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Tailoring drugs

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26th Oct 2011
Lynnette Hoffman   all articles by this author

Predicting which patients respond to psychiatric medications would revolutionise treatment, but translating research into clinical practice is proving difficult. Lynnette Hoffman reports.

THERE’S a story Professor Julio Licinio sometimes tells to illustrate the power of personalised medicine. It’s a true one, about three Turkish cousins, all morbidly obese. 

Professor Licinio was working at the University of California in Los Angeles when he heard about a man in Turkey with a genetic mutation that stopped his body from producing leptin, the hormone that signals to the body that it’s full, so it was little wonder that the man was severely obese.

Professor Licinio had already been researching the interaction of leptin between mind and body, and after travelling to Turkey to meet the man and other members of the extended family who shared the mutation, he eventually brought the three relatives to the University of California, Los Angeles (UCLA).

Along with being chronically obese, the cousins had other endocrine-related health problems.

Every day for 10 months the cousins injected themselves with leptin.

The weight melted away.

One of the cousins, the only male of the three, lost more than half his body weight.

He literally flew into LA needing two aeroplane seats, and flew back fitting fine into just one. His body fat dropped from 43% to 10%.

The two female cousins also lost dramatic amounts of weight; more than 40 kg each.

They exercised moderately, but hadn’t restricted their eating at all.

Neural imaging tests showed different regions of their brains activating in response to food stimuli before and after receiving the hormone.

This all occurred in 1998.

But to Professor Licinio it illustrates something that usually takes far longer to achieve – personalised medicine at work, benefiting people in real life. 

He lectures often about the challenge of translating lab work into clinical practice.

But in this circumstance, one family with an extremely rare genetic mutation is receiving a treatment tailored precisely for them, and it’s working.

Maybe Professor Licinio tells this story as a motivator.

For the past 12 years his research has taken a different path, looking at the pharmacogenomics – the study of the impact of genetic variation on medications – of depression.

Now in Australia, he’s the director of the John Curtin School of Medical Research at ANU.

Specifically, he’s trying to understand mechanisms for psychiatric drug response and non-response, working to identify and confirm genes that predict that response, or non-response, as the case may be. 

“The goal is to find out why some people respond to antidepressants and other people don’t, and then use that information to develop treatments,” he says.

“You want to give the right drug to the right person – but there is another clinical problem that I think is even bigger, which is that some people won’t respond to anything at all...

“I remember very vividly one of my patients from many years ago, who had been taking ­Prozac for a few weeks, saying to me, ‘Doctor, why don’t you tell me to have a glass of water every morning, because it would have the same effect’.”

Professor Licinio’s team has had some breakthroughs.

They identified gene variants that affect response and non-response to antidepressants.Their findings were later confirmed by a group in China.

A double-blinded randomised control trial compared treatment response to fluoxetine with the older drug desipramine, chosen because the mechanism was so different to fluoxetine.

Researchers took DNA from all the participants to try to understand the genetic basis to differential responses to antidepressants.

And sure enough, they found specific gene variants that were related more to one drug than to the other.

They’re already working on the next step, sequencing DNA across the whole genome in an effort to find genes that predict both extreme response and extreme non-response to the medication. The findings could be critical.

“Last count I looked, there were 24 antidepressants on the market. Some people respond very well to one or to a few, but not to others, and when you take an antidepressant you have to take it for a few weeks to find out if it’s going to be effective,” Professor Licinio explains.

“For a lot of people, if one course of one drug doesn’t work, they’re already depressed to begin with, so they get even more discouraged and they just get out of treatment and become chronically depressed. So it’s very important to get it right the first time around or at least the second time around, but not be trying drug after drug like we do now.”

So far no genes of major effect have been identified – and given how much research has already been done, Professor Licinio believes it’s unlikely they exist.

What’s more probable, he believes, is that it’s rare gene variants that are at work.

Thus, a situation like the three Turkish cousins is unlikely.

Translating laboratory res­earch of the pharmacogenomics of psychiatric drug responses to clinical practice is still a long way off. As yet, there’s still no blood test available to easily determine if a person possesses one of the gene variants.

Another area of research that is often discussed and recommended, but not often actually begun, is the area of genetic optimisation to identify which antidepressant would work best for each person. 

“That tends to be very costly because you have to get large groups of people,” Professor Licinio says.

“It’s really expensive and time consuming, and funding tends to go toward hypothesis driven work.”

Still, Professor Licinio remains optimistic, if realistic. 

“Some people underestimate what a long-term proposition it is,” he says.

“When we get there, we’ll look back at the way we practise medicine and we’ll be shocked, because it’s basically guesswork today.”

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