In schizophrenia, as summarized by Dr. Ken Davis, there is now evidence of glial cell defects at the level of: (1) their size and number in the cerebral cortex; (2) their deficient activation as marked by decreases in glial fibrillary acidic protein (GFAP) and mRNA (a marker of glial health and activity) in both bipolar illness and schizophrenia; (3) the pathological appearance of the nucleus and cytoplasm of glial cells (as visualized on electron microscopy); and (4) in the breakdown of the smooth myelin sheath that surrounds neurons that is made by the glial oligodendrocytes or Schwann cells. Glial pathology in individuals with schizophrenia is also documented by brain imaging techniques (such as magnetic resonance imaging [MRI]) which reveals white matter alterations (using MRI) and alterations in glial white matter tracts (using defusion tensor imaging).

  This convergence of evidence greatly increases our understanding of one aspect of the pathophysiology of these major illnesses. A pathology involving glial cells, rather than nerve cells (which conduct nerve impulses in all the major messenger systems in the brain), makes sense in psychiatric illnesses where there are no specific neurological defects as seen in many of the more classic illnesses treated by neurologists. Yet glial cells are intimately involved in the biochemical metabolic and neurotrophic support of the function of neurons, and glial actions at the synapses are crucial to normal neuronal transmission. Glia take up excess glutamate (which can be neurotoxic) and produce neurotrophic factors which keep cells alive, as well as interacting with other systems in transmitter-like actions. Thus, a loss of normal glial function could have dramatic impacts on normal neuronal function.

 

III.  Clinical Implications

  So why is that important for bipolar disorder? How do these new findings represent a paradigm shift with accompanying new clinical and therapeutic implications? The answer is that we have now begun to acquire specific and replicable insights into some aspect of the neuropathology of bipolar illness and schizophrenia which can then be targeted for therapeutics. Moreover, the implications for current treatments and their clinical application are much clearer with some potentially dramatic surprises as well.

  Previous studies have shown that lithium appears to be neurotrophic (neuron-growing) and neuroprotective, but new data presented at the meeting by Dr. Husseini Manji and others reveals that in addition, lithium helps grow new glial cells both in culture and in animals and does so at clinically relevant blood levels of lithium in the range of 0.5 to 1.0 meq/L.

  As in schizophrenia, there are regionally selective and different alterations in glial cell number, size, and function in bipolar illness compared to normal controls. There is decreased glial cell density and at the same time increased size of glial nuclei in specific areas of the prefrontal cortex. This is associated with markers of decreased glial activation (decreases in mRNA and protein for GFAP). In one specific part of the cortex—the subgenual portion of the anterior cingulate gyrus which is critically involved in the modulation of mood and motivation—there is a forty percent decrease in cortical size attributed largely to insufficient glial elements.

  Whereas stress and the stress hormone cortisol (corticosterone in the rodent) have been reported to decrease the birth of new cellular elements (neurogensis) in the CNS, lithium and the antidepressants counter this effect.

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  This had heretofore only been thought of as the generation of new neurons, but now it has also been documented for the development of new glial cells as well. Dr. Manji and colleagues have indicated that lithium causes cultured glial cells to secrete factors into the medium which can then be extracted, and this extract is effective in growing other cells. This extract causes stem cells to increase the production of new glia cells, but they also retain some neuronal markers (and may thus preserve their capacity for ultimately turning into neurons or glia).

  The skeptical individual might still ask “so what”? The difference is that we can now for the first time re-conceptualize lithium as a primary repair and prevention treatment for the loss in glial cells and neurons that have now been documented in bipolar illness. Lithium increases the cell survival factors brain-derived neurotrophic factor (BDNF) and Bcl-2 and decreases cell death factors Bax and p53. These effects are also likely to be clinically important as they occur with clinically relevant blood levels, and pre-treatment of animals with lithium decreases both the size of an anoxic stroke or a neurotoxin-induced stroke and the degree of associated neurological dysfunction.

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  These data are consistent with previous research showing that patients that remain on long-term lithium have a decrease in the excess medical mortality that comes with untreated bipolar or unipolar recurrent depression. It is well known that depression is a predisposing factor for stroke, heart attacks, and a variety of other medical conditions that can lead to premature death from medical causes other than suicide. It had never been mechanistically clear how lithium exerts these beneficial effects on medical health, but now a variety of mechanisms for increasing neuronal and glial survival are readily available, and can begin to be documented as links in the process (or not) by which lithium exerts its range of psychotrophic effects, including bipolar illness prevention.

  Importantly, lithium has been clearly shown to decrease the rate of suicide in patients with bipolar illness and bring it much closer to the rate in the general population. New evidence at the ACNP meeting from Dr. Fred Goodwin and associates suggests that this is also the case in patients on long-term lithium treatment, as opposed to valproate. In a very large group of many thousands of patients, those treated with lithium had a significantly lower rate of suicide compared with those on long-term treatment with valproate.

  Several new studies of lithium, lamotrigine, and placebo now unequivocally support the older studies indicating that lithium decreases manic episode recurrence when administered in long-term prophylaxis and is superior to lamotrigine in this regard (although lamotrigine is a superior antidepressant treatment compared to lithium). These studies, along with those showing a decreased incidence of suicide and normalization of medical-related morbidity and mortality with lithium, increase the importance of lithium in the therapeutics of bipolar illness to a new level.

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