Husseini Manji MD, Chief of the Laboratory of Molecular Pathophysiology at the National Institute of Health, has been investigating the effects of lithium and Depakote on the brains of rats and humans. A recent finding yielded the astounding result that lithium "significantly increases total gray matter volume in the human brain of patients with manic-depressive illness."
But first a brief word on bcl-2, which Dr Manji describes as one of the most important neuroprotective proteins. Unfortunately, it is normally found in very low levels in most areas of the adult brain. If the level of bcl-2 could be enhanced, researchers speculate, this might advance the treatment of Alzheimer's, Parkinson's, and so on. Bipolar, here, needs to be considered in the context of these degenerative diseases, as postmortem studies of bipolar brains have shown an atrophy of neurons in the frontal cortex. Depression, too, may be included, based on a three-year-old study..
Recently, Dr Manji and his associates found that in the rat frontal cortex, both lithium and Depakote doubled bcl-2 levels. As Dr Manji told this Newsletter: "The effects were most pronounced in layers II and III - the very same regions that investigators studying bipolar disorder have found evidence for loss or atrophy of cells." In other areas of the brain - the striatum and hippocampus - lithium increased bcl-2 levels, but Depakote did not. Similar lithium-induced increases in bcl-2 were also observed in cells of human neuronal origin.
Additionally, other findings have shown that lithium protects neurons against a variety of insults, including models of stroke and Huntington's. According to Dr Manji: "It is very likely that these neuroprotective effects are mediated mainly by bcl-2."
This brings us to brain cell growth. Lithium, by increasing bcl-2 levels, may reverse the atrophy of cells (ie cells that have shrunk). There is also the possibility that lithium may be enhancing the growth of new nerve cells to replace old ones which have died.
The findings showing increases in gray matter in humans have to be treated as preliminary, Dr Manji cautions, but the data regarding increased bcl-2 levels and lithium's neuroprotective effects is "very solid," and has been replicated by several independent laboratories.
All which leads to a possible new therapeutic use for lithium - as prevention against further deterioration of the brain. "Early intervention," Dr Manji told this Newsletter, "may be critical ... I think that if we can prevent some of the brain changes from taking place in the first place, perhaps we can alter the course of the illness, so that it isn't the recurrent devastating illness that it is for so many."
Dr Manji anticipates doing studies on humans at low doses (blood levels of 0.3-0.4 or 300 to 600 mg a day) and performing MRI scans on them over a number of years. Thus, even patients who do not benefit from lithium in treating their mood swings may one day find themselves on low doses as simple protection against the many terrible processes that attack the brain. Today's population of lithium-users, it goes without saying, may already be enjoying that advantage.
Our thanks to John Mcmanamy from Suite 101
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