Lori L. Altshuler

OBJECTIVE: The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders. METHOD: An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder. RESULTS: There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder. CONCLUSIONS: Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.

OBJECTIVE: The longitudinal course of 51 patients with treatment-refractory bipolar disorder was examined to assess possible effects of heterocyclic antidepressants on occurrence of manic episodes and cycle acceleration. METHOD: Using criteria established from life charts, investigators rated the patients' episodes of mania or cycle acceleration as likely or unlikely to have been induced by antidepressant therapy. Discriminant function analyses were performed to assess predictors of vulnerability to antidepressant-induced mania or cycle acceleration. Further, the likelihood of future antidepressant-induced episodes in persons who had had one such episode was assessed. RESULTS: Thirty-five percent of the patients had a manic episode rated as likely to have been antidepressant-induced. No variable was a predictor of vulnerability to antidepressant-induced mania. Cycle acceleration was likely to be associated with antidepressant treatment in 26% of the patients assessed. Younger age at first treatment was a predictor of vulnerability to antidepressant-induced cycle acceleration. Forty-six percent of patients with antidepressant-induced mania, but only 14% of those without, also showed antidepressant-induced cycle acceleration at some point in their illness. CONCLUSIONS: Mania is likely to be antidepressant-induced and not attributable to the expected course of illness in one-third of treatment-refractory bipolar patients, and rapid cycling is induced in one-fourth. Antidepressant-induced mania may be a marker for increased vulnerability to antidepressant-induced cycle acceleration. Antidepressant-induced cycle acceleration (but not antidepressant-induced mania) is associated with younger age at first treatment and may be more likely to occur in women and in bipolar II patients.

OBJECTIVES: Functional neuroimaging methods have proliferated in recent years, such that functional magnetic resonance imaging, in particular, is now widely used to study bipolar disorder. However, discrepant findings are common. A workgroup was organized by the Department of Psychiatry, University of Cincinnati (Cincinnati, OH, USA) to develop a consensus functional neuroanatomic model of bipolar I disorder based upon the participants' work as well as that of others. METHODS: Representatives from several leading bipolar disorder neuroimaging groups were organized to present an overview of their areas of expertise as well as focused reviews of existing data. The workgroup then developed a consensus model of the functional neuroanatomy of bipolar disorder based upon these data. RESULTS: Among the participants, a general consensus emerged that bipolar I disorder arises from abnormalities in the structure and function of key emotional control networks in the human brain. Namely, disruption in early development (e.g., white matter connectivity and prefrontal pruning) within brain networks that modulate emotional behavior leads to decreased connectivity among ventral prefrontal networks and limbic brain regions, especially the amygdala. This developmental failure to establish healthy ventral prefrontal-limbic modulation underlies the onset of mania and ultimately, with progressive changes throughout these networks over time and with affective episodes, a bipolar course of illness. CONCLUSIONS: This model provides a potential substrate to guide future investigations and areas needing additional focus are identified.

BACKGROUND: Few studies of the neurocognitive performance of patients with bipolar disorder have been performed while patients are in the euthymic state. METHODS: Twenty-five euthymic bipolar patients (12 with and 13 without a history of alcohol dependence) were compared with 22 normal control subjects on a neuropsychological test battery assessing a range of cognitive domains. The relationship between subjects' neurocognitive performance and the course-of-illness variables (lifetime episodes and duration of mania, depression, or both), as well as current lithium level, was determined. RESULTS: The results indicated differences across the groups, with the bipolar patients with and without alcohol dependence performing more poorly than controls on tests of verbal memory. Furthermore, bipolar subjects with a history of alcohol dependence had additional decrements in executive (i.e., frontal lobe) functions when compared with controls. For subjects in the bipolar group, lifetime months of mania and depression were negatively correlated with performance in verbal memory and several executive function measures. CONCLUSIONS: Our findings support the presence of persistent neurocognitive difficulties in patients with long-standing bipolar disorder who are not in the psychiatrically acute state or who are suffering the effects of alcohol abuse and suggest that there may be an aggregate negative effect of lifetime duration of bipolar illness on memory and frontal or executive systems.