studied a treatment algorithm for stabilization and maintenance of pediatric bipolar disorder Two phases of treatment- goal of the first phase was mood stabilization Discussed evidence used for development of the algorithm

13. 13 Pavuluri et. al. 2004

14. 14 Pavuluri et. al. 2004 Noted Level B studies in children indicate mood stabilizers as the primary agents Lithium or divalproex as first line agents, followed by carbamazepine

15. 15 Pavuluri et. al. 2004 Good evidence for addition of atypical antipsychotic agent for more severe or psychotic mania cases Atypical antipsychotic agent monotherapy first line for predominant irritability or aggression

16. 16 Pavuluri et. al. 2004 Positives: Specific to the pediatric population Development of treatment algorithm Discussion of level of evidence used Negatives: Treatment not specific to acute mania Use of three mood stabilizers, four atypical antipsychotics

17. 17 Bourin et. al. 2005 Review of the literature regarding treatment of acute mania Highlights the conceptual differences between the US and Europe

18. 18 Bourin et. al. 2005 Discusses individual medications (mood stabilizers, antipsychotics, and benzodiazepines) alone and in combinations Also discusses efficacy of certain agents, forms of mania that predict treatment response, and alternate agent choices in a systematic manner

19. 19 Bourin et. al. 2005 Recommends first line use of mood stabilizers lithium and divalproate, with carbamazepine as second line Also recommends use of atypical antipsychotics as monotherapy or adjunct to mood stabilizer treatment Discussed use of “third gen” anticonvulsants in detail

20. 20 Bourin et. al. 2005 Positives: Specific to treatment of acute mania Discusses available evidence in a systematic fashion Recent review of the literature Negatives: Not specific to children Emphasis on US vs Europe

21. 21 McClellan, Werry 1997 “Practice Parameters” series represent exhaustive review of the available literature and expert concensus Specific section regarding treatment of acute manic symptoms Explicitly discusses rationale for choice of medication

22. 22 McClellan, Werry 1997 Recommend mood stabilizers (lithium and divalproex) as first line agents Carbamazepine recommended as second line mood stabilizer Adjunctive treatment with atypical antipsychotics or benzodiazepines may be necessary

23. 23 McClellan, Werry 1997 Positives: Focused on treatment of children Section on acute mania treatment Authority that establishes “standard of care” Negatives: 38 pages long! Dated literature review with no recent update available

24. 24 Conclusions First line treatment for acute mania in children and adolescents Mood stabilizer: lithium or divalproex Consider carbamazepine second Consideration of adjunctive treatment Atypical antipsychotics, especially in mania with psychosis or agitation Possibly antipsychotic monotherapy