Goldstein: Personalized Medicine in 2020

-from Nature

Personalized medicine

David B. Goldstein

Duke University

Over the past decade, powerful genotyping tools have allowed geneticists to look at common variation across the entire human genome to identify the risk factors behind many diseases. Two striking findings will define the study of disease for the decade to come. First, common genetic variation seems to have only a limited role in determining people's predisposition to many common diseases. Second, gene variants that are very rare in the general population can have outsized effects on predisposition.

For example, rare mutations that cause the elimination of chunks of the genome can raise the risk of diseases such as schizophrenia, epilepsy or autism by up to twentyfold. Some researchers view these major risk factors as aberrations. My guess is that as more genomes are sequenced, many other high-impact risk factors will be identified.

If so, here's one confident but uncomfortable prediction of what personalized genomics could look like in 2020. The identification of major risk factors for disease is bound to substantially increase interest in embryonic and other screening programmes. Society has largely already accepted this principle for mutations that lead inevitably to serious health conditions. Will it be so accommodating of those who want to screen out embryos that carry, say, a twentyfold increased risk of a serious but unspecified neuropsychiatric disease?

Some advances will be relatively uncontroversial, such as the development of tailored therapeutic drugs based on genetic differences that are otherwise innocuous. Others will be transformational, such as the identification of definitive genetic risk factors that provide new drug targets for conditions that are often poorly treated such as schizophrenia, epilepsy and cancers. Over the next decade millions of people could have their genomes sequenced. Many will be given an indication of the risks they face. Serious consideration about how to handle the practical and ethical implications of such predictive power should begin now.

Are You Chemically Unbalanced?

This will be quick; I'm actually headed off to work.

In his "In Practice" blog, Peter Kramer discusses the issue of whether the concept of a chemical imbalance is still a useful one and he looks at the evidence for and against such a theory, concluding that the concept met a premature death.
"Since 1993, other biochemical contributors to depression have claimed their roles, especially “stress hormones” and factors that influence nerve cell growth. The new overarching biological model of depression (I outline it in Against Depression) integrates all three factors—monoamines, stress, and cell growth—but serotonin dysregulation remains very much on the table as a contributor to depression."

Dr. Kramer talks about PET scans and genes and differential rates of monoamine metabolism, and the stupid little bouncing Zoloft mascot with the smiley face.

For the shrink in the field, so far it doesn't mean much. I can't order a test to find out if someone has too much of one enzyme breaking down any given neurotransmitter and thereby telling me what to prescribe. I'm waiting. In the meantime, what I do have is patients who come in wanting to know what they have. "Do I have a chemical imbalance?" Now what does that even mean? Do you have too much serotonin in some places in your brain and not enough in others? How would I know that? Too much (compared to what?) monamine oxidase breaking down your noradrenergic neurotransmitters? Should we inhibit them and this will make you better? Let me get my probe.

What I do know is that while I don't know what is meant by a "Chemical Imbalance," my patients do. For them it is a term that explains things, that writes the story, that has meaning. There's something socially acceptable about it. "I have poor coping skills" is pejorative and equally unprovable. "I have a chemical imbalance" is somehow explanatory, though still unprovable in a day-by-day psychiatric practice.

So, generally, if a patient with Major Depression asks, "Do I have a Chemical Imbalance?" I simply say "yes." It seems to work.

DBH Gene in Cocaine-Induced Paranoia

So I thought I'd make another post about how more is being learned about our genetic makeup and how that may relate to medication side effects. In this instance, the "medication" is cocaine, which causes a huge release of dopamine. Some folks get really paranoid after using cocaine. This study asked the question "Is reduced breakdown of dopamine associated with paranoia symptoms in cocaine users?"

First some background. The above graphic shows that the neurotransmitter dopamine (or DA) is converted into norepinephrine (or NE, sometimes also called noradrenaline, or NA) by the enzyme dopamine beta-hydroxylase (DBH). You can see that all this enzyme does is add the little -OH (or hydroxy) part to the dopamine molecule to make norepinephrine.

Kalayasiri 2007 showed that a particular mutation (C1021T) in the dopamine beta-hydroxylase (DBH) gene was associated with significantly increased paranoia in a small group of cocaine abusers (see top graph). Cocaine users were blindly provided with different doses of cocaine (bet it was easy to find subjects) and their level of paranoia was rated every few minutes using a Visual Analog Scale (VAS). Users with the TT variant of the gene rated their paranoia level consistently higher than those with the CC or CT gene variant. It has elsewhere been shown that the TT form of the DBH gene is broken, and so is much weaker at converting DA to NE. The resulting higher levels of dopamine in the TT people may be why they get more paranoia.

[Genetics 101 Note: when you see this type of notation, "C1021T", all it means is that at position 1021 along the double-stranded DNA for that particular gene, there is either a C or a T nucleotide at this single point on either DNA strand... if each of your two DNA strands (one from Mom, one from Dad) contain one or the other, then you are homozygous for either one (CC or TT)... if Mom gave you a C and Dad gave you a T, then you are a CT (called heterozygous). Thus there are 3 genetic variants (in this case, CC, CT, or TT) which can exist at this single nucleotide position. These single nucleotide variants, or "polymorphisms", are referred to as SNPs, or Single Nucleotide Polymorphisms. Different SNPs can result in that particular gene's product or function to be enhanced or diminished, resulting in functional variations which may contribute to individual variations in one's response to disease, drugs, or the environment.]

Because this paranoia and related symptoms are uncomfortable to most people, it may serve as a deterrent to using cocaine. In fact, folks with the TT genotype might be at reduced risk of becoming addicted to cocaine because their DBH gene does not work as well. In fact, the alcohol deterrent drug, disulfiram (Antabuse), also happens to block the DBH enzyme (remember, the DBH gene contains the instructions to make the DBH enzyme). This would result in someone with a normally functioning enzyme (from a CC or a CT SNP) to have an enzyme that works like someone with a TT SNP. Antabuse has been shown to be helpful in treating cocaine addiction.

As further evidence of this connection, Schank 2006 used DBH knockout mice to demonstrate hypersensitivity to cocaine in these animals, suggesting that low DBH activity in some cocaine abusers may increase the drug-related dysphoria and aversion, making them less likely to become addicted to the drug.

We hypothesize that the ratio of dopamine (DA) to norepinephrine within noradrenergic vesicles is elevated in TT [homozygous] subjects, so that during cocaine intoxication, DA-mediated neurotransmission is relatively elevated in regions richly innervated by noradrenergic and dopaminergic fibers (e.g., prefrontal cortex). Alternatively, given observations of up-regulated high affinity DA receptor binding sites in DBH knockout mice, TT homozygotes may be hypersensitive to DA, and thereby [may] be more vulnerable to cocaine-induced paranoia.

Pretty cool.

My Three Shrinks Podcast 22: Forced Treatment

[21] . . . [22] . . . [23] . . . [All]

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Note: Chapter 6 is up on Double Billing:

Click Here

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Aarghh!! This is the second version of these show notes. Blooger helpfully auto-saved the first one into oblivion (how do you turn this "feature" off?).

Anyway, Welcome back! Dinah's friend, Victor, joins us again this week, providing his insights into salutations and valedictions. And, for our US listeners, don't forget to celebrate National Duckling Month this weekend (oh, and Memorial Day, too).

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May 27, 2007: #22 Forced Treatment

Topics include:

• Physician-Assisted Executions. The American Medical News had a story by Kevin B. O'Reilly about how some states are trying to force physicians to participate in executions. The ethics of such activities are debated.
  
  
• Realizing the Promise of Pharmacogenomics. A draft federal report is available for public comment (by June 1) about the development of pharmacogenetics and the impact of genomic medicine on the future of health care. You can find the report and comment form here. "The report identifies a number of challenges for the development of pharmacogenomics and its effective integration into health care practice, including the need to improve the health-information infrastructure, to provide education and training for practitioners, and to maintain the confidence of all stakeholders by effectively addressing ethical, legal and social issues arising from pharmacogenomics."
  
  
• Dopamine, Genetics, and Environmental Stressors in ADHD. As an example of the above, this month's Archives of General Psychiatry has an article by Manfred Laucht, et al., showing evidence of an interaction between a mutation in the Dopamine Transporter (DAT) gene and severe environmental stress (e.g., abuse) triggering symptoms of ADHD. Also mentioned in the podcast is data suggesting that certain Serotonin Transporter Promoter (5HTTP) mutations predict one's response to SSRI antidepressants, the development of side effects to these drugs, and the propensity to develop psychiatric symptoms.
  
  
• Forced Outpatient Treatment in PA. Liz Spikol, who writes the blog and newspaper column, Trouble with Spikol, for the Philadelphia Weekly, writes about Pennsylvania Senate Bill 226, which would make it easier to make people with severe mental illness who are "unlikely to survive safely in the community without supervision." A long debate on the podcast ensues (half the 'cast) about the ethics and practicality of such tactics.
  
  
• Don't miss Roy's telling of the official (according to psychologist, Richard Wiseman) funniest joke in the world (around the 25 minute mark). Just to be on the safe side, be sure you aren't driving when you listen to it.
  

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Find show notes with links at: http://mythreeshrinks.com/. The address to send us your Q&A's is there, as well. This podcast is available on iTunes (feel free to post a review) or as an RSS feed. You can also listen to or download the .mp3 or the MPEG-4 file from mythreeshrinks.com. Thank you for listening.

FDA Drugs: February 2007

2007: Mar | Feb | Jan . . . 2006: Dec | Nov | Oct | Sep

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FDA Drugs: February 2007

• Warning Letter: Signature Genetics. Seryx is the company that markets an excellent (but expensive) pharmacogenetics program which will take your blood or cheek cells and analyze your DNA for various genotypes which affect how your body metabolizes certain drugs, many of which are psychotropic drugs. This information may be used to help a prescriber make decisions about starting dosages or drugs or combinations of drugs to use or avoid. This topic is a whole 'nother post I could do, but this type of testing can be used inappropriately (2002 Quackwatch page), as well. Anyway, this computer program is considered by the FDA to be a "device", and it has not applied for FDA approval, so the FDA is telling it to stop until approval is obtained.
• Wellbutrin (bupropion) Medication Guides updated: PDF versions of Medication Guides for Wellbutrin and Wellbutrin SR were updated.
• Generic Focalin (dexmethylphenidate) approved.
• Only 22 New Drugs Approved in 2006: Merrill Goozner comments on his blog, GoozNews, about the lowering of innovation in the pharma industry.
• FDA Starts Podcasts: The FDA Commissioner, Dr. Andy von Eschenbach, has started a series of drug safety-oriented podcasts. The first one just announces the series. Go to the XML feed to subscribe.
• ADHD Drug Warnings: The FDA is requiring all manufacturers of drugs used to treat ADHD, including Adderall, Concerta, Ritalin, and Strattera, to develop Medication Guides to warn patients about the risks of cardiovascular (sudden death, stroke, heart attack, blood pressure) and psychiatric (mania, psychosis, aggression) side effects.
• Vyvanse releases Medication Guide: Shire's Vyvanse (lisdexamfetamine dimesylate) was listed last month (before the name was changed from Vynase) as a new ADHD drug. It is a prodrug, meaning it is metabolized into an active drug by the body. Advantages are said to be that it is once-daily and that it is less likely to be abused (ie, 4 out of 5 drug abusers prefer other stimulants to this one). It now has full approval as a Schedule II drug (for full prescribing info, see link to Label Info here.)
• Changes in Nardil (phenelzine) Prescribing Info: added severe renal impairment or renal disease to list of contraindications; added cautions about use in diabetes; and added warning about drug interaction with guanethidine (Ismelin).
• Changes in Cymbalta (duloxetine) Prescribing Info: a number of changes were made, though I cannot tell how substantive these were. Lilly did receive a new indication for the treatment of GAD (Generalized Anxiety Disorder) with Cymbalta.
• Changes in Effexor XR (venlafaxine) Prescribing Info: the following was added under the Precautions section: "Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse events should be considered in venlafaxine-treated patients who present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation and discontinuation of venlafaxine therapy should be considered."
• Zimulti or Acomplia (rimonabant) review extended: This cannibinoid receptor antagonist, which is being reviewed as a weight loss drug (you guessed it... it blocks the munchies, even if you are not smoking pot), was to have a final decision on approval status on April 26. The review period has been extended to July 27. (I reported in November's update that this drug was approved in Mexico.) The latest proposed brand name is Zimulti. The hearing for this drug will be held on June 13, 2007, before the Metabolic & Endocrinologic Drugs Advisory Committee. When the background resource documents are ready, they will be found here.
• Warning Letter: Provigil (modafinil). Cephalon got slapped for promoting its wakefulness-promoting drug (indicated for use in narcolepsy, obstructive sleep apnea, and Shift Work Sleep Disorder) by distributing a document by Dr. Kerasidis which states the drug is effective in multiple sclerosis, Parkinson's, depression, ADD, and chronic fatigue syndrome. Interesting, in that this document was provided as testimony to the Maryland Dept of Health and Mental Hygiene's Committee which is responsible for making decisions about which drugs will be placed on the Medicaid formulary list.
  

FDA Drugs: January 2007

2007: Mar | Feb | Jan . . . 2006: Dec | Nov | Oct | Sep

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FDA Drugs: January 2007

• Vynase (now Vyvanse) gets approvable letter: New River Pharm and Shire are poised to release a new ADHD drug, lisdexamfetamine (was NRP-104).
• Generic Wellbutrin XL approved: by Anchen Pharma.
• Wellbutrin Package Insert was modified: to reflect the following additional info regarding its use in people with renal failure: "An inter-study comparison between normal subjects and patients with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure." Also added was mention of double vision and increased intraocular pressure as reported adverse reactions.
  
• FDA releases Guidance on Pharmacogenetic data. The FDA released definitions for genomic biomarkers, pharmacogenomics, and pharmacogenetics.
• Alexza is working on Schizophrenia Agitation drug: The drug is an inhaled form of loxapine, a typical antipsychotic.
• New Antidepressant: Pristiq. Wyeth, who makes Effexor XR (venlafaxine), received an approvable letter for Pristiq (desvenlafaxine succinate), which is a metabolic derivative of Effexor; both drugs are serotonin-norepinephrine reuptake inhibitors (SNRIs). Approvable letters have conditions which must be met before the product can be marketed. The Wyeth facility in Puerto Rico must pass FDA's muster, and the marketing plan must be approved, prior to its release for the Major Depression indication. Wyeth is also going after an indication for Vaso-Motor Symptoms (VMS) related to menopause ("hot flashes" in English).
  

FDA Drugs: December 2006

2007: Mar | Feb | Jan . . . 2006: Dec | Nov | Oct | Sep

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I'm a bit behind on listing relevant FDA update info, so I'll get you all up to date.

• Zyprexa (olanzapine) labeling change: Label was revised to state that "Rare postmarketing reports of hepatitis have been received. Very rare cases of cholestatic or mixed liver injury have also been reported in the postmarketing period." [.pdf]
• Bifeprunox for Schizophrenia: Phase III results were released showing that patients did better on this than on placebo over 6 months (not hard to beat placebo). They also reported weight and lipid profile reductions. Their New Drug Application was submitted to the FDA in October.
• Invega (iloperidone) results: These results are interesting in that they looked at efficacy and side effects data stratified by whether or not one had a particular pharmacogenetic genotype. They do not identify the genotype, but I suspect it is something like DRD4 or DAT-1. So far, however, we have yet to see the promise of a pharmacogenetic test which one would perform prior to prescribing a drug. For this to really work, the test will have to be free and the results available promptly.
• Melt-in-your-mouth Methadone: Roxane got a dissolvable 40mg methadone approved.
• Invega (iloperidone) approved: This is an active metabolite of Risperdal/risperidone, very similar to this atypical antipsychotic. [label] [detailed review]