Lithium increases gray matter in the brain.

Able to stabilize the mood swings of many people with manic depression, lithium revolutionized psychiatric therapy when the drug came on the scene several decades ago. Yet neuroscientists remain perplexed at how this potent medication works.

Scientists in Detroit have now provided a clue that could help resolve that mystery. They find that about a month of treatment with the drug increases the volume of gray matter in a person's brain. Gray matter, the so-called thinking part of the brain, is made up primarily of the main bodies of nerve cells and their short connections.

"This is a highly significant finding and may shed light on the therapeutic mechanism of lithium," says De-Maw Chuang of the National Institute of Mental Health in Bethesda, Md.

Another study by some of the Detroit scientists hints that lithium stimulates production of new brain cells. This observation raises hope that the drug can treat strokes, Alzheimer's disease, and other conditions that kill brain cells. It may also support a radical new theory that the birth and death of brain cells underlie depression.

There have been hints before that lithium safeguards nerve cells. Two years ago, Chuang's group showed that the drug protects nerve cells from fatal over-stimulation by the brain chemical glutamate (SN: 3/14/98, p. 165). Husseini K. Manji of Wayne State University in Detroit and his colleagues then found that lithium4reated nerve cells overproduce a protein, bcl-2, that helps cells resist signals to commit suicide.

Manji next joined with his colleague Gregory J. Moore to carry out a brain-imaging study of people starting lithium treatment for manic depression. After 4 weeks, about the time it takes for lithium's mood-stabilizing effects to emerge, the drug had increased the volume of brain gray matter by about 3 percent in 8 of the 10 people studied, the researchers report this week at the Society for Neuroscience meeting in New Orleans. They also describe this result in the Oct. 7 LANCET.

"This is the first demonstration of a pharmacological increase of human brain matter," says Moore.

The researchers propose that most of the increased volume results from nerve cells sprouting additional branches to nearby cells, a sign of healthy brain cells. A small part of the increased gray matter may even consist of new brain cells.

In New Orleans, Manji's group reported that lithium boosted new nerve cell production in one brain region of rodents. Mice receiving lithium had about 25 percent more new brain cells in the hippocampus than untreated mice did.

In past mouse studies, a diverse slate of proven antidepressant therapies, including electroconvulsive therapy, exercise, and drugs such as Prozac, has triggered the birth of nerve cells in the hippocampus.

This earlier work and other evidence have prompted some scientists to theorize that depression stems from problems with a brain's natural ability to generate new cells in the hippocampus. That remains speculation, however. Indeed, only recently have scientists accepted that the adult human brain can grow new cells (SN: 10/31/98, p. 276).

Lithium's ability to protect nerve cells and increase production of new ones may make the drug useful in more illnesses than manic depression, suggests Moore. Chuang, for example, reported last year that lithium reduces brain-cell loss in a rodent version of Huntington's disease.

The drug also protects rodent brains from cell death after a stroke, even if researchers wait to administer the drug. "We can give lithium up to 3 hours after the onset of stroke," says Chuang.

Manji proposes testing lithium in people with Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis, more commonly known as Lou Gehrig's disease.