title: Mood stabilization and destabilization during acute and continuation phase treatment for bipolar I disorder with lamotrigine or placebo.
abstract: BACKGROUND
  During post-acute phase pharmacotherapy for bipolar disorder, there has been little empirical study to establish when emerging mania symptoms (1) are of clinical significance and (2) reflect iatrogenic events versus the natural course of illness.
  
  
  METHODS
  Secondary analyses were conducted in a previously studied group of bipolar I disorder (DSM-IV) outpatients randomly assigned to lamotrigine monotherapy (n=171) or placebo (n=121), and a larger prerandomization group (N=966) during open-label titration of lamotrigine, following an index depressive episode. Time until the emergence of mania symptoms, at varying severity thresholds, was examined over 6 months for lamotrigine versus placebo, while controlling for potential confounding factors in Cox proportional hazard models. Subject enrollment occurred between July 1997 and August 2001.
  
  
  RESULTS
  Rates of mood elevation during both acute open-label and randomized continuation phases of lamotrigine treatment were comparable to those seen with placebo during the randomized phase. The hazard ratio for the emergence of mania symptoms with lamotrigine was not significantly different from placebo (hazard ratio=0.79; 95% CI, 0.53 to 1.16), with an upper bound that suggests no meaningful increase in susceptibility toward mania with lamotrigine. By contrast, clinically meaningful rises in mania symptom severity were predicted by baseline residual manic symptoms prerandomization and by the number of manic, hypomanic, or mixed episodes in the past year.
  
  
  CONCLUSIONS
  Based on a composite definition of mood destabilization involving a range of severity thresholds for emerging signs of mania, lamotrigine confers no meaningful elevated risk relative to placebo for mood destabilization in bipolar I disorder. Rather, illness burden related to residual or lifetime mania features may hold greater importance for explaining mania relapses or breakthrough manic features during lamotrigine continuation pharmacotherapy.
authors.affiliation: Affective Disorders Program, Silver Hill Hospital, New Canaan, Connecticut, USA. joseph.goldberg@mssm.edu
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Goldberg
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Calabrese
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Saville
authors.forename: Mark A
authors.initials: MA
authors.lastname: Frye
authors.forename: Terence A
authors.initials: TA
authors.lastname: Ketter
authors.forename: Trisha
authors.initials: T
authors.lastname: Suppes
authors.forename: Robert M
authors.initials: RM
authors.lastname: Post
authors.forename: Frederick K
authors.initials: FK
authors.lastname: Goodwin
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D018692:Antimanic Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000139:chemically induced / Q000175:diagnosis* / Q000188:drug therapy* / Q000517:prevention & control / Q000523:psychology; D003866:Depressive Disorder / Q000188:drug therapy / Q000523:psychology; D005260:Female; D006801:Humans; D007049:Iatrogenic Disease; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D010919:Placebos; D016016:Proportional Hazards Models; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D055502:Secondary Prevention; D012720:Severity of Illness Index; D016019:Survival Analysis; D016896:Treatment Outcome; D014227:Triazines / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D018692:Antimanic Agents; D010919:Placebos; D014227:Triazines; D000077213:Lamotrigine