- [Dr.

Borenstein] Welcome to Healthy Minds, I'm Dr.

Jeff Borenstein.

Everyone is touched by psychiatric conditions, either themselves or a loved one.

Do not suffer in silence.

With help, there is hope.

(soft music) Today on Healthy Minds-- - The Pharmacogenetic test can really have a big benefit in terms of getting the patient better, faster, and avoiding side effects.

- That's today on Healthy Minds.

This program is brought to you in part by the American Psychiatric Association Foundation, the John and Polly Sparks Foundation and the WoodNext Foundation.

(soft music continues) Welcome to Healthy Minds, I'm Dr.

Jeff Borenstein.

Pharmacogenetics.

How can a genetic test help a psychiatrist determine the best optimal treatment for an individual?

Today I speak with leading expert, Dr.

James Kennedy, about pharmacogenetics.

(soft music continues) Jim, thank you for joining us today.

- You're welcome.

- I want to jump in and ask you about pharmacogenetics.

What is it and how can people benefit from this?

- Pharmacogenetics is a bit of an uncommon term, and it's two words together, pharmaco, which relates to pharmacology and drugs, and genetics, which is the variation in our genome that we inherit.

The combination of genetics with trying to decide what the right medication is for a patient is called pharmacogenetics.

So it takes the standard drugs that are available and proven to be safe, all FDA approved.

And the genetics is information that we get from a simple saliva sample and that provides us with information on that particular person's DNA variation in the genes that we know are important for medication response and side effects.

- Over the years, the approach of psychiatry, as is the case with other areas of medicine, is trial and error.

We think this medicine may be the best choice and we try it.

This really takes it a step beyond that so that we can make a decision based upon that individual.

- Yes, that's right, trial and error has been the only way up until recently, you know, the last 10 years or so, when we can quickly and easily and inexpensively get really good information about that particular individual's genetic makeup.

Prior to that, you know, it was maybe the medication that was least expensive or was the medication that the doctor had a sample of or a trained physician would prescribe based on the mechanism or the hypothesized mechanism of the drug in a generic person's brain.

But those mechanisms are not very well understood to the present.

How antidepressants work and how antipsychotics work, it's still a young science to figure that out.

So that has created this trial and error situation.

And in contrast, if you think of another disorder like treating blood pressure, high blood pressure, I mean, you have a clear readout of how, what your blood pressure is, you have a number and you can, you know, choose a drug and then get a pretty quick response.

You get a quick decision on the physician's part.

But in psychiatry, we don't have that readout of very objective scores for severity of depression or severity of auditory hallucinations, these voices that are unseen inside the patient's head.

So it's unfortunately in psychiatry, we're really, we have been stuck in this trial and error situation where we don't know exactly how the drugs work and we don't have the measures, the very accurate measures that other fields of medicine have.

- And also because some of the medicines that we use can take some time to work.

It may not work right away, but it may work down the road or at a different dose.

And we don't know for sure as opposed to, let's say, the blood pressure example where if it's gonna work, it's gonna work pretty quickly.

So you know a yes or no right away.

- Yeah, that's an important point with this delay, particularly with all the antidepressants.

They take three to five weeks or more to start working.

And where pharmacogenetics really helps is if the patient knows that this drug has been chosen based on their individual DNA, they're much more likely to stick with it and adhere to the dosing and taking the drug every day.

So they stay with the instructed way of the prescription and they hang in there, whereas other patients will take it for five days and, you know, it makes them a bit agitated that it's very common to get nausea and headache like almost any other medication.

And it's very hard to imagine, you know, you're feeling depressed and anxious and now you take this, you know, foreign chemical that we call a drug and it, what antidepressants tend to do is they raise your energy level a bit before you feel psychologically better.

And so patients can feel very uncomfortably agitated and restless and a bit of insomnia, also.

So we really need to do everything we can to help them through that initial three to five weeks to determine whether it works or not.

And I can tell you, as a clinician, it's wonderful when, you know, you see the patient, the four week point and they're still, "Eh, you know, I'm not sleeping very well.

I don't think this drug is working."

And you know, you say, "Okay, well just hang in there."

And then they come back four, you know, at eight weeks and they are, they say, "Wow, doc, my life is completely different."

And they're, you know, responding and the energy and the hopefulness and interest in doing things, moving into the future, the initiative, those two things have now been assembled by the drug in that person.

And it's a wonderful thing to see.

- It is, every time it happens clinically, it's like a miracle.

You're really making a big difference in somebody's life.

- Right.

- I want you to explain to us exactly how the genetic test works.

What is it telling the clinician about the individual?

- The old way was you had to do a, stick a needle in a person's vein and draw out a blood sample and the standard thing was to check the level of the drug in the person's bloodstream.

But that's expensive and it takes a long time.

It can be very helpful, but-- And now, we can, we don't need the blood, just with a saliva sample where you spit in a tube and you can even put that in a mailer bag and you can put it in the postal service and mail it in to the lab.

So very easy.

And then we, or a commercial lab, receive the sample and we can extract well enough DNA just from the cells in the saliva to get really nice accurate results from the DNA in that saliva.

And the results are generated by amplifying up all the genes that we know are involved in how the drug passes through your body.

If you swallow the pill, it then gets absorbed from the stomach and goes through the liver.

And there's a lot of variation genetically in how fast or slow a person's liver breaks down a particular medication.

And then after that, it gets to the brain and there's further genetic variation in how well it gets across the barrier that exists, the blood brain barrier to get into the brain tissue and how well it attaches to the receptors or the enzymes that are the specific target of the drug.

So it's quite straightforward and once you have a panel of genes that are relevant for pharmacogenetics, like you can examine them in two to three hours in the lab in a process, and then there's some checking and cleaning of the data.

And in our work with several thousand patients leading up till now, when we do it all in the right synchrony, we can get results back to the doctor in 36 hours, which is a real nice quick turnaround time.

- If somebody's watching right now and they have depression and they are beginning treatment, what do they tell their doctor?

And what does the doctor do to take advantage of this approach?

- They could say that they've heard about this test that involves genetics and response to medications, would be a very lay person phrasing for it.

And they could ask if that test is available.

And there's no FDA approved test because the tests are evolving.

With our government healthcare system here in Canada, in Toronto, they're not quite convinced that the benefit outweighs the cost.

But we are well on the way to showing that there's clearly a big benefit for the cost.

And just, as a side note, the Dutch government in Holland, about a year or so ago, has approved the government reimbursement 100% of the real core set of a few genes that predict how fast or slow a patient will metabolize and process all the antidepressant and antipsychotic drugs.

- So if somebody wanted to do this now, they would perhaps need to pay for it out of pocket.

And how much does it cost?

Typically?

- There's a very wide range, 'cause there's a lot of bells and whistles.

An important part is how the information is displayed to the physician and to the patient.

But generally it's not really complicated.

The drugs can be sorted into like high, medium, or low suitability.

Sometimes a color coding is used like a traffic light, you know, a red, yellow, green where the drugs that are not gonna work for you are put in a red box and the ones that your genetic makeup is really good to handle are in a green box.

And of course yellow is in between.

So, you know, the point about the price is currently the lower end of cost is a few hundred dollars, say $300.

You can get a reasonable test at that price and the higher end is, you know, upwards to $2,000.

So it takes a bit of consumer understanding to understand what they're getting for what they're paying.

When you think about getting a person better faster and avoiding the trial and error of having to test two drugs or even three drugs, each of which takes several weeks.

I mean, the cost of that time and the suffering and the risk for the patient really falling off the rails, getting more depressed, discouraged, you know, might start considering suicide.

That's a big cost.

And so the pharmacogenetic test can really have a big benefit in terms of getting the patient better faster and avoiding side effects that would really make the patient, you know, uneasy about continuing with this dubious drug.

- The potential for this is really to be a game changer in how people get treatment.

And you've done some research comparing the use of this approach versus the use of the typical approach that we have of the more like trial and error.

Tell us about that research.

- This was a randomized controlled trial.

It was for patients who were quite depressed, you know, they had major depression, so they had multiple different symptoms of depression.

You know, lack of interest, a sense of hopelessness, lack of energy, maybe a loss of appetite.

So they had very significant depression and most of them had tried two antidepressants already and they weren't happy with how they were doing.

So there was treatment resistant.

We then arranged the pharmacogenetic testing of everybody as they entered the trial and then we followed them for 12 weeks.

And there was a lot of variation at a four week point, and the eight week point, kind of as expected.

But where the test really shown was there was a, almost twice as many patients who got the pharmacogenetic test made it all the way to what we call remission of their depression, which means they were no longer impaired by the depression.

They could go back to work, go back to school, they'd be reconnected with their family.

So the test was really good at getting people all the way to better.

And so that was the big finding of that randomized controlled trial.

- So that is an example, scientifically, of evidence that this approach really does make a difference for people when you take a group of people and try the regular way and the new approach, seeing such a big difference.

- Yes.

So gold, you know, gold standard, many people call it randomized controlled trials.

- Where do you see this going over the next five, 10 years?

How do you see this progressing in terms of clinical care as well as the actual science behind this?

- Right, there's a lot of opportunities across the whole spectrum from bench to, you know, normally one would say bedside or clinic, but another beyond that is implementation.

You know, at a society population level, as the the Dutch government has done recently.

We still have a lot of progress to be made across that spectrum, so basically in the lab, what's a really powerful change is that we can feed much more detailed information about the person's DNA.

And by detail I mean instead of taking a measure of variation at different points across these drug processing genes, we can get every single letter in the DNA alphabet through complete sequencing of these genes.

Every single letter so that if another letter that no one knew about is off in the DNA, you know, one could, it's kind of like a mutation in the sense of processing the drug, that can be seen very reliably in each individual patient.

So there's gonna be, the information's gonna be much more detailed and granular and we'll be missing less of the variation in the DNA.

And you know, we have 3 billion base pairs, 3 billion letters in our, across all of our chromosomes.

And so any given human, you know, they've got a lot of variation in letters here and there that are different than the next human being.

And so we need to measure that detail and we now have the technology to do that.

So that's going to be a big sort of laboratory science advance that will be progressively incorporated.

And another area is the layers of information on the DNA.

So what I've been talking about up 'til now is the letters of the DNA alphabet that are in the string, like I call it the blueprint of our genetic makeup.

And that doesn't change over our lifetimes.

However, there's another layer which is epigenetics, and that's another great tool because epigenetics is the measurement of how these other small molecules attach to the DNA, they're methyl groups, very small molecules that can stick to the letters of the DNA alphabet.

And if they stick there, they kind of block these signaling coming into either turn the gene on and up or turning it off.

And so this is called epigenetic modification.

And those attachments, those little sticky molecules that stick to the letters of the DNA blueprint, so they can adjust the amount and timing of how the gene works.

And so all that is to say, we can now measure quite accurately where those little sticky notes, if you like, are attached to the DNA sequence.

And so we have a whole other layer of information that gets to the more subtle or smaller ups and downs of these genes that work to process the drugs after they've entered the bodies of the liver and the brain and so on.

- I think if we think back to when you and I might have been in medical school, the idea that there was a test that could go off to a lab to help us decide which is the right medicine for a patient who's experiencing depression or other psychiatric illness, that was a dream and it's now a dream that is coming true.

- Yes, indeed.

And another layer, if I may, is now the whole computational revolution.

So if you think, I told you that we're gonna get way more information at the DNA blueprint level, then we're gonna get more information at the sticky add-ons, the epigenetic level.

So that's gonna be a lot of information about each individual patient.

So the computational tools are now, as we all know, with AI being the latest, you know, we're getting much better as this information gets bigger and bigger for each patient, we can use these computer programs to sort out all the variation and add up the little pluses and you know, the little ups and downs into an overall summary effect in that particular patient of how their genetic makeup is going to handle this drug, which basically means how rapidly it's absorbed, how fast or slow it's broken down in the liver, and how well it gets into the brain, and then how well it attaches to its target in the brain.

- These are very exciting times and a lot of this is due to the work that you and colleagues have done over these years.

And I want to, Jim, thank you for the work you've done and continue to do.

And thank you for joining us here today to share this extremely important and exciting information.

Thank you.

- Thank you.

(soft music) - If you are beginning treatment for depression or have had treatment without a good response yet, perhaps making use of pharmacogenetics can help.

Remember, with help, there is hope.

(soft music continues) Do not suffer in silence.

With help, there is hope.

(soft music continues) This program is brought to you in part by the American Psychiatric Association Foundation, the John and Polly Sparks Foundation and the WoodNext Foundation.

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