Discovery of pathway leading to depression reveals new drug targets

December 06, 2012

Scientists have identified the key molecular pathway leading to depression, revealing potential new targets for drug discovery, according to research led by King's College London's Institute of Psychiatry. The study, published today in Neuropsychopharmacology, reveals for the first time that the 'Hedgehog pathway' regulates how stress hormones, usually elevated during depression, reduce the number of brain cells.

Depression affects approximately 1 in 5 people in the UK at some point in their lives. The severity of symptoms can range from feelings of sadness and hopelessness to, in the most severe cases, self-harm or suicide. Treatment for depression involves either medication or talking treatment, or usually a combination of the two.

Recent studies have demonstrated that depression is associated with a reduction in a brain process called 'neurogenesis'- the ability of the brain to produce new brain cells. However, the pathway responsible for this process has, until now, remained unknown.

In this study, Dr Christoph Anacker from King's Institute of Psychiatry and his team studied human stem cells, which are the source of new cells in the human brain, to investigate the effect of stress hormones on brain cell development. The study was funded by the National Institute for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King's College London and the Medical Research Council UK.

Stress hormones, such as cortisol, are generally elevated in stress and depression. The team studied stem cells in a laboratory and found that high concentrations of cortisol damaged these stem cells and reduced the number of newborn brain cells. They discovered that a specific signalling mechanism in the cell, the 'Hedgehog pathway', is responsible for this process. Then, using an animal model, the team confirmed that exposure to stress inhibited this pathway in the brain.

Finally, in order to test the findings, the researchers used a compound called purmorphamine, which is known to stimulate the Hedgehog pathway. They found that by using this drug, they were able to reverse the damaging effects of stress hormones, and normalise the production of new brain cells.

Dr Christoph Anacker, lead author of the study from King's Institute of Psychiatry says: "By decreasing the number of new-born cells in the human brain, stress hormones damage many important brain functions and may contribute to the development of depression after a period of chronic stress. By inhibiting the Hedgehog signalling pathway, stress hormones reduce the development of immature 'stem' cells into mature 'brain' cells."

Dr. Anacker continues: "With as much as half of all depressed patients failing to improve with currently available treatments, developing new, more effective antidepressants still remains a great challenge, which makes it crucial to identify new potential mechanisms to target. The discovery of antidepressants has so far been mainly by serendipity. Developing a drug with a defined effect on the brain, such as increasing the number of new-born brain cells, and with a clear target, such as Hedgehog signalling, will allow us to develop much more specific antidepressants in the future."
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Notes to editors:

For a copy of the paper or interviews with the author, please contact Seil Collins, Press Officer, King's College London, Institute of Psychiatry.

Paper reference:

Anacker, C. et al. 'Glucocoticoid-related molecular signalling pathways regulating hippocampal neurogenesis' Neuropsychopharmacology (2012).

Funding:

The study was funded by the National Institute for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King's College London and the Medical Research Council UK with additional funding from a Commission of European Communities 7th Framework Programme Collaborative Project Grant, a NARSAD Young Investigator Award, Research Councils UK, Italian Ministry of Health, Regione Lombardia and the Italian Ministry of Health.

About King's College London:

King's College London is one of the top 30 universities in the world (2012/13 QS international world rankings), and was The Sunday Times 'University of the Year 2010/11', and the fourth oldest in England. A research-led university based in the heart of London, King's has more than 24,000 students (of whom more than 10,000 are graduate students) from nearly 140 countries, and more than 6,100 employees. King's is in the second phase of a £1 billion redevelopment programme which is transforming its estate.

King's has an outstanding reputation for providing world-class teaching and cutting-edge research. In the 2008 Research Assessment Exercise for British universities, 23 departments were ranked in the top quartile of British universities; over half of our academic staff work in departments that are in the top 10 per cent in the UK in their field and can thus be classed as world leading. The College is in the top seven UK universities for research earnings and has an overall annual income of nearly £525 million (year ending 31 July 2011).

King's has a particularly distinguished reputation in the humanities, law, the sciences (including a wide range of health areas such as psychiatry, medicine, nursing and dentistry) and social sciences including international affairs. It has played a major role in many of the advances that have shaped modern life, such as the discovery of the structure of DNA and research that led to the development of radio, television, mobile phones and radar.

King's College London and Guy's and St Thomas', King's College Hospital and South London and Maudsley NHS Foundation Trusts are part of King's Health Partners. King's Health Partners Academic Health Sciences Centre (AHSC) is a pioneering global collaboration between one of the world's leading research-led universities and three of London's most successful NHS Foundation Trusts, including leading teaching hospitals and comprehensive mental health services. For more information, visit: www.kingshealthpartners.org.

The College is in the midst of a five-year, £500 million fundraising campaign - World questions|King's answers - created to address some of the most pressing challenges facing humanity as quickly as feasible. The campaign's five priority areas are neuroscience and mental health, leadership and society, cancer, global power and children's health. More information about the campaign is available at www.kcl.ac.uk/kingsanswers.

King's College London

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