Here's why some people with depression seem unresponsive to treatment

A new study has found that serotonin-deficient brains are more vulnerable to social stress.

According to a Duke study, following exposure to stress, mice genetically deficient in serotonin did not respond to a standard antidepressant, fluoxetine (Prozac), which works by boosting serotonin transmission between neighboring neurons.

The new results may help explain why some people with depression seem unresponsive to treatment with selective serotonin reuptake inhibitors (SSRIs), the most common antidepressant drugs on the market today. The findings also point to several possible therapeutic strategies to explore for treatment-resistant depression.

The results are very exciting because they establish in a genetically defined animal model of serotonin deficiency, that low serotonin could be a contributing factor to the development of depression in response to psychosocial stress and can lead to the failure of SSRIs to alleviate symptoms of depression, said senior author Marc Caron.

In the new study, researchers used a transgenic mouse strain called Tph2KI that has only 20-40 percent of normal levels of serotonin in its brain. These mice harbor an extremely rare mutation that was first identified in a small group of people with major depression.

In the new study, lead author Benjamin Sachs tested the responses of these mice to a type of psychosocial stress: social defeat stress.

The researchers then found that a 3-week treatment with Prozac following the stress exposure alleviated depression-like symptoms in normal mice, but not mutant mice.

Prozac and other SSRIs work by blocking the ability of cells to recapture serotonin, so it makes sense that the drugs would be less effective in animals with abnormally low levels of serotonin to begin with, Caron said.

The study appears in the Proceedings of the National Academy of Sciences.