Abstract
From a neurobiological perspective there is no such thing as bipolar disorder. Rather, it is almost certainly the case that many somewhat similar, but subtly different, pathological conditions produce a disease state that we currently diagnose as bipolarity. This heterogeneity – reflected in the lack of synergy between our current diagnostic schema and our rapidly advancing scientific understanding of the condition – limits attempts to articulate an integrated perspective on bipolar disorder. However, despite these challenges, scientific findings in recent years are beginning to offer a provisional “unified field theory” of the disease. This theory sees bipolar disorder as a suite of related neurodevelopmental conditions with interconnected functional abnormalities that often appear early in life and worsen over time. In addition to accelerated loss of volume in brain areas known to be essential for mood regulation and cognitive function, consistent findings have emerged at a cellular level, providing evidence that bipolar disorder is reliably associated with dysregulation of glial–neuronal interactions. Among these glial elements are microglia – the brain’s primary immune elements, which appear to be overactive in the context of bipolarity. Multiple studies now indicate that inflammation is also increased in the periphery of the body in both the depressive and manic phases of the illness, with at least some return to normality in the euthymic state. These findings are consistent with changes in the hypothalamic–pituitary–adrenal axis, which are known to drive inflammatory activation. In summary, the very fact that no single gene, pathway, or brain abnormality is likely to ever account for the condition is itself an extremely important first step in better articulating an integrated perspective on both its ontological status and pathogenesis. Whether this perspective will translate into the discovery of innumerable more homogeneous forms of bipolarity is one of the great questions facing the field and one that is likely to have profound treatment implications, given that fact that such a discovery would greatly increase our ability to individualize – and by extension, enhance – treatment.
Highlights
Despite significant advances in our understanding of the underlying neurobiology of bipolar disorder, its timely diagnosis and efficient treatment remain daunting clinical challenges
Given the importance of glial pathology in the pathogenesis of bipolar disorder and the key role played by GDNF in stabilizing microglia activation and the propagation of peripheral inflammatory signaling in the CNS, we hope that future, methodologically rigorous studies may elucidate its disease state-dependent changes
This study suggests significant regional differences in gamma-aminobutyric acid (GABA) transmission between unipolar and bipolar depression
Summary
Despite significant advances in our understanding of the underlying neurobiology of bipolar disorder, its timely diagnosis and efficient treatment remain daunting clinical challenges. Several studies and two recent meta-analyses have reported elevated levels of peripheral inflammatory cytokines in bipolar depressed and manic patients compared with healthy controls [193,194,195,196,197,198,199].
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