BioEd Online

A type of drug has been found that starts working much faster against depression than current medications. Behavioural and molecular tests in rats show that the compounds kick into action in days, rather than weeks.

But the drugs — called serotonin receptor agonists — won't be replacing Paxil (paroxetine) soon. None has yet been approved for treating depression in humans, and some have been scrapped because of concerns over side effects.

But researchers are still keen to pursue them, because the most popular type of antidepressant, called selective serotonin reuptake inhibitors (SSRI), can take up to two months to start easing symptoms. And for one-third of people with depression, they don't work at all.

"This is a very good first step in identifying and potentially having a rapidly acting antidepressant," says Ronald Duman, a drug expert at Yale University in New Haven, Connecticut. "But there's a lot of work to done."

Seratonin sponges

SSRI's such as Prozac have become a household name over the past three decades, garnering many millions of prescriptions every year in adults, children and even pets. The drugs work by stopping neurons from greedily keeping hold of a neurotransmitter called serotonin, so allowing more of the pleasure-providing molecule to reach protein receptors in nearby brain cells.

But in most patients, the drugs take weeks to work, says Guillaume Lucas, who did the work as a graduate student at McGill University in Montreal, Canada. "In major depression you have a real risk of suicide," he says.

This lag is caused by specialized proteins called autoreceptors, which sop up the extra serotonin. After several weeks these receptors get used to the extra serotonin and release the molecule, allowing it to spread to where it is needed to lift mood.

Super recognition

Lucas and his supervisor Guy Debonnel, who died last year, reasoned that serotonin's action could be increased by activating the proteins that recognize it, rather than by boosting the amount circulating between neurons. This could circumvent the early counteraction of autoreceptors, and speed up the effect.

The team found two compounds that did the job — one from a chemical supply company and the other from an abandoned clinical trial for irritable bowel syndrome.

In one test, rats were exposed to stress such as water deprivation, flashing lights and crowding for several weeks, while some received an antidepressant. The researchers then tested them for sugar consumption. Depressed rats, the researchers knew from previous studies, are less likely to partake in sweet treats. The rodents that received an antidepressant were less sugar-shy than controls, and the ones that got the new serotonin receptor agonists regained their sweet tooth a week earlier than those given an SSRI.

Two other behavioural tests in rats showed that the drugs were fast-acting, as did several molecular studies. After three days, rats receiving serotonin receptor agonists showed signs of new neuron growth — another indicator of antidepressant action — whereas the SSRI-treated rats did not. The results are reported in Neuron¹.

Challenges ahead

Although the studies were done in rats, the researchers suggest that serotonin receptor agonists might also be speedier than SSRIs in humans. "We can expect therapeutic benefits to appear four to five times more rapidly," says Lucas, who is now at the University of Montreal.

Lucas, who has patented the idea of melding serotonin receptor agonists with SSRI's, hopes to see clinical trials start as soon as compounds are found that are safe in humans. Sanofi-Aventis, a pharmaceutical company based in Paris, is testing another serotonin receptor agonist as a treatment for dementia, he says.

The study stands out because it looked at several different ways of monitoring depression in rats and found the same answer, says Duman. But he cautions: "It really has to be taken with a grain of salt because these are rodent models, and they're a long way from what could happen in human studies of depression."