Blue genes

Published, 16-Jun-2010 in Australian Doctor.
Available here. (Registration required.)

Will the hunt for genes predicting antidepressant response replace the one-size-fits-all approach? By Michael Slezak

ANNE, a 26-year-old law student from Sydney, has been prescribed more than a dozen different medications in an attempt to treat her depression and anxiety.

She was first diagnosed and medicated for depression in 2001 after she finished school. Following a brief hospitalisation for depression in 2004, she spent the next four years moving from one drug to another, trying to find one that worked — each time facing new withdrawal symptoms and side effects, including galactorrhoea, reduced bone density, anorgasmia, decreased libido, somnolence and insomnia.

“I’d start one and I’d say I had these side effects or it was making me feel like this,” says Anne (not her real name). “I’d taper down one and then try another. I don’t remember how many I tried but it was a lot.

“After a while I did start to think that maybe nothing would work and I’d just have to try to figure it out on my own,” she says. “I think those were the worst times. When you think that if being on huge amounts of psychotropic medication can’t help me, what can?”

Many GPs would find Anne’s case all too familiar. Medicating depression is a trial-and-error affair, says Associate Professor Michael Baigent, psychiatrist and director of the mental health sciences programs at Flinders University.

“There are a number of people who get prescribed two or three or four. And you’ve got to wonder whether they’re going to respond at all,” says Professor Baigent. “Often, the patient gets put off the idea of taking medication.”

As the authors of a major study wrote recently, exactly which patients will respond to which drugs is a mystery: “After 50 years of experience with antidepressant drugs, the large individual variation in antidepressant treatment outcomes remains poorly understood.”1

In this context, a growing number of experts are hoping that pharmacogenetics — using a patient’s genetic profile to guide treatment — will help remove the clinician’s blindfold and allow them to find the right drug the first time.

Ever since the sequencing of the human genome, scientists have been promising that genomics would one day lead to an era of personalised medicine. In recent years, that promise has begun to reach fruition. Gene tests are already used to find the right treatment for a number of cancers, HIV and thrombosis.

With recent studies showing that in most cases antidepressants are no more effective than placebo, it would seem that using gene testing to predict antidepressant and anxiolytic efficacy has the potential to change the lives of people like Anne.

What’s more, the fact that depression costs the Australian economy $3.3 billion in lost productivity suggests that a test that provides the right medication quickly could also have a considerable impact on the economy.2

PROFESSOR Ma-Li Wong is leader of the pharmacogenomics group in the John Curtin School of Medical Research at Australian National University. Her research is part of a growing field that focuses on trying to find the genetic basis of antidepressant response.

“I’ve been trying to find out why some people respond to antidepressants and others don’t,” she says. “This is an interesting question because there’s a big variation in response.”

Indeed, while some patients respond well to antidepressants, a recent study found that 65% of patients do not achieve remission after their first medication trial.3

Professor Wong is optimistic about the clinical usefulness of pharmacogenetics in psychiatry.

“We will have some results,” she says. “We won’t find a solution for everyone but we will help a portion of the population.”

And there appear to be good reasons for optimism. Early studies, for example, have shown that antidepressant response clusters in families, and is very similar among twins, suggesting that genetic factors may be important.4,5

The most obvious place to look for these factors is among genes that code for proteins we already know are specifically targeted by antidepressants.

This ‘candidate gene’ approach has produced mixed results. In April, a study focusing on genes that regulate the stress hormone corticotropin showed that one gene was significantly associated with response to the common SSRI citalopram in African and Hispanic Americans, but not European Americans.

Other studies focusing on genes that code for the serotonin transporter and the serotonin receptor, meanwhile, have found small, but statistically significant, associations with antidepressant response.1,6

But the weakness of this approach is that we might not even be on the right track about which genes are good candidates, Professor Wong explains.

“We may have some hints about which genes are involved in antidepressant action, but we are a long way from a complete understanding.”

That’s why some researchers are taking a broader approach, conducting genome-wide association studies that look at every gene in the body.

“This new kind of approach does not make any prior assumptions,” Professor Wong says. “You cast a very wide net and see what fish you can catch.”

Rather than focusing attention on a select number of genes, this approach compares entire genomes, searching for genetic variants shared by people who respond well to antidepressants. An approach that has only become possible as genomic technology has become faster and cheaper, it requires sifting through up to 10 million polymorphisms.

As the results of this technique have begun to trickle in, they have unearthed some novel genes for further investigation.

A study published this year in the American Journal of Psychiatry, for example, found a number of genes that predict antidepressant response. Importantly, none of them were located anywhere near any known genes previously thought to be good candidates.1

“This finding demonstrates the importance of exploring the whole genome rather than concentrating on coding regions of known genes and their flanking sequences,” wrote the authors.

NOT everyone shares Professor Wong’s optimism about the degree to which pharmacogenetics will help people with depression.

Associate Professor Jon Jureidini, psychiatrist and chair of Healthy Skepticism, worries that people suffering from depression will pin their hopes on pharmacogenetic research, which he describes as “pie in the sky”.

He is also concerned that such tests might lead to over-medication.

“What’s probably going to happen is that anyone who has a mild complaint about their wellbeing is going to have one of these tests run on them and if they seem to be responsive to antidepressants they’ll get a trial of it,” says Professor Jureidini, who is also head of the department of psychological medicine at the Women’s and Children’s Hospital, Adelaide.

Associate Professor Baigent agrees that such a strong emphasis on medication is concerning.

“I’d also love to see a test that could tell which psychological treatment [patients] would respond to,” he says. “[But] one of the risks with this is to forget about the importance of psychosocial approaches that are effective for people with depression.”

Other observers fear that the costs of pharmacogenetic research may outweigh its benefits.

“Remarkably few people in psychiatry or other branches of medicine seem to be paying attention to the enormous costs of this approach,” wrote Dr Charles Dean, Assistant Professor of Psychiatry at the University of Minnesota Medical School.8

“Would pharmaceutical companies bear the brunt of the costs? History indicates that the industry has shown little interest in developing medications that cannot be sold widely.”

Professor Wong is keenly aware of this problem.

“The main barrier for this research is that it is very expensive,” she says. “You enrol patients and then you have to evaluate their response. To do so, you need to see the patient often — maybe every week or so. And then you have to do their genetic testing … and those kinds of tests are very expensive.”

Getting drug companies to pay for this research is difficult, says Professor Wong.

“Their strategy is to find blockbuster drugs that have minor side effects and most people will respond to … If there is another drug that you can get that you don’t need the pharmacogenetic testing for, that is going to be better for the drug companies.”

Pharmaceutical companies don’t agree. Aidan Power, vice-president and global head of molecular medicine at Pfizer, points out that “most of the research in pharmacogenetics has actually been conducted by pharmaceutical companies”.

Dr Power rejects the suggestion that pharmaceutical companies would not be interested in pharmacogenetics because of their attachment to blockbuster drugs.

“In any portfolio of drugs some will be blockbusters and others will serve smaller patient populations,” he says.

Professor Lon Cardon, senior vice-president of genetics at GlaxoSmithKline, acknowledges that developments in pharmacogenetics will inevitably mean fewer patients being treated with each drug.

“But whether that means a smaller market share or economic model … I don’t think we’ve seen that. I don’t think that’s been fleshed out,” he says.

How exactly pharmacogenetics would make money for pharmaceutical companies is not completely clear, but Professor Cardon suggests that individuals might be willing to pay more for better-targeted drugs.

“The healthcare community has yet to see medicines that work very well for whom they’re targeted. Possibly there’s a premium on that. Possibly there’s a different structure yet to be developed.”

But this idea of a premium is something that Professor Dean is worried about.

“Given what the industry has charged for enormously popular drugs … one can only imagine what would be charged for an … antidepressant used by only a few thousand patients,” he wrote in the Annals of Pharmacotherapy. “What would be the financial implications for patients and their families, as well as their employers and health plans? How could these costs be sustained?”

In the face of these economic concerns, Professor Dean suggests there may be more gains to be had by sticking with the ‘one drug fits all’ approach.

But Professor Wong points out that the benefits of pharmacogenetic research are yet to be seen. There might be effective drugs that have been ignored because of their associated adverse effects — but those adverse effects might only occur in a genetic subgroup of the population.

“Do you think that there is out there any individual or insurance company who will refuse to pay for genetic testing to avoid severe side effects with a risk of death?” she asks.

Professor Wong believes that once we have compelling data showing the advantages of more personalised treatments, public demand will force drug companies to invest in pharmacogenetic approaches.

She says that, as a result, drug companies will move away from “blockbuster” medications and towards, what some have called “minibusters”. “It is just a matter of time,” she says.

FOR Anne, these concerns seem rather removed from real life. She is finishing her law degree, and feels less anxious and depressed than she has in the past. Her current regimen of quetiapine and sertraline is working for her, and the days of hospitalisation are a distant memory.

Reflecting on the possibility of a pharmacogenetic test, Anne says “it would have meant that I didn’t have to go through several years of trial and error before finding something that actually worked for me”.

But speaking like someone who has diligently undergone psychological therapy, she has even found some positive aspects of her years of unsuccessful drug trials.

“It’s also part of learning to accept that there are some things that drugs just can’t do,” she says.

This kind of positive reaction is going to be necessary since, according to Professor Wong, we have a way to go in any case.

“We still don’t understand well what the genes are for susceptibility to depression,” she says. “We’re a long way from clinically useful results.”

References

1. Uher, R. American Journal of Psychiatry 2010; 167:555-564.

2. Hilton, M http://www.beyondblue.org.au/index.aspx?link_id=4.1028

3. Madhukar H, American Journal of Psychiatry 2006; 163:28-40.

4. O’Reilly, RL. Biological Psychiatry 1994;36:467-471.

5. Vesell, ES. Pharmacological Reviews 1978; 30:555-63.

6. Lucae, S. European Neuropsychopharmacology 2010; 20:65-68.

7. Crowley, JJ. Neuropsychopharmacology 2006; 31:2433-42.

8. Dean, CE. Annals of Pharmacotherapy 2009; 43:958-62.