Research produces strong evidence for a new class of antidepressant drugs

Scientists have shown for the first time that a chemical in the brain called galanin is involved in the risk of developing depression.

And the research, undertaken by a European research team, points to a strong reason to develop drugs that modify galanin functioning as a new class of antidepressant drug.

Galanin is a neuropeptide (a small protein) that was discovered and investigated over 30 years ago by various groups including the Swedish scientist Tomas Hokfelt. He is one of the senior authors of the paper published in the journal PNAS.

Hokfelt and others made the fundamental discovery that neurones can release peptides alongside their classical transmitters and that galanin and noradrenaline are one such pair. Both have long been implicated in pain and stress and therefore depression but in the past it had been difficult to study peptides in humans.

The new research by scientists from Sweden, Hungary and the UK demonstrates that galanin is an important stress mechanism in the human brain that influences how sensitive or resilient people are to psychosocial stress.

Lead author Gabriella Juhasz, who is a Research Fellow at the University of Manchester and the Semmelweis University in Budapest, said: "Our research shows that some versions of the gene coding for galanin protect against the risk of depression and anxiety but only in people who have experienced early life neglect or trauma, or recent adverse events.

"Furthermore, the three genes for the three receptors through which galanin acts also influence the risk of depression in people experiencing early or recent life adversity. Crucially, all the galanin related genes are widely separated on different chromosomes and the odds are stacked against four random genes acting in the same way by chance."

Results from the research indicate that although the results are statistically reliable, galanin effects modify the substantial effects of stress by only a few percent. Indeed the moderate overall genetic influence (about 35%) on depression is likely to be mediated by many small genetic effects interacting with each other and with psychosocial factors converging on stress mechanism in brain.

Co-author Professor Bill Deakin, from the University of Manchester, said: "The findings provide a strong reason to develop drugs that modify galanin functioning as a new class of antidepressant drug. And new drugs are badly needed as almost all commonly prescribed antidepressants act on serotonin and they are often not very effective.

"Our research confirms what previous reports have shown about the variation in the serotonin 'transporter' gene and how it influences the risk of depression. We found that the galanin effects are substantially greater than the effects of serotonin."

The research team also say there is increasing evidence suggesting that depression, obesity, diabetes and Alzheimer's disease may be varying manifestations of shared underlying abnormalities of body metabolism.

"Galanin may be part of this general vulnerability since it has a significant role in appetite and obesity," added Professor Deakin.

Depressive illness is often triggered by life stresses and adverse events in early childhood such as neglect and abuse make people more vulnerable to later depression. Depressive illness also runs in families and variation in genes (DNA) accounts for about a third of the risk of developing Depressive illness.

Despite the application of advanced DNA mapping techniques spanning the whole genome to large numbers of people with and without depression, no definite evidence has been found for any genes whose variation is associated with depression. This is because such studies are too big to record psychosocial stress on every individual and so genetic factors that work through modifying response to stress cannot be detected.

This study used a novel Bayesian network-based analysis to calculate the relevance of gene – stress interactions in depression. Bayes was an English vicar who proposed his famous theorem in the early 18Th century. It was neglected for a century or more and its elaborations are still expanding into to many aspects of understanding risk. The Bayesian approach offers an efficient new way to identify genetic effects in disorders with a strong environmental component.

The study was carried out in two populations, in Manchester and in Budapest, each with more than a thousand people. They provided blood for DNA and information about their psychosocial experiences and psychiatric symptoms. We confirmed the reliability of self-reported experiences and symptoms by interviewing a subset of 260 participants. The fact that the galanin system findings were the same in both countries and the same in men and women confirms their reliability.

More information:
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Provided by University of Manchester