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A complicated link between aggression and antidepressant drugs

by Angela Herring of news@Northeastern

Nearly half a mil­lion chil­dren in the U.S. take anti­de­pres­sants. In 2007, the Cen­ters for Dis­ease Con­trol and Pre­ven­tion released a warning for flu­ox­e­tine, one of the most highly pre­scribed psy­chi­atric med­ica­tions. The drug’s pri­mary com­pound seemed to be causing a host of neg­a­tive side effects in a subset of the young users.

“It’s hap­pening,” said Rich Mel­loni, pro­fessor of psy­chology and director of the Pro­gram in Behav­ioral Neu­ro­science in the Col­lege of Sci­ence. “Kids are becoming irri­tated, aggres­sive, impul­sive, agi­tated, hos­tile. So you ask the ques­tion: Why?” As behav­ioral neu­ro­bi­ol­o­gists, Melloni’s team is using ado­les­cent animal models to gain an under­standing of why these neg­a­tive side effects occur. Their find­ings are pub­lished in this month’s issue of the journal Behav­ioral Neuroscience.

First, he and his research team admin­is­tered reg­ular doses of flu­ox­e­tine to healthy ado­les­cent ham­sters. The ani­mals received either a low, mod­erate or high dosage, equiv­a­lent to what a human ado­les­cent would receive to treat con­di­tions such as anx­iety, depres­sion or obsessive-​​compulsive dis­order, respectively.

They then observed the ham­sters’ behavior when pre­sented with an intruder — or the mere scent of an intruder — in their cage. Ham­sters that received the low dosage con­sis­tently demon­strated sig­nif­i­cant increases in aggres­sive behavior.

Next the researchers looked at the ham­sters’ brains. They were sur­prised by what they found.

Mel­loni said that when a mol­e­cule called vaso­pressin is present at high levels in the brain, the aggres­sion system works in over­drive. Another mol­e­cule, sero­tonin, has the oppo­site affect.

“Think of sero­tonin as your brake for aggres­sion and vaso­pressin as your gas,” said Mel­loni. If you want to go fast, he said, you can press on the gas, ease off the brake, or engage in a com­bi­na­tion of the two. Flu­ox­e­tine, so to speak, is designed to push on the brake in order to help people deal with the symp­toms of depres­sion. But the aggres­sive ham­sters’ brains had prob­lems with both their gas pedals and their brakes.

Flu­ox­e­tine is a “sero­tonin reup­take inhibitor,” meaning that it increases sero­tonin levels by pre­venting the mol­e­cule from being reab­sorbed by the body. Lower sero­tonin has been linked to depres­sive symp­toms in some patients.

But other neu­ro­log­ical sys­tems also con­tribute to depres­sion, such as the mol­e­cules dopamine and nor­ep­i­neph­rine. When these sys­tems are impaired, patients can show sim­ilar symp­toms as if they had an impaired sero­tonin system.

“Take that kid that presents with the same symp­toms, but he has a dopamine or nor­ep­i­neph­rine problem,” said Mel­loni. “But when you give him a sero­tonin drug, he may get aggres­sive, he may get worse.”

Melloni’s find­ings sug­gest that the chil­dren who expe­ri­ence the aggres­sive side effects of flu­ox­e­tine may not have begun with an impaired sero­tonin system at all. “There’s the like­li­hood,” said Mel­loni, “that by virtue of the fact that our clin­ical diag­nosis is not based in neu­ro­bi­ology, but rather in symp­to­mology, that we may be giving kids a sero­tonin drug inappropriately.”

The next step in the research is to per­form the same tests on ham­sters with “ruined” sero­tonin sys­tems. “Then let’s give these impaired ham­sters [flu­ox­e­tine] and see if they become aggres­sive,” Mel­loni said. “My guess is they are not going to be.”

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