06 September 2007

Serotonin Receptor Agonists: Better than SSRI's?

Serotonin has been shown to be important in depression and anxiety. But what is the best "serotonin approach" to treating depression? SSRIs (selective serotonin reuptake inhibitors) such as Prozac are generally effective, but may take several weeks to achieve maximum effect. Another approach is for a drug to directly stimulate serotonin receptors--serotonin (5HT) agonists.

Recent research into 5HT4 receptor agonists, using rats as subjects, appears to promise faster and more efficacious serotonergic antidepressants.
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.

The important thing to remember is that although some humans may behave like rats, humans are not rats. Research on models of depression in rats may not transfer directly to good results in humans. Drug safety in humans and drug safety in rats are certainly not the same, either.

In an area of therapeutics such as depression, regulatory agencies will likely require extensive clinical studies before approval. It is important to point out, however, that depression is a potentially fatal disease. Any drug that promises rapid emergence from deep clinical depression, and which is also safe for short to intermediate term use, may find an important function in the treatment of depression--even if it is not approved for long term use.

This is an interesting result of the study:
They found that the action of the drugs on the 5-HT4 receptor "deeply modified" serotonin transmission by enhancing firing of dorsal raphe neurons in the hippocampus. In addition, three days of treatment also significantly promoted neurogenesis in the subgranular zone of the dentate gyrus of the hippocampus, an effect normally seen after a minimum of two weeks of treatment with classical antidepressants or SSRIs.

If depression kills neurons, and effective antidepressant therapy promotes new neuron growth, the new approach to stimulating serotonin receptors appears to do its formative work on neuronal stem cells more quickly than SSRIs.

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