title: The direct and indirect effects of lurasidone monotherapy on functional improvement among patients with bipolar depression: results from a randomized placebo-controlled trial.
abstract: BACKGROUND
  Bipolar depression is characterized by depressive symptoms and impairment in many areas of functioning, including work, family, and social life. The objective of this study was to assess the independent, direct effect of lurasidone treatment on functioning improvement, and examine the indirect effect of lurasidone treatment on functioning improvement, mediated through improvements in depression symptoms.
  
  
  METHODS
  Data from a 6-week placebo-controlled trial assessing the effect of lurasidone monotherapy versus placebo in patients with bipolar depression was used. Patient functioning was measured using the Sheehan disability scale (SDS). Descriptive statistics were used to assess the effect of lurasidone on improvement on the SDS total and domain scores (work/school, social, and family life), as well as number of days lost and unproductive due to symptoms. Path analyses evaluated the total effect (β1), as well as the indirect effect (β2×β3) and direct effect (β4) of lurasidone treatment on SDS total score change, using standardized beta path coefficients and baseline scores as covariates. The direct effect of treatment on SDS total score change and indirect effects accounting for mediation through depression improvement were examined for statistical significance and magnitude using MPlus.
  
  
  RESULTS
  In this 6-week trial (N = 485), change scores from baseline to 6-weeks were significantly larger for both lurasidone treatment dosage groups versus placebo on the SDS total and all three SDS domain scores (p < 0.05). Through path analyses, lurasidone treatment predicted improvement in depression (β2 = -0.33, p = 0.009), subsequently predicting improvement in functional impairment (β3 = 0.70, p < 0.001; indirect effect = -0.23). The direct effect was of medium magnitude (β4 = -0.17, p = 0.04), indicating lurasidone had a significant and direct effect on improvement in functional impairment, after accounting for depression improvement.
  
  
  CONCLUSIONS
  Results demonstrated statistically significant improvement in functioning among patients on lurasidone monotherapy compared to placebo. Improvement in functioning among patients on lurasidone was largely mediated through a reduction in depression symptoms, but lurasidone also had a medium and statistically significant independent direct effect in improving functioning.
authors.affiliation: Sunovion Pharmaceuticals Inc., Marlborough, MA, USA. krithika.rajagopalan@sunovion.com.
authors.forename: Krithika
authors.initials: K
authors.lastname: Rajagopalan
authors.affiliation: Evidera, 1417 Fourth Avenue, Suite 510, Seattle, WA, 98101, USA. elizabeth.bacci@evidera.com.
authors.forename: Elizabeth Dansie
authors.initials: ED
authors.lastname: Bacci
authors.affiliation: Evidera, Bethesda, MD, USA. kathy.wyrwich@evidera.com.
authors.forename: Kathleen W
authors.initials: KW
authors.lastname: Wyrwich
authors.affiliation: Sunovion Pharmaceuticals Inc., Fort Lee, NJ, USA. andrei.pikalov@sunovion.com.
authors.forename: Andrei
authors.initials: A
authors.lastname: Pikalov
authors.affiliation: Sunovion Pharmaceuticals Inc., Fort Lee, NJ, USA. antony.leobel@sunovion.com.
authors.forename: Antony
authors.initials: A
authors.lastname: Loebel
keywords: Bipolar disorder; Depression; Patient functioning; Sheehan disability scale