The Success of Antidepressants Depends on Serotonin Reserves

A new study finds that mice genetically modified to have less brain serotonin aren't as resilient to stress.
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(Photo: Xavier Béjar/Flickr)

(Photo: Xavier Béjar/Flickr)

Treating depression with drugs is a tricky thing. Among the most commonly used and effective antidepressants are a class of drugs called selective serotonin reuptake inhibitors, or SSRIs. Exactly how serotonin and SSRIs combine to work their magic has remained a bit mysterious since the drugs' introduction in the late 1980s. A new study further complicates the issue by suggesting that chronically low levels of serotonin might actually hinder the effectiveness of antidepressants following stressful life events.

Researchers know that depression is, among other things, linked to serotonin deficiencies and what psychologists call psychosocial stress, which can range from social exclusion to enduring poverty. At the same time, researchers know that SSRIs increase levels of serotonin outside brain cells—that's where "reuptake inhibitor" comes from—which makes it easier for one brain cell to send a signal to another. While it's fairly evident that's how SSRIs work against depression, it's less clear how low serotonin levels affect responses to stress or to antidepressants prescribed in the wake of a stressful event.

Researchers Benjamin Sachs, Jason Ni, and Marc Caron put ordinary mice and genetically modified mice—with 60 to 80 percent less brain serotonin—through something of an ordeal: seven straight days of social defeat stress, which in plain English means getting bullied by a bigger, more aggressive mouse. 

To find out, Duke University researchers Benjamin Sachs, Jason Ni, and Marc Caron put ordinary mice and genetically modified mice—with 60 to 80 percent less brain serotonin—through something of an ordeal: seven straight days of social defeat stress, which in plain English means getting bullied by a bigger, more aggressive mouse. Seven days isn't usually enough to have a long-term effect on mice; nonetheless the genetically modified mice spent about half as much time hanging around other mice after getting bullied, indicating that reductions in brain serotonin do increase mice's susceptibility to stress.

To study potential effects of  low serotonin levels on the effectiveness of antidepressants, the team put a different set of ordinary and genetically modified mice through 10 days of social defeat stress, resulting in both groups avoiding social interactions. Next, they treated these mice with the SSRI fluoxetine for three weeks. The ordinary mice returned to healthy mouse social lives, but there was little sign of improvement in the genetically modified, serotonin-deficient mice.

While mice aren't the same as people, the results do suggest new factors that could contribute to scientists' understanding of depression and other mental illnesses, the team writes in Proceedings of the National Academy of Sciences. Combined with the observation that an SSRI didn't help mice with low levels of serotonin recover following a period of stress—getting bullied for days—the results also indicate a need for new strategies beyond SSRIs to treat mental illness, at least in some patients.

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