Antidepressants Get Personal, So Be Happy

"Within a few years," says The New York Times, personalized depression drugs will be the norm. A recent study published in Science suggests that certain identifiable genetic mutations may predict reactions to common antidepressants. "Nearly all drugs are metabolized by a group of enzymes that vary greatly in activity from person to person. If patients have a genetic mutation that results in either deficient enzyme activity or none, they would be likely to have serious side effects if exposed to the drug that is metabolized by the enzyme."

This is particularly heartening in light of recent stories about a greater suicide threat for some teens on Prozac. This is exactly the sort of pharmacological incompatibility that may be solved in the near future:

Instead of the hit-or-miss approach…it will soon be possible for a psychiatrist to biologically personalize treatments. With a simple blood test, the doctor will be able to characterize a patient's unique genetic profile, determining what biological type of depression the patient has and which antidepressant is likely to work best.

More on psychoactive substances from reason here and here.

Comments

[thoreau]

Admittedly I haven't followed this closely, but haven't we been promised an era of personalized medicine for some time?

I speculate that the latest discoveries in RNA, while obviously very relevant and potentially useful for personalized medicine, will also push it back a bit: There's a whole new layer of complexity to the cell's "operating system", and so it will take longer to figure out what the relevant markers are for the activity of a drug.

Then again, I could be wrong.

[Erik]

This is really quite excellent news. I think even Szasz will be happy to hear this--the more accurate the arrows in the quiver, the less times you have to shoot.

[Rattlesnake Jake]

"Instead of the hit-or-miss approach...it will soon be possible for a psychiatrist to biologically personalize treatments. With a simple blood test, the doctor will be able to characterize a patient's unique genetic profile, determining what biological type of depression the patient has and which antidepressant is likely to work best."

It sounds good, but what about people who have a phobia about blood tests?

[Dan T.]

Hmmm...so what's the proper libertarian position on this one?

On one hand, certainly we should allow pharm companies to compete in the marketplace to provide the drugs that will best satisfy the needs of their customers.

On the other hand, once you get to the point where pharm companies get too good at sedating and pacifying people it will be much easier to control them. What happens when "dissent" becomes something than can be drugged away?

[Pro Libertate]

thoreau,

Scoff all you will, but I'm designing a custom-tailored virus for you that will infect your mind in such a way that you will dedicate your life to coming up with a healthy, non-HFCS alternative sweetener. Yeah, I'm doing this for hire.

[thoreau]

PL-

Yes, but the virus can be neutralized with maple syrup.

To be serious, if personalized antidepressants can actually work, the next thing to try is personalized antipsychotics. Some of those drugs have pretty significant side effects, but once they find something that works they often stop experimenting and just live with the side effects. (Or at least that's how it seems to be for the people I've known who take those drugs.) As crude as this approach is, it's deemed safer than taking somebody off an antipsychotic that works.

If genetic testing makes it possible to choose antipsychotics more effectively, perhaps they can do a better job of finding something that works without side effects.

[TallDave]

I'm skeptical of pharmaceutically-induced happiness for anything other than recreational enjoyment.

There was a Forbes article a little while back suggesting cognitive behavioral therapy (teaching people to make themselves happy) is probably the best alternative for most people.

http://en.wikipedia.org/wiki/Cognitive_behavioral_therapy

Apparently they get better results when combined with drugs, but as someone who's dealt with a lot of people in these situations I like the idea of treating irrationality rather than unhappiness.

[Matthew]

Between legislators, the FDA, and personal injury lawyers, this will take decades to actually happen, if it ever does.

[Okapi]

My wife worked in bio-informatics before having kids, and I can assure you that we are still decades away from personalized medicine. And if medicine becomes socialized in the US, it will never happen (companies won't be able to justify the huge investments required).

The basic problem is this: for the most part we don't really know how or why drugs work (we use trial and error to find new drugs) and the more we learn about the human genome, the more we realize how ignorant we still are (for instance, do a google search on "junk DNA").

We are a long way from the promised land...

[The Wine Commonsewer]

I'm looking forward to personalized wine that tastes great and has no calories. That, of course, is the big appeal of drugs. Less calories than red wine. Except pot that is. Well you know what I mean.

[Reinmoose]

Largely the problem with this is that, as it stands, antidepressants are over prescribed. In many of the cases patients are better of developing coping mechanisms. Likewise, if a person is unhappy, I would advise working toward happiness instead of trying to suppress unhappiness. I know it's not that simple most of the time, but I'm speaking a bit from experience on this. From the standpoint of the general public, antidepressants fall into the "quick fix" category with diet pills/fad diets, supplements, censoring of various types of media, welfare systems, etc. I think it'll only get worse if people think that they have nothing to lose by going on an antidepressant because it is personalized for them? not that we're actually going to be able to do that anytime soon.

[Pro Libertate]

I just dialed 482--smug amusement at the quaint ways of my fellows.

[Bronwyn]

If I may use a Fark cliche, I am a geneticist working in a pharmacogenetics lab and I'm really getting a kick out of your replies.

No, really. I am and I do...

In fact I am at this very moment optimizing a protocol to test for a variant in the promoter of the serotonin transporter gene. If I may expound for a couple of minutes, I will tell you how this works.

The gene has a length variation, called a polymorphism. Some people have a long version, others have a shorter version - the difference is only 44 base pairs long, but it makes a 2-fold difference in gene expression.

This is where the layperson's eyes tend to glaze over, but it would be really great if everyone could understand this so please bear with me.

Folks with the Long version express the gene more than the Short folks. This means that Longs have more efficient serotonin reuptake than Shorts.

Antidepressants like Prozac and Lexapro and so on inhibit serotonin reuptake (SSRI stands selective serotonin reuptake inhibitor).

Put this together... Longs are sucking up the serotonin like a Hoover, so there's lots of room for improvement. Therefore, Longs on SSRIs tend to show greater improvement in their depression scores than do Shorts. It so happens that, although both Longs and Shorts can be depressed or have PTSD, the Longs tend to have worse symptom scores in certain categories than Shorts. The scoring for these things is mind-bogglingly complex and it often sounds like gibberish to me, but that's because I'm a molecular biologist, not a psychologist - so let's just leave it at that.

So. Longs may suffer more from certain symptoms, but they have plenty of room to improve, so the drugs work.

The Shorts are the opposite. They've got plenty of serotonin floating freely already, so there's little room for improvement with SSRI treatment. They may be depressed, but because their depression isn't due to a lack of serotonin, an SSRI is useless.

Now here's the scary part. SSRIs can have lots of bad side effects and Shorts are far more susceptible to these side effects than Longs. Therefore, it's really unwise to treat a Short with an SSRI - they're less likely to see a benefit and more likely to see a lot of side effects.

The metabolism genes, which determine whether and to what degree a drug will build up in your body or pass right through, understandably will also have a significant effect on whether a drug will help or hurt you.

We can put together profiles of these genes and get a pretty good picture of what will work for you, whether you'll suffer side effects and how bad they'll be and so on.

This is what the company I work for is all about. The roadblocks are many, but the two biggest ones are: (1) physicians aren't trained very well in genetics and they're eyes glaze over almost as quickly as any layman's so they are slow to accept these concepts, much less agree to adopt them into practice and (2) drug companies spend billions of dollars creating and marketing drugs - they have little interest in finding out that their drug will only work for x number of people or that it might kill y number of people.

Celebrex is a great example. It works and it works very very well, but a small percentage of people have a certain genetic variation and celebrex tends to kill them. The drug was yanked from the shelves because of these people and because pharmacogenetics has not yet been adopted into standard practice.

Yet. The FDA is finally figuring this stuff out and Barack Obama, for all his faults, has introduced legislation to encourage more study in pharmacogenetics.

I'll shut up now but will happily expound further if anyone would like to hear more.

[Dr. Chris Cooper]

First it enters your brain, chemically.

Then it isolates your happiest memory, chemically.

Finally it holds that memory in the front of your mind, chemically.

[Bronwyn]

Ok, I will say this in response to Okapi.

We're not as far from it as you think - google "pharmacogenetics" or look up Gentris and Standing Stone for examples. My company performs many of the genetic tests for their patients and for dozens of other companies, physicians' groups and hospitals for hundreds of patients. I'll go ahead and shamelessly plug it: check out PGxl Laboratories.

google "warfarin and pharmacogenetics" to see how the science is saving lives

insurance companies and medicare have made us preferred providers because patients who get the right drugs in the right doses cost them less money (insert appropriate grumbling about how the insurance industry and socialized medicine sucks)

It's the pharmaceutical companies that will be the hard sell for this stuff. What company in its right mind would spend billions of dollars to make designer drugs for only a small fraction of the population? Throw in the complexities of variant gene frequencies among different populations and age and diet and drug receptors versus drug metabolizing genes and it's a nightmare for drug discovery.

Right now it's easier to design the treatment strategy for the individual using existing drugs than to design drugs for individuals.

[Already nostalgic]

This will make H&R obsolete.

[thoreau]

Bronwyn-

I can understand that companies don't want to limit their market. OTOH, what about drugs that are showing only weak statistical significance in trials right now, but might show great statistical significance in a sample selected for certain genetic traits? Couldn't genetic testing be a means to get more drugs to market, so they have more partial successes and hence fewer failures?

Or is that naive?

[Bronwyn]

thoreau-

It's not naive at all. You got it right, exactly.

Imagine how many drugs have been dropped because only 3% of patients responded!

The good news is that big pharmas have a nice habit of selling the rights to such substances to researcher groups who can better afford to run with them. The bad news is that these groups may have less funding or may take longer to get the drugs to market.

[Bronwyn]

I'm sorry, I misspoke a bit there. It's a nice habit of theirs, but they don't do it often. I imagine there is a large room full of dusty shelves containing the tales of pharmaceutical Couldhavebeens...

[poco]

I don't find it that complicated, having read this interesting article last year about genes and life stress:

In humans, each 5-HTT gene has two alleles, and each allele occurs in either a short or a long version. Scientists are still figuring out how the short allele affects serotonin delivery, but it seems that people with at least one short 5-HTT allele are more prone to depression. And since depression is associated with unemployment, struggling relationships, poor health and substance abuse, the short allele could contribute to a life going awry.

About one-third of the white population have two copies of the protective long allele. About one-half have one long allele and one short one. And about 17 percent have two short alleles.

[Reinmoose]

Bronwyn -
You are very polite. We don't encounter a lot of your type around here.

I think most of the commenters on this thread (including myself) are more skeptical of personalized depression drugs coming within "a few years" for more political reasons than scientific. I could be wrong.

[thoreau]

Reinmoose-

Politics might have something to do with it, but there are all sorts of breakthroughs that have always been "right around the corner" and are likely to remain there for some time.

Personalized medicine may very well be on its way, but the skepticism should be understandable in light of the other technologies that have been promised and never delivered.

Bronwyn, best of luck. It's nothing personal, I'm just skeptical because I've seen a lot of things promised from all sorts of fields.

[Bronwyn]

poco - excellent - that's precisely what I'm looking at. As it happens, l/l and l/s are typically put together in the same category, as (L)ong carriers versus (S)hort carriers because the long appears to have the dominant effect.

I've been seeing more articles on the topic too, and I'm glad to know people are paying attention. People can be skittish about their genes, particularly when it comes to using genetics to indicate disease risk. No one wants their insurance company or employer to know that they carry a gene variant that makes them more likely to have some chronic and expensive disease.

We tread a fine line with this. Researchers can play all they want with linking genes to disease risks (obesity, heart disease, cancer...) but few others will touch it with a ten-foot pole.

Reinmoose- I've had my troll moments, believe me, but when it's a topic so close to my heart, I try to be good 🙂

It pisses me off to see headlines like "personalized drugs" because it's absolutely inaccurate and misleading. This isn't about personalizing drugs at all, it's about personalizing treatment. A physician shouldn't just whip out their PDA and rubberstamp prescriptions any more. There's no excuse for it.

And you're right, politics can and will hold us back, but not entirely.

Now if you want to see me foam at the mouth, we can talk about the genetics and politics of pain management and how, if only pigs could fly and asshats didn't run the government, people like Richard Paey could be exonerated on the basis of their genes.

We are *thisclose* to having a test panel that would show which patients actually NEED those massive doses of opiates, which ones are going to become dependent... we can prove that dependency and addiction are categorically separate. It just kills me to know that the Karen Tandy's of the world will ignore and discount these facts, no matter how hard the evidence.

As soon as we've got the pain management test up and running, I'm going to put out a call for people to hook me up with Richard Paey and other patients and physicians who've been persecuted by the FDA.

[Bronwyn]

thoreau - It's not just a promise anymore, it's happening. It's what people pay us to do.

The problem is that not enough people know about or understand it, or they're too skeptical to try 🙂 I understand your skepticism.

The other problem is that not enough people like me are taking the basic research into clinical application. There's a huge disconnect between academia and industry that's holding back all sorts of good and wonderful, life- and money-saving things.

[thoreau]

Ah, the benchtop to bedside problem...

Good luck with it!

[Bronwyn]

thanks!

And hey, if any of you ever have a heart attack or stroke or DVT, call me. I'll make sure you get the right dose of warfarin!

[Ellie]

This news is very heartening to me, as somebody who's bounced around on several kinds of antidepressant before settling on one that works "pretty well" where the side effects are "not too bad."

TallDave: It's probably true that CBT is the better option for most people, but my n=1 is about 10% therapy and 90% drugs, so I'm very supportive of better antidepressant availability.

[Okapi]

Bronwyn - actually, what you're working on is pretty much exactly what my wife worksed on at Rosetta Inpharmatics (since acquired by Merck).

They were looking at how gene expression impacted drug effectiveness; the goal from Merck's point of view was to reduce the cost of drug discovery.

Merck looks for drugs that work for 66% of the population because that's the only way to segment the real effect from a placebo effect. If they could reduce the target audience through genetic screening, they could vastly increase the liklihood of a drug getting approved.

When I said that personalized medicine won't arrive for decades, I meant PERSONALIZED medicine. What you are talking about is nothing close to personalized. It's all about tendencies and likelihoods and splitting people into a small number of groups (not splitting them into 6 billion unique groups).

Here's an example: my wife worked on a genetic test which could indicate for which women chemo was likely to be necessary in cases of breast cancer. But, the genetic test was not 100% accurate - it just showed a tendency. It couldn't tell you with absolute certainty that chemo wasn't necessary, so everyone opted for chemo anyhow. I think the same thing will happen with SSRTs.

[Bronwyn]

Okapi -

Ah, yes. You are making the right distinction. I focused on the wrongness of "personalized drugs" and missed the wrongness of "personalized medicine".

Pretty much the only thing we can really truly personalize is dosing. Variants in certain of the Cytochrome P450 genes and physical characteristics can be used to precisely nail down the appropriate dose for an individual patient.

Otherwise, I entirely agree with you.

Was your wife looking at tamoxifen, by any chance?