Adding environmental factors to pharmacogenomics improves treatment outcome

Hopefully you’ve read our previous discussion of pharmacogenomics but in case you haven’t (and you should), it is the science of personalized medicine (medications and medication-dosing) based on an individual’s genetic code. Well, nothing ever stays simple with genetics and although by now it is pretty clear that aside from considering what is knows as functional variation in genetic code (what everyone was talking about during that whole human genome project thing – changes in human genetic code that directly affect protein function) we also need to consider epigenetics – or that part of the genetic code that we used to think meant nothing (right, that was going to work out) and we now know influences that expression of all those other genes we care about.

Pharmacogenomics – Personalized medicine in treatment for heart disease

Well, it seems that some real advances are being made in the area of heart medication in terms of pharmacogenomics. From aspirin dosing to issues concerning medications that help with clotting after open-heart surgery, the medical field has been working hard on figuring out what drugs and what doses people who vary on specific genes should be prescribed. The article  by Baye and Wikle that drew my attention back to this topic brings up an important consideration that I believe will play a significant role in making sure that medications for substance abuse benefit equally from pharmacogenomics – what they call biogeographical ancestry. Biogeographical ancestry is the politically correct way of asking where on earth people are from, and given the relatively (a few hundred years) recent mixing of African descendants with people from Central and South America, Caucasians with Africans, and a whole other slew of mixes, knowing ones geographical ancestry adds a whole lot of knowledge to our genetic equation because the genetic code hasn’t had the time to mix together fully and so it still clumps together in ways that make analyzing its variability much easier.

Pharmacogenomics and addiction treatment?

What the heck does this have to do with drug abuse you ask? Well even aside from a strong recent push by NIDA director Dr. Nora Volkow, it is becoming clearer and clearer, at least to me, that medication are going to play a bigger and bigger role in treating addictions. Drugs like Vivitrol, Suboxone, and Zyban are making a real difference in the success rates of those seeking help from addictions and I think that as we get better and better at tailoring the drug selection and doses, those medications, and other that haven’t even been discovered yet, will help us get over the initial hump in treatment – the danger zone.

You see, most people who abuse drugs are not what we call addicts. They’re using more than they should and likely need a nudge from their doctor or some real reason, like a likely oncoming heart attack, to tame their use or stop altogether. In fact, the vast majority of drug abusers stop on their own. However, there’s always that group of people who can’t stop on their own and even though right now we only get to treat them once they get in real trouble (cops, hospital, marriage, you name it), as we start incorporating screening for drug abuse into our medical system we will begin finding more of them at an earlier point in their drug troubled life. For them especially, but also for the chronic relapsers, these medication can make a world of difference and give them a chance at a life that may otherwise seem impossible – a life without drug abuse.Our experience with bupropion and quitting smoking proves that knowing a person’s genetic variability can really help determine their effective use of medications.

But for all the people these drugs help, there are always horror stories about individuals who’ve become addicts to the medication or for whom the meds themselves produced such horrible side-effects that staying addicted almost seems better. For them, I believe pharmacogenomics will make all the difference. And once we figure out who will and who won’t benefit from which drugs at what doses I think that the medical field in general, and substance abuse medication therapy in particular, will benefit greatly.

Citation:

Baye, T. M. & Wikle, R. A. (2010) Mapping genes that predict treatment outcome in admixed populations. Pharmacogenomics Journal, 10: 465-477

Here’s a link to an upcoming conference on pharmacogenomics for anyone interested in the topic:

Personalized Medicine: Principles to Practice
March 1, 2011
Dallas, TX, USA

This symposium brings together leaders in the field to address key aspects of the science of therapeutic individualization, the enabling technologies underpinning this biomedical revolution, and the evolution in policies that will advance personalized medicine principles into healthcare management tools for individuals and populations.

www.nature.com/natureconferences/prmd2011

Why the addiction-brain connection has to be part of the addiction treatment picture

Dr. Dodes recent article, apparently trying to blow up the myth of addiction as a neurophysiological disorder, sounded persuasive, although its underpinning was oversimplified and it’s understanding of the brain-science involved in addiction, and other associated mental health disorders, was lacking. Hopefully, by presenting a more complete picture of the evidence for a brain-aspect to addiction, I can un-bias the discussion somewhat. I, for one, don’t believe that neuroscience will ever be the only factor important in addiction – an individual’s environment, social influences, and other factors will always end up playing important parts as well – still, I think that to dismiss all of the evidence for biological factors at play in the development of addiction is foolhardy. Especially when there’s so much of it that was glossed over in Dr. Dodes’ introduction.

Pleasure center activation is only part of the picture in addiction

Firstly, supporters of the notion that addiction is, at least partly, an outcome of specific brain function point not only to pleasure center activation, but also to a whole host of findings showing genetic variability that is either protective from, or a risk factor for, dependence on drugs and likely also behavioral addiction like eating disorders, compulsive gambling, and maybe sex addiction as well (you can start out looking up ALDH2-2 variability and alcoholism and cocaine addiction, DRD4 and stimulant addiction, and many more).

While it is true that all those who consume addictive substance activate the brain similarly, there are considerable differences in the specific of that activation in reaction to drugs. Some release more dopamine while others have more “active” versions of specific important receptors; neurotransmitter recycling is quick in some, but not all, and drug metabolism is different in different individuals in ways that have been shown to be important not just for addiction risk, but also for the probability of treatment success. Just look at the nicotine and CPY26 literature for an example. It’s right there.

Additionally an entire body of literature exists that shows differential activation, as well as structural differences, between addicts and non-addicts in regions as varied as the OFC, PFC, Insula, and more. This is not to mention a slew of evidence that shows different behavioral test performance on risk-taking, impulsivity, and delay-discounting, all personality variables highly associated with addiction. If one simply ignore all of this evidence, it may be easy to believe that there is no biological explanation for these phenomena, but that’s just wrong.

To say that mesolimbic activation (what the good doctor called “pleasure centers”) is the only evidence for physiological factors in addiction is dismissive at best.

Drug addiction develops in only some drug users

The notion that not everyone who takes drugs becomes addicted is nothing close to evidence against a brain explanation for addiction. Everyone’s motor–cortex, striatum, and substantia nigra (the areas of the brain responsible for movement) activate in the same way during movement, but only a small group ends up suffering from Parkinson’s or Huntington’s disorders. One fact does not preclude the other but instead may specifically point to the fact the group which develops the disorder has somewhat different neurological functioning. Researchers aren’t concerned with explaining why all individuals can become addicted to drugs, but rather why that small subgroup develops compulsive behavior. A short reading of the literature makes that fact pretty clear. Additionally, while Dr. Dodes’ claims otherwise, imaging technology HAS produced evidence explaining this “mystery”, including differences in the ways addicted smokers respond to smoking-related triggers, and an increased dopamine response in cocaine addicts to cues, and well as to cocaine.

As mentioned in the motor disorder section above, ingestion of chemicals is not at all necessary for brain disorders to occur or indeed develop later in life. Dr. Dodes example of shifting addiction could be used as evidence for an underlying neurological difference just as well as it would serve to make his point… Or even better. If there’s a faulty basic mechanism attached to rewarding behaviors, it doesn’t really matter what the behavior is, does it? Sex addiction, gambling, and more can all be explained using a similar mechanism, though drugs of abuse may just have a more direct impact. I know, I’ve written about them all.

The Vietnam vet heroin story used by Dr. Dodes as evidence that emotional, rather than physiological, factors are responsible for addiction actually fits right in line with the notion of predisposition and underlying differences, and I’m surprised to hear a physician point to group differences as an indicator of no neurobiological basis. Indeed, when it comes to the emotional reactivity associated with drug associated cues, normal learning literature, as well as drug-specific learning research, has revealed over and over that drug-related stimuli activate brain regions associated with drug reward in the same way that natural-reward predictors do for things like food and sex. Once again, these facts are part of the basic understanding of the neuroscience of learning, with or without drug abuse involvement.

My own dissertation work shows that it is very likely that only a subsection of those exposed to nicotine will develop abnormal learning patterns associated with that drug. However, among those, learning about drug-related stimuli (as in “triggers”) continues in an exaggerated manner long after the other “normal” animals have stopped learning. That sort of difference can lead to a seriously problematic behavioral-selection problem whereby drug-related stimuli are attended to, and pursued, more so than other,  non-drug-related ones. If that sounds familiar, it should, since drug users continuously pursue drug-associated activities and exposures in a way that seems irrational to the rest of the world. It just might be due to such a mechanism and others like it.

Some important points about science in Dr. Dodes’ article

One very true fact about mental health pointed out by Dr. Dodes is that diseases like schizophrenia, which used to be explained simply as demon possession and evidence of witchcraft can now be, to a large extent, explained by the study of behavioral neuroscience and cognition. The same is true for bipolar disorder, depression, ADHD, and a host of other such conditions. In fact, the study of psychology has only been able to rely on technological advances that allow us to “see” brain function for a few short decades, leading to incredible advances in the field that I think will continue. The thinking that no such advances have, or will continue to be, made in the study of addiction is, in my opinion short sighted.

As I mentioned above, I don’t for a second think that the entire explanation for drug abuse and addiction will come from neurophysiological evidence. The doctor points out that “If we could take a more accurate image of addiction in the brain, it would encompass much of the history and many of the events that make us who we are.” I agree that we need to advance our technology as well as expand our understanding, but I think that to discount neuroscientific explanations completely is a big mistake.

Choice and control in addiction – Genetics and neuroscience of drug abuse

Dr. Jaffe recently gave an online lecture (webinar) for HealthCentral on the processes involved in choice and control of behavior during addiction and drug abuse. We’ve written quite a bit on here about the neuroscience of impulsivity issues and the genetic predisposition to addiction and this talk really covers some of the most important aspects of this topic. I’m also attaching a link to the presentation materials that go along with this talk so that you can follow along (Wellsphere Webinar 1 – Choice Vs. Control). There was definitely quite a bit of material (on both neuroscience and genetics) that we couldn’t get to, so hopefully having the presentation will help you follow along and learn.

We hope you enjoy!

Control Versus Choice in addiction


Watch live video from HealthCentral on Justin.tv

If you need help finding treatment for your own, or a loved one’s addiction, make sure to give our Rehab-Finder a try: It’s the only evidence-based, scientifically created, tool for finding rehab anywhere in the United States!

The alcoholism gene? That’s quite a long story!

If you were trying to find something to blame alcoholism on, genetics would be a good place to start: As much as 50-60% of the risk of becoming an alcoholic is determined by a person’s genes (1). We’ve discussed the genetics of addiction in general as they relate to other condition like ADHD, depression, and anxiety, but the risk that a person may become an alcoholic also depends on their sensitivity to alcohol’s effects, development of tolerance, susceptibility to withdrawal symptoms and alcohol-related organ damage, among others.

Alcohol related genes and alcoholism

The genetic causes of alcoholism are not always simple and straight-forward, especially because genes interact with one another (and the environment) in ways that can create unexpected results. However, some aspects of the genetics of alcoholism are clear, like the case of the genes that affect the speed with which liver enzymes will break down (metabolize) alcohol and its byproducts. Some people have a gene variation which produces liver enzymes that have trouble breaking down acetaldehyde (ALDH2-2, very common among Asians), a basic breakdown product of alcohol. As the levels of acetaldehyde increase, people experience flushing, nausea and rapid heartbeat which makes them less likely to consume alcohol and therefore less likely to become alcoholics. Not surprisingly, alcoholism rates have been historically low in Asian populations. However, recent increasing trends of alcoholism in Japan show that if you work at it hard enough, even a genetic predisposition that is supposed to protect you from alcoholism is no match for good old social pressures to drink.

Researchers have identified one neuropeptide (called NPY) that is located near known alcohol-related traits and indicates an alcohol preference in rats, consequently increasing response to alcohol (1). The effects of alcohol are increased with certain forms of NPY and  that gene has been linked to addiction-related, and anxiety, behaviors (2). It is also generally accepted that genes that affect the activity of serotonin and GABA (one of alcohol’s main targets in the brain and body) are likely to be involved in alcoholism risk.

It is important for everyone to remember that there is a predisposition to becoming an alcoholic and that alcoholism is a disease, not simply an outcome of poor behavior . There are ways to treat both the physical symptoms and the underlying addiction in alcoholics.

We’ve barely scraped the surface of the numerous influences on alcohol’s effects, and the predisposition to alcoholism, but hopefully this post leaves you with a slightly better appreciation of the complexity of the matter…

Co-authored by: Jamie Felzer

Citations:

1. Alcohol Alert-National Institute on Alcohol Abuse and Alcoholism. No.60. July 2003

2. Anxiety and alcohol abuse disorders: a common role for CREB and its target, the neuropeptide Y gene. Trends in Pharmacological Sciences, Volume 24, Issue 9, September 2003, Pages 456-460.

The brain after cocaine – White matter damage and addiction treatment

The brain damage left behind after long-term cocaine use can apparently tell us quite a bit about how well a cocaine addict will do in addiction treatment – as long as we assess the right kind of damage.

Different kinds of brain matter

I’ve talked before about the fact that use of cocaine, and other drugs, can bring about long-term changes in the brain that sometimes include the actual destruction of neural pathways. What you may not know is that brain matter consists of several different components including the cell bodies of neurons (known as gray matter) and the tracts of axons that transmit messages across the brain (known as white matter). There are other parts as well, but those are the two important ones to know for this article.

Gray matter is important because brain transmission isn’t possible without a cell body, which is its operations center. But white matter is equally important because without it, the messages don’t get anywhere. It’s like having a telephone without a communication network – The phone can work perfectly and no one will ever hear you speak.

Until recently, it’s been pretty hard to measure the structure of white matter because it consists of very thin bands that twist and turn throughout the brain. But recent advancements in fMRI imaging and analysis have allowed us to look at it by measuring the direction in which water molecules flow through white matter. It’s called DTI (Diffusion Tensor Imaging) and it’s pretty complicated, but all you need to know is that it lets us know a lot about the integrity of axons in the brain.

White matter and cocaine

Use of cocaine has already been shown to cause damage to brain white matter. A recent study conducted at Yale examined whether the degree of damage can tell us anything about how well people will do in addiction treatment. Researchers took 16 participants and gave them a host of tests as well as some brain scans before sending them off to an 8 week treatment program. The addiction treatment utilized was outpatient and provided different individuals with different combinations of CBT, medication (antabuse), individual, and group therapy. At the end of treatment, the number of clean urine tests (out of 56 total tests) was used as a measure of treatment success. The more clean urines, the better, something I think we need to adopt overall instead of the all-or-nothing view that abstinence is the only form of improvement.

The bottom line: Using three different measures, the researchers found that individuals with more damaged white matter provided less clean urines throughout the addiction-treatment period. Another important fact – the damages areas that were found to be associated with treatment success were found all over the brain. Interestingly, brain damage wasn’t associated with the length of drug use, but it may have been associated with the extent of use (in terms of years and amount used), something the researchers didn’t report on.

Brain matter and addiction treatment outcomes

One day, we’ll have a battery of tests that will let us tailor treatment more effectively towards specific addicts. Genetics, brains scans, and more, will be able to tell us where an addict is especially weak so that we can focus on those areas first. Some may need specific help with impulsivity and weakened learning systems whereas others may be better off with treatment that addresses past trauma and an oversensitive stress response system.

As this research shows, brain scans can offer us a glimpse into the aspects of an addict’s brain that have been compromised. But we’re not there yet – right now, all we know is that certain genes, brain function patters, and experiences, are associated with a greater risk for addictive behavior or a lower chance of recovery. Getting better at more specifically tailoring treatment is still a little farther than we’d like.

Citation:

Jiansong Xu, Elise E DeVito, Patrick D Worhunsky, Kathleen M Carroll, Bruce J Rounsaville & Marc N Potenza (2010). White Matter Integrity is Associated with Treatment Outcome Measures in Cocaine Dependence, Neuropsychopharmacology 35, 1541–1549.

Is anonymity the final shame frontier in addiction?

I’m a drug addict and a sex addict, and as far as I’m concerned, staying anonymous let’s me remain buried in shame, and a double life, that keeps me always one step ahead of those close to me. Did I say too much? Did I give away my secrets? None of those  questions matter when everyone knows everything there is to know about you. For a disease couched in anxiety, obsessions, and compulsive behavior, there’s very little that can be more triggering.

The difficulty of confessing addiction

Obviously I’m not naive to the consequences of confessing to others, and I’ve had a few very uncomfortable conversations that ended in people losing my number or superiors telling me they didn’t need to know. When it comes to the former, it’s their choice, and it might be a wise one, but having those who stay close to me know my truths keeps me safe by making me accountable and protects others from being hurt. And I can hurt with the best of them. Maybe that’s why when it comes to physician treated addicted physicians, there are no secrets, no anonymity, the family and employers are made part of the process. Some notable addiction providers (like Journey Healing Centers and others) have programs that explicitly involve the family in the treatment process as well. Getting the secrets out works to break away from the shame.

We’re only as sick as our secrets, even together

On an organizational level, I understand the need for anonymity to avoid having any specific member represent the group. But that logic only holds when everyone is told to remain anonymous. Otherwise, the entire group represents itself, which is, if nothing else, truthful. If one person slips, relapses, or goes into a homicidal rampage, it only makes the rest of us look bad if no one knows that millions others are “the rest of us.”

Over and over I hear people talk about the secret of their addiction and the lies they have to tell to cover up their shameful acts. Unfortunately, that only contributes to the stigma of addicts and makes it all the more difficult  to get some perspective on the actual problem: We do things we don’t want to over and over regardless of how much they hurt us or those around us

If you’ve read anything on this site, you know that I believe in many factors that contribute to addiction, including biology, environment, experience, and their interactions. Still, when it comes down to it, the misunderstanding of addiction is often our number one problem. And anonymity does nothing to reduce that misunderstanding.

How we can make a difference

Media portrayals only exacerbate the problem as they show us stories of addicted celebrities who are struggling but then leave the story behind before any recovery occurs. That way we only get to see the carnage but have to look pretty hard to see anything more.

But we can change all this with a small, courageous, action. We can let those around us know that we’re addicts, that we’re doing our best to stop our compulsive behavior and that we want them to hold us accountable. If we slip, we can get back up because we don’t compound the shame of a relapse with lies we tell, and those around us know that even a relapse can be overcome because they’ve seen those examples over and over in all the other “confessed” addicts around.

It’s time to leave the addiction “closet” and start living. We may not be able to change who we are easily, but we can change the way we go about living and make it easier on ourselves and on others. By breaking our anonymity, we can help assuage our own shame and let everyone know that addiction is everywhere and that it can be successfully overcome.

Just a thought…

Like advancements in medical care and science? Then support animal research

There was a Pro-Test for Science rally on the UCLA Campus today.  The goal of the rally was to spread awareness about the utility of animal-research and to help combat extremists and prove to the community and world that the ethical use of animals for biomedical research is absolutely vital to the progress and success of advancements in science.

Many of the treatments that we discuss on this site are available because of extensive research with animals. In fact, many scientific discoveries have been possible largely because animal research is an available tool for researchers. Immunizations, medical treatments for Parkinson’s, Alzheimer’s, and diabetes treatments have all been advanced greatly through the use of biomedical research with animals. Of course, great care is always taken to ensure humane treatment of the animals used.  Animals prove a vital part of advancements in medicine, genetics and other research.

Biomedical scientists endure many trials in order to become experts in the type of research techniques we’re talking about here, including extensive schooling, years of training and of course many thousands of hours spent in a lab, all for the benefit of humanity.  They should not have to additionally endure the harassment of extremists and fear for their safety and the safety of their loved ones who often are caught in the middle.

Debate is healthy; discussion is good. But the harassment and terrorizing of researchers must stop if we’re to consider ourselves an open, educated, society. All biomedical researchers want is to better society by finding cures for the many things that plague our world today, so what everyone should really be doing is thanking them.

Co-authored by Jamie Felzer