Neuroplasticity and Cellular Resilience in Bipolar Disorder

Video  |  Audio (Length:  35 min.)

Husseini K. Manji, MD
Bibliography

H.K. Manji
National Institute of Mental Health, Bethesda, MD, USA

Abstract
Attempts to comprehend the brain's role in mania and depression began in earnest as clinically effective mood altering drugs began to appear in the late 1950s and early 1960s. Over the next three decades, clinical studies attempted to uncover the biological factors mediating the pathophysiology of manic-depressive illness utilizing a variety of biochemical strategies. Studies were, by and large, designed to detect relative excess or deficiency associated with pathological states; not surprisingly, progress in unraveling the unique neurobiology of this disorder was slow using such strategies in isolation. However, the last decade of the 20th century has truly been a remarkable one for biomedical research. The “molecular medicine revolution” has brought to bear the power of sophisticated cellular and molecular biologic methodologies to tackle many of society’s most devastating illnesses. The rate of progress has been exciting indeed, and hundreds of G protein coupled receptors and over a dozen G proteins and effectors have now been identified and characterized at the molecular and cellular level. This has allowed the study of a variety of human diseases which are caused by abnormalities in cell to cell communication; studies of such diseases are offering unique insights into the physiologic and pathophysiologic functioning of many cellular transmembrane signaling pathways. Psychiatry, like much of the rest of medicine, has entered a new and exciting age demarcated by the rapid advances and the promise of molecular and cellular biology and neuroimaging. Although we have yet to identify the specific abnormal genes or proteins in bipolar disorder, there have been major advances in our understanding of this illness, as well as in the mechanisms of action of the most effective treatments. The behavioral and physiological manifestations of bipolar disorder are complex and are likely mediated by a network of interconnected neuronal circuits. Since signal transduction pathways play a critical role in regulating the functional balance between neurotransmitter systems, they represent attractive putative mediators of the therapeutic effects of mood stabilizing agents. New genomics and proteomics technologies are also being utilized to facilitate the identification of genes that are regulated by mood stabilizers, and have led to novel and completely unexpected targets, most notably neurotrophic signaling cascades.  The identification of neurotrophic signaling cascades as targets for mood stabilizers is particularly noteworthy since – although bipolar disorder has traditionally been conceptualized as a neurochemical disorder -- there is now evidence from a variety of sources demonstrating regional reductions in CNS volume, as well as reductions in the numbers and/or sizes of glia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggest that severe bipolar disorders are associated with impairments of structural plasticity and cellular resilience. It is thus noteworthy that recent preclinical studies have shown that critical molecules in neurotrophic signaling cascades (most notably CREB, BDNF, bcl-2 and MAP kinases) are long term targets for mood stabilizing agents.  Consistent with these biochemical effects, mood stabilizing agents (most notably lithium) have been demonstrated to exert robust neuroprotective and neurotrophic effects in a variety of preclinical paradigms. Complementary human studies have shown that chronic lithium significantly increases gray matter content in a regionally selective manner, suggesting a reversal of illness-related atrophy and an increase in the volume of the neuropil. These unique and unexpected properties of lithium and valproate suggest that they may have broader utility as adjunctive agents in the treatment of a variety of neuropsychiatric disorders associated with cell atrophy or loss. Furthermore, the growing body of preclinical and clinical data suggests that for many refractory patients, new drugs simply mimicking many ‘traditional’ drugs which directly or indirectly alter neurotransmitter levels and those which bind to cell surface receptors may be of limited benefit. For these patients, optimal treatment may only be attained by providing both trophic and neurochemical support; the trophic support would be envisioned as enhancing and maintaining normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. There are a number of pharmacologic “plasticity enhancing” strategies which may be of considerable utility in the treatment of mood disorders. Among the most immediate ones are NMDA antagonists, glutamate release reducing agents, AMPA potentiators, cAMP phosphodiesterase inhibitors, and glucocorticoid receptor antagonist. An increasing number of strategies are also being investigated to develop small molecule agents to regulate the activity of growth factors, MAP kinases cascades, and the bcl-2 family of proteins; this research hold much promise for the development of novel therapeutics for the treatment of severe, refractory mood disorders.

Shared Genetic Susceptibility for Bipolar and Schizophrenic Disorders

Video  |  Audio (Length:  31 min.)

Wade Berrettini, M.D., Ph.D.
Bibliography

W. Berrettini
University of Pennsylvania School of Medicine, Philadelphia, PA, USA

Abstract
Schizophrenic and bipolar disorders are similar in several epidemiologic respects, including age-at-onset, lifetime risk, course of illness, worldwide distribution, risk for suicide, gender influence (men and women at equal risk for both groups of disorders) and genetic susceptibility. Despite these similarities, schizophrenia and bipolar disorders are typically considered to be separate entities, with distinguishing clinical characteristics, non-overlapping etiologies and distinct treatment regimens. Over the past three decades, multiple family studies are consistent with greater nosologic overlap than previously acknowledged. First degree relatives of bipolar probands are at increased risk for bipolar, schizoaffective and unipolar disorders. First degree relatives of schizophrenic probands are at increased risk for schizophrenic, schizoaffective and unipolar disorders. Molecular linkage studies (conducted during the past decade) reveal that some susceptibility loci may be common to both nosologic classes, including those located at 18p11.2, 22q11-13, 13q32, 8p22 and 10p14. This indicates that our nosology will require substantial revision during the next decade, to reflect this shared genetic susceptibility, as specific genes are identified.

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