Researchers have identified the mechanism by which some antidepressants stimulate the formation of new brain cells, an insight that could lead to improved drugs.

Antidepressants combat depression by increasing levels of serotonin in the brain. But they can also help by stimulating the formation of new brain cells, a process called neurogenesis, which plays an important role in memory.

Depressed patients are thought to release greater amounts of glucocorticoid stress hormones, such as cortisol, which reduce neurogenesis, causing symptoms such as impaired memory and low mood. Previous research has shown that antidepressants block the effect of the glucocorticoid hormones and restore neurogenesis, but the mechanism by which this happens was unknown.

Now, scientists at King's College London in the UK have found that antidepressants affect neurogenesis by interacting with the glucocorticoid receptor, leading to expression of key genes needed for stem cells to differentiate and proliferate. The group exposed cultures of human stem cells from an area of the brain called the hippocampus to a range of antidepressants, including sertralene, which is marketed as Zoloft by Pfizer.

'We've seen that the glucorticoid hormones and the antidepressants activate the same protein, called the glucorticoid receptor,' explained Christoph Anacker, who led the study group. 'But they activate this receptor in very different ways'. Glucocorticoids decrease neurogenesis, whereas antidepressants increase it.

The researchers say that their work provides a model for depression in the laboratory and a platform for drug discovery to develop antidepressants that are more effective and lead to fewer side effects. 'It demonstrates that antidepressants have effects which go beyond simply increasing the transmission of serotonin in the brain,' says Daniel Smith, an expert in clinical psychology at Cardiff University, UK. 'Current antidepressants have quite a broad range of effects and interact with a large number of different receptors in the brain.' The work could lead to new drugs that target the glucocorticoid receptor more specifically, he adds.

By 2020, depression is expected to be the second most damaging disease globally as measured across a range of indicators. One in five women and one in 10 men are likely to experience the disease at some point.

References

C Anacker et al, Mol Psychiatr, 2011, DOI:10.1038/mp.2011.26