NEUROSCIENCE:
Prozac Treatment of Newborn Mice Raises Anxiety

The U.S. Food and Drug Administration this month ordered drugmakers to put strong new labels on serotonin-based antidepressants, warning that they may raise the risk of suicidal behavior in children. Now a study by researchers at Columbia University indicates that fluoxetine (the generic name for Prozac), paradoxically, seems to raise anxiety levels in newborn mice.

The study, published on page 879 of this issue, "suggests that fluoxetine and probably other SSRIs [selective serotonin reuptake inhibitors] may have additional unexpected problems," says Miklos Toth, a pharmacology professor at Cornell University's Weill Medical College in New York City. Some scientists caution, however, that the mice in this study were at a much younger developmental age than children likely to be treated for depression.

Fluoxetine is the oldest of the SSRIs and the only one approved for pediatric use. It operates primarily on the serotonin transporter (5-HTT), which is responsible for helping neurons vacuum back up excess serotonin that they have released. By blocking the transporter, the drug enables serotonin to linger in synapses, making more available to be taken up by target receptors.

Previous animal research had shown that in early life serotonin acts as a growth factor in the brain, modulating nerve cell growth, differentiation, and migration. Interfering with this function can have behavioral consequences. Mice who have had their serotonin transporters genetically knocked out--and thus reuptake disrupted--exhibit increased depression- and anxiety-related behaviors.

The Columbia researchers, led by psychobiologist Mark S. Ansorge, sought to determine whether fluoxetine would have the same effect as knocking out the two copies of the transporter gene. They bred sets of mice with one, two, or no functioning copies of the 5-HTT gene. Then they randomly gave either saline injections or fluoxetine--at doses equivalent to therapeutic ones for humans--to newborn mice between 4 and 21 days old in each group. Nine weeks after the last injection, mice were given tests that revealed their emotional states.

Chemical imbalance. Mice treated with Prozac as newborns showed reduced exploratory behavior when tested on an elevated maze. CREDIT: JOHN WOOD

The authors conclude that disruption of 5-HTT early in brain development affects the development of brain circuits that deal with stress response. Co-author René Hen explains that when serotonin reuptake is blocked, the increased levels in the synapse lead to "abnormal activation [of] a bunch of receptors" during a critical phase of development. "Overstimulation could result in abnormal development" in areas of the limbic system, he says.

The scientists believe that their work could help explain a noteworthy finding announced last year from a longitudinal study of New Zealanders (Science, 18 July 2003, p. 386): that people with a polymorphism that reduced their 5-HTT activity were more likely than others to become depressed in response to stressful experiences.

Another implication, of course, is for those exposed to SSRIs at a tender age. The authors say the period of brain development studied in the mice corresponds roughly to the last trimester of pregnancy through age 8 in humans. So, they conclude, "the use of SSRI medications in pregnant mothers and young children may pose unsuspected risks of emotional disorders later in life."

Toth notes that in contrast to humans, a partial deficit (having one defective 5-HTT allele) is not enough to adversely affect mice's behavior. So "it is possible that humans are more sensitive than rodents to the adverse effect of fluoxetine." But he agrees with Harvard child psychiatrist Timothy Wilens, who says that the "very early exposure calls into question the generalizeability [of these results] to children." Columbia psychiatrist John Mann, who was not associated with this study, adds: "This has nothing to do with the issue of SSRIs in kids because they get the SSRI well after the equivalent period in this study."

Mann says, however, that "this is an important study" because it shows that even transient loss of transporter function during a critical period in brain development may lead to depression in adulthood.