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Study reveals new target for antidepressants

By Kate Kelland


LONDON (Reuters) – British scientists using human stem cells say they have found out how antidepressants make new brain cells — a finding that should help drug researchers develop better and more efficient medicines to fight depression.

Previous studies have shown that antidepressants such as tricyclics and selective serotonin reuptake inhibitors (SSRIs) generate new brain cells, but until now scientists had not been clear how they did it.

In a study published in the journal Molecular Psychiatry that used Pfizer’s Zoloft and other antidepressants, researchers from King’s College London’s Institute of Psychiatry found that the drugs regulate the glucocorticoid receptor (GR) — a key protein involved in the stress response.

The study also showed that all types of antidepressant are dependent on the GR to create new cells, the scientists said.

“Having identified the glucocorticoid receptor as a key player in making new brain cells, we will now be able to use this novel stem cell system to model psychiatric illnesses in the laboratory, test new compounds and develop much more effective, targeted antidepressant drugs,” said Christoph Anacker, a doctorate student at the IoP who led the study.

Depression is common, affecting some 121 million people worldwide, according to the World Health Organization. It is among the leading causes of disability worldwide and less than 25 percent of sufferers have access to effective treatments.

Recent studies have demonstrated that depressed patients show a reduction in a process called neurogenesis — the development of new brain cells. Researchers believe this reduced neurogenesis may contribute to the debilitating psychological symptoms of depression, such as low mood or impaired memory.

Anacker’s team used human hippocampal stem cells, the source of new cells in the human brain, to investigate the effects of antidepressants on brain cells in a lab dish.

They treated the cells with Zoloft, known generically as sertraline — an SSRI used to treat depression.

The SSRI class also includes Eli Lilly’s Prozac and GlaxoSmithKline’s Paxil. Carmine Pariante, who worked with Anacker on the study, said the findings would also hold true for a newer class of antidepressants known as serotonin and norepinephrine reuptake inhibitors (SNRIs), which include Pfizer’s Effexor and Eli Lilly’s Cymbalta.

“For the first time in a clinically relevant model, we were able to show that antidepressants produce more stem cells and also accelerate their development into adult brain cells,” Anacker said in a statement about the findings.

“We discovered that a specific protein in the cell, the glucocorticoid receptor, is essential for this to take place,” he explained. “The antidepressants activate this protein which switches on particular genes that turn immature stem cells into adult brain cells.”

Pariante said it might be some time before new types of antidepressants could be developed to the stage of testing in patients, but he reckoned it could happen within five years.

“We have some tools with which we can probe the glucocorticoid receptor but… we don’t yet have a drug which is ready to be tested. What we do have, however, is a specific target on which drug companies… can dedicate their attention,” he said in a telephone interview.

(Reporting by Kate Kelland; Editing by Mike Nesbit)

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