Antidepressants make for sad fish

TAMPA, Fla. — In the fish world, baby is just another word for lunch. So it behooves aquatic larvae to be ever vigilant. Yet those who as embryos or hatchlings encountered water polluted with trace concentrations of an antidepressant are much more likely to become lunch.

Tons of medicine ends up in the environment each year. Much has been excreted by patients. Leftover pills may also have been flushed down the toilet. Because water treatment plants were never designed to remove pharmaceuticals, water released into rivers by these plants generally carries a broad and diverse array of drug residues.

In 2006, a pair of chemists reported that antidepressants downstream of water treatment plants were making it into the brains of fish.

Meghan McGee of St. Cloud State University in Minnesota studies larval fathead minnows. Recently she set out to see whether exposure to specific antidepressants would affect the fish. Fish exposed as embryos or hatchlings to trace concentrations of the antidepressant venlafaxine, marketed as Effexor, didn’t react as quickly as normal to stimuli signaling a possible predator. This laid-back reaction could prove to be a “death sentence,” she observes.

McGee’s is one of many studies probing behavioral impacts on aquatic wildlife from pharmaceutical pollution, especially antidepressants. Emerging data from these studies were reported in Tampa, Fla. November 16-20 at the North American annual meeting of the Society of Environmental Toxicology and Chemistry, or SETAC. Overall, the studies show that antidepressants can impair a fish’s ability to eat, to avoid being eaten — and perhaps even to attract a mate.

“I was surprised how often I was seeing these antidepressants,” recalls Melissa Schultz of the College of Wooster in Ohio, one of the chemists who documented at a SETAC meeting in 2006 that antidepressants reach fish brains. “Pretty much any water sample in the vicinity of a wastewater treatment plant will test positive for some group of antidepressants,” she finds.

The most common ones showing up in water: venlafaxine, bupropion — marketed as Wellbutrin, and citalopram — sold as Celexa. What showed up in fish brains were both the drugs and their metabolites, or breakdown products. “The most common ones we saw were metabolites of Prozac [fluoxetine] and Zoloft [sertraline],” Schultz says. The second most abundant were the parent compounds: Prozac and Zoloft. “So profiles of these drugs in the brain weren’t matching the profiles we were seeing in the water.” Why remains a mystery.

In their new study, the St. Cloud State researchers exposed minnows to venlafaxine alone or as a mix of four antidepressants and quantified how quickly fish reacted to a stimulus signaling a possible predator. For the stimulus, the researchers chose to send a vibration into the fish’s water. “My wife’s cell phone got hijacked for the task,” explains study leader Heiko Schoenfuss. An electronic chip that allowed the phone to vibrate was removed and placed beneath the dish in which each tiny hatchling was placed. Pressure sensors along the sides of fish naturally detect vibrations, which can signal an approaching big fish.

Incubating eggs were exposed to the drugs for five days before hatching, then the larvae spent 12 days in clean water before testing. In another set of experiments, new hatchlings swam in drugged waters for 12 days before encountering the chip’s vibrations. McGee’s team selected antidepressant concentrations for this study based on values that had been measured downstream of water treatment plants.

Only venlafaxine slowed the time it took minnows to recognize and respond to the vibrations. The mix of antidepressants slowed the velocity at which fish fled. When the response time and swimming velocity were accounted for, the new study found that drugged fish reacted slowly to avoid predators. Untreated fish “responded about twice as fast as the pharmaceutically exposed larvae,” McGee says.

That wouldn’t be so bad if predators were comparably slowed by these similarly low concentrations of antidepressants — billionths of a gram per liter of water. But such nanogram concentrations of fluoxetine didn’t slow the speed at which hybrid striped bass scarf down fathead minnows, according to preliminary data reported at this year’s SETAC meeting by Joseph Bisesi Jr. and his colleagues at Clemson University’s Institute of Environmental Toxicology in Pendleton, S.C.

To see what concentrations would affect feeding, Bisesi’s group upped water concentrations to between 10 and 40 micrograms per liter — values 100 to 1,000 times higher than needed to affect minnow-escape responses in the St. Cloud study. Only then did some of the normally aggressive and hungry bass start to lose their voracious appetites.

Each bass was offered four minnows once every three days. Any not eaten in 25 minutes were removed. Prior to drug exposures, young-adult bass quickly devoured prey, sometimes all four within 10 seconds, Bisesi notes. But six days into a 27-day exposure to fluoxetine, several fish in the higher concentration groups began to show behavior changes. Some waited a minute or two before going after their first fish. Some spit a minnow out after capturing it or failed to eat more than two. A few developed severely aberrant swimming patterns — such as hanging vertically in the water or resting at the surface, dorsal fin exposed — as minnows cavorted beneath them.

Many of the antidepressants in these tests work in people by altering levels of serotonin, a neurotransmitter, in the brain. However, Schoenfuss reported at SETAC that fluoxetine also functions like an estrogen — at least in adult male fathead minnows. It triggered the minnows’ production of vitellogenin, a yolk protein normally made only by egg-laying females. The drug also diminished the macho facial bumps and coloration that females prize in their mates.

So clearly these drugs may have multiple modes of action, Schoenfuss says, particularly “once they enter the water and are taken up by nontarget organisms” — like fish. Ironically, his feminized male minnows actually proved more aggressive at guarding nests than did unexposed males. Joanne Parrott of Environment Canada and her colleagues reported at the meeting on a similar boost in males’ nest-protecting aggression among fathead minnows exposed to venlafaxine.

Of course, all these experiments are quite artificial. Explains Schultz: “When a fish is exposed to wastewater, it’s not just getting a dose of antidepressants, it’s also encountering lots of other things” — including other drugs. In the future, she says, “we’ll have to look at how these might all interact.”