Dec 7th 2000
From The Economist print edition
THE Prozac generation may be on to something after all. Research about to be published in the Journal of Neuroscience by Jessica Malberg of Yale University and her colleagues suggests that antidepressants not only relieve the symptoms of depression, they also serve to stimulate the growth of new brain cells.
Nobody really knows how antidepressant drugs achieve their effect, though it is somehow related to the fact that they boost the levels of monoamines—which are a class of neurotransmitters, the molecules that nerve cells use to send signals to other nerve cells. The oldest antidepressants are the monoamine oxidase inhibitors, which were developed several decades ago. These prevent the destruction of a variety of neurotransmitters, notably serotonin, norepinephrine and dopamine. More recently, selective serotonin re-uptake inhibitors have been developed (the best-known being Prozac). These stop that particular neurotransmitter being sucked back into the nerve cell that generated it, so that the message the chemical carries is transmitted for longer than normal. But just how tinkering with monoamine levels takes the edge off despair is unclear. Nor is it known why antidepressants take so long to have their effects—often weeks after the first dose.
One explanation for the delay might be that the drugs are not altering mood directly, in the way that cocaine (a dopamine re-uptake inhibitor) does. Instead, they may be rewiring the neural circuitry. This would take time, and might involve the growth of new nerve cells—a possibility that has only recently been recognised for adult brains.
The idea makes sense, because depression often seems to be associated with a shrinkage of the hippocampus, a part of the brain involved in learning and memory. A recent study using magnetic-resonance imaging, a non-invasive body-scanning technique, found that people who had been seriously depressed for many years had hippocampuses that were 10% smaller than average. Post-mortem counts of brain cells in depressed people seem to back that up.
To test the hypothesis that antidepressants work by correcting this shrinkage of the hippocampus, Dr Malberg and her team treated groups of rats with three different classes of antidepressant. One group had Prozac. Another group got tranylcypromine, a monoamine oxidase inhibitor. A third group was given reboxetine, a drug that affects only norepinephrine.
Each group of rats was given an injection once or twice a day, at doses roughly equivalent to those prescribed to people. In addition, a control group received haloperidol, a drug used to treat mood disorders in schizophrenics. Another control group received no treatment at all. And in order to see if the antidepressants were causing extra brain cells to grow, the researchers also injected their rats with a substance called bromodeoxyuridine. This is absorbed selectively by cells that are dividing at the time of its injection. It thus acts as a label by which newly generated cells can be identified.
Rats killed after only a few days of drug treatment showed no extra cell growth. After several weeks, however, the antidepressant-treated rats had significantly more new cells sprouting in their brains than those in the control groups—and those cells seemed to survive longer than control-group cells. Follow-up studies showed that many of these newly generated cells (which are, initially, unspecialised for any particular job) were turning into nerve cells. Animals who got the schizophrenia drug did not have any more new brain cells than untreated animals.
These results, if
confirmed, would neatly explain the “therapeutic lag” between the
administration of an antidepressant and its beneficial effects. But they also
open up a more startling possibility. Existing mood-altering drugs, especially
those used recreationally rather than clinically, are often accused of killing
brain cells. Drugs that instead stimulate the growth of such cells might be
useful in a range of degenerative illnesses, such as Parkinson’s disease, that
are now hard to treat. Expect more research on the relationship between
neurotransmitter levels and brain-cell growth in the future.