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You don't have to know statistics to be able to figure out that 70% is a whopping significant number.

Now what about ALL the meds that cause prolactinemia? Guess they all do the same number on the pituitary. Haven't they been out long enough to have the same effect, is it dose dependent or what?

I just read that Risperdal is close to going out of patent protection (the parent co's stock is plummeting). Could that be why they're allowing this kind of info to leak out - now that it "doesn't matter"?

Of course, they ARE coming out with a similar compound. I can hardly wait to see how they market it...Hmm. Let's see, basically "it's such an improvement on earlier AAPs that if you or your loved one doesn't wangle it from your insurance company, you are bound to get brain damage.

Including - fishing in the air - even a pituitary tumor!" We'll sit back and watch. (wishing for pukie emoticon a lot these days).

Refer in Health Care System Sucks for a compendium of all barf inducing studies - as soon as my stomach can stand it

http://www.medscape.com/viewarticle/533771_print

Antipsychotic Drugs Linked to Pituitary Tumors]

Allison Gandey

Medscape Medical News 2006.

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[

Risperidone was linked to 54 (70%) of 77 cases of pituitary tumors reported in the FDA's database and was followed by haloperidol and ziprasidone.

What I can gather from this statement, there are 77 cases of pituitary tumors reported in the FDA's database. The study states that 70% of THESE cases were linked to risperidone.

At this point, they haven't extablished a direct connection but one of the difficulties in figuring out what is causing what could be that pituitary tumours are associated with hyperprolactinemia. If someone is on an AP which is expected to cause that side effect, it might be easy to miss the signs until they become significant.

And then maybe there are some cases that are directly connected, but they probably have to go through casebycase and detail every single one more thoroughly than has already been done and do a long term study.

I really don't think that this would call for a black box warning just yet though. Everyone is aware of the prolactin issues and doctors are aware of the effects it can have on the body.

I don't know if anyone quite has a total grasp on how much psychosis and the pituitary are interconnected, or exactly how. I don't know if this could mean anything at all in terms of the study, but I thought it was interesting: http://bjp.rcpsych.org/cgi/reprint/185/1/5.

I don't really see it as leaking out though, this sounds like it is data over a few years. Some good may come out of it hopefully- a reminder to pay attention to hormone levels more. They are really important in the management of mental illness and some symptoms can be attributed to many different things.

Anyway. Interesting read.

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I just read that Risperdal is close to going out of patent protection (the parent co's stock is plummeting). Could that be why they're allowing this kind of info to leak out - now that it "doesn't matter"?
Damn! You figured it out. It's all a conspiracy. Even I am a paid pharma mole whose sole job is to spend all day on CrazyBoards providing false information in order to sucker you crazys into using our ineffective meds. Ahem....BTW, the US patent on Risperdal expires in 2008, I'm not sure when the Japanese patent expires (invented there, BTW).

This report has NOTHING to do with Janssen/J&J. The researchers making this report work for the FDA. They special in Data Mining, and their previous report dealt with the association between Gambling and Parkinsons Disease drugs. Before that they published a paper describing the advanced computerized statistical methods that are required to make these associations.

You don't have to know statistics to be able to figure out that 70% is a whopping significant number.

Yes you DO need to know statistics. The underlying point of this paper is that it required highly advanced computer statistical data mining techniques to make these associations.

No, 70% is NOT a whopping number without more information. Considering that Risperdal was the best selling AAP until late 2005, it wouldn't be unusual for absolute numbers of tumors to be higher than all other drugs, even if they all caused exactly the same percentage of tumors.

Now, lets look again at the absolute numbers. 77 pit. tumors "associated" with AAP's since the first introduction of Clozaril in 1989. That works out to 4.5 tumors per year over 17 years. For Risperdal it is 54 tumors over 13 years equals 4.6 tumors per year average.

The NIMH says there are 2.4 million Schizophrenics and 5.7 million Bipolars who are potential users. I cannot readily find sales information for Risperdal or any of the AAP's for comparison. However, 77 tumors over 17 years for even a million users is pretty rare.

[edit: Checking http://www.emedicine.com/med/topic1379.htm monographs, microadenomas (less than 10mm) are found in 10% of the population and macroadenomas (greater than 10mm) are found in 25% of the population. Therefore, not even considering AAP use, 35% or 840,000 Schizophrenics have pituitary tumors, before they walk through the Pdocs door. So how bad does 77 tumors sound versus nearly a million natural tumors? Umm, I'll take not crazy over crazy and undermedicated, please.]

So to put this in perspective, pituitary tumors are scary, however the data provided in this study does not in any way prove that AAP's cause them. Merely that advanced data mining techniques have found an association. It would not be a surprise however, given that known adversed affects associated with the pituitary, and the fact that the Risperdal PI sheet shows a slightly increased pituitary tumor incidence in mouse models.

So, if you doctor recommends AAP's discuss the advantages and risks. If you are taking the meds and have unusual hormonal changes, call your doc. And I promise you will NOT grow a second head on AAP's. ;)

a.m. (If anyone can get me a copy of the whole article that would be nice)

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Heya rt, AM,

Yah lots of prolactin. Lots of galactorrhea.

I'm also skeptical about the adenoma connection simply b/c of a dearth of evidence.

Be interesting to see if this goes anywhere.

AM: It looked to me like the whole article was on that webpage. Am I missing something (entirely possible, I leave my (considerable) powers of observation at the office)?

--ncc--

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NCC,

No, the Medscape article is not the full article. The Medscape reporter has quoted some material, paraphrased others and placed his own spin on the original report.

a.m.

Ok, I'll hang my but out: Here is the journal summary:

Pharmacotherapy. 2006 Jun;26(6):748-58.

Atypical antipsychotics and pituitary tumors: a pharmacovigilance study.

Szarfman A, Tonning JM, Levine JG, Doraiswamy PM.

1 Office of Pharmacoepidemiology and Statistical Sciences, Immediate Office, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland.

Study Objective. To analyze the disproportionality of reporting of hyperprolactinemia, galactorrhea, and pituitary tumors with seven widely used antipsychotic drugs.

Design. Retrospective pharmacovigilance study.

Data Source. United States Food and Drug Administration's Adverse Event Reporting System (AERS) database.

Intervention. We initially identified higher-than-expected postmarketing reports of pituitary tumors associated with risperidone, a potent dopamine D(2)-receptor antagonist antipsychotic, by analyzing reporting patterns of these tumors in the AERS database. To further examine this association, we analyzed disproportionate reporting patterns of pituitary tumor reports for seven antipsychotics with different affinities for blocking D(2) receptors: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and haloperidol.

Measurements and Main Results. To conduct both of these analyses, we used the Multi-item Gamma Poisson Shrinker (MGPS) data mining algorithm applied to the AERS database. The MGPS uses a Bayesian model to calculate adjusted observed:expected ratios of drug-adverse event associations (Empiric Bayes Geometric Mean [EBGM] values) in huge drug safety databases. The higher the adjusted reporting ratio, or EBGM value, the greater the strength of the association between a drug and an adverse event.

Risperidone had the highest adjusted reporting ratios for hyperprolactinemia (EBGM 34.9, 90% confidence interval [CI] 32.8-37.1]), galactorrhea (EBGM 19.9, 90% CI 18.6-21.4), and pituitary tumor (EBGM 18.7, 90% CI 14.9-23.3) among the seven antipsychotics, and one of the highest scores for all drugs in the AERS database. Some tumors were associated with visual field defects, hemorrhage, convulsions, surgery, and severe (> 10-fold) prolactin elevations. The EBGM values for risperidone for these adverse events were higher in women, but high EBGM values for these events were also seen in men and children. Moreover, the rank order of the EBGM values for pituitary tumors corresponded to the affinities of these seven drugs for D(2) receptors.

Conclusion. Treatment with potent D(2)-receptor antagonists, such as risperidone, may be associated with pituitary tumors. These findings are consistent with animal (mice) studies and raise the need for clinical awareness and longitudinal studies.

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Heya AM,

Yah I can't make sense out of it either.

We need a biostatistician around here.

Surely there must be a crazy biostatistician out there just *itching* to join us.

--ncc--

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As my mind unpeels the onion layers of unanswered questions here, one stands out:

WHAT precislely is the FDA's database of pituitary tumors, and how does it differ from any old database of pituitary tumors (this is key)??

JFTR I have studied Statistics, for all the good it does me except for defensive reading of the average newspaper headline. But evidentally not BIOstatistics.

What is data mining? I thought it wasn't allowed to just go willy nilly declaring "significant" findings without peforming elaborate balancing checks, essentially eliminating a certain percentage of "Eurekas".

That was (I thought) a mathematical and ethical requirement, to guard against spurious "significant findings" - ones appearing merely as a byproduct of the number of cross correlations checks one runs. What am I remembering wrong (except any of the actual names or tests or tables or… ;) )?

BTW googling a bit about hyperprolactinemia, I see disconcertingly, that it is considered causal (not merely associated with) decreased bone density, osteoporosis. and depression.

Those are biggies in my book. I notice my son is significantly less depressed since switching back to Seroquel (which is considered "prolactin sparing"). Certainly, prolactin elevation should be taken seriously in choosing an AP or AAP/ More seriously than to date, anyhow.

Antipsychotic medications are truly the prime example of the "which sucks less?" test, IMO. Still within the realm of the possible, it's good to know what one is looking at down the road when choosing a medication. Women do this all the time when weighing hormone replacement therapy (and no, the nurses study did NOT answer all the questions about this.). It's definitely a choose your disease, game there too. :)

Personally, I chose death over disability (with other factors at work too) - i.e. cancer over osteoporosis, especially as the former is far less certain.

As far as the D2 blockers go, well, I just wish they'd hurry the hell up with the glutamate research. I can't believe that after forty years, we're still basing all AP therapy on variations of the "dopamine hypothesis" (of which this pituitary tumor business is but a single offshoot).

rt

*******

PS a year and a half IS just around the corner, when it comes to a patent coming up for expiration - especially , when it's a company's biggest seller. That remark that it was about to expire, recurred repeatedly referring to Risperdal, from a market perspective. I didn't come up with it on my own (and I was aware the year was 2008. Actually, I started out trying to google when it first came on the market, to see how long pts had been exposed , before developing the tumors).

It certainly IS influencing their stock price and their own marketing planning. Not saying this research is actually coming out now BECAUSE of that deadline, but it's not as far-fetched as you might like to think, AM.

I 've been reading a LOT about the drug lobby (and more) lately. It's incontrovertible (by me, anyhow) and very disturbing. I have by now, a mind boggling collection of links about it from eminently respectable journals. I would spend more time on it, but I'm trying to avoid the topic to do more pressing personal things. Happened across it almost by chance, but it's getting hard to google about meds without tripping over it. Pretty soon even you diehards will be facing it - and getting mad too.

Things like this are entirely possible - research being suppressed until its convenient, that is. There are many ways researchers can be rewarded for delaying publication - by grants, etc. It's not all sleazeball bought endorsements, or kneecaps being broken. Stomach getting queasy, so I'll leave this for now.

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AHA (sort of) ! All except for the Gamma Poisson Shrinker (which is clearly a kind of radioactive technique for obtaining shrunken fish heads, for those who get off on that sort of thing) - and a tad more... ;)

As I understand it, somebody got the idea of the possible links between (prolactin elevating) APs and adenomas, owing to the (already known) association between hyperprolactinemia etc, and pituitary tumors.

So they examined the Adverse Event reporting database (THAT's the FDA database) comparing the incidence of adenomas to the reporting for seven AAPs.

So they actually started with a hunch/hypothesis and were checking it out.

They chose a fancy shmancy retrospective analytic technique to compare actual reported adverse events so-called, with what one would have expected in a normal distribution - one where they all would have had the same rate of AER (comparing them to each other, right??).

The more the distribution was unequal the more there was a probability that that particular compound is causally implicated in the "adversity"!

Then they compared them in on a few measures, such as the degree the compounds block D2, cause galactorrhea, elevate prolactin. etc) . Cross-correlating the tumor incidence with these measures. they came up with a very neat point by point relationshio between degree of prolactin elevation and rank order of #s of tumors found.

(On assumes/hopes they controlled for time of exposure too. Some are much newer than Risperdal. Saw no fish about this)

Voila! A publishable study!

Besides , the company wasn't going to have a hissy fit since it's about to forego patent profits soon, and have another AAP bun in the oven anyway. (Couldn't resist this, A.M. :cussing: ). More importantly, they can't (probably) be acused of pulling a VIOXX and having already known about this (from clear - squelched - clinical trials).

Besides (and this is what I THINK I have gotten - awaiting correction if not), the main point of this study is to comparie these meds to each other vis a vis this particular adverse event!

By finding that they differed (assymetrically = unpredictably) the researchers have in one fell swoop, demonstrated:

a) a probable causal (though they aren't calling it such) relationship between the prolactin elevating properties of Risperdal and pituitary tumors AND

b ) the probability that prolactin elevation itself CAN cause adenomas on a dose* related basis, at least via this mechanism (D2 blocking).

How often this actually occurs relative to "consumers", we don't know.

And we knoe even less how this incidence compares to that in the general population! For all we know (a far stretch, only given for illustrative purposes), AAP induced hyper-prolactinemia may well cause pitutary tumors. However, there could be other protective factors making theirs more benign and self-limiting.

This might make it something like the still-mysterious finding that a far higher percentage of people with sz smoke - relative to the general population. For some reason, though, far fewer of them get lung cancer!

(Not that anything like this is going on here. Just an example of how the date we're presented with, is very inconclusive.... Only that "more investigation is warranted" -- and a headline on Medscape! )

I find it irritating that the authors anecdotally (only) describe the scariest symptoms of a few - how many? - of these tumors, without saying anything about the tumors as a whole (This makes their findings sound more important :) ).

But how many tumors, actually produced such bad effects, how large were they, and what kinds? Were they secretory or not, etc?

The only thing that give one some pause for thought, is that since most adenomas are asymptomatic, one does wonder how many more actually exist in this population - ones which were not even reported and thus are not in the FDA database.

(Whew. No more reporting research for a while, I might even have to crack my stat textbook! )

rt

Sorry... :cussing::wtf:

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Those are biggies in my book. I notice my son is significantly less depressed since switching back to Seroquel (which is considered "prolactin sparing"). Certainly, prolactin elevation should be taken seriously in choosing an AP or AAP/ More seriously than to date, anyhow.

It's also considered a decent anti-depressant.

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Its with frustrated resignation, the the satistical methods used to reach these conclusions are so advanced that they have no meaning to me. Ok, they give me numbers, but that I can't even evaluate. meh.

a.m.

the numbers shouldn't have any meaning to you. they are presented out of context. all that "hyperprolactinemia (EBGM 34.9, 90% confidence interval [CI] 32.8-37.1]" means is that 34.9 is the number they came up with using that algorithm. and i'm assuming they came up with a number for zyprexa and other meds as well. but since we don't know the scale those numbers can't mean anything to us. we just don't have enough information. so those numbers don't tell us anything about how likely it is to get a tumor. baysean by itself doesn't mean much.

which is my way of saying that it's not that the statistics are so advanced you can't understand them. if you had more information you could understand it. even if you know stats, all that information basically tells you is how they did their math. that number, by itself, means nothing at all.

just like 70% means nothing. 70% of what?

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i say if it works then go for it, especially talking about the heavier-hitting disorders that Risp. is used to treat. i say it all the time- between 15%-20% of people with BP (types 1 and 2) complete suicide, while 50% attempt. I don't know the numbers for other disorders, like MDD or schizophrenia, but the numbers for BP are very, very high (my dad, for example).

i'd rather risk lactation and any other glandular issue than risk the 1 in 5 suicide rate. if risp. is what it takes and other options are just as risky or don't work, then i don't see the point in wondering or panicking about it. we're all just doing what we can.

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The more I hear about Risperdal and the longer I'm on it, the less I like it. I'd go back to Seroquel but I'd like to stay awake for a few hours out of the day, don'tcha know. It was relatively easy for me not to carry out my "bad girl" plans when I was already unconscious all the time. So I suppose it's back to Abilify for me as soon as I figure out this whole Wellbutrin thing.

I don't know whether I'm going up to Cocktails or Depression but I gotta figure this mess out tout de suite.

Tara

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