Of the 199 study participants, 122 (61.3%) were women. The mean age at intake into the Collaborative Depression Study was 36.7 years (SD=12.9). Additional demographic and clinical characteristics of the sample are presented in . Follow-up time ranged from 3 years to 30 years, with a median of 24 years (mean=21.0, SD=8.2).
Demographic and Clinical Characteristics of Patients with Bipolar Disorder at Intake into the Collaborative Depression Study (N=199)
The analyses included 199 participants with 1,077 exposure intervals over the course of follow-up. It is likely that many of the intervals would not have met criteria for inclusion in the acute randomized clinical trials reviewed by the FDA. For example, 8.9% of participants made a suicide attempt in the 3 months preceding the exposure interval. Additionally, based on the psychiatric status ratings at exposure interval commencement, 33.1% were at most mildly symptomatic and 15% had psychosis or extreme functional impairment.
Most of the intervals did not involve antiepileptic drug exposure, as defined for our analyses; 216 were exposed (20.1%) and 861 were unexposed (79.9%). On average, exposed participants spent 35.6% of their follow-up time on antiepileptics (median=24.3; SD=22.5; range=0.2–92.1). The participants’ mania severity at the commencement of exposed intervals was significantly higher than for the unexposed intervals (psychiatric status ratings for exposed intervals, mean=2.6, SD=1.12; for unexposed intervals, mean=1.9, SD=1.08; z=5.51, p<0.001). Severity of hypomania did not differ across groups (psychiatric status ratings for exposed intervals, mean=1.1, SD=0.46; for unexposed intervals, mean=1.1, SD=0.37; z=1.78, p=0.075). Overall, 60.6% of the exposed intervals began when the participant was in a mood episode, compared with 47.2% of the unexposed intervals (z=2.85, p=0.004).
Of the 216 exposed intervals, 113 involved carbamazepine (53.3%), 24 involved lamotrigine (11.1%), and 101 involved valproate (46.8%). (The sum of exposed intervals for each medication exceeds the total number of exposed intervals because there was concomitant use of these antiepileptics.)
Propensity for Antiepileptic Exposure
The propensity model () shows that participants with more severe manic symptoms (odds ratio=3.83, 95% CI=2.39–6.14; z=5.59, p<0.001) or hypomanic symptoms (odds ratio=5.93, 95% CI=2.09–16.86; z=3.34, p<0.001) were significantly more likely to receive antiepileptics. Those who were treated with antipsychotics were significantly less likely to receive antiepileptics (odds ratio=0.50, 95% CI=0.32–0.79; z=−2.97, p=0.003). There were also significant omnibus effects of age, social class, and site, but not marital status.
Model of Propensity for Exposure to Any of the Three Antieplileptic Drugs for Patients with Bipolar Disorder in the Collaborative Depression Studya
Primary Results: Safety Analyses
Unadjusted rates of suicidal behavior were 6.3% among 847 unexposed intervals (52 attempts [6.1%] and one suicide [0.1%]) and 5.1% among 216 exposed intervals (nine attempts [4.2%] and two suicides [0.9%]), as depicted in . The unadjusted number needed to harm was 86, favoring antiepileptic drugs. The drug-specific rates of suicidal behavior were 3.5% for carbamazepine (4/113), 12.5% for lamotrigine (3/24), and 5.0% for valproate (4/101).
Rates of Suicide Attempts and Suicides for Anti-epileptic Drug-Exposed and Unexposed Intervalsa
Of the 1,077 exposed and unexposed intervals, 852 (79.1%) were matched based on the caliper of 0.10 propensity score standard deviation units and thus were included in the safety model. The rates of suicidal behavior in this matched set (6.4% unexposed, 5.2% exposed) are similar to those in the larger study sample. The risk of suicidal behavior was not significantly elevated among participants exposed to antiepileptics (hazard ratio=0.93, 95% CI=0.45–1.92; z=−0.20, p=0.814), controlling for variables in the propensity score through matching. Sensitivity analyses were conducted to examine results with a caliper of 0.40, in which 1,063 of 1,077 (98.7%) intervals were matched. Once again there was a nonsignificant association (hazard ratio=0.87, 95% CI=0.42–1.79; z=−0.38, p=0.707).
In 600 (70.8%) of the 847 unexposed intervals (again, defined as an interval with no antiepileptic, no antidepressant, and no lithium), the participants had no contemporaneous exposure to other mood-stabilizing treatments (such as antipsychotics or ECT). For intervals classified as unexposed, higher rates of suicidal behavior were observed among participants receiving other mood stabilizers (7.7%) compared with those not receiving mood stabilizers (5.7%), but this difference was nonsignificant (odds ratio=1.38, 95% CI=0.66–2.87; z=0.851, p=0.395).