title: Adjunctive Maintenance Lamotrigine for Pediatric Bipolar I Disorder: A Placebo-Controlled, Randomized Withdrawal Study.
abstract: OBJECTIVE
  This study aimed to compare the efficacy of lamotrigine versus placebo in 10- to 17-year-olds with bipolar I disorder (BP-I) who were receiving conventional bipolar disorder treatment.
  
  
  METHODS
  In this randomized withdrawal trial, patients with BP-I of at least moderate severity received lamotrigine during an ≤18-week open-label phase. Patients who maintained a stable lamotrigine dose for ≥2 weeks and Clinical Global Impression-Bipolar Severity of Illness (CGI-BP[S]) score of ≤3 for ≥6 consecutive weeks were randomized to double-blind lamotrigine or placebo for ≤36 weeks.
  
  
  RESULTS
  Of 301 patients enrolled, 298 comprised the open-label intention-to-treat population, with 173 (58%) randomized. Of these patients, 41 (24%) completed the study. In the open-label phase, the mean (SD) baseline CGI-BP(S) rating was 4.4 (0.57), and the mean (standard error [SE]) time to stabilization was 101 (1.6) days. During the randomized phase, mean (SE) time to occurrence of a bipolar event (TOBE) for lamotrigine versus placebo (primary endpoint) was 155 (14.7) versus 50 (3.8), 163 (12.2) versus 120 (12.2), and 136 (15.4) versus 107 (13.8) days for the 3 index mood states (depressed, manic/hypomanic, mixed). The primary stratified log-rank analysis of TOBE was not statistically significant (hazard ratio [HR] = 0.63; p = .072); however, the prespecified Cox regression analysis favored lamotrigine (p = .047). In 13- to 17-year-olds, log-rank analysis of TOBE significantly favored lamotrigine (HR = 0.46; p = .015), but not in 10- to 12-year-olds (HR = 0.93; p = .877). Dermatologic events were reported in 4% (open-label phase) and 2% (randomized phase) of patients receiving lamotrigine. Suicidality-related adverse events were reported in 7% (open-label phase) and 7% (randomized phase) of patients receiving lamotrigine.
  
  
  CONCLUSIONS
  Although the primary analysis failed to detect a benefit of add-on lamotrigine for BP-I in 10- to 17-year-olds, lamotrigine may be effective in a subset of older adolescents. Clinical trial registration information-Lamictal as Add-on Treatment for Bipolar I Disorder in Pediatric Patients; http://clinicaltrials.gov/; NCT00723450.
authors.affiliation: Johns Hopkins University and Kennedy Krieger Institute, Baltimore, MD. Electronic address: RFindli1@jhmi.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Findling
authors.affiliation: Lucille Packard Children's Hospital at Stanford, Stanford, CA.
authors.forename: Kiki
authors.initials: K
authors.lastname: Chang
authors.affiliation: Children's National Health System and George Washington University, Washington, DC.
authors.forename: Adelaide
authors.initials: A
authors.lastname: Robb
authors.affiliation: GlaxoSmithKline at the time of the study; PAREXEL International, Research Triangle Park, NC.
authors.forename: Vicki J
authors.initials: VJ
authors.lastname: Foster
authors.affiliation: GlaxoSmithKline at the time of the study; Neuren Pharmaceuticals, Melbourne, Australia.
authors.forename: Joseph
authors.initials: J
authors.lastname: Horrigan
authors.affiliation: GlaxoSmithKline at the time of the study; PAREXEL International, Research Triangle Park, NC.
authors.forename: Alok
authors.initials: A
authors.lastname: Krishen
authors.affiliation: GlaxoSmithKline at the time of the study.
authors.forename: Art
authors.initials: A
authors.lastname: Wamil
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC.
authors.forename: John E
authors.initials: JE
authors.lastname: Kraus
authors.affiliation: University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Melissa
authors.initials: M
authors.lastname: DelBello
mesh_terms: D000293:Adolescent; D018692:Antimanic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001714:Bipolar Disorder / Q000188:drug therapy*; D002648:Child; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077213:Lamotrigine; D008297:Male; D016016:Proportional Hazards Models; D011569:Psychiatric Status Rating Scales; D011788:Quality of Life; D016896:Treatment Outcome; D014227:Triazines / Q000008:administration & dosage* / Q000009:adverse effects; D014481:United States
chemical_list: D018692:Antimanic Agents; D014227:Triazines; D000077213:Lamotrigine
keywords: adjunctive therapy; adolescent; bipolar I disorder; lamotrigine; pediatric