Prozac triggers increase in aggression in mice

Emma Young, San Diego

The anti-depressant Prozac causes a dramatic increase in aggressive behaviour in mice the day after the drug is administered, US researchers have found.

Prozac, or fluoxetine, has been associated with isolated reports of suicide and crimes of violence in people. "But this has been difficult to study in other animals," says George Wagner of Rutgers University. "Our findings represent the first demonstration that the drug can actually increase defensive aggression in other species."

When the mice received alcohol along with Prozac, their aggression scores on the following day were even higher. "Our data indicate a potentially serious interaction between Prozac and alcohol," Wagner adds.

However, the implications for the millions of people who take Prozac worldwide are unclear, Wagner says. The mice in his study were given a single, very high dose of the drug. The effects of regular, much smaller doses over a long period of time might be different, he says.

John Mann of Columbia University, US, says: "This is a very interesting observation. But individual case reports of people exhibiting suicidal or aggressive behaviour have been found with practically every psychotropic medication. Every double blind study of people taking Prozac to date has not indicated an association with increased aggression."

Protruding object

Mann's team investigated the effects of Prozac alone, alcohol alone, and Prozac plus alcohol on two types of aggression: offensive and defensive.

"Offensive would be two males fighting over territory, for example," says Mann. "Defensive involves an aggressive response to a painful or frustrating stimuli."

Mice in the three drug groups were put in a cage together, to investigate offensive aggression, or given a mild electric shock, to investigate defensive aggression. In the second case, the mice's tendency to bite an inanimate object protruding into their cage in response to the shock was measured.

Prozac is thought to work by prolonging the presence of the neurotransmitter serotonin in the brain. Low levels of serotonin are associated both with alcohol consumption and with aggression. The team expected that alcohol alone would boost aggression - and that this effect would be counteracted by an accompanying dose of Prozac. Prozac alone was expected to decrease aggressive behaviour.

On the day the drugs were given, that was exactly what they found. But on the second day, they found that defensive aggressive behaviour in mice that had received Prozac alone rocketed by between 15 and 20 per cent, compared with baseline measurements. In mice that had also received alcohol, it increased by between 20 and 25 per cent. There was no effect on offensive aggressive behaviour.

Impulsive behaviour

Prozac causes a decrease in levels of a serotonin metabolite called called 5-hydroxyindoleacetic acid (5HIAA). Low levels of 5HIAA have been associated with suicides, especially violent ones, as well as with other violent or impulsive behaviour.

Wagner's team recorded the lowest levels of 5HIAA on the day after the mice received the Prozac.

"We found lower levels of 5HIAA in our mice long after they received fluoxetine," says Wagner. "That may help explain their increased aggression."

The team now plans to investigate the effects of chronic Prozac use on aggression in animals.

Wagner presented his research at the Society for Neuroscience annual conference in San Diego.

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