A NEW understanding of how lithium helps people with manic depression may
lead to a treatment with fewer side effects. Patients have been taking lithium
to treat manic depression, or bipolar disorder as doctors call it, for half a
century. But the drug causes tremors, drowsiness and diarrhoea, and long-term
use leads to kidney disease.
About 1 per cent of Americans suffer from bipolar disorder, which gets its
name from sufferers鈥� violent mood swings. Roughly 10 per cent of patients
eventually kill themselves during a depressive episode.
Now Robert Lenox at the University of Pennsylvania has discovered why lithium
is effective as a long-term treatment. The drug works by preventing gradual
changes in the hard-wiring of the brain鈥檚 emotional centres. This is the first
time that anyone has explained why lithium works as a long-term treatment.
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A single dose of lithium has no effect on someone suffering an episode of
manic depression. But long-term treatment may eliminate episodes or reduce their
severity. Episodes become more frequent and intense in untreated patients.
The effects of lithium are long-lasting. If patients stop taking their
regular dose it can be several months before they suffer a relapse. 鈥淚t鈥檚 only
important in the development of the disease,鈥� says Lenox.
So Lenox decided to see if lithium might be involved in neural
plasticity鈥攖he ability of brain cells to rewire the connections between
them. By studying the drugs鈥� effects in tissue cultures and animal brains, he
found that lithium lowers levels of a protein called MARCKS, which binds to
actin, a protein found in the membranes of brain cells.
Lenox believes that lithium displaces magnesium in an enzyme responsible for
transcription of the MARCKS gene. 鈥淚t could be manic depressives have
too much MARCKS because of a faulty gene,鈥� he says.
The more MARCKS in the brain, the more flexible the cell membranes are and
the more easily the cells can change or grow. Lenox also discovered that
standard antidepressants, which don鈥檛 work for bipolar disorder, had no effect
on MARCKS.
Lenox now wants to develop more specific ways of inhibiting the production of
MARCKS that have fewer side effects than lithium.