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Adrian Llerena on the Need For Pharmacogenetics That Clinicians Can Use

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At A Glance

Name: Adrián Llerena

Title: Director, Unit of Research and Clinical Psychopharmacology, Mérida Psychiatric Hospital, Mérida, Spain; Department of Pharmacology and Psychiatry, Faculty of Medicine, University of Extremadura, Badajoz, Spain; Professor Pharmacology and Clinical Pharmacology, University of Beira Interior, Covilhã, Portugal

Background: MD from the University of Extremadura, Spain — 1984; PhD in Pharmacogenetics from the University of Extremadura, Spain — 1988

Adrián Llerena’s research on pharmacogenetics and psychiatric drugs is published in more than 70 international publications; since 1988, he has studied the drug metabolism profiles of different populations, the affects of menstrual cycle and ovariectomy on pharmacogenetics, and QTc-interval lengthening in patients taking antipsychotic drugs, among other interests.

He is the European Project Coordinator Study of Schizophrenia in Hungary (University of Debrecen), Estonia (University of Tartu), Sweden (Karolinska Institute), and Spain (University of Extremadura), and the recipient of grants from the Spanish Ministry of Education and Science and the Spanish Ministry of Science and Technology.

You have some misgivings about the way pharmacogenomics is being pursued for the clinic — what do you think is missing?

We decide that patients, during treatment, turn to the phenotype. People are thinking just about genetics, but genetics is just a predisposition factor. In fact, people have functions that can change through life interactions. We describe very many people who are poor and extensive metabolizers. Of course, if you are a poor metabolizer, you are more prone to have side effects from that. But what might happen in practice, is that the poor metabolizers are not in treatment, because when they get the drug, they feel bad. And they refuse to take it.

Because its level is too high.

Yeah, it’s common sense. Clinical monitoring. If you go back to the doctor and said, ‘The drug doesn’t fit with me, because I feel bad,’ the doctor will change the drug to another one that probably will fit with your metabolism. This has been done for centuries without really knowing the cause of this. The problem to me is the normal metabolizers. Because during treatment in psychiatry, they change from normal to poor metabolizers, although genetically they are extensive [metabolizers]. They are normal genetically, but due to the treatment, they change. Of course if somebody is genetically deficient, they are prone to get a very high plasma concentration, but if you take very many drugs at the same time, or very high doses, he will begin to become a poor metabolizer, no matter if he’s an extensive metabolizer — ‘normal.’

What happened in psychiatry is that, we have conducted a study in Europe — we followed schizophrenic patients in four countries for many years. What happens in clinical practice is that psychiatric patients are taking several drugs at a time — three or four. So by definition, there are interactions. I think this is one of the big issues in pharmacogenetics. Many studies predict drug response on the basis that the patients are taking one drug at a time, but frequently this is not real life — people are taking several. So, if they take several drugs at a time, an interaction will happen, and very many patients on [many antipsychotic drugs] will act so that the person becomes a poor metabolizer. But maybe because he’s taking antihypertensive drugs that interact with the psychiatric treatment, the blood level may get high.

Because they compete for the same enzyme.

Exactly. In a simple way, if you have an enzyme with low capacity, and you need to go through a pathway, and it’s occupied by one [substrate], the next one will just have to wait. It’s simple. Very many enzymes have limited capabilities. Of course, ultra-rapid metabolizers, their capabilities are much bigger. But no matter. If you get that many drugs at the end, genetics may not be the most important factor.

What happens is that the plasma level goes high. If the plasma level goes high, people are thinking about side-effects. But, there is another theoretical possibility in patients taking drug inhibitors — risperidone, fluoxetine [prozac], and many other psychiatric drugs are active due to their metabolite. So if you block the pathway, potentially risperidone will reach a high level, and of course that may lead to some side effects, but at the same time, the drug effect may decrease. You will find, potentially, this paradoxical situation in which you are giving a drug to a patient, and if you increase the dose, the drug effect will go lower.

And this is when they are on several drugs at a time?

Yes, when they are on several drugs at a time, because the metabolite will decrease. So you may get higher side effects and lowered effect. You know, many drugs remain in the body more than a week, so you find that one week later, it changes — even if the patient is not taking the drug, because the metabolite remains in the body. So this is one clinical situation, the lack of efficacy due to an interaction, but secondly the side effects get high. But what we have been following is QTc interval lengthening (related to potential sudden death) in treatment with antipsychotic drugs — mostly in schizophrenic patients. We published the relationship of the CYP2D6 genetic polymorphism and plasma concentration in people undergoing treatment — with haloperidol, thioridazine, and risperidone — and the relationship with increasing QTc interval lengthening.

Theoretically, during drug inhibition, thioridazine may increase, but mesoridazine, which is the metabolite, might go down. Actually, mesoridazine is marketed in several countries, including the USA. The metabolite in the body of a person taking thioridazine might decrease, and the drug effect might be lower, so if one tries to increase the drug, because the patient doesn’t respond, and there are risks of a higher side effect. So this is a major issue.

And the other thing is that we are trying to predict the use of pharmacogenetics — I think it’s extremely useful if we are very consistent and we don’t expect to solve all the problems at one time. We can solve just some problems, and that is more than enough if they are clinically relevant for a given patient. For example, the case that I showed today with a patient with mental retardation taking a drug — haloperidol — he received risperidone and the level was high. If you measure plasma level and you can decrease the drugs, that works. Genetics, as such, is just a predisposition factor that we must use in the context of therapeutics.

The gene action is continuously interacting with environmental factors. We showed how smoking in psychotic patients is related to the decrease of plasma concentration. Many of the psychotic patients develop hallucinations and side effects — the dry mouth, the sexual activity decreases, blood pressure goes down. It might happen that by smoking, some of these side effects decrease. So smoking is a factor. And at the end, it’s an interaction between environment and genetics.

But the first question — the enzymes and receptors are in the body doing something with their own physiological functions. In that sense we described the relationship between personality traits and the pharmacogenetics of the CYP2D6 enzyme. So, one can say that ‘the way that we are may change the way that the drug acts on ourselves.’ This is a combination of things. The same drug given to you and to me would never produce exactly the same effect, because the interaction between your genes and your environmental factor will be different from mine. Moreover, the interaction between the drug action and your own endogenous action — in the mechanism in which the drug is acting — will produce the final therapeutic effect.

So we really have to have the doctors say, ‘Pharmacogenetics is just a tool to optimize the drug therapy.’ From a therapeutic point of view, important things are:

1) To support patients taking the drugs. If the patients don’t take the drugs, pharmacogenetics is not important. Clinicians are the most important people in this field. A lot of them are listening to our discussions about whether we can predict or not predict [the genetic relationship to drug response]. But the discussion is about an ideal situation that never happens: patients taking a drug regularly, all the time, every day. Unfortu- nately, that not always happens! In very many patients, the problem is compliance. Very many patients don’t take drugs exactly as prescribed. And if they take drugs, sometimes they take very many at a time.

2) To support the capability of every patient to help himself. Doing something that can help the drug action. This is very important because that exists — the final therapeutic effect is going to be the sum of the drug action plus the endogenous action, supporting the drug action, originating from the patient. This relationship is [one of] personality traits and pharmacogenetic factors.

3) Pharmacogenetics may help the optimization of drug therapy.

How do you see the future of pharmacogenomics given your study area?

If you have common sense, it’s fine.

If you have a patient with a drug that doesn’t work, and you’re looking for reasons why, pharmacogenomics can help you to know the reasons. If you know the reasons, you have a tool to handle the dosage. Sometimes a drug that is the best for certain diseases in which you only have a few types — in that case pharmacogenetics is crucial to optimize drug therapy.

In that case, when you have only one drug that is the best, but this person has an adverse reaction, if you have a tool that you can use to make an evaluation, and you know that this person is a poor metabolizer, you can evaluate the recommended dose. Because you have a tool to support your decision.

You only need to use common sense. In this type of clinical situation, really pharmacogenetics supports therapeutic decisions.

 

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