If the Prozac doesn't work...

September 19, 2003

...don't lose hope. A new generation of tailor-made antidepressants is being developed using cutting-edge genetics, writes Samuel Barondes

Philip became severely depressed after losing his girlfriend and being laid off from work. The -year-old computer programmer attempted suicide by washing down a dozen sleeping pills with a pint of gin. He was given Prozac for the first time while he was in hospital. After a few weeks, his depression lifted and his mood returned to normal. Now Philip, like millions of other people around the world, takes a pill every morning to prevent the gloom coming back. At his latest quarterly visit to our clinic at the University of California, he happily reported: "I'm at the top of my game." Prozac has become a mainstay of his life.

The drug was introduced as a treatment for severe depression in 1987 by the pharmaceutical company Eli Lilly. It targeted a single brain chemical called serotonin and avoided many of the undesirable side-effects that had plagued earlier antidepressants. The results were far better than the company had hoped for, and Prozac fast became one of the world's bestselling drugs. Its success spawned the development of a number of related drugs such as Cipramil, Faverin, Lustral and Seroxat.

These drugs were no universal remedy, however. In fact, about a third of depressed people get no relief from either Prozac or its competitors.

Others, who do get some benefit, quit taking the drugs because of undesirable side-effects such as loss of sexual interest. Because of these limitations, drug companies have continued to try to find more effective products, using the same trial-and-error approach to test new types of chemicals that worked in the past. Yet they have little to show for an investment of billions of dollars. None of their variations has proved a panacea. None is significantly better than Prozac.

But there is hope. A new strategy for tackling depression is taking shape.

In future, some antidepressant drugs will be genetically targeted on individuals. If the approach during the Prozac generation was to find a blockbuster of the one-size-fits-all variety - a drug that could be prescribed for everyone - the next generation will be about tailor-made drugs.

This approach is based on evidence that severe depression often runs in families but that the precise nature of people's genetic vulnerability to the condition can vary from family to family. Although this mood disorder is common, affecting at least 10 per cent of women and 5 per cent of men at some time in their lives, those of us who have an affected parent or sibling are between two and five times as likely to be stricken, depending on the particular familial genetic vulnerability.

Not long ago, the observation that depression runs in families sparked explosive debates between those who attributed it to learnt familial patterns of behaviour and those who took it as evidence of an inherited predisposition. Now most psychiatrists agree that nurture and nature both play a part. They also agree that the best next step in studying heredity's role in depression is to identify the alternative forms of the genes, or gene variants, that transmit this propensity.

These gene variants, which arose during the course of human evolution by random changes in DNA structure, are responsible for many of our differences, including our individual appearance, talents and vulnerability to particular illnesses. Until recently, their existence could only be inferred. But new techniques of DNA analysis are making it possible to identify specific gene variants that contribute to particular attributes.

Instead of arguing about the relative importance of nature and nurture, we are searching for those gene variants that contribute to a predisposition to depression.

One way to find them is to compare the DNA of family members who have depression with those who do not. If only those with the illness have a certain variant of a particular gene, the correlation suggests that this may play a role. If the same variant is also found only in the affected members of a sufficiently large number of other families, this constitutes proof that the correlation is significant.

Scientists around the world are studying the DNA of people with depression to try to identify relevant genetic variations. And there have been some reports of success. Scientists at London's Institute of Psychiatry have correlated vulnerability to depression with a variant of the gene that makes a protein that controls how long serotonin works in the brain.

Working with colleagues at the University of Otago in New Zealand, they have found that people with a common variant of this gene are especially likely to become depressed if hit by recurrent stressful life events, such as romantic setbacks and loss of a job - the sorts of problems that triggered Philip's suicidal depression.

Another gene variant with a strong correlation with vulnerability to depression has recently been reported by a group from the University of Pittsburgh. They confined their attention to a group of high-risk families in which at least one member had recurrent episodes of severe depression that had started by the age of 25. They found that women in these families who inherited a particular variant of a gene called CREB1 - which controls many brain cell functions - were more likely than those without to become depressed. To their surprise, males with the same variant were unaffected.

It seems that some aspect of being female - be it hormonal, psychological or otherwise - works in concert with this gene variant to make them vulnerable to the mood disorder.

These two genetic discoveries are just a start. Other studies indicate that there are many gene variants that influence susceptibility to depression.

In coming years, dozens will be identified, and as this information accumulates, inexpensive DNA tests will help pinpoint which variants are at work in depressed people. Like other specialists, psychiatrists will come to rely on genetic testing to help categorise patients and to guide the treatments they prescribe to each individual.

The treatments themselves will also be affected. Identification of a gene variant that influences the risk of depression, such as a variant of CREB1, brings to the table a great deal of knowledge about the protein that the gene controls, how it functions in the brain, and its interaction with other brain proteins. This will lead to the discovery of novel targets for antidepressant drugs, some of which will likely prove more effective in one group of individuals than in others. This is easier said than done, but it is likely that there will be great progress of this type over time.

Genetic studies will also improve the use of currently available drugs.

People have gene variants that influence how their bodies handle these pharmaceuticals. For example, about 5 per cent of people of European origin have a pair of defective variants of a gene that makes an enzyme called 2D6. This enzyme controls the breakdown of Prozac and some other antidepressants. People with the defective variants of this gene suffer from side-effects due to large amounts of the undegraded drug building up in their bodies.

The practical upshot of this research will unfold over the next few decades. As the many gene variants that influence vulnerability to depression are discovered and DNA tests for these and variants linked to side-effects become available, psychiatrists will be better able to decide which drugs to use on patients - and which to avoid. Those prone to severe depressions can look forward to better and more appropriate pharmacological and psychological treatments based on information about their particular genetic and psychological profiles. Many depressed patients, such as Philip, respond well to current treatments. Now there is new hope for those who do not.

Samuel H. Barondes is director of the Center for Neurobiology and Psychiatry at the University of California, San Francisco. He is also author of Better than Prozac: Creating the Next Generation of Psychiatric Drugs , published by Oxford University Press, £16.99.

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