Antidepressant Use Early On Affects Mice

In an experiment in mice, researchers have found that treatment with an antidepressant early in life increases the appearance of depression and anxiety-like symptoms in adulthood.

The researchers gave daily doses of fluoxetine, better known by the brand name Prozac, to mice from four days after birth until their normal weaning age of 3 weeks -- a period that roughly corresponds in humans to a fetus in the third trimester of pregnancy up to early childhood.

At 12 weeks -- adulthood for mice -- the test animals showed signs of abnormal behavior.

The study, which will be published this week in the journal Science, is seen as a starting point for determining the long-term effects of prescribing antidepressants for pregnant mothers and young children.

“It underscores that there is really very little known about how medications that affect the central nervous system affect child development,” said Dr. Victoria Hendrick, a professor of psychiatry at UCLA who treats and studies depression in pregnant women.

Prozac, a widely prescribed antidepressant, is part of a class of drugs that enhance the action of the brain chemical serotonin, which is known for its role in regulating mood.

Serotonin also serves as a growth factor, helping organize neural circuitry in a maturing brain.

The researchers suggest in the study that manipulating serotonin levels in the young mice altered normal brain development. One place that might have been affected was the prefrontal cortex, an area that helps regulate emotions and continues developing into early adulthood.

The drugs could be “altering the maturation of brain areas that are responsible for dealing with novelty and stress,” said Dr. Jay Gingrich, a psychiatrist and the paper’s senior author.

Diagnosing depression and anxiety in mice requires some creativity.

Compared with a control group, the adult mice that received Prozac early on waited longer to enter a brightly illuminated area for a food pellet. They also took more time to flee from a chamber that delivered intermittent electric shocks through the floor. And they explored less when placed in a simple maze.

Experts cautioned that mice were at best an imperfect model for studying human brain chemistry.

“The mouse has a rudimentary prefrontal cortex,” said Paul Plotsky, a neuroscientist at Emory University in Atlanta. “It is not nearly as complex as what you see in a rhesus monkey or a human.”

In addition, a mouse metabolizes drugs much faster than a human does.

But using human subjects to study the long-term effects of antidepressants in children would be difficult, since a controlled study would require following the participants for a decade or more. More likely, epidemiological studies will be used to gather data.

Currently, antidepressants such as Prozac, which belong to a class of drugs known as selective serotonin reuptake inhibitors, are regularly prescribed to pregnant women.

Studies of their use have focused on short-term safety.

No evidence has turned up linking the drugs to birth defects. One study concluded that certain SSRIs, taken by mothers in the third trimester, increase the risk of perinatal complications such as respiratory distress. Another found motor skills slightly deficient in the young children of mothers who had taken the drugs during pregnancy.

Those risks, however, are often minor compared with the risk an unstable mother poses to a fetus or infant. One study showed that anxiety in pregnant women could increase levels of a hormone that has been linked to premature birth.

Some psychiatrists require pregnant women and their partners to sign a release form before using antidepressants.

“I inform them about the risk -- the unknown risks and what we know,” said Dr. Regina Casper, a psychiatrist at Stanford University. “I say: ‘I cannot give you a recommendation. You need to decide for yourself.’ ”

This study is unlikely to affect clinical practice, Casper and others said.

Prescriptions of SSRIs for children are already under fire, with the Food and Drug Administration recently requiring “black box” labels on antidepressants warning of an increased risk of suicide in minors. In addition, there are few efficacy studies showing that SSRIs work in children.

In 2002, U.S. doctors wrote 2.7 million antidepressant prescriptions for children up to 11 years old and 8.1 million for children between the ages of 12 and 17, according to the FDA.