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Multi-state outcome analysis of treatments (MOAT): application of a new approach to evaluate outcomes in longitudinal studies of bipolar disorder.

ABSTRACT: Survival analyzes are usually based on a single point in time predefined event. Dissatisfied with this approach to evaluating maintenance treatment outcomes, we developed the Multi-state Outcome Analysis of Treatments (MOAT) methodology using a combined database from two FDA registration studies of lamotrigine, lithium and placebo. MOAT partitions total survival time into clinically distinct periods operationally defined by cutpoints on rating scales. For bipolar disorder (BD), the clinical states are remission, subsyndromal and syndromal mania, mixed states or depression. MOAT results can be crossed with information about tolerability and functioning to yield an outcome system integrating efficacy and tolerability. As found in the original analysis, both drugs were associated with longer time in study compared with the placebo. MOAT supplements this by finding that both drugs increased the time remitted compared with placebo. However, a substantial amount of time in all three treatments was spent in subsyndromal depression. Time with manic symptoms was reduced with lithium, but not lamotrigine. Patients on placebo neither benefitted nor had adverse effects from the assignment but experienced more syndromal levels of symptoms and were terminated from the study sooner than either drug treated group. Lithium was associated with both benefit in time manic and worse tolerability compared with placebo. In summary, lamotrigine was associated with limited therapeutic benefit but not harm; lithium with both benefit and harm; and placebo with neither. MOAT describes not only quantity but also quality of time spent in longitudinal studies, providing a more clinically informative picture than Kaplan-Meier survival analysis.

SUBMITTER: Bowden CL

PROVIDER: S-EPMC4573671 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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Project description:OBJECTIVE:Migraine is a common comorbidity of bipolar disorder and is more prevalent in women than men. We hypothesized comorbid migraine would be associated with features of illness and psychosocial risk factors that would differ by gender and impact outcome. METHOD:A retrospective analysis was conducted to assess association between self-reported, physician-diagnosed migraine, clinical variables of interest, and mood outcome in subjects with DSM-IV bipolar disorder (N = 412) and healthy controls (N = 157) from the Prechter Longitudinal Study of Bipolar Disorder, 2005-2010. Informed consent was obtained from all participants. RESULTS:Migraine was more common in subjects with bipolar disorder (31%) than in healthy controls (6%) and had elevated risk in bipolar disorder women compared to men (OR = 3.5; 95% CI, 2.1-5.8). In men, migraine was associated with bipolar II disorder (OR = 9.9; 95% CI, 2.3-41.9) and mixed symptoms (OR = 3.5; 95% CI, 1.0-11.9). In comparison to absence of migraine, presence of migraine was associated with an earlier age at onset of bipolar disorder by 2 years, more severe depression (? = .13, P = .03), and more frequent depression longitudinally (? = .13, P = .03). Migraine was correlated with childhood emotional abuse (P = .01), sexual abuse (P = 4 × 10?³), emotional neglect (P = .01), and high neuroticism (P = 2 × 10?³). Protective factors included high extraversion (P = .02) and high family adaptability at the trend level (P = .08). CONCLUSIONS:Migraine is a common comorbidity with bipolar disorder and may impact long-term outcome of bipolar disorder, particularly depression. Clinicians should be alert for migraine comorbidity in women and in men with bipolar II disorder. Effective treatment of migraine may impact mood outcome in bipolar disorder as well as headache outcome. Joint pathophysiologic mechanisms between migraine and bipolar disorder may be important pathways for future study of treatments for both disorders.

Project description:OBJECTIVE:The authors sought to identify diagnostic risk factors of manic, mixed, or hypomanic episodes in the offspring of parents with bipolar disorder ("high-risk offspring"). METHOD:High-risk offspring 6-18 years old (N=391) and demographically matched offspring (N=248) of community parents without bipolar disorder were assessed longitudinally with standardized diagnostic instruments by staff blind to parental diagnoses. Follow-up assessments were completed in 91% of the offspring (mean follow-up interval, 2.5 years; mean follow-up duration, 6.8 years). RESULTS:Compared with community offspring, high-risk offspring had significantly higher rates of subthreshold mania or hypomania (13.3% compared with 1.2%), manic, mixed, or hypomanic episodes (9.2% compared with 0.8%), and major depressive episodes (32.0% compared with 14.9%). They also had higher rates of attention deficit hyperactivity disorder (30.7% compared with 18.1%), disruptive behavior disorders (27.4% compared with 15.3%), anxiety disorders (39.9% compared with 21.8%), and substance use disorders (19.9% compared with 10.1%), but not unipolar major depressive disorder (major depression with no bipolarity; 18.9% compared with 13.7%). Multivariate Cox regressions showed that in the high-risk offspring, subthreshold manic or hypomanic episodes (hazard ratio=2.29), major depressive episodes (hazard ratio=1.99), and disruptive behavior disorders (hazard ratio=2.12) were associated with subsequent manic, mixed, or hypomanic episodes. Only subthreshold manic or hypomanic episodes (hazard ratio=7.57) were associated when analyses were restricted to prospective data. CONCLUSIONS:Subthreshold manic or hypomanic episodes were a diagnostic risk factor for the development of manic, mixed, or hypomanic episodes in the offspring of parents with bipolar disorder and should be a target for clinical assessment and treatment research. Major depressive episodes and disruptive behavior disorders are also indications for close clinical monitoring of emergent bipolarity in high-risk offspring.

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Multi-state outcome analysis of treatments (MOAT): application of a new approach to evaluate outcomes in longitudinal studies of bipolar disorder.

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