Studies with rats have revealed the potential in an entirely new class of antidepressants that take effect after only days of treatment versus the weeks required for current drugs.

The researchers, Guillaume Lucas and colleagues, said that they hope their findings will spur development of such new antidepressant drugs so that clinical testing can begin quickly.

Depression can be treated by enhancing the action of the neurotransmitter serotonin in the brain. Such neurotransmitters are the chemical signals that one neuron launches at another to trigger a nerve impulse in the target neuron. The most widely used antidepressants—called selective serotonin reuptake inhibitors (SSRIs)—work by inhibiting recycling of serotonin after a nerve impulse, increasing its concentration in the connections between neurons.

However, a different class of drugs exists that directly enhances nerve impulses of serotonin neurons. In their experiments, Lucas and colleagues tested in rats the effects of two such "serotonin receptor agonist" compounds, called RS 67333 and prucalopride, that target serotonin type-4 receptors.

In initial experiments, they compared the two drugs with the widely used SSRI citalopram in a test of the effectiveness of these drugs on a measure of antidepressant activity in rats. In this test, rats are forced to swim, and the time it takes for them to give up and become immobile is determined. Both of the serotonin receptor agonists strongly reduced this time of immobility, indicating an antidepressant action.

In further studies, the researchers found that only three days of treatment with the serotonin receptor agonists induced antidepressant-related changes in the brains of the animals that were only achieved after weeks of treatment with SSRIs. For example, the serotonin receptor agonists triggered changes in neuronal activity associated with antidepressant properties and also enhanced generation of new brain cells in the hippocampus—a beneficial effect of SSRIs on depression.

The researchers also found that the serotonin receptor agonists quickly and effectively alleviated symptoms of chronic depression in the rats. In one such rat model of chronic depression, mild stress has been shown to reduce intake of sugar water—a behavior alleviated by weeks of treatment with SSRIs. The researchers found that one of the serotonin receptor agonists took effect after only three days and appeared to completely alleviate the symptom after a week.

"Overall, the results presented here show a clear potential for [serotonin receptor] agonists as putative antidepressants with a rapid onset of action," wrote the researchers. "According to the different experimental models studied, they may act four to seven times more rapidly than classical [antidepressants] and possibly with greater efficacy. Presently, RS 67333 and prucalopride are virtually the only available selective [serotonin receptor] agonists that are able to cross the blood-brain barrier; we hope that this study may contribute to the development of new compounds, so that clinical trials can be conducted in the near future," they wrote.

Researchers, led by Dr. Guillaume Lucas under the supervision of the late Dr. Guy Debonnel, include Guillaume Lucas of Université McGill and Université de Montréal in Montréal; Vladimir V. Rymar of of Université McGill in Montréal; Jenny Du of Université de Montréal in Montréal; Ouissame Mnie-Filali of Université Claude Bernard Lyon 1 in Lyon; Christina Bisgaard of Aarhus Psychiatric University Hospital in Aarhus; Stella Manta of Université McGill in Montréal; Laura Lambas-Senas of Université Claude Bernard Lyon 1 in Lyon; Ove Wiborg of Aarhus Psychiatric University Hospital and OWn Research Aps in Aarhus; Nasser Haddjeri of Université Claude Bernard Lyon 1 in Lyon; Graciela Piñeyro of Université de Montréal in Montréal; and Abbas F. Sadikot and Guy Debonnel of Université McGill in Montréal.

This work was supported by grants from the Instituts de Recherche en Santé du Canada (IRSC/CIHR).

Lucas et al.: "Serotonin4 (5-HT4) Receptor Agonists Are Putative Antidepressants with a Rapid Onset of Action." Publishing in Neuron 55, 712-725, September 6, 2007. DOI 10.1016/j.neuron.2007.07.041.