James Watson Live!

"To succeed in science, you have to avoid dumb people... Even as a child, I never liked to play tag with anyone who was bad as I was. If you win, it gives you no pleasure. And in the game of science-or life-the highest goal isn't simply to win, it's to win at something really difficult. Put another way, it's to go somewhere beyond your ability and come out on top."
-- James Watson, "Succeeding in Science: Some Rules of Thumb", Science, 261, 24 (September 1993): 1812. September 1993.


Snowy here in Maryland.

Yesterday, there was just a little snow, a three-inch surprise in the morning, and schools were closed, things were surprisingly still. My agenda included a trip to Hopkins to hear Nobel prize winner James Watson speak. Was it canceled? Did I really want to risk being caught in the snow coming home? No, it wasn't canceled. And when would I ever get the chance to hear James Watson speak? So yes, I did risk the weather, and it was fine.

I've never seen Hurd Hall so packed. No chandeliers, but people were hanging off the balcony, snow date and all. There weren't a lot of psychiatrists there, even though the lecture was sponsored by the Department of Psychiatry, but this meant I got a front row seat in the reserved section.

Dr. Watson was an entertaining speaker, to say the least. He structured his talk around his "rules" for life, and said there were rules involved in the race to find the structure of DNA. Oh, I wish I written them down. He started something like this, "I was a boy on the South Side of Chicago and the first rule was Don't fight bigger boys or dogs." His second rule of life had something to do with putting a spin on balls. The rules around the story of the discovery of the double helix included things like don't be the smartest person in the room, don't research the same thing that everyone else is researching, leave a job before you get bored with it, speak to your competitors.... it was all told with a sense of humor and I should probably have taken notes for a few good quotes and a better taste of the rules themselves, but who knew? Oh, and I didn't have a pen. I have to do something about that.

Dr. Watson's account of the discovery of the structure of DNA is written in The Double Helix but since the publication of the book, letters have been found that shed more light on the relationships between the players, and Watson quoted some of these letters. They weren't quite what you'd expect from geniuses who were changing the course of science, and I suppose I forget that all stories have interpersonal dynamics and the associated banter as part of their plot.

You knew who Watson liked and who he didn't -- the stories weren't subtle, and oh, he said some things that were a bit off from the politically correct...it made for entertainment. Did he really say that? I won't repeat them, because we try to be a politically correct blog here, but you can get the flavor from the quote above.

Genetic Friendships

Here's an interesting article I came across about the role of genetics in friendships. Two researchers studied genetics found in social networks. They asked people in two longitudinal studies to name their friends, then they compared certain genetic markers. They found that the DRD2 gene, which is associated with alcoholism, tends to cluster among friends. In other words, DRD2 positive people tend to be friends with other DRD2 people. Conversely, the CYP2A6 gene carriers tended to make friends with CYP2A6 negative people. This gene is associated with people who have open personality styles. In other words, a tendency to seek out variety and new ideas.

I'm not sure what to make of all this except to say I think it's interesting that there may be a biologically driven reason why Dinah and I are friends. In many ways we're the exact opposite. Dinah is a whirling dervish of multi-tasking in a way that I find exhausting, yet she seems to thrive on it. I'm an obsessionally detail-oriented and data-driven person who never loses her car keys (or drowns a cell phone). I enjoy living this way but have no doubt that Dinah would go mad from boredom within hours if we ever woke up and found our lives had been switched. I can guess which one of us has the CYP2A6 gene. The scientists would say that we are friends because we have complimentary genetics---traits that balance off and help one another. And I guess that's true. Our book might not ever have been finished if Dinah hadn't kept us moving and on task. And it wouldn't have been as organized and readable if I hadn't followed up with the editing. So it all works out in the end.

Now we just need to find a gene that protects against cell phone loss.

Doggy Genes and OCD

The timing couldn't be more perfect for an article in the New York Times on the genetics of compulsive behaviors in poochies.

In Scientists Find a Shared Gene in Dogs with Compulsive Behavior, Mark Derr talks about the work of Dr. Nicholas Dodman on doberman's who compulsively suck their flanks (hmm, what exactly does that mean?) and a genetic link:

Dr. Dodman and his collaborators searched for a genetic source for this behavior by scanning and comparing the genomes of 94 Doberman pinschers that sucked their flanks, sucked on blankets or engaged in both behaviors with those of 73 Dobermans that did neither. They also studied the pedigrees of all the dogs for complex patterns of inheritance. The researchers identified a spot on canine chromosome 7 that contains the gene CDH2 (Cadherin 2), which showed variation in the genetic code when the sucking and nonsucking dogs were compared.

Should ClinkShrink be worried? Might she adopt a dog with a psychiatric disorder? Should her would be pup have genetic testing? Derr goes on to write:

Recent rough estimates by Dr. Karen L. Overall, a veterinarian specializing in animal behavior at the University of Pennsylvania School of Medicine, suggest that up to 8 percent of dogs in America — five million to six million animals — exhibit compulsive behaviors, like fence-running, pacing, spinning, tail-chasing, snapping at imaginary flies, licking, chewing, barking and staring. Males with the problem outnumber females three to one in dogs, she found, whereas in cats the ratio is reversed.

Ah, but it's not just the poochies with this problem: other critters have compulsive behaviors, and treatment is available. Mr. Derr tells us:

Other domestic animals, notably cats and horses, as well as some of the animals at zoos, exhibit compulsive behaviors, including wool-sucking in Siamese cats, and locomotion disorders like stall walking and weaving in confined horses and pacing in captive polar bears, tigers and other carnivores used to ranging across large territories.

Although antidepressants, particularly selective serotonin reuptake inhibitors and clomipramine, a tricyclic antidepressant, and behavior modification have proved effective at controlling compulsive behavior in dogs and people, they do not appear to correct underlying pathologies or causes, Dr. Ginns said. Those causes are likely to be as varied as the compulsive behaviors and as complex as the interplay of multiple genes and the environment.

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.

Rethinking Antidepressants

Thanks to Henry for sending this link.

On cnet news, Elizabeth Armstrong Moore writes about research presented at this month's Neuroscience conference in Chicago:

Depression researcher Eva Redei presented research at the Neuroscience 2009 conference in Chicago this week that calls into question two tenets of depression science: that stressful life events are a major cause of depression, and that an imbalance in neurotransmitters triggers depressive symptoms.

Armstrong goes on to report that the research looks at the overlap of genes in RATS (not peeps) and notes that antidepressants work better for stress then depression and the genetic overlap between the two is minimal (--oh, why isn't Roy writing this, he's so much more eloquent than I am about the genetic stuff).
Armstrong goes on to say:

To test the long-held belief that stress is a major cause of depression, Redei looked for similarities between these two sets of genes. Out of more than 30,000 genes on the microarray, 254 were related to stress and 1,275 to depression. Only 5 were found in both samples.

"This finding is clear evidence that at least in an animal model, chronic stress does not cause the same molecular changes that depression does," Redei says. She is now looking at the genes that differ in the depressed rats so that she can narrow down targets for drug development.

Antidepressants are also often ineffective, Redei says, because they aim to boost the neurotransmitters serotonin, norepinephrine, and dopamine, whose reduced levels have been associated with depression. But this strategy is now also being called into question.

It's sort of news to me that we thought stress "causes" depression. I guess I thought extreme stressors (as opposed to general 'stress') can precipitate depression in those inclined to become depressed. Many people suffer extreme distress without getting major depression and many people with histories of major depression weather severe storms without a recurrence. What is nice about this research is that it challenges us to think in new ways, and I think sometimes research gets hooked around theories that aren't definitely proven and creativity gets stifled. Anything that nudges that can't be bad....

Only Perfect People Should Have Children

I hope you know that the title of this post is sarcastic.

A reader wrote to us and asked if we'd address the issue of whether people with bipolar disorder should have children:

"I have been asked how I could have had children knowing I had bipolar and the person asking would never have known I had bipolar if i did not told them."

I enjoyed thinking about this, but I'm punting. I really don't like the idea of putting a value judgment on who should or shouldn't have children. Truly, there are a lot of people out there who shouldn't have babies (because they can't take care of them), but do, and a lot of wonderful people who've been born to people who maybe shouldn't have had babies, but did, and we're all glad they got born anyway. There are no guarantees in life, and I've never heard anyone put out a blanket statement that people with psychiatric disorders shouldn't have children.

Thoughts?

Shrink Rap: Grand Rounds is up at Emergiblog

Check out this week's Grand Rounds on Emergiblog.

Notables:

• Doctor Anonymous' BlogTalkRadio interview of NeoNurseChic about her chronic headache pain.
• Dr Deb Serani blogs about the Mental Health Parity law.
• InsureBlog discusses the Personal Genome Project.
• Colorado Health Insurance Insider writes about autism and insurance.
• The Anesthesioboist takes on Descarte's mind-body dualism.

Latest Genetic News in Schizophrenia

Schizophrenia has been long thought to be a heterogeneous disease, with many different pathways all leading to an illness with similar symptoms among its affected ranks. It is believed to be caused by a combination of genetic and environmental triggers, as there is a 50% chance of getting it if your identical twin does and a 10-15% chance if your parent or sibling does. Various environmental triggers appear to increase the risk of getting it, such as in utero infections, being born in the winter, and growing up in a family where there is a lot of yelling and emotional expressiveness. About one percent of the population has schizophrenia.

A recent study in Science of whole genome DNA in hundreds of people with and without schizophrenia finds that rare DNA mutations may more of a role to play than previously thought. From Scientific American: "In this study, researchers combed the genomes of 150 schizophrenia sufferers and 268 healthy individuals for never-before-seen copy number variations (CNVs)—mutations that result in large swaths of DNA encompassing multiple genes either being deleted or duplicated. Some such mutations have been found to be benign, but others have been implicated in ailments such as autism and cancer. The team of scientists, from research facilities across the U.S., found novel gene alterations in 5 percent of the healthy volunteers and 15 percent of the schizophrenia patients; new CNVs showed up in 20 percent of those subjects who developed symptoms at or before the age of 18."

53 different mutations were found in these patients. As more of these studies look at whole genomes from families with a high number of affected individuals (like mine, with 7 or 8 people with schizophrenia spectrum diagnoses), we will learn more about what goes wrong in these illnesses and how to better treat them.

My Three Shrinks Podcast 24: Dr Phil on Skype

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Okay, folks, this one's a bit on the long side, but well worth it. Around the 28-minute mark is an "interview" with talk-show psychologist Dr. Phil. See below for my notes about it, but let's just say that Dinah has vowed to get even with Clink and me. Or, click here to listen to just the prank and the mash-up song.

Also, listen in to us next week in Podcast #32 as Doctor Anonymous joins us as a guest blogger (this one's for real).

AND CHECK OUT ALL OUR OTHER POSTS FROM THIS WEEKEND. Click or scroll....

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June 10, 2007: #24 Dr. Phil on Skype

Topics include:

• Genetics of Cocaine-Induced Paranoia. Roy talks about a recent article in Biological Psychiatry by Kalayasiri which suggests 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. Genetics is playing an increasing role in understanding how we respond to drugs AND to our environment.
• Dinah wins an award for her writing.
• Expectation Vs. Evidence-based Medicine. We get into a detailed discussion about how patients' perceptions and expectations get in the way of evidence-based medicine (with examples from Flea's post on admitting children and direct-to-consumer advertising). "Doc, my friend got better with DrugX so I want to try it." "It goes back to 'who deserves care'."
• Dr. Phil visits My Three Shrinks. THIS IS A MUST-LISTEN SEGMENT! Clink and I play a trick on Dinah by "calling" Dr. Phil on Skype and he "interviews" us. This is a riot!! Dinah is such a good sport. [link to DrPhil Soundboard]
• Dark Tourism. After reading a NYT piece on touring prisons, Clink discusses the concept of dark tourism, where people seek out notorious sites to see (like cemeteries and prisons). She sent us a humongous scholarly piece on the subject (see Clink's Travelogue for more fun). Dinah talked about visiting catacombs in Paris where the walls are made of human bones, and here's a pic of those. (Note from Dinah, I wanted to put the picture and the link in, but I didn't listen to the podcast to hear if I was editted out. They do those things, you know).
  
  
  
  

• Special DrPhil/MTS mashup treat at the end. Credit KLF (aka The Timelords aka The JAMs) for the song, Doctorin' the Tardis, which you can find on emusic for 25 cents, or on iTunes for 99 cents.
  

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.

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.

Serotonin Knockouts are a Pain in the SSRI

[PWT=pain withdrawal threshold... a lower number means greater sensitivity to mechanical pain. Carrageenan was used as the source of mechanical pain here. In A, you see that duloxetine (Cymbalta) restored PWT to normal in both normal mice (WT) and mice without serotonin brain cells (Lmx1b), thus indicating a pain-relieving effect. However, in B at the bottom, fluoxetine (Prozac) did NOT improve the PWT after injection of carrageenan (focus on the black bars), indicating that Prozac does not help this kind of pain in mice without serotonin, meaning that serotonin is an important part of pain regulation, but norepinephrine may be even more important.]

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Okay, Dinah, here's something (though it doesn't really "shake things up").

Check out this article in the Journal of Neuroscience by ZQ Zhao et al., showing pretty good evidence (like we needed more) that the brain neurotransmitter, serotonin (or 5HT), is involved in pain regulation.

What they did was use knockout mice -- mice which have been genetically altered to remove or disable the gene which codes for a given protein -- which have had the codes for serotonin neurons in the brain removed. So, these mice do not have serotonin-producing brain cells. This permits the researchers to see the effect that selective serotonin reuptake inhibitors (SSRIs) and other antidepressants have (or don't have) on the mice.

They were interested in the anti-pain (also called nociceptive) effects of these antidepressants, and the role that serotonin plays. For example, we know that antidepressants which have BOTH serotonin and norepinephrine (NE) effects (SNRIs, like Cymbalta and Effexor) are better at reducing pain than those with solely serotonin effects (SSRIs, like Prozac and Paxil).

So, these particular mice have normal pain responses to hot things, reduced pain responses to mechanical pain (eg, pinch, squeeze, crush... in this study, they simply poked them with different sizes of fishing line), and elevated pain responses to inflammation (eg, an infection, arthritis, etc). The acute analgesic properties of antidepressants were simply nonexistent in these mice. Their acute pain responses were unaffected by antidepressants. However, SNRIs did reduce their responses to chronic pain, while SSRIs did not.

Although the noradrenergic system in Lmx1b^f/f/p mice appears to be normal, the analgesic effect of the TCA amitriptyline on acute thermal pain behavior was strongly attenuated in Lmx1b^f/f/p mice. Because a total absence of analgesic effect was observed in Lmx1b^f/f/p mice treated with fluoxetine and duloxetine, the residual analgesic effect observed in Lmx1b^f/f/p mice treated with amitriptyline is likely caused by mechanisms other than blockade of 5-HT and NE reuptake, such as channel modulation and NMDA receptor antagonism (Lawson, 2002; Wang et al., 2004). Together, our data indicate that although the NE component seems to be critical in the analgesic effect of antidepressants, endogenous 5-HT is also of fundamental importance for the analgesic effect of these drugs, especially in reducing thermal sensitivity.

They conclude that "Together, our data indicate that although the NE component seems to be critical in the analgesic effect of antidepressants, endogenous 5-HT is also of fundamental importance for the analgesic effect of these drugs, especially in reducing thermal sensitivity."

The main reason I posted this is just to demonstrate the cool things one can do with genetics. You can knock out a gene; in this case, the one responsible for turning a developing neuron into a serotonin-producing neuron. You can then figure out what the consequences of that absent gene are. Finally, this also emphasizes how we can learn how to fine-tune our knowledge about pain control, so that more effective -- and less addictive -- treatments can be developed.

My Three Shrinks Podcast 22: Forced Treatment

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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.
  

My Three Shrinks Podcast 9: My Three Chromosomes

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We decided to listen to Sophizo's suggestion and set up an email address for listeners to send questions to, and we will answer a couple in each podcast (starting with Podcast #11). We won't be able to answer them all, and we will not be able to answer any personal clinical questions. Send an email to mythreeshrinksATgmailDOTcom.
Also, feel free to go to iTunes and write a review (we had one, but it disappeared). We now have over 300 regular listeners (wow!), so maybe someone has something to say about us (maybe even something nice).
Last request: Dinah is only up to mid-season 2 in Lost, so she requests you post no spoilers for her on our blog, or she will be Positively Lost.

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February 4, 2007:
Topics include:

• AJP: Genetics of depression. Two related articles in this month's Green Journal are from the GenRED study (Genetics of Recurrent Early-onset Major Depression). The Levinson article reports significant linkage for an area on chromosome 15 in 631 families with recurrent early-onset major depression ("early onset"=<40 yrs old). The Holmans article reports results of a genome scan in 656 families, finding significant linkage in areas of chromosomes 8, 15, and 17.
• Mandatory screening for depression? Clink conducts a thought exercise.
  
• Blogs & Identity. We talk about Dr. Anonymous' recent troubles after Fox News brands his one of 5 great medical blogs, and our feelings about blogging behind anonymous names (or not). See Dr A's post on the Myth of Anonymous Blogging. Moof's post is also worth reading on this topic. (We suspect his video blog may have given away his identity.) We look forwards to the congressional hearings on who leaked his identity and how high up this thing goes.
  
• Whither Public Psychiatry? Where have all the public sector psychiatrists gone? The number of HPSAs (Health Professional Shortage Areas) have decreased, while there seems to be less physician trainees who accept partial payment of their educational costs in return for a pledge to work in a HPSA after completing their training. But, Maryland has the most psychologists per capita in the US. (Search for Maryland psychiatrists at mdpsych.org.)
  
• Questions for us? Email at mythreeshrinksATgmailDOTcom. We'll answer some starting with Podcast #11 (in two weeks).

Next week: Biochemical effects of chocolate on mood (we really mean it this time). Also false positive drug tests, and children of psychiatrists.
Last week's musical snippet was from the 1986 release, Modigliani (Lost in Your Eyes), from their eponymous album by Book of Love [lyrics].

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Find show notes with links at:

http://psychiatrist-blog.blogspot.com/2007/02/my-three-shrinks-podcast-9-my-three.html
This podcast is available on iTunes. You can also listen to or download the .mp3 or the MPEG-4 file from mythreeshrinks.com. Thank you for listening.

technorati tags:speed, genetics, depression, GenRED, chromosome, blogs, podcast, public, psychology, psychiatry, psychiatrist, AJP, article

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FDA Drugs: November 2006

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

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Just a quick list of psychiatry-relevant FDA and related notices...

• More Ambien (zolpidem) generics (and here) get tentative approval. Sanofi's patent expired on Oct 21, 2006, but they triggered an automatic 6-month extension by applying for pediatric use. We should start hearing about generic Ambien around April or May. The first approved generic manufacturer gets an automatic 6-month exclusivity before the flood gates open up, and other manufacturers can get into the game. There are about a dozen manufacturers all lined up for tentative approval.


• Phase I results promising for NGX426. NGX424 gets coverted in the body to tezampanel, an AMPA/kainate receptor antagonist, which makes it a non-narcotic pain medicine. The company, TorreyPines, seems to be looking at indications for migraines and neuropathic pain, though this class of drug may be useful on epilepsy and anxiety, as well.


• Drugs to turn on specific genes. This is one of the new holy grails. As described in the linked PNAS article, using RNA interference techniques, you make a little piece of double-stranded RNA (dsRNA) that is designed to bind to a specific gene, say, the gene that contains the instructions for making amyloid precursor protein (APP), which is involved in causing Alzheimer's dementia, or maybe the gene that codes for a particular variant of the CETP protein, which has been associated with increased longevity. According the article, sometimes this technique will silence a gene, and sometimes it will crank up the volume. Drugs of the future would be used to selectively turn on, off, up, down genes, like fiddling with 100,000 dials on a huge mixing board, trying to get just the right mix. A fascinating, but scary, proposition.


• Mirapex (pramipexole) approved (label .pdf) for Restless Legs Syndrome. This is old news now, thanks to the marketing blitz on this indication.


• Generic Zyprexa (olanzapine) gets tentative approval. There are now 5 companies with approved versions of generic Zyprexa, waiting to launch when either Lilly's patent expires (2011) or someone successfully challenges their patent application (now in process).


• Rimonabant (brands Acomplia or Zimulti) approved in Mexico. The sexy new diet drug is already approved in Europe, and is now on our shores. Rimonabant is a CB1 cannibinoid receptor antagonist, so it will also block the munchies from smoking marijuana. Sanofi Aventis has already submitted a new drug application to the U.S. FDA, followed by a resubmission in October.


• Seroquel marketing warning letter. AstraZeneca received an FDA letter warning that they violated the rules by underemphasizing the risk of diabetes with Seroquel in a piece of marketing material. They also failed to note some other risks.


• Warning: Tamiflu side effects - delirium, self-injury. Roche and FDA sent out notification letters warning of reports about self-injury and delirium occurring in people, especially children, who have the flu and take Tamiflu. They note that these reactions may also occur from the flu itself.


• Warning: Methadone side effects - cardiac, breathing, death. FDA put out a public health advisory warning of "reports of death and life-threatening adverse events such as respiratory depression and cardiac arrhythmias in patients receiving methadone. These adverse events are the possible result of unintentional methadone overdoses, drug interactions, and methadone's cardiac toxicities (QT prolongation and Torsades de Pointes)."

Search the FDA's "Orange Book" for more drug data.

technorati tags:ambien, NGX426, FDA, iRNA, insomnia, mirapex, pramipexole, zolpidem, RLS, zyprexa, olanzapine, rimonabant, acomplia, zimulti, seroquel, quetiapine, tamiflu, methadone, methadon, psychiatry, psychology, medications

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Methuselah's Genes

Two interesting new research pieces came out this past week or so on aging and dementia.

First, this piece about a gene which is found more often in folks who live 100 years, suggesting that people with the val-val variant of the CETP gene (cholesteryl ester transfer protein) may have a better shot at living a longer life. Centenarians with this genetic variant were also five times less likely to have dementia. The gene, found on Chromosome 16 (OMIM), produces a protein involved in lipid metabolism which results in larger, less sticky, cholesterol particles. The article came out in today's Neurology.

I looked in PubMed for similar articles from this author (Barzilai) and found this April 2006 article in PLoS Biology looking at several longevity-related genes in this same population. This article describes two genes which are more prevelant in really old people: the val/val (also known as I405V) variant of CETP and the -641C variant of the APOC3 gene (another one that deals with lipids).

Here's what's really cool. This guy has gathered this big group of centenarians and is doing genome-wide scans to determine which genes may be associated with longer (and healthier) lives. This work comes out of Albert Einstein's Institute for Aging Research.

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The second item is the NEJM article, from Gary Small at the UCLA Center on Aging, which showed that a molecule (FDDNP) binds to the amyloid plaques and tau protein tangles which are characteristic for Alzheimer's disease. After an injection of this experimental tracer chemical, a PET scan can then show where this stuff is in the brain. If there's enough of it, and in the right places, chances are good that you have (or are developing) Alzheimer's dementia.

This is just a research tool, at the moment. Neither this imaging tool, nor the above genetic tests, can be used clinically in the assessment of dementia risk or diagnosis. Maybe one day.

technorati tags:aging, longevity, brain, dementia, Alzheimer's, genes, FDDNP, APOC3, CETP, PET, UCLA, Einstein, psychiatry

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