Discovery of pathway leading to depression reveals new drug targets
January 7, 2013
Newborn brain cells (red) and their cell nuclei (blue) as well as synaptic markers (green), which are needed for mature cells to communicate with each other (credit: Dr Christoph Anacker)
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 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.
Effect of stress hormones on brain cell development
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 the Centre for the Cellular Basis of Behaviour (CCBB) at 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.
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.
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 normalize 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.”
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.
Comments (7)
by Guest
@Khannea Suntzu
Actually the next news item “Induction of adult cortical neurogenesis by an antidepressant” describes how Big Pharma’s Prozac induces “newly generated neurons” whereas here stimulating the Hedgehog pathway normalizes the production of new brain cells. Not too bad for a 35 year old medicine.
by stevewaclo
While I have not the slightest doubt depression is an all too real malady, perhaps caused by stress induced “chemical imbalance”, I have become convinced over many years it is primarily a situational problem. No medication will produce a long term “cure” for anyone struggling with seemingly insoluble issues in their life, unless they ultimately find ways to deal successfully with those issues. Perhaps the meds may provide brief respite to enable positive action, but it’s all in the fundamentals of one’s life.
Best wishes and Happy New Year all
by Jerry
Studies show medication alone is about as effective as counselling alone for chronic depression. Combined they are extremely effective and the best bet to recovery. It’s just that it takes a lot of courage to admit and fix things and the pills just make you sort of spaced/bland. So many people happily ignore needing to go that extra step (and unfortunately cost) to fix the problem and not just continue to mask it.
by beatriz valdes
I feel that using a drug that makes you change your behaviour long enough, will actually change the way the related neurons behave. One example: a person who is socially deficient, anxious, insecure, takes the appropriate drug long enough to get into a new habit of being social, and enjoying the experience, has a good chance to keep in his or her personality those gains.
by Khannea Suntzu
In the meantime a generation of people in the ‘developed’ world has lost years to over a decade being abused and exploited by a cavalier medical industry. Antidepressant abuse has ruined the lives of millions and damaged their endocrinal health. Will the next crop of pharmological moneymakers be any more trustworthy?
What else have consumers become other than cash cows?
by Paul Edson
Reality prompts the comment; “The scientists and community involved in research must eat.” It costs money to perform the research needed to make ethical and useful medical decisions. Isn’t it best you select the way to make money available as ethically and efficiently as possible? You can seek the money by “free” enterprise or by taxing those involved in free enterprise and having a bureaucracy direct the use of the funds. There is potential for waste and abuse in both processes.
I find it difficult to condemn “big Phara” research with a blanket of distain that also suggests those involved in the research described in this article are not ethical but amoral people simply out for the money.
Improvement of the system needs to be reached by patience and cultural agreement as to how best to proceed in my opinion; acting in the immediacy of anger is usually counterproductive.
by Joe
Boy, you must be smart to know that millions have used these medications and not been helped but rather exploited. I won’t speak on behalf of millions but will say that I have taken an anti-depressant for years and it has helped me immeasurably. I find it so interesting that people that have no idea first-hand how depression affects someone can speak as if they know so much. Most people are unable to imagine what it is like to have depression and go through a long period of time with a poor quality of life.
I also happen to think that most medical professionals are in it to help people rather than exploit them. I know that is why I became a physician.
Overall, I don’t think your comment is helpful in the least.