Using comparative effectiveness design to improve the generalizability of bipolar treatment trials data: contrasting LiTMUS baseline data with pre-existing placebo controlled trials

J Affect Disord. 2014 Jan;152-154:97-104. doi: 10.1016/j.jad.2013.05.052. Epub 2013 Jul 8.


Background: Efficacy-based double-blind placebo controlled trials were conducted to establish efficacy and safety for FDA approval. Such designs allowed and encouraged the use of exclusion criteria to improve assay sensitivity and internal validity. The LiTMUS trial increased the representation of real-world individuals with bipolar disorder despite the acknowledgment that this compromises assay sensitivity.

Method: To maximize generalizability, LiTMUS used broad inclusion and narrow exclusion criteria: participants experiencing mood symptoms of sufficient intensity (at least with a CGI-BP ≥ 3) that would warrant a change in treatment, and that lithium treatment would be a reasonable therapeutic option if they were randomized to it. At baseline demographic, illness, clinical, and treatment characteristics were collected. The LiTMUS study design and baseline sociodemographic data were compared to previous efficacy studies.

Results: As compared to the previous bipolar disorder efficacy studies, LiTMUS participants were of similar age, gender, weight and illness severity; however LiTMUS participants were more racially and ethnically representative of the general population, had a greater number of mood episodes in the past 12 months, more Axis I/II comorbidity, a greater number of prior suicide attempts, and higher functional capacity.

Conclusions: LiTMUS was a comparative effectiveness trial that had broad inclusion and minimal exclusion criteria that produced a more representative sample comprised of real-world participants. This design enables the results of the LiTMUS study to be a more representative of real world pharmacotherapuetic outcomes.

Limitations: Limitations include possible selection bias, paucity of sociodemographic data in efficacy trials, and lack of a placebo.

Keywords: Baseline characteristics; Bipolar; Comparative effectiveness; Generalizability.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antimanic Agents / administration & dosage
  • Antimanic Agents / therapeutic use*
  • Bipolar Disorder / drug therapy*
  • Comparative Effectiveness Research / methods*
  • Female
  • Humans
  • Interview, Psychological
  • Lithium Compounds / administration & dosage
  • Lithium Compounds / therapeutic use*
  • Male
  • Middle Aged
  • Psychiatric Status Rating Scales
  • Quality of Life / psychology
  • Research Design
  • Single-Blind Method
  • Treatment Outcome
  • Young Adult


  • Antimanic Agents
  • Lithium Compounds