Chunshan Li

Longitudinal Course of Bipolar I Disorder: Duration of Mood Episodes

CONTEXT The phenomenology of bipolar I disorder affects treatment and prognosis. OBJECTIVE To describe the duration of bipolar I mood episodes and factors associated with recovery from these episodes. DESIGN Subjects with Research Diagnostic Criteria bipolar I disorder were prospectively followed up for as long as 25 years. The probability of recovery over time from multiple successive mood episodes was examined with survival analytic techniques, including a mixed-effects grouped-time survival model. SETTING Five US academic medical centers. PARTICIPANTS Two hundred nineteen subjects with bipolar I disorder. MAIN OUTCOME MEASURES Level of psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation every 6 months for the first 5 years of follow-up and annually thereafter. RESULTS The median duration of bipolar I mood episodes was 13 weeks. More than 75% of the subjects recovered from their mood episodes within 1 year of onset. The probability of recovery was significantly less for an episode with severe onset (psychosis or severe psychosocial impairment in week 1 of the episode) (hazard ratio [HR] = 0.746; 95% confidence interval [CI], 0.578-0.963; P = .02) and for subjects with greater cumulative morbidity (total number of years spent ill with any mood episode) (HR = 0.917; 95% CI, 0.886-0.948; P < .001). Compared with the probability of recovery from a major depressive episode, there was a significantly greater probability of recovery from an episode of mania (HR = 1.713; 95% CI, 1.373-2.137; P < .001), hypomania (HR = 4.502; 95% CI, 3.466-5.849; P < .001), or minor depression (HR = 2.027; 95% CI, 1.622-2.534; P < .001) and, conversely, a significantly reduced probability of recovery from a cycling episode (switching from one pole to the other without an intervening period of recovery) (HR = 0.438; 95% CI, 0.351-0.548; P < .001). CONCLUSIONS The median duration of bipolar I mood episodes was 13 weeks, and the probability of recovery was significantly decreased for cycling episodes, mood episodes with severe onset, and subjects with greater cumulative morbidity.

Manic/hypomanic Symptom Burden and Cardiovascular Mortality in Bipolar Disorder

Objectives: To compare the risk for cardiovascular mortality between bipolar I and bipolar II subtypes and determine correlates of cardiovascular mortality. Bipolar disorder conveys an increased risk of cardiovascular mortality. Methods: Participants with major affective disorders were recruited for the National Institute of Mental Health Collaborative Depression Study and followed prospectively for up to 25 years. A total of 435 participants met the diagnostic criteria for bipolar I (n = 288) or bipolar II (n = 147) disorder based on Research Diagnostic Criteria at intake and measures of psychiatric symptoms during follow-up. Diagnostic subtypes were contrasted by cardiovascular mortality risk using Cox proportional hazards regression. Affective symptom burden (the proportion of time with clinically significant manic/hypomanic or depressive symptoms) and treatment exposure were additionally included in the models. Results: Thirty-three participants died from cardiovascular causes. Participants with bipolar I disorder had more than double the cardiovascular mortality risk of those with bipolar II disorder, after controlling for age and gender (hazard ratio = 2.35, 95% Confidence Interval = 1.04-5.33; p = .04). The observed difference in cardiovascular mortality between these subtypes was at least partially confounded by the burden of clinically significant manic/hypomanic symptoms which predicted cardiovascular mortality independent of diagnosis, treatment exposure, age, gender, and cardiovascular risk factors at intake. Selective serotonin uptake inhibitors seemed protective although they were introduced late in follow-up. Depressive symptom burden was not related to cardiovascular mortality. Conclusions: Participants with bipolar I disorder may face a greater risk of cardiovascular mortality than those with bipolar II disorder. This difference in cardiovascular mortality risk may reflect manic/hypomanic symptom burden. CDS = collaborative depression study; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; RDC = Research Diagnostic Criteria; PSR = Psychiatric Status Rating.

Antiepileptic drugs for bipolar disorder and the risk of suicidal behavior: a 30-year observational study.

OBJECTIVE In 2009 the U.S. Food and Drug Administration issued a warning regarding suicidality and antiepileptic drugs based on meta-analyses of 199 randomized trials (over 43,000 subjects with different illnesses) of 11 antiepileptics. The present study examines the hypothesis that the three antiepileptics approved for bipolar disorder (carbamazepine, lamotrigine, and valproate) are associated with an elevated risk of suicide attempts and suicides. METHOD A prospective observational study was conducted at five U.S. academic medical centers from 1978 to 2009. Analyses included 199 participants with bipolar disorder for whom 1,077 time intervals were classified as either exposed to an antiepileptic (carbamazepine, lamotrigine, or valproate) or not exposed to an antiepileptic, an antidepressant, or lithium during 30 years of follow-up. RESULTS Participants who had more severe manic symptoms were more likely to receive antiepileptic drugs. Mixed-effects grouped-time survival models revealed no elevation in risk of suicide attempt or suicide during periods when participants were receiving antiepileptics relative to periods when they were not (hazard ratio=0.93, 95% CI=0.45-1.92), controlling for demographic and clinical variables through propensity score matching. CONCLUSIONS In this longitudinal observational study, the risk of suicide attempts or suicides was not associated with the antiepileptics approved for bipolar disorder.

Social problem solving and depressive symptoms over time: a randomized clinical trial of cognitive-behavioral analysis system of psychotherapy, brief supportive psychotherapy, and pharmacotherapy.

OBJECTIVE Depression is associated with poor social problem solving, and psychotherapies that focus on problem-solving skills are efficacious in treating depression. We examined the associations between treatment, social problem solving, and depression in a randomized clinical trial testing the efficacy of psychotherapy augmentation for chronically depressed patients who failed to fully respond to an initial trial of pharmacotherapy (Kocsis et al., 2009). METHOD Participants with chronic depression (n = 491) received cognitive-behavioral analysis system of psychotherapy (CBASP; McCullough, 2000), which emphasizes interpersonal problem solving, plus medication; brief supportive psychotherapy (BSP) plus medication; or medication alone for 12 weeks. RESULTS CBASP plus pharmacotherapy was associated with significantly greater improvement in social problem solving than BSP plus pharmacotherapy, and a trend for greater improvement in problem solving than pharmacotherapy alone. In addition, change in social problem solving predicted subsequent change in depressive symptoms over time. However, the magnitude of the associations between changes in social problem solving and subsequent depressive symptoms did not differ across treatment conditions. CONCLUSIONS It does not appear that improved social problem solving is a mechanism that uniquely distinguishes CBASP from other treatment approaches.

Risk of suicidal behavior with antidepressants in bipolar and unipolar disorders

OBJECTIVE To examine the risk of suicidal behavior (suicide attempts and deaths) associated with antidepressants in participants with bipolar I, bipolar II, and unipolar major depressive disorders. DESIGN A 27-year longitudinal (1981-2008) observational study of mood disorders (Research Diagnostic Criteria diagnoses based on Schedule for Affective Disorders and Schizophrenia and review of medical records) was used to evaluate antidepressants and risk for suicidal behavior. Mixed-effects logistic regression models examined propensity for antidepressant exposure. Mixed-effects survival models that were matched on the propensity score examined exposure status as a risk factor for time until suicidal behavior. SETTING Five US academic medical centers. RESULTS Analyses of 206 participants with bipolar I disorder revealed 2,010 exposure intervals (980 exposed to antidepressants; 1,030 unexposed); 139 participants with bipolar II disorder had 1,407 exposure intervals (694 exposed; 713 unexposed); and 361 participants with unipolar depressive disorder had 2,745 exposure intervals (1,328 exposed; 1,417 unexposed). Propensity score analyses confirmed that more severely ill participants were more likely to initiate antidepressant treatment. In mixed-effects survival analyses, those with bipolar I disorder had a significant reduction in risk of suicidal behavior by 54% (HR = 0.46; 95% CI, 0.31-0.69; t = -3.74; P < .001) during periods of antidepressant exposure compared to propensity-matched unexposed intervals. Similarly, the risk was reduced by 35% (HR = 0.65; 95% CI, 0.43-0.99; t = -2.01; P = .045) in bipolar II disorder. By contrast, there was no evidence of an increased or decreased risk with antidepressant exposure in unipolar disorder. CONCLUSIONS Based on observational data adjusted for propensity to receive antidepressants, antidepressants may protect patients with bipolar disorders but not unipolar depressive disorder from suicidal behavior.

Two propensity score‐based strategies for a three‐decade observational study: investigating psychotropic medications and suicide risk

The US Food and Drug Administration issued separate warnings for suicidality with antidepressants and antiepileptic drugs in the past 5 years. This study describes methods for examining the association of these agents with suicide attempts and suicide deaths in more broadly generalizable samples than examined by the US Food and Drug Administration. An observational study of mood disorders was examined that includes three decades of prospective assessments. Because of sample size differences, two distinct longitudinal implementations of the propensity adjustment are used in separate analyses of antidepressants and antiepileptic drugs. Propensity score quintile-stratified safety analyses were used with the large antidepressant data set; whereas, propensity score matched safety analyses were used with the smaller antiepileptic drug data because stratification was not feasible. In each case, mixed-effects survival models compared the safety of participants when receiving the respective class of medication to periods when they did not receive that medication. When participants were more severely ill, they were significantly more likely to receive either class of psychotropics. Propensity quintile-stratified safety analyses found that risk of suicide attempts or suicides was significantly reduced when participants received antidepressants. In contrast, propensity score matched safety analyses found neither significant risk nor protection from suicidality among participants receiving antiepileptics.

Recovery from multiple episodes of bipolar I depression.

OBJECTIVE To describe the duration of bipolar I major and minor depressive episodes and factors associated with time to recovery. METHOD As part of the National Institute of Mental Health Collaborative Depression Study, 219 participants with bipolar I disorder based on Research Diagnostic Criteria analogs to DSM-IV-TR criteria were recruited at 5 academic medical centers from 1978 to 1981 and followed for up to 25 years with the Longitudinal Interval Follow-Up Evaluation. The probability of recovery over time from depressive episodes, the primary outcome measure, was examined with mixed-effects grouped-time survival models. RESULTS The median duration of major depressive episodes was 14 weeks, and over 70% of participants recovered within 12 months of episode onset. The median duration of minor depressive episodes was 8 weeks, and approximately 90% of participants recovered within 6 months of onset of the episode. Aggregated data demonstrated similar durations of the first 3 major depressive episodes. However, for each participant with multiple episodes of major depression or minor depression, the duration of each episode was not consistent (intraclass correlation coefficient = 0.07 and 0.25 for major and minor depression, respectively). The total number of years in episode over follow-up with major plus minor depression prior to onset of a major depressive episode was significantly associated with a decreased probability of recovery from that episode; with each additional year, the likelihood of recovery was reduced by 7% (hazard ratio = 0.93; 95% CI, 0.89-0.98; P = .002). CONCLUSIONS Bipolar I major depression generally lasts longer than minor depression, and the duration of multiple episodes within an individual varies. However, the probability of recovery over time from an episode of major depression appears to decline with each successive episode.

Empirical typology of bipolar I mood episodes

BACKGROUND Much remains unknown about the phenomenology of bipolar I disorder. AIMS To determine the type of bipolar I mood episodes that occur over time, and their relative frequency. METHOD A total of 219 individuals with Research Diagnostic Criteria bipolar I disorder were prospectively followed for up to 25 years (median 20 years). Psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation. RESULTS Overall, 1208 mood episodes were prospectively observed. The episodes were empirically classified as follows: major depression, 30.9% (n = 373); minor depression, 13.0% (n = 157); mania, 20.4% (n = 246); hypomania, 10.4% (n = 126); cycling, 17.3% (n = 210); cycling plus mixed state, 7.8% (n = 94); and mixed, 0.2% (n = 2). CONCLUSIONS Cycling episodes constituted 25% of all episodes. Work groups revising ICD-10 and DSM-IV should add a category for bipolar I cycling episode.

Subject-level matching for imbalance in cluster randomized trials with a small number of clusters.

In a cluster randomized controlled trial (RCT), the number of randomized units is typically considerably smaller than in trials where the unit of randomization is the patient. If the number of randomized clusters is small, there is a reasonable chance of baseline imbalance between the experimental and control groups. This imbalance threatens the validity of inferences regarding post-treatment intervention effects unless an appropriate statistical adjustment is used. Here, we consider application of the propensity score adjustment for cluster RCTs. For the purpose of illustration, we apply the propensity adjustment to a cluster RCT that evaluated an intervention to reduce suicidal ideation and depression. This approach to adjusting imbalance had considerable bearing on the interpretation of results. A simulation study demonstrates that the propensity adjustment reduced well over 90% of the bias seen in unadjusted models for the specifications examined.