New Antidepressants Should Target Stress Hormone Effect

New Antidepressants Should Target Stress Hormone Effect

A stress hormone undermines the production of new brain cells, contributing to the development of depression - blocking this effect should be the target of new antidepressant medications, researchers from King's College London wrote in Proceedings of the National Academy of Sciences (PNAS).

The scientists say they successfully used a drug compound to block this harmful effect of stress on cells, and managed to restore the brain's ability to produce an adequate number of new cells (neurogenesis*). If the brain cannot produce new brain cells, or enough of them, the likelihood of developing depression grows significantly.

* Neurogenesis refers to the production of new nerve tissue, or new nerve cells. Brain cells are types of nerve cells.

Depression is a very prevalent and growing mental health problem

Throughout the western world and other industrialized countries, as well as an increasing number of middle-income nations, depression has become a widespread and increasingly prevalent disease.

According to the Centers for Disease Control and Prevention (CDC), about 9.1% of American adults meet the criteria for depression. However, a team from Johns Hopkins Bloomberg School of Public Health found that Americans are over-diagnosed for depression.

A team from Northwestern University reported in JAMA (March 2013 issue) that 1 in every 7 new moms suffers from depression.

The authors of this study say that 1 in every 5 people in the UK has depression at some point in their lives.

The World Health Organization (WHO) estimates that by 2030, depression will be the major cause of the global burden of diseases.

Treatments for depression today fail many patients

Current treatments for depression include talking therapy, medication or both. Self-help books and websites have also been shown to help people with depressive symptoms.

In about 40% of cases, current antidepressant medications do not help relieve symptoms, highlighting the need for more effective treatments.

The brain needs to carry on producing new cells properly

For depression to be treated successfully, the adult brain's ability to carry on producing new brain cells needs to be restored completely.

At molecular level, we know that cortisol levels rise in response to stress. Cortisol, a stress hormone, acts on the glucocorticoid receptor (GR). Scientists still do not know how exactly GR decreases neurogenesis - we need to understand the mechanism.

Lead author Professor Carmine Pariante, said:

"With as much as half of all depressed patients failing to improve with currently available medications, developing new, more effective antidepressants is an important priority. In order to do this, we need to understand the abnormal mechanisms that we can target.

Our study shows the importance of conducting research on cellular models, animal models and clinical samples, all under one roof in order to better facilitate the translation of laboratory findings to patient benefit."

Pariante and team studied animal models before confirming their findings in human blood samples. They started off by studying hippocampal stem cells in humans, the source of new human brain cells. They applied cortisol to the cells to determine what the effect on neurogenesis was. They found that SGK1, a protein, played a major role in mediating the effects of stress hormones on the activity of the GR and neurogenesis.

The researchers measured the effect of cortisol over time and found that higher levels of SGK1 prolong the negative effects of stress hormones on neurogenesis. SGK1 was found to increase and prolong the long-term effect of stress hormones - SGK1 keeps GR active, even after cortisol had been removed from the cells.

The team then used GSK650394, a pharmacological compound (drug compound) that inhibits SGK1. GSK650394 inhibited the detrimental effects of stress hormones, allowing the number of new brain cells to eventually increase.

Finally, the scientists confirmed their findings by studying SGK1 levels in animal models and human blood samples of 25 people without depression.

First author Dr Christoph Anacker, said:

"Because a reduction of neurogenesis is considered part of the process leading to depression, targeting the molecular pathways that regulate this process may be a promising therapeutic strategy. This novel mechanism may be particularly important for the effects of chronic stress on mood, and ultimately depressive symptoms.

Pharmacological interventions aimed at reducing the levels of SGK1 in depressed patients may therefore be a potential strategy for future antidepressant treatments."

Written by Christian Nordqvist
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