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).
  

Happy Easter

Here's wishing the best to all our readers and listeners: to new life, new hope and fresh beginnings.

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]
  

"You Toucha This Egg, I Breaka You Wing"

Okay, so this phrase is a take-off from a classic bumper sticker. But I just couldn't resist posting this interesting, but not psychiatric at all, article which was in the same PNAS issue as the VEGF article.

Cowbirds are one of those bird species that are too lazy to raise their own kin, so they sometimes sneak their own eggs into other species' nests, hoping that the unsuspecting host will raise the birds as their own.

TURNS OUT that after they add the foreign egg, they will hang around to make sure that the new host doesn't dump the imposter. If they do, the connected cowbirds will push the host parents' eggs out of the nest.

Otherwise, if the surrogate parents accept the offer they can't refuse and raise the little calfbirds, then the avian mafioso lets them be. Now that's a made egg.

Of Course I'm Depressed

MWAK asked a question in the comments on my "Taxing Taxonomy" post and I started to answer but decided to turn it into a blog post.

MWAK asked how to distinguish between major depression and bereavement. The good news is that you don't have to. If the patient meets criteria for major depression, they have major depression and you should refer the patient. The exclusionary bereavement criterion is misleading. The Archives article shows that the syndrome is independent of cause: major depression that develops in the context of bereavement or in the context of medical hospitalization or the context of incarceration or in the context of job loss is clinically indistinguishable.

The good thing about using a clinical syndrome definition is that it separates diagnosis from etiology. This frees the clinician from zeroing in on one etiology at the cost of another. This is important in psychiatry because an attribution error can be physically risky. The bereaved clinically depressed 75 year old woman may also be suffering from hypothyroidism. The bereaved 35 year old gay man who lost his companion to AIDS may also have an HIV-associated affective syndrome. A diagnosis of a clinical syndrome is only the first step. The importance of psychiatry (as opposed to non-medically trained mental health professionals) is that we know the next step is a good diagnostic workup.

The need to attribute causation really only seems to come into play with when we're talking about major depression even though there are other psychiatric syndromes that can be precipitated by life stress: the first episode of psychosis in schizophrenia for example, or mania. Yet we don't attribute mania to life circumstances. If someone is impulsively spending thousands of dollars, talking a mile-a-minute and staying up all night cleaning the house we don't say "Of course you're happy, you have a great husband and a great job and great kids (or a great dog)." We say, "Please please go back on your lithium." (My favorite causation story is of a psychologist who once asked me, "Is this inmate demented because of the stress of getting an 80 year sentence?" I explained that it was from the stress of having an 80 year old brain.)

The other thing the Times story didn't mention is that all the groups in the study had recurring episodes. Both the loss- and bereavement-triggered groups had a mean of two to four episodes. The trigger was identified only for the index (first) episode. You could make an argument that someone might get misdiagnosed once---but four times? And at least 5% of subjects were hospitalized. I think Roy might have something to say about this. How many times do you see people on your inpatient unit for "intense normal sadness" (the authors' classification) as opposed to clinical depression?

The authors were concerned about the stigma of a posssibly inaccurate diagnosis. Given the information they presented about their own subjects, I'd rather err on the side of caution.

VEGF: the New antidepressant

Vascular Endothelial Growth Factor (VEGF) stimulates the growth of new capillaries. In the brain, VEGF also stimulates the growth of new brain cells. A recent PNAS article, by Jennifer L. Warner-Schmidt and Ronald S. Duman from Yale, demonstrates that VEGF is a middle-man in the antidepressant response mechanism (better abstract here).

They show in rats that:

• VEGF goes up with ECT, with an sSRI (fluoxetine/Prozac), and with an sNRI (desipramine/Norpramine)
  


• This increase in VEGF is associated with new neuronal growth in the hippocampus


• Treatment with ECT, fluoxetine, or desipramine is associated with new neuronal growth in the hippocampus
  


• Injecting VEGF is associated with an antidepressant response in animal models of depression


• Blockade of the VEGF receptor with Flk-1 blocks the growth of new neurons in the hippocampus (in all 4 experimental arms--ECT, fluoxetine, desipramine, or VEGF injection)
  


• Blockade of the VEGF receptor blocks the behavioral response to ECT, fluoxetine, or desipramine in animal models of depression

This study adds to the weight of evidence that one of the end results for antidepressant treatment is stimulating new brain cell growth. It is not clear whether this is related or not to these drugs' effects on serotonin or norepinephrine, but it appears it may be possible to bypass neurotransmitter mechanisms (and avoid their subsequent side effects) and go directly to neurogenesis. This may lead to some entirely new treatments for depression and bipolar disorder down the road (way down the road).

Taxing Taxonomy

During our last podcast we answered a question about whether or not pedophilia was a disease. Another earlier question we addressed was whether or not schizotypal personality disorder was related to schizophrenia. Our readers/listeners aren't the only ones questioning how to approach psychiatric diagnoses.

Today's American Journal of Psychiatry has a dense article on the "Conceptual Taxonomy of Psychiatric Disorders". It's an overview of philosophical approaches to the classification of mental disorders written by the folks working on DSM-V. The abstract alone is worthy of a philosophy major. I made it through the entire article but I promise never to bring it up on the podcast. The article considers whether or not psychiatric disorders are more like chemical elements (they exist naturally outside of ourselves, have common properties, and must be defined by exploration and discovery---known as essentialism) or whether at the other extreme they are created arbitrarily by mutual agreement separate from any underlying truths---known as nominalism.

And that's only one of the six "dimensions of categorization" they propose applying to current medical models. Thank goodness Dinah and I only had to consider the four perspectives. (Although I have to admit I enjoyed the part where they compared making a diagnosis across a continuum to slicing a meatloaf!)

Another diagnosis-related issue was addressed in a recent New York Times article discussing a study of depressive symptoms among the bereaved. In an article published in the Archives of General Psychiatry researchers compared bereaved depressed subjects with depressed patients suffering from other losses with regard to number and duration of symptoms, functional impairment and other measures. They found no difference between the two groups and concluded that many life losses could be used as an exclusion criteria for major depression. (My translation: "Of course you're depressed, look what you've been through.")

I think this article will serve to muddy the waters rather than clarify them. I deal with this issue frequently among my patients after a new diagnosis of major depression: "Of course I'm depressed, look where I am!" In fact the majority of prisoners are not clinically depressed. Most of the death row inmates I've seen have not been clinically depressed. All this study does is support the idea that psychosocial stress can precipitate disease---we already knew that. It supports the idea that current diagnostic criteria can define a syndrome separate from causation, which is a good thing. The one thing it doesn't address---at all---is how the disorder should be treated. And that's the main thing the New York Times article talked about.

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Maybe I Am A Therapist

Just a couple of vignettes from today that I enjoyed:

Patient: "How do you know that bipolar disorder is a disease?"

Me: I go on about genetics and chromosomes and changes in neurotransmitters and response to medication. Then I do what I should have done to begin with: I ask the patient what he thinks is the cause of his multiple hospitalizations and suicide attempts.

Patient: "I think it's a government conspiracy."

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(During intake assessment patient reveals he just had a bad phone call home. Brief crisis intervention provided.)

Patient: "Hey doc, can I come back down again and talk to you sometime?"

Me: "We have psychologists here if you'd like some counselling. I can set you up with one. I just work with medications; I don't really do counselling myself."

Patient: "Why not? You're a good one!"

Call Me Back When.....

I was reading our neighborhood tabloid the other day and I was struck by one of the advertisements: it was for a doctor's practice. There was his photo, a distinguished looking gentleman, and the ad, like every other doc's ad, listed his virtues. I wish I could find it so I could put a direct quote. I called a neighbor to ask if he had the paper and he suggested I look on-line, to which I replied, "I want one of the ads for a blog post." Funny, my neighbor hung up quickly. I contemplated rummaging through our re-cycling, already outside, in the dark, if it's still there it's soaked no doubt-- Anything for the Blog. Instead, I'll wing it.

So the doc's ad began with the bullet-point claim that he Returns Phone Calls Promptly. Gray hair, years of practice, and that's the first thing he wants to proclaim about his professional persona. The second bullet point contends that he offers Same Day Appointments. After those two sales points, he goes on to mention that he has 25 years of experience and an impressive list of educational and academic appointments. His picture reveals that he sports a friendly smile.

It seems like a funny statement that a distinguished doc is advertising that he returns his phone calls and offers Same Day appointments, as if this is a bonus. Shouldn't everyone return their calls or at least have them screened, prioritized, dealt with in some way, even if simply to have a nurse say "That sounds important, why don't you come in to see the doctor?" And same day appointments: Pediatricians see kids the same day, why is it so hard to find an adult doc who does the same. Why are these things Bonuses? And if you're wondering why such a doc needs to advertise, your guess is as good as mine, but the ad said nothing about insurance participation and I'd bet he's running a concierge, fee-for-service practice.

I suppose we've had this discussion in a variety of ways on Shrink Rap already-- we've talked about emergency call-back policies, and this past weekend I commented that I get annoyed with friends who don't return my calls in Sunday Morning: Coffee & The New York Times . Actually, it's worse than that-- I really don't maintain close friendships with people who don't return my calls; most of my friends are conscientious people who get back to me promptly. And they are all very busy people.

What about professionally? What's reasonable in terms of having a doc return a non-emergent call? For me, I return almost every call the same day, only rarely the next day. I may wait until Sunday night or Monday for a weekend call that is clearly not urgent, say an appointment to be rescheduled, as I assume no one expects such things to be dealt with on a Saturday. Honestly, though, it's not about great patient care, it's not so I stick it as a bullet-point as an ad, it's not because I'm so devoted. Simply put, I return calls promptly because I like to keep my mental To-Do List as clear as possible, it's about not having this nagging thing to remember in the back of my brain.

But it's nice to know that if I ever do need a brownie point on my shrink score-card, this one's a shoe-in.

My Three Shrinks Podcast 14: No April Fool

[13] . . . [14] . . . [15] . . . [All]

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Hard to believe we went so long without a podcast. Sorry about that, folks, but life got too hectic for a spell. We didn't do anything special for April Fools Day (except some funny YouTube links), but we still think you'll like today's podcast.

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April 1, 2007:


Topics include:

• Q&A: Midwife with a Knife, an OB/GYN, asks us about whether pedophilia is a disease or something else, and what we think about civil (as opposed to criminal) commitment for it. Clink uses one of her 50-cent words on us (ephebophilia, a term that Clink says was coined by John Money in his book, Love Maps). See also The Last Psychiatrist's posts on this here and here.
  
• NYT article: "The Brain on the Stand", by Jeffrey Rosen. Clink talks about this article about brain diseases being put on trial to explain bad behavior.
• Q&A: Dr Anonymous wants us to say more about our recent posts (here and here) on humor and medicine. This whole discussion (and the numerous comments on the blog) was started by Roy's lyrics to "Walk Like a Psychiatrist."
  

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Find show notes with links at: http://mythreeshrinks.com. 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.

April Fools

Okay, we did not do anything for April Fools Day on the podcast, but I thought I'd post a few bust-out-loud funny videos from YouTube...

Fake water bed

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Newscaster gets snowed

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Chinese take-out prank call

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Dancing chalkboards

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Topless car wash

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Dead deer talking

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Creature from the Black Lagoon

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Darth Vader's lighter side

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Sunday Morning: Coffee & The New York Times

Somehow, this one caught my eye:

Daughters of the Dinah, Unbound

Apparently, there's a yearly lesbian retreat in California called The Dinah. Okay.....

And then there's the piece where I had to check the by-line to make sure I wasn't the author, I could have been:

Too Busy To Notice You're Too Busy

Alena Tugend (not me) writes:

RECENTLY I’ve found myself annoyed by how busy my friends seem. Putting aside the possibility that they are avoiding me, some are so on the go that they barely have time to tell me they do not have time to talk. Every phone call, no matter how short, seems to be interrupted by several others. That is, of course, if I actually get a live person on the other end of the phone.
I consider my life to be somewhat filled and fulfilling. I have a husband and two children, work part time, volunteer, exercise several times a week (well, usually) and socialize regularly. For the record, I do not have a baby sitter, but do have a house cleaner for about four hours every two weeks.
But, and I am almost embarrassed to admit this, I also have time to read novels, catch a movie or play once in a while and have the occasional long lunch with a friend.
In our busy, busy world, however, I sometimes feel as if I am the odd one out.
Although those who are overworked and overwhelmed complain ceaselessly, it is
often with an undertone of boastfulness; the hidden message is that I’m so busy
because I’m so important.

She goes on to talk about people are too leashed to their blackberry/cellphone/Ipod/email lives. The thing is, I'm just as guilty as all of them, and I still have time for movies, novels, lunches, and the one that makes everyone lift their eyebrows and say "You have too much free time" : A blog. I just don't get it when my friends, even the stay at home moms, don't have time to return phone calls...

And then there's the review of Jerome Groopman's book: Where Does It Hurt? which reads:

"This elegant, tough-minded book recounts stories about how doctors and patients interact with one other. In the hands of Jerome Groopman, professor of medicine at Harvard and a staff writer for The New Yorker, these clinical episodes make absorbing reading and are often deeply affecting. "

Happy April Fool's Day, I'm back to coffee and the paper, and we're making a podcast this afternoon Roy, no cookie dough, but I have chocolate chips for you. Clink, why do I always have trouble formatting my block quotes?

Laughter is a drug

This started out as a comment to respond to some comments in Your Doctor is Making Jokes About You, but it got so long that I thought I'd post it. Midwife's comments (dang, I see she removed them but they deserved to remain) about being able to laugh at tragic circumstances provoked some anonymous comments about insensitivity, which is the other side of the coin to humor (all humor has this Janus quality... it is insensitive to laugh at that poor chicken's difficulty getting to the other side of the street). Mid wife apologized for inciting a riot.

There's no riot. This is a healthy discussion about what it is like to work in a job where one deals with human tragedy on a daily basis.

The problem, I believe, that the anonymous poster has trouble getting his or her arms around, is that physicians (and here I mean all health care "professionals") are not perfect. We do not possess some unique ability that shields us from anger, fear, depression, loneliness, despair. Yet, for some reason, there is an expectation that we are somehow above these human foibles.

We are not.

In the past week, I have dealt with near-lethal suicide attempts, single women who have had their children taken away from them (probably forever) because their brain illnesses currently prevent them from providing adequate parenting, people who have recently lost a loved one, a home, a job, their freedom. I have also dealt with people making more incremental steps of improvement in their life (another week of sobriety, making it to their follow-up appointment, getting a job, making a new friend).

And, I'm afraid, this is a typical week.

Just writing this comment, I feel tears welling up. That's fine. I'm in touch with my pain. I'm down with that. Woo. But I cannot be in touch with it all the time. That may work for some, but for me it would impair my ability to be effective.

So humor is my way of managing these emotions, both in me and in others. And I use it like I use a medication... with a particular dose to achieve a desired outcome (that is, in my work with patients and staff... at home, my humor is much more random... in my posts, it is somewhere inbetween, depending on the topic). (Mind you, I am not talking about "humor" where one laughs at another's misfortune in a way that is intentionally harmful/evil/superior to that person... that is not what I am talking about here.)

My intent is to heal... both myself and others. Just like a drug may have unintended side effects and be harmful, so might humor. I choose medication which I think is uniquely appropriate for a given patient. My patients do not get angry and hurt when a drug makes them have a dystonic reaction. A shot of Cogentin makes it better, and I avoid that type of drug again. They know my intent was to help.

Similarly, I choose the words I use intentionally for a given patient because it is important to use language that they often use. It helps us understand each other. When my humor has an unintended side effect and is experienced as harmful, my patients also do not get angry and hurt. An Apology makes it better, and I avoid that type of humor again. They know my intent was to help.

On the internet, when one stumbles onto a near year-long, extended conversation about psychiatry, mental health, blogging, ducks and fish, it is all too easy to jump right in, read some comments that appear hurtful or mocking, and take offense. This casual blog observer does not know what the intent is, unless they take the time to understand. Similarly, in the hospital, it would be easy to judge me, for example, as insensitive if I am administering one of my therapeutic aphorisms and someone walks past the door, only to hear "You gotta cut this shit out, Joe," or "So your right arm became paralyzed just after your boss told you that you didn't do a good job on the report that you've spent all month working on? I tell ya, it's a good thing it happened when it did, because if that woulda happened to me, I would have wanted to punch him right in the nose."

My approach (in life, but especially on the net) is to assume benign intent. This takes work, because I am, deep down, somewhat suspicious. But at the end of the day, I am convinced that this way of viewing the world makes the world a better place.

March Madness: Visitor Survey Results

Results are in. We put up a poll all month (March 2007) to see who visits our blog. PollDaddy was used, and duplicate votes were mimized via use of cookies.

> 20% physicians (incl 13% psychiatrists & 7% other docs)
> 9% nurses
> 7% psychologists
> 7% social workers and counselors

> A total of 43% of voters were (mostly mental) health care professionals.
> 29% were patients
> 29% were "others"

Just wanted to share these results with you all. Thank you for your interest in our inspired ramblings.

-The Management

[revised 3/31]

TGIF?

So last night, I went to "the movies." Actually, it was to a film with discussion, sponsored by The Baltimore-Washington Psychoanalytic Institute. The movie was a Russian film called The Return, about two teenage boys who venture off with a cold, oppressive father who has returned after a mysterious 12-year absence (--prison camp, maybe?). The movie was horribly depressing and to add to the somber, miserable feel it left, the discussant mentioned that one of the teenage actors died in a boating accident shortly before the release of the film-- my misery couldn't even be contained with "it's just a movie." I woke up still haunted.

Is it time to go back to work yet?