Rapid Onset of Action Seen for Experimental Antidepressants

MONTREAL, Sept. 5 -- Antidepressants that directly enhance serotonin signaling appear to have a much faster onset of action in animal models of depression than selective serotonin reuptake inhibitors (SSRIs), said investigators here.

Rats given one of two serotonin -- (HT₄) agonists -- a new class of drug-showed behaviors and brain changes within three days that were suggestive of antidepressant effects that would take two to three weeks to achieve with an SSRI, reported Guillaume Lucas, Ph.D., of McGill University, and colleagues in the Sept 6 issue of Neuron.

The authors provide "and extensive and convincing data set" suggesting that this new class of molecules is fasting-acting and potentially efficacious, but whether they will see the light of day as therapies for human depression is still unknown, cautioned Ronald S. Duman, Ph.D., of Yale, in an accompanying editorial.

"These agents will require extensive testing in clinical trials for confirmation, because of limitations inherent in rodent models of depression and antidepressant response and because of potential side effects," Dr. Duman wrote.

"It seems likely," he continued "that these new results presented in this report will stimulate efforts to develop safe 5-HT₄ agonists that enter the brain and that can be used to further test this hypothesis in preclinical and ultimately clinical trials that could lead to a much needed novel, rapid, and improved class of antidepressants."

Unlike SSRIs, which interfere with the reuptake, or recycling of serotonin, 5-HT₄ agonists increase the firing of serotonergic neurons, achieving their maximal effect within about three days.

In contrast, SSRIs "increase synaptic levels of 5-HT relatively quickly (hours or days), but there is a delay in therapeutic response (weeks or months) due to the likely requirement for adaptations at both pre- and postsynaptic sites," Dr. Duman wrote.

Dr. Lucas and colleagues first compared the effects of two 5-HT₄ agonists, RS 67333 and prucalopride, with the SSRI citalopram (Celexa) in rats subjected to the forced swim test. The test measures the duration of immobility of the subjects as a surrogate for depression.

They found that both 5-HT₄ agonists significantly reduced the time of immobility by about 50% compared with controls, whereas citalopram reduced immobility time by about 23% (P

"Most notably, libido is decreased in many SSRI-treated patients, and it is possible that 5-HT₄ agonists may not cause similar effects, although this will require further testing," he continued. "Expression of 5-HT4 receptors in the prefrontal cortex and hippocampus is associated with increased learning, memory, and cognition, another potential beneficial effect of 5-HT4 agonists."

Dr. Duman also noted, however, that because 5-HT₄ receptors are also expressed in the gastrointestinal system and the heart, that 5-HT₄ agonists could have unforeseen adverse effects.