Interesting article in Clinical Psychiatry News, Psychoactive Drug Nomenclature System Devised, by Mitchel Zoler.
Joseph Zohar, David J. Nutt, David J. Kupfer, Hans-Jurgen Moller, Shigeto Yamawakie, Michael Spedding, and Stephen M. Stahl have all been busy coming up with a new way to describe psychoactive medications. It's a 5 Axis system (I guess they were homesick for DSM-IV), and the plan is for it to be web-based, so it can be in a constant state of revision.
The idea behind it is that, according to the example in the article, you have a patient with an anxiety disorder, for whom you prescribe, say, celexa, which is an antidepressant. So the patient wonders why you're telling him he has one condition, and giving him a drug for another.
Here's my list of the axes-but you can view them in the article, in a nice table, complete with two examples:
Axis 1- Class and Relevant Mechanism
What neurotransmitters it affects, and what it does at the molecular level.
Axis 2- Family
This seems to overlap with Axis 1.
Axis 3- Neurobiologic Activity
Includes neurotransmitter effects, and broader physiologic effects.
Axis 4- Efficacy and Major Side Effects
What conditions it's good for, and what else it does on the experiential level.
Axis 5- Indications
Formal FDA approvals, I think.
The Pros:
The physicist, Richard Feynman, had an interesting father. He would say to young Feynman, "You see that bird over there? I can tell you its name, but first, I'll tell you what it does."
Names, categories, titles, they're all important, but they often don't give you that much information about whatever they're naming. "Sparrow" doesn't tell you anything. You need to connect that word with a certain type of bird.
So it's a good idea to describe drugs by what they are and what they purportedly do. You end up with a lot more information than you get from "SSRI" or "Prozac".
And on the flip side, "antidepressant" only tells you one thing that a particular drug does. If it does other things, you won't know it from that one word.
I quite like the idea of putting all the relevant information out there right from the start.
The Cons:
Who is this for? I can see where it would be useful for medical students studying for pharmacology exams. Or for psychiatrists, to tweak our memories, or help us clarify things to our patients, although personally I'd like an Axis 6 with Cyp450 enzyme data.
But what about non-psychiatrist prescribers. Could this be a sneaky way to promote off-label prescribing? If you look at the chart in the article, Axis 4 for amytriptyline is "anxiety;chronic pain", not "depression", which is listed in Axis 5 as "Major Depressive Disorder".
And does listing the known molecular mechanism of action, e.g "Increases synaptic 5-HT and norepinephrine" right next to the conditions the drug is used to treat, e.g. "Depression", sneakily imply that too little synaptic 5-HT causes depression, and more synaptic 5-HT is what "cures" depression? Because we just don't know if that's true.
Is this system for patients? Will it really be helpful, or more helpful than just telling these details to patients as part of discussions surrounding medication?
The question of who this system is for, as well as the plan to make the classification system web-based are particularly relevant, in light of the fact that I couldn't access the original article. Well, I could, for $35.95.
My feeling is that this idea is being presented as an ongoing collaborative model, but really, it's proprietary. And forgive me if I have concerns about where they're heading with it. This quote is from the Zoler article:
"This is the first step in a long process. We’re trying to wake up a 50-year-old nomenclature into a living document that will be used over the next decades and may someday merge with DSM [Diagnostic and Statistical Manual of Mental Disorders]," said Dr. Stephen M. Stahl, a panel member and psychiatrist affiliated with the University of California, San Diego.
What will it mean to "merge with DSM"? Will new diagnoses be created based on how medications are being prescribed? Or with what frequency they're being prescribed? After all, David Kupfer, one of the authors, was the chair of the DSM-5 task force.
And how will this affect getting FDA approval for medications? If a drug is being used off label at a high frequency, will this be a way to extend a patent? In other words, is noting the usage of a drug a way of establishing that said drug is effective for a different indication than the one it was originally approved for.
My main concern stems from the memory of those little books I got from drug reps when I was a resident. Nice little pictures with colorful neurotransmitters happily making their way around a bunch of big receptors. All written by Stephen M. Stahl.
The final paragraph of the Zoler article:
Dr. Zohar said he has been an adviser or consultant to or received research support from eight drug companies. Dr. Nutt said he has been an adviser or consultant to eight drug companies. Dr. Stahl said he has been an adviser or consultant to more than 30 drug companies. Dr. Goodwin said he had been an adviser or consultant to 12 drug companies.
Bottom line: I think more information about medications is a good thing. But not if it's misleading. And not if there's an ulterior motive to presenting the information. Hopefully, this type of system can be used for the good of patients.
Showing posts with label psychopharmacology. Show all posts
Showing posts with label psychopharmacology. Show all posts
Saturday, November 30, 2013
Thursday, October 17, 2013
Generics
A recent letter in the NY Times got me thinking about generics. Specifically, how good are generics, compared to their brand name counterparts. (For the purposes of this post, I'm going to ignore the question of how good the brand names are, and how we know that, etc.) The letter, by Jack Drescher, states that, "the current accepted standard for bioavailability can range from 80 to 125 percent of the brand-name drug’s delivery system." But what does that mean?
About a year ago, people taking a certain generic form of Wellbutrin XL 300mg, called budeprion, started reporting what sounded like symptoms of depression. The FDA went on to announce the in-equivalence of this generic, which was taken off the market. This past Thursday, the FDA released an update:
Based on data submitted by Watson, FDA has determined that that company’s generic bupropion HCl ER 300 mg tablet product is not therapeutically equivalent to Wellbutrin XL 300 mg. Watson has agreed to voluntarily withdraw this product from the distribution chain. Also, FDA has changed the Therapeutic Equivalence Code for the Watson product from AB (therapeutically equivalent) to BX (data are insufficient to determine therapeutic equivalence) in the Orange Book. FDA does not anticipate a drug shortage.
We recommend that patients taking the Watson product continue taking their medication and contact their health care professional or pharmacist to address any concerns.
So how does a generic drug come to be?
First, let's have some definitions and review.
According to the World Health Organization, "A generic drug is a pharmaceutical product, usually intended to be interchangeable with an innovator product, that is manufactured without a license from the innovator company and marketed after the expiry date of the patent or other exclusive rights."
What makes a generic drug "interchangeable with an innovator product" is the fact that it contains the same Active Pharmaceutical Ingredient (API), and demonstrates Bioequivalence:
Generics are not required to replicate the extensive clinical trials that have already been used in the development of the original, brand-name drug. These tests usually involve a few hundred to a few thousand patients. Since the safety and efficacy of the brand-name product has already been well established in clinical testing and frequently many years of patient use, it is scientifically unnecessary, and would be unethical, to require that such extensive testing be repeated in human subjects for each generic drug that a firm wishes to market. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner) to the pioneer drug.
One way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream and its concentration in the bloodstream in 24 to 36 healthy, normal volunteers. This gives them the rate and extent of absorption-or bioavailability-of the generic drug, which they then compare to that of the pioneer drug. The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the pioneer drug.
Using bioequivalence as the basis for approving generic copies of drug products was established by the Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Act. Brand-name drugs are subject to the same bioequivalency tests as generics when their manufacturers reformulate them.
You may recall this graph:
It's blood concentration vs. time for an oral drug. Sequential blood samples are taken after ingestion of the drug, to generate the curve. Peak concentration, Cmax occurs at time, Tmax.
Rate of Absorption = Cmax/Tmax.
and Total Extent of Absorption = Area Under the Curve (AUC)
(which is simply the integral of the function that describes the curve).
A generic drug is considered equivalent to the brand drug if its Rate of Absorption and Extent of Absorption do not significantly differ from those of the brand drug. In other words, the curves look the same, or almost the same.
How much is almost?
Once they've established bioequivalence, generic drugs are given Therapeutic Equivalence Codes. There are different codes for different types of meds, e.g. tablets vs. injectables. The highest rating seems to be AA-drugs that "contain active ingredients and dosage forms that are not regarded as presenting either actual or potential bioequivalence problems or drug quality or standards issues. However, all oral dosage forms must, nonetheless, meet an appropriate in vitro test(s) for approval." I'm not clear on what would constitute a "bioequivalence problem". An example of an AA drug is Acetaminophen/codeine, and this is what the heading looks like in the Orange Book (see below):
AB seems to be a more typical rating for generics. There are some subcategories in which a drug is rated compared to a specific version of the drug, for example, levothyroxine:
About a year ago, people taking a certain generic form of Wellbutrin XL 300mg, called budeprion, started reporting what sounded like symptoms of depression. The FDA went on to announce the in-equivalence of this generic, which was taken off the market. This past Thursday, the FDA released an update:
Based on data submitted by Watson, FDA has determined that that company’s generic bupropion HCl ER 300 mg tablet product is not therapeutically equivalent to Wellbutrin XL 300 mg. Watson has agreed to voluntarily withdraw this product from the distribution chain. Also, FDA has changed the Therapeutic Equivalence Code for the Watson product from AB (therapeutically equivalent) to BX (data are insufficient to determine therapeutic equivalence) in the Orange Book. FDA does not anticipate a drug shortage.
We recommend that patients taking the Watson product continue taking their medication and contact their health care professional or pharmacist to address any concerns.
So how does a generic drug come to be?
First, let's have some definitions and review.
According to the World Health Organization, "A generic drug is a pharmaceutical product, usually intended to be interchangeable with an innovator product, that is manufactured without a license from the innovator company and marketed after the expiry date of the patent or other exclusive rights."
What makes a generic drug "interchangeable with an innovator product" is the fact that it contains the same Active Pharmaceutical Ingredient (API), and demonstrates Bioequivalence:
Generics are not required to replicate the extensive clinical trials that have already been used in the development of the original, brand-name drug. These tests usually involve a few hundred to a few thousand patients. Since the safety and efficacy of the brand-name product has already been well established in clinical testing and frequently many years of patient use, it is scientifically unnecessary, and would be unethical, to require that such extensive testing be repeated in human subjects for each generic drug that a firm wishes to market. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner) to the pioneer drug.
One way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream and its concentration in the bloodstream in 24 to 36 healthy, normal volunteers. This gives them the rate and extent of absorption-or bioavailability-of the generic drug, which they then compare to that of the pioneer drug. The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the pioneer drug.
Using bioequivalence as the basis for approving generic copies of drug products was established by the Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Act. Brand-name drugs are subject to the same bioequivalency tests as generics when their manufacturers reformulate them.
You may recall this graph:
It's blood concentration vs. time for an oral drug. Sequential blood samples are taken after ingestion of the drug, to generate the curve. Peak concentration, Cmax occurs at time, Tmax.
Rate of Absorption = Cmax/Tmax.
and Total Extent of Absorption = Area Under the Curve (AUC)
(which is simply the integral of the function that describes the curve).
A generic drug is considered equivalent to the brand drug if its Rate of Absorption and Extent of Absorption do not significantly differ from those of the brand drug. In other words, the curves look the same, or almost the same.
How much is almost?
"Most regulators worldwide have decided that a 20% variation is generally not clinically significant.
Two versions of a drug are generally said to be bioequivalent if the 90% confidence intervals for the ratios of the geometric means (brand vs. generic) of the AUC and Cmax fall within 80% and 125%. The tmax (brand vs. generic) must also be comparable — and there should not be any significant differences between different patients." (same source as graph).
Once they've established bioequivalence, generic drugs are given Therapeutic Equivalence Codes. There are different codes for different types of meds, e.g. tablets vs. injectables. The highest rating seems to be AA-drugs that "contain active ingredients and dosage forms that are not regarded as presenting either actual or potential bioequivalence problems or drug quality or standards issues. However, all oral dosage forms must, nonetheless, meet an appropriate in vitro test(s) for approval." I'm not clear on what would constitute a "bioequivalence problem". An example of an AA drug is Acetaminophen/codeine, and this is what the heading looks like in the Orange Book (see below):
AB seems to be a more typical rating for generics. There are some subcategories in which a drug is rated compared to a specific version of the drug, for example, levothyroxine:
For those who are interested in the whole shpiel, this is a link to Approved Drug Products with Therapeutic Equivalence Evaluations , aka The Orange Book. It's called The Orange Book because the original edition was published in October, and with Halloween coming up, they decided on an orange cover.
And here's another link to FDA slides on bioequivalence:
And here's another link to FDA slides on bioequivalence:
Wednesday, June 12, 2013
DSM-5 in Action
Last week, I saw a new patient who was referred to me by her therapist for evaluation for med management, specifically, for depression.
The therapist wasn't certain the patient needed meds. And the patient wasn't sure she needed, or wanted meds.
She was suffering-that was the only certain thing.
I'm a decent psychopharmacologist, despite the fact that I mostly do therapy and analysis. The reason I'm good with meds is not because I'm an expert on the Cytochrome p450 system, or I'm the first shrink on the block to prescribe a brand new med. I believe it's because I listen to my patients, so important feelings/experiences/symptoms don't get overlooked, or boxed into neat little 15-minute med check categories that don't really fit.
So I listened to this patient, and while I was listening, I started thinking about everything I've learned regarding DSM-5. Like, maybe Major Depression, as defined by the DSM, doesn't really exist. (Note: I am NOT saying I don't believe depression exists. I'm just referring to the DSM definition of depression). And even if it does exist in DSM form, if I run through the checklist, and the patient meets five of the nine criteria, does that imply that she'll benefit from medication? And if she doesn't meet 5/9, does that mean she won't?
And what about the meds? What exactly am I treating? And how? A world-outlook? A traumatic childhood loss? If I can't be sure there's a disease process going on, and I can't be sure which aspect of the disease, if such it is, I'm treating, and no one even knows how the meds work, then why would I medicate?
I thought about how easy it would be to say to her, "You meet criteria for MDD, here's a pill, take it and you'll feel better." But I just couldn't bring myself to do that. I didn't believe it would help.
This is not the first patient I've sent home prescription-less. But it's the first time I've thought about it this way. In the past, I might've said to myself, the patient doesn't meet criteria, and therefore doesn't have the disorder in question, and consequently won't benefit from medication for this condition.
But now I'm reminded of the joke about the philosophy exam question, asking students to describe the physical characteristics of the chair at the front of the room. One student's response: What chair?
What disorder?
I came up with the following analogy: Suppose I decide that people who have more than 5 bad hair days per month carry a diagnosis of BHDD (Bad Hair Day Disorder). Am I describing an entity? Yes, people who have too many bad hair days. Does that make it a disorder, or disease?
I'm not sure the analogy is valid. At least some of the DSM diagnoses have a basis in clinical experience.
The truth is, and I realized this while I was writing, that I do find the DSM criteria for MDD useful, as a line of questioning.
This patient did not fit into any nice little DSM category. And I didn't try to make her fit. My thinking was, let's explore what she's been experiencing, using DSM criteria as a starting point. And that was useful.
I haven't purchased a copy of DSM-5. I don't want to. And I resent that, despite all the protests to the contrary, it remains the "bible" of psychiatry, and decisions are made based on its contents-reimbursement decisions, legal decisions.
But I do wish it could be what it professes to be: a guideline. Then it could sit on my book shelf with all the other books I use as references and guidelines, not with pride of place, and not with shame, either.
The therapist wasn't certain the patient needed meds. And the patient wasn't sure she needed, or wanted meds.
She was suffering-that was the only certain thing.
I'm a decent psychopharmacologist, despite the fact that I mostly do therapy and analysis. The reason I'm good with meds is not because I'm an expert on the Cytochrome p450 system, or I'm the first shrink on the block to prescribe a brand new med. I believe it's because I listen to my patients, so important feelings/experiences/symptoms don't get overlooked, or boxed into neat little 15-minute med check categories that don't really fit.
So I listened to this patient, and while I was listening, I started thinking about everything I've learned regarding DSM-5. Like, maybe Major Depression, as defined by the DSM, doesn't really exist. (Note: I am NOT saying I don't believe depression exists. I'm just referring to the DSM definition of depression). And even if it does exist in DSM form, if I run through the checklist, and the patient meets five of the nine criteria, does that imply that she'll benefit from medication? And if she doesn't meet 5/9, does that mean she won't?
And what about the meds? What exactly am I treating? And how? A world-outlook? A traumatic childhood loss? If I can't be sure there's a disease process going on, and I can't be sure which aspect of the disease, if such it is, I'm treating, and no one even knows how the meds work, then why would I medicate?
I thought about how easy it would be to say to her, "You meet criteria for MDD, here's a pill, take it and you'll feel better." But I just couldn't bring myself to do that. I didn't believe it would help.
This is not the first patient I've sent home prescription-less. But it's the first time I've thought about it this way. In the past, I might've said to myself, the patient doesn't meet criteria, and therefore doesn't have the disorder in question, and consequently won't benefit from medication for this condition.
But now I'm reminded of the joke about the philosophy exam question, asking students to describe the physical characteristics of the chair at the front of the room. One student's response: What chair?
What disorder?
I came up with the following analogy: Suppose I decide that people who have more than 5 bad hair days per month carry a diagnosis of BHDD (Bad Hair Day Disorder). Am I describing an entity? Yes, people who have too many bad hair days. Does that make it a disorder, or disease?
I'm not sure the analogy is valid. At least some of the DSM diagnoses have a basis in clinical experience.
The truth is, and I realized this while I was writing, that I do find the DSM criteria for MDD useful, as a line of questioning.
This patient did not fit into any nice little DSM category. And I didn't try to make her fit. My thinking was, let's explore what she's been experiencing, using DSM criteria as a starting point. And that was useful.
I haven't purchased a copy of DSM-5. I don't want to. And I resent that, despite all the protests to the contrary, it remains the "bible" of psychiatry, and decisions are made based on its contents-reimbursement decisions, legal decisions.
But I do wish it could be what it professes to be: a guideline. Then it could sit on my book shelf with all the other books I use as references and guidelines, not with pride of place, and not with shame, either.
Sunday, December 9, 2012
Quick CPT Link
I just want to refer anyone who is interested to the blog, Shrink Rap, for 4 quick video tutorials on CPT and E&M coding.
And a shout out to Dinah for mentioning Psych Practice at the end of the last video.
The videos are clear, and Dinah claims they're boring, but they're not because of her fun style.
And a shout out to Dinah for mentioning Psych Practice at the end of the last video.
The videos are clear, and Dinah claims they're boring, but they're not because of her fun style.
Abilif-Eyeballs
What's up with the eyeballs in Abilify ads? Like this one:
Are they supposed to be cute?
A pair of eyeballs following around someone taking an antipsychotic. Seriously?
Oh yeah! This isn't an ad for Abilify the antipsychotic. It's an ad for Abilify the antidepressant augmentation med.
And if you watched through the ad, did you notice that 40 of the 90 seconds are spent describing side effects? Okay, you probably didn't bother to count like I did, but you get the idea.
I do not like drug ads on TV. But why?
Is it because they're a blatant manipulation of lay people by Big Pharma? Well, there is that.
Dammit, if pharmaceutical companies are going to manipulate people, then by golly let those people be doctors so we can get free pens and clipboards out of it.
Did you know that the amount of money pharmaceutical companies spend on advertising is 19 times what they spend on research? Huffington Post Link
One figure I found (click here) is 4.8 Billion dollars spent annually on direct to consumer marketing. That doesn't even include pens.
Now, don't get me wrong. I don't hate pharmaceutical companies the way I hate insurance companies. After all, the meds we prescribe have to come from somewhere. And some of them actually work. You can't blame a trillion-dollar conglomerate for tryin' to make a buck. They have products to offer that actually do some people some good. Unlike insurance companies, which offer a product designed to do as little as possible of the job it was purchased to do (i.e. reimburse).
Plus, drug companies will take you out to dinner every now and then. When was the last time United Healthcare bought you so much as a cookie?
I think it bothers me that the ads are misleading. Depression not improving? Here, this'll fix it.
In a recent study (2012), Fava, et al assessed the efficacy of low-dose aripiprazole added to antidepressant therapy (ADT) in 225 major depressive disorder (MDD) patients with inadequate response to prior ADT.They concluded that low-dose (2-5mg) aripiprazole was well-tolerated, but had only marginal efficacy in augmenting ADT.
The commercial never mentioned that. Nor did it state, or even imply, that abilify's original indication was for psychosis. It's as though, just when you thought antidepressants were inadequate to the task of treating depression, a magical pill appeared and saved everyone.
So they're lying. Or exaggerating. But is this really any worse than advertising candy bars, or laundry detergent, or tires?
I think there's a fine line between empowering people to be active participants in their health care, and convincing them they have greater expertise than they do, which is the real way drug ads mislead. You don't need to know much about candy bars to chose one. And maybe you should do a little research when you're purchasing new tires. But you don't need years of education and hands-on experience to make those decisions.
If I needed my car fixed, I wouldn't go to a mechanic and say, "I know what's wrong with my car and which components you need to fix it." And Google is not the great equalizer people would like it to be.
So watch out for those eyeballs.
Are they supposed to be cute?
A pair of eyeballs following around someone taking an antipsychotic. Seriously?
Oh yeah! This isn't an ad for Abilify the antipsychotic. It's an ad for Abilify the antidepressant augmentation med.
And if you watched through the ad, did you notice that 40 of the 90 seconds are spent describing side effects? Okay, you probably didn't bother to count like I did, but you get the idea.
I do not like drug ads on TV. But why?
Is it because they're a blatant manipulation of lay people by Big Pharma? Well, there is that.
Dammit, if pharmaceutical companies are going to manipulate people, then by golly let those people be doctors so we can get free pens and clipboards out of it.
Did you know that the amount of money pharmaceutical companies spend on advertising is 19 times what they spend on research? Huffington Post Link
One figure I found (click here) is 4.8 Billion dollars spent annually on direct to consumer marketing. That doesn't even include pens.
Now, don't get me wrong. I don't hate pharmaceutical companies the way I hate insurance companies. After all, the meds we prescribe have to come from somewhere. And some of them actually work. You can't blame a trillion-dollar conglomerate for tryin' to make a buck. They have products to offer that actually do some people some good. Unlike insurance companies, which offer a product designed to do as little as possible of the job it was purchased to do (i.e. reimburse).
Plus, drug companies will take you out to dinner every now and then. When was the last time United Healthcare bought you so much as a cookie?
I think it bothers me that the ads are misleading. Depression not improving? Here, this'll fix it.
In a recent study (2012), Fava, et al assessed the efficacy of low-dose aripiprazole added to antidepressant therapy (ADT) in 225 major depressive disorder (MDD) patients with inadequate response to prior ADT.They concluded that low-dose (2-5mg) aripiprazole was well-tolerated, but had only marginal efficacy in augmenting ADT.
The commercial never mentioned that. Nor did it state, or even imply, that abilify's original indication was for psychosis. It's as though, just when you thought antidepressants were inadequate to the task of treating depression, a magical pill appeared and saved everyone.
So they're lying. Or exaggerating. But is this really any worse than advertising candy bars, or laundry detergent, or tires?
I think there's a fine line between empowering people to be active participants in their health care, and convincing them they have greater expertise than they do, which is the real way drug ads mislead. You don't need to know much about candy bars to chose one. And maybe you should do a little research when you're purchasing new tires. But you don't need years of education and hands-on experience to make those decisions.
If I needed my car fixed, I wouldn't go to a mechanic and say, "I know what's wrong with my car and which components you need to fix it." And Google is not the great equalizer people would like it to be.
So watch out for those eyeballs.
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