Thursday, September 24, 2009

This Is Not A Democracy

A douche bag* writes, "In no other state (referring to California) can a ruthless minority cause the chaos, disruption, pain, and near-bankruptcy that our state has suffered. A majority of the voters can end the tyranny of the minority. Democracy means majority rule. One sentence will do the job (referring to changing Prop. 13). Of course, there will be blow back. Conservatives will say, as they always do, that this is just a ruse to raise taxes. But this about democracy, not about how or whether revenues are raised. What the majority of citizens want, a majority of elected representatives will enact. The question is simple: Do you want democracy?" (1).

Answer: NO!

Here's a link to the federal constitution (2)

Indulge me here. Click the link to the federal constitution. Hit ctrl-f on your key pad. Type in the word "democratic" or "democracy." How many hits? Zero! As it turns out, this country and the individual states that comprise it, are guaranteed a REPUBLICAN form of government. The structure of our government was based on Rome (a republic), not Athens (a democracy).

What's the difference? A republic protects minority rights, a democracy doesn't. A republic (per our declaration of independence) states that all citizens have "inalienable rights" (except for that whole 'slavery' thing). In a democracy you have "civil liberties" bestowed upon you by the majority. The constitutions that form the various state governments and the federal government put restrictions on what those governments (and thus "the people") can and cannot do (e.g., "congress shall pass no law..."). People are allowed to do what they want, as long as they don't harm another person or violate the rights of another.

I don't want majority rule in this country. The majority of people are idiots. The idiot quoted above used the phrase "tyranny of the minority" However, it is the current tyranny of the majority that prevents many minority groups from having equal protection under the law.

Since when has "majority rule" been equal to "morally right." The majority of people in California voted to prevent homosexuals from having legal marriages; "what the majority of citizens want, a majority of elected representatives will enact" is a bad way to run a government.

There is only suppose to be a finite set of laws that apply to everyone equally. Outside of that, we are responsible for our own actions. The problem as I see it, is that there is too much democracy in this country.

Shortly after the forming of this republic, Benjamin Franklin was asked, "Well Doctor, what have we got? a Republic or a Monarchy?" to which he replied, "A Republic, if you can keep it." Sadly, we lost it (3).

The states lost their suffrage with the passage of the 17th amendment. Also during the progressive era was the "initiative and referendum" movement in many states (damn you South Dakota!). Ballot propositions now allow "the people" to alter their state constitutions by a simple majority (50% +1). Constitutions are the backbone of our governing system. An amendment can have far reaching consequences; thus, constitutions are suppose to be difficult to amend (hence the 2/3 majority required to amend the federal constitution).

The less power "the people" have to affect others, the better.

Here's why it's a good idea to have a 2/3 majority required for tax increases (4).

* The douche bag in question is George Lakoff, a professor at UC Berkeley. Since his specialty is cognitive science, he is eligible to receive the coveted Silver Douche Award (The Douchey), for his excellence in douche baggery.

Congrats George Lakoff! You're a douche!

Wednesday, September 23, 2009

Would You Like Paper? Plastic? Or a Mexican?

This from the San Francisco Chronicle (1), "The San Jose City Council has passed one of the country's strictest shopping bag bans, voting to bar retailers from giving out most paper and plastic bags. The ordinance passed Tuesday would prohibit stores from giving out free plastic shopping bags. Paper bags made with at least 40 percent recycled materials would be permitted, but only for a fee. "

The government (local, state, and federal) are never apart of the solution, only the problem.

Friday, September 11, 2009

Jack Kemp Is Not Dead

He never even existed. It's Donald Trump in hollywood style make-up. Spread the word..

Update: Asenapine and Iloperidone

A very vigilant and diligent person left some interesting comments on a few of my recent posts.

Regarding Asenapine:
"The asenapine FDA reviews are currently available but I don't know for how much longer. When FDA approved asenapine they did not include the reviews in the usual database for released reviews. Even if they are available in the future the way they published them is going to be very very difficult for anyone to find in the future. This looks very suspicious to me." -Salmon

Regarding Iloperidone:
"I've been going through the FDA reviews the last few days. It looks like this drug induces psychosis in a substantial fraction of patients resulting in a lot of problems in getting clean efficacy data in the phase III trials. Also it appears to be causing all kinds of precancerous lesions in a variety of tissues as well as blocking pGP resulting in testicular and uterine atrophy and dilation of the cerebral ventricles. Consequently Novartis dropped it. The 4th phase III study used to justify approval used a MMRM approach rather than LOCF this way they could combine the patients who dropped out due to drug induced psychosis with those who dropped out due to lack of efficacy and fudge a statistically significant result on the patients remaining in the study.

The medical officer recommended they turn it down so they had to but then it appears they forced her out had a meeting with Vanda 6 weeks later and magically found a way to accept previously unacceptable data. (They also lowered the dose range to 12 mg so they could claim they met regulatory requirements for numbers of patients studied for safety reasons even though there is insufficient data to support this dose." -Salmon

Here is some more (1, 2). Be sure to read the comments section of both posts.

And be sure to read his thorough analyses here (3, 4).

Thursday, September 10, 2009

Lurasidone = Asenapine = Iloperidone

Last week I asked, rhetorically, whether I should waste my time reviewing the published researched on the potential new antipsychotic drug Dainippon (lurasidone). Luckily for me, there isn't much (1a, 1b).

Well that's not entirely true. I did come across this study titled, "公司已在美国启动供给N0的前列腺素" (2), and this one, "使用静脉注射免疫球蛋白" (3). At least, I think those are research articles..., I'm not quite sure.

Anyway, the great news is that there are plenty of press releases (4, 5) to extol the virtues of this drug prior to it being reviewed by the FDA and the psychiatric community (I just made myself laugh, that never happens 6).

Here are some quotes from this press releases:

"lurasidone was well-tolerated and had a relatively low discontinuation rate."

"Lurasidone's effect on weight was similar to placebo (median change 0.3 kg for overall lurasidone group vs. 0 kg for placebo) as was its effect on lipid and glucose measures. Lurasidone was also well tolerated with a lower overall discontinuation rate (31%) compared to placebo (43%) and few adverse event-related discontinuations (6% and 2% for the overall lurasidone group and placebo, respectively)."

"Adverse events seen in the trial were generally mild. The most commonly reported adverse events for lurasidone (greater than 5% and at least twice the rate of placebo) were akathisia (17.6% vs. 3.1% placebo), somnolence (11.7% vs. 5.5%), parkinsonism (6.8% vs. 0), and increased weight (5.1% vs. 2.4%)."

"The development program for lurasidone is intended to establish efficacy for the core symptoms of schizophrenia, characterize its safety profile and explore its effects in the treatment of cognitive impairment and other areas not adequately addressed by current therapies"

"If you look at the weight gain, the lipid changes, it's among the most benign of any antipsychotic drugs, clearly better than olanzapine, clozapine and Seroquel"

"From the point of view of efficacy and side effect profile, once a day administration, the fact that the lower dose works as well as the higher dose, I think this is going to have a very good chance of major acceptance among my colleagues"
Douche bag.

That last quote is from this press release (5), and that lower dose he is referring to is 40mg. I guess he didn't read this press release (4), which reported this, "also evaluated two other fixed doses of lurasidone, 40 mg/day and 120 mg/day, which did not demonstrate separation from placebo on the PANSS or CGI-S at study endpoint."

Here are the reported adverse events from this article (1):
From the press releases, "The most commonly reported adverse events for lurasidone (greater than 5% and at least twice the rate of placebo) were akathisia (17.6% vs. 3.1% placebo), somnolence (11.7% vs. 5.5%), parkinsonism (6.8% vs. 0), and increased weight (5.1% vs. 2.4%)."

"The most common adverse events reported at a frequency of at least 5% and at least twice the rate of placebo among the combined lurasidone doses in these trials were akathisia (11.6% vs. 4.7% placebo), somnolence (14.3% vs. 7.1%) and nausea (14.8% vs. 6.1%)."

Then there is this beauty, "the adverse events were generally mild, such as restlessness and sleepiness." That last statement just made my third testicle descend.

All side effects are from the 80mg dose.The above-referenced study had a relatively small sample size (n=90), which I think downplays the akathisia (8.9%), while the summarized studies in the press releases are larger (n=500 & n=392) and have the high rates of akathisia.

Important Point: Akathisia is not a MILD side effect. Just asked anyone who has ever experienced it.

"These data showed that lurasidone was well tolerated with a low propensity for EPS."

More Important Point: Akathisia and parkinsonism ARE extrapyramidal symptoms.

Here are the side effect profiles from two other antipsychotic drugs:
asenapine & risperidone

iloperidone & haloperidol
Wow, lurasidone has a higher report rate of akathisia than haloperidol! (17.6% versus 13.6%). Correction, that's high (really high) dose haloperidol (15mg) . Taken together, lurasidone does not look any different, just more of the same.

"Zyprexa and similar drugs can cause significant weight gain and have been linked to increased risk of diabetes...Lurasidone was well tolerated with a discontinuation rate nearly identical to placebo -- 40 percent versus 39 percent." Have they forgotten that there already is a class of drugs that do not cause those severe metabolic changes? They're the first generation antipsychotics.

"...but this class of drugs as a whole is so superior to the first generation drugs said Meltzer." In what way is that Dr. Meltzer? Efficacy? No. Side effects? Nope. Patient tolerance? No again.

I'm feeling the need to be sued for defamation: Dr. Meltzer is a flabby bag of douche!

There's no point in reviewing the efficacy results here. Just read any random antipsychotic clinical trial. The numbers are all the same. No new psychiatric drug, antidepresant, antipsychotic, mood stabilizer, whatever, has been shown to be more effective than its predecessors in a clinically meaningful way.

Key points to remember:
1. This drug is being pushed as safer. So is asenapine and iloperidone. So will any new drug on the horizon. It's marketing. You don't manipulate the identical set of brain receptors and get less side effects. You only get different side effects.
2. The majority of the authors on these study are employees of the pharma company sponsoring the trial. The same is true for the asenapine and iloperidone studies. That's called bias. Double blind does not mean a damn thing.
3. The remainder of the second generation antipsychotics are becoming generic. That means they will be prescribed less. That means there will be a void, which can be filled by newer more expensive drugs. Since these drugs are more of the same, patients don't necessarily receive a lower quality of care, while at the same time drug pimps can continue to rake in the cash (7).

I was right. This was a waste of time (8, 9). I'm through reviewing drug research.

* Special thanks to Neuroskeptic and Cypher for teaching me how to lift images from secured files =)

Nakamura M, Ogasa M, Guarino J, Phillips D, Severs J, Cucchiaro J, & Loebel A (2009). Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial. The Journal of clinical psychiatry, 70 (6), 829-36 PMID: 19497249

Thursday, September 3, 2009

Saphris: It's Different without Actually Being Different

On August 14th, the FDA approved Schering-Plough's second generation antipsychotic drug Saphris (asenapine) for the acute treatment of schizophrenia, and the acute treatment of mania/mixed episodes associated with bipolar I disorder (1).

Question: Should I, at all be concerned that there are more actual published peer-reviewed articles of this drug being tested in rats (2, 3, 4, 5, 6 ) than in humans (7; seriously, this is the only published peer-reviewed article I can find)?

I'm not going to discuss the controversy surrounding this drug (interested persons go here: 8, 9).

What I'm going to address is the marketing angle that is being used to push this product. Namely, that its "unique human receptor signature" (10) confers a "favorable clinical profile" (7) over other antipsychotics; specifically, that it has a "high degree of safety and tolerability" as well as being a "useful option in patients with negative symptoms" (7).

Here are the various receptor affinities for the drug:

What does this mean? "Asenapine has high affinity for an ensemble of receptors, including the 5-HT receptor subtypes 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7; adrenoceptor subtypes alpha1A, alpha2A, alpha2B and alpha2C and dopamine D3 and D4 receptors. The interaction of asenapine with each of these receptors occurred at a higher affinity than that for any of the other drugs tested" (10). In other words, Clozapine is for pussies, Asenapine is hung like horse!

The skinny of this article is that each of these receptors, when blocked by this drug, may confer improvement in emotional and cognitive functioning.

Oh you didn't know? Apparently other antipsychotics don't improve the negative and cognitive symptoms of schizophrenia, which was pointed out ad nauseum in the only published peer-reviewed study I could find (7): "Although all antipsychotics ameliorate such symptoms to varying degrees, none are completely effective in all symptoms domains. Thus, there is a need for newer, more effective agents to treat the the full range of symptoms expressed in schizophrenia." Two paragraphs later, "Current pharmacotherapy for schizophrenia is limited by inconsistent or inadequate control of negative, affective, and cognitive symptoms, as well as by distressing side effects." In case you're retarded, they reiterate, "Antipsychotic pharmacotherapy offering improved effectiveness in treating the full range of positive, negative, affective, and cognitive symptoms associated with schizophrenia, plus improved tolerability, therefore remains an important unmet clinical need."

It's common in these types of articles to state the same message throughout the paper (i.e., abstract, introduction, discussion); however, all this was in the introduction only, and in adjacent paragraphs.

The manufacturer is pushing the drug on the premise that it improves the negative and cognitive symptoms of schizophrenia better than other drugs, in addition to having a better safety profile.

The safety profile angle has been used before (11). While the drug demonstrated less weight gain compared to risperidone or olanzapine, it has an elevated level (18%) of extrapyramidal symptoms (EPS) comparable to first generation antipsychotics (12).

Don't worry folks, there's a way to obscure that little fact. All you have to do is generate a drug trial where you compare the drug to the very potent D2 blocker, haloperidol, thus making any incidence of EPS seem minuscule (13).

The sample size of this study (7) is quite small compared other clinical trials (n=174). At the end of 6 weeks, only 73 subjects completed the study. That high rate of attrition is common for schizophrenia trials, keeping in mind that the patients included in these types of studies are pretty high functioning (no co-morbid medical or psychiatric illnesses, able to provide consent).

Normally, this is the part where I copy the result charts for you visual learners out there, but the cocksuckers secured the PDF file, thus preventing me from copying the data. Anyway, "at end point, mean changes from baseline were -15.9 with asenapine versus -5.3 with placebo (p<.005); the change with risperidone (-10.9) was nonsignficant versus placebo." No statistical comparison was conducted between the two active treatments, but a 5 point difference most likely is not signficant.

What about those pesky positive symptoms? "At end point, mean change from baseline were -5.5 for asenapine versus -2.5 for placebo (p=.01); change with risperidone (-5.1) was also signficant versus placebo (P<.05)."

And the negative symptoms? "At end point, mean changes from baseline were -3.2 for asenapine versus -0.6 for placebo (p=.01); change with risperidone (-1.05) was nonsignificant versus placebo." It appears that the drug is actually better at improving the negative symptoms of schizophrenia. Not quite, "Mean baseline scores were 24.1, 23.1 and 21.9 for the asenapine, placebo, and risperidone groups, respectively." If you subtract the changes, total mean scores are 20.9 and 20.85 for the asenapine and risperidone groups, respectively. The asenapine group was more severe to start with, thus allowing more room for improvement. Moreover, the asenapine mean changes were no greater than the changes produced by iloperidone, haloperidone, and risperidone in this study (14). In other words, asenapine is more of the same.

Next comes the faulty logic and far reaching conclusions of the discussion section. In reference to the drug's "unique human receptor signature" the authors state that "this pharmacologic profile may explain, at least in part, the effectiveness and toelrability of asenapine in controlling a wide range of schizophrenia symptoms." If one reads a lot of research, then you'll know that these results are no different than any other drug on the market. This is pure advertising. Personally, I cannot wait for the next conference I attend. I can't wait to see the pharma puppet actually try to push this "unique human receptor signature" shit on his audience.

"In conclusion, this double-blind, placebo-and risperidone-controlled 6-week study showed that asenapine 5mg b.i.d. was effective and well tolerated in the treatment of acute schizophrenia and may be a useful option in patietns with negative symptoms." If you say it enough times, eventually it becomes true...

This study plus one more were what the FDA use to approve this drug for use in schizophrenia. All other research for this drug can be found in a single issue of Schizophrenia Research (Volume 98), which is a supplement issue, and it includes only abstracts that were presented at a conference (XIVth Biennial Winter Workshop on Schizophrenia and Bipolar Disorders). Stingy douchebags!

That second study (13), had a larger sample size (n=458) and compared asenapine to placebo and haloperidol. Haloperidol match asenapine on the primary measure, but for some reason, haloperidol's effect on negative symptoms were not reported, only asenapine's were (mutherfuckers!).

Saphris is going to be pushed as being good for negative symptoms. That's what I took away from these advertise, err, research articles. I tried to find more data at (15), but that was fucking pointless (Usually, when I jerk off I have something to show for it).

Another drug (lurasidone) is also ready for an FDA indication for schizophrenai as well (16). Guess what angle they're going with? "It's among the most benign of any antipsychotic drugs, clearly better than olanzapine, clozapine and Seroquel," Should I even waste my time with this drug?

Potkin SG, Cohen M, & Panagides J (2007). Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial. The Journal of clinical psychiatry, 68 (10), 1492-500 PMID: 17960962

Update: (February 8, 2010) . The February 8th issue of the medial letter (Vol 52, Iss. 1331) they have a piece on Saphris 
"ADVERSE EFFECTS — The most common adverse effects occurring in >5% of patients taking asenapine and at least twice as frequently as in those taking placebo were akathisia, oral hypoesthesia and somnolence in schizophrenia trials, and dizziness and extrapyramidal symptoms other than akathisia in bipolar trials. Weight gain in clinical trials was greater than with placebo, but less than with risperidone or olanzapine."
"DRUG INTERACTIONS — Asenapine serum concentrations may increase when the drug is taken with a strong inhibitor of CYP1A2 such as fluvoxamine (Luvox, and others). Asenapine is a weak inhibitor of CYP2D6; serum concentrations of paroxetine (Paxil, and others), which is both a substrate and inhibitor of CYP2D6, increased almost 2-fold when taken with asenapine."
"CONCLUSION — Asenapine (Saphris) is a new second-generation antipsychotic agent. Available data on its efficacy are not impressive. It can cause extrapyramidal symptoms and weight gain. Because it has poor bioavailability when swallowed, the drug must be administered sublingually to achieve therapeutic blood levels; whether schizophrenic or acutely manic patients will be able to adhere to this requirement is an additional concern."