Mice lose the blues quickly with experimental drug

Speedy relief from depression may one day come in the form of a new family of compounds. Two new antidepressant molecules start to work in just days — not the weeks or months that current antidepressants take to kick in, a study in mice suggests.

“It’s a totally new and, for me, a very unexpected way to produce rapid antidepressive action,” says neuroscientist Scott Thompson of the University of Maryland School of Medicine in Baltimore.

The results, published October 29 in Molecular Psychiatry, are the latest in the intense hunt for drugs that can ease depression quickly. In 2000, the hallucinogenic drug ketamine was discovered to ease depression in just hours, a finding that encouraged the search for fast-acting antidepressants that would lack ketamine’s side effects. A paper published October 15, also in Molecular Psychiatry, reports that a ketamine-like compound called lanicemine eased depressive symptoms in people without causing severe side effects.

Ketamine and lanicemine target a protein in the brain called the NMDA receptor. But the newcomers take a different approach. These compounds latch on to a protein called the serotonin 2C receptor, which, like the NMDA receptor, sits on the outside of nerve cells in the brain.

Neuroscientist Mark Opal of the University of Chicago and colleagues tested two such compounds on mice conditioned to show signs of depression, such as ignoring sugar water offered to them. After just five days of treatment, the mice experienced a turnaround, once again preferring sugar water, for instance. Animals on the antidepressant citalopram (sold as Celexa) showed no improvement during this time.

Five days was the earliest that Opal and his colleagues tested the mice. “It’s possible that these compounds could work one or two days after treatment,” he says.

Although the compounds latch on to a protein that detects the chemical messenger serotonin, their therapeutic heft probably comes from a different messenger: dopamine. The serotonin 2C receptor sits on neurons that churn out dopamine, a molecule involved in motivation and pleasure. Opal and his team think that these new compounds work by boosting dopamine in key parts of the brain.

Because they work differently, these new compounds might ultimately form the basis of combination therapy. Pairing the compounds with drugs such as Prozac or Paxil, which change brain levels of serotonin, might be a fast, effective way to treat depression, Thompson speculates. He cautions, though, that it’s too soon to say whether the compounds will work in people.