Michael A. Cerullo

In this article, we examined evidence for the acute treatment of depression in bipolar I disorder, focusing on double-blind, placebo-controlled studies with a definite primary outcome measure and published in peer review journals. Quetiapine and olanzapine/fluoxetine are currently approved by the FDA for the treatment of bipolar depression, and a number of additional agents (including other atypical antipsychotics, mood stabilizers, antidepressants, and novel compounds) have been studied with varying degrees of efficacy. The medication with the most evidence for efficacy in bipolar depression is quetiapine, with five studies showing positive efficacy compared to placebo. In contrast, five studies of lamotrigine were negative, although meta-analyses of the pooled have found some treatment effects. Two studies of olanzapine and olanzapine/fluoxetine and three small studies of divalproex showed significant efficacy in treating bipolar depression. Two studies of aripiprazole found no differences compared to placebo. Early research on lithium in bipolar depression had significant methodological flaws, and only one study of lithium met our primary search criteria. To better understand the role of antidepressants, we also examined studies of antidepressants as adjunctive treatment of bipolar depression in participants taking mood stabilizers or atypical antipsychotics. These studies reported mixed results for a variety of antidepressants, but the majority found no differences compared to placebo. Other studies of adjunctive treatment were also discussed. There has been one positive adjunctive study each of lamotrigine, omega-3 fatty acids, modafinil, and armodafinil, while there was one negative trial each of omega-3 fatty acids, ziprasidone, and levetiracetam.

Cerullo MA, Fleck DE, Eliassen JC, Smith MS, DelBello MP, Adler CM, Strakowski SM. A longitudinal functional connectivity analysis of the amygdala in bipolar I disorder across mood states. Bipolar Disord 2012: 14: 175–184. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S.Objective:  Bipolar I disorder is characterized by affective symptoms varying between depression and mania. The specific neurophysiology responsible for depression in bipolar I disorder is unknown but previous neuroimaging studies suggest impairments in corticolimbic regions that are responsible for regulating emotion. The amygdala seems to play a central role in this network and is responsible for appraisal of emotional stimuli. To further understand the role of the amygdala in the generation of mood symptoms, we used functional magnetic resonance imaging (fMRI) to examine a group of patients with bipolar I disorder longitudinally.Methods:  fMRI was used to study regional brain activation in 15 bipolar I disorder patients followed for up to one year. Patients received an fMRI scan during an initial manic episode and a subsequent depressive episode. During the scans, patients performed an attentional task that incorporated emotional pictures. Fifteen healthy comparison subjects were also scanned at baseline and then at four months. Whole‐brain functional connectivity analysis was performed using the left and right amygdala as seed regions.Results:  Significant changes in amygdala functional connectivity were found between the manic and depressed phases of illness. The right amygdala was significantly more positively correlated with the left inferior frontal gyrus during mania and with the right insula during depression. There were no significant differences in left amygdala correlations across mood states in the bipolar I disorder group.Conclusions:  In the transition from a manic/mixed episode to a depressive episode, subjects with bipolar I disorder showed unique changes in cortical–amygdala functional connectivity. Increased connectivity between the insula and right amygdala may generate excessive positive feedback, in that both of these regions are involved in the appraisal of emotional stimuli. Increased correlation between the right amygdala and the inferior frontal gyrus in mania is consistent with previous findings of decreased prefrontal modulation of limbic regions in mania. These differences in connectivity may represent neurofunctional markers of mood state as they occurred in the same individuals across manic and depressive episodes.