Fanapt: The Little Drug That Could

Last week, the FDA announced the approval of a novel second generation antipsychotic drug for use in the acute treatment of schizophrenia (1). I believe that this drug has been in development since 1995 (2) and was suppose to hit the market in 2001 (3, 4). It also has a very similar pharmacological profile to Risperdal, which means that there is nothing novel about this drug. Except for the name; first it was called "Fiapta," and then "Fanapta." Now it's called "Fanapt," which kind of sounds like that thing I did to my penis last night.

Alas, this drug, much like my uncle Arlen, has a checkered past. "Hoechst Marion Roussel Inc. made initial inquiries into the drug; however, in May 1996, they discontinued research, and in June 1997 gave research rights to Titan Pharmaceuticals. Titan then handed over worldwide development, manufacturing and marketing rights to Novartis in August 1998. On June 9, 2004, Titan Pharmaceuticals announced that the Phase III development rights have been acquired by Vanda Pharmaceuticals. The original launch date was scheduled for 2002. On November 27, 2007, Vanda Pharmaceuticals announced that the US FDA had accepted their new drug application for iloperidone, confirming the application is ready for FDA review and approval. On July 28, 2008, the FDA issued a "Not Approvable" (here) letter to Vanda Pharmaceuticals concerning the drug, stating that further trials are required before a decision can be made concerning marketed usage of iloperidone" (5). Other development problems can be read here (6).

So the drug is almost 15 years old and has been passed around more than Harry "Suitcase" Simpson. That means we should know a lot about this drug, since the peer-review processing is the "gold standard" of scientific integrity. CLpsych has been following the progress of this drug since 2006. Over three years, this is what he has said regarding the available research:

"I could find not a single published trial of ilopderidone in either PubMed or Clinicaltrials.gov."

"iloperidone, [has] languishing for years in development and [does] not [have] a single publicly available efficacy trial."

"It is now 2008 and I cannot find a single published clinical trial on the drug."

"So this drug has been in the clinical trials phase of development for nearly a decade, and there is no published data to show its efficacy."

As of April 2008, that is no longer the case. I was able to track down all (1o years worth) the published research in the Journal of Clinical Psychopharmacology Vol. 28, No.2, Supplement 1. If you recall, the "Not Approvable" letter was in July 2008. This issue came out in April 2008. Clearly, the drug maker was so confident of FDA approval, they put out a truncated version of the research so they could begin marketing it (most of this research took place between 1998-2002).

As a side note, a "supplement" issue is an issue that was paid for directly by a sponsor (e.g., Vanda Pharmaceuticals), which allows the sponsor to publish almost anything, as long as it looks "scientific." Last week, some people were upset when Merk was revealed to have published a "fake journal" (7a, 7b). Supplements are basically the same thing, though they don't elicit as much outrage.

In this "issue" are five articles: an introduction, one paper that summarizes three phase 3 trials (8), one paper that is a "pooled analysis" of the same three phase 3 trials aimed at discussing the safety profile (9), one 4-week comparator trial against ziprasidone (10), and one paper that summarizes three long-term efficacy trials (11). In the entire issue, four articles cover a total of 7 different clinical trials. This was done to make the database "accessible for better understanding of the overall clinical profile of iloperidone"(9).

All five of these articles have many of the same authors including Mihael Polymeropoulos, the CEO of Vanda Pharmaceuticals; and Peter Weiden, a board member for Vanda. As a matter of fact, all the researchers, with the exception of one (Andrew J. Cutler) are employees of Vanda. I'm assuming the "better understanding" they want to provide to us is the most marketable understanding.

In the Vanda press release (1) it is mentioned that two clinical trials were the bases for the FDA's approval. One 4-week study against zirprasidone (N=604) and one 6-week study against Risperdal (N=706). It appears as if this article (10) from the supplement issue is the 4-week study; however, the N in that study is 606. I believe it is study 3 in this paper (8), which is the 6-week study.

To the best of my knowledge, no new trials have been completed since 2006. I thought new trials were supposed to be conducted in order to obtain approval. So what did Vanda do to receive FDA approval after initially being rejected? I don't fuckin' know.

When I read each of these papers, I came across this sentence multiple times, "Iloperidone is a novel antipsychotic in clinical development." At what point does "more of the same" stop being "novel?" The drug has been around for 15 years, and it's another "me too" drug.

Below is a picture pertaining to the receptor affinities (12)

To understand this, you might want to read the four most important articles on psychiatry, ever! (13, 14, 15, 16) All second generation antipsychotics hit up these receptors, but in different combinations and strengths. Here we can see that iloperidone is a potent alpha-2 blocker, 5HT2a blocker, and a Dopamine-2 and -3 blocker. Based on this image, in order to get to a therapeutic dose (defined as 70% D-2 blockage), many other receptor systems will have been brought on board. Can you say "side effects?"

"And side effects this drug has," said Yoda. But we all knew that, the question is, are the side effects any different, worse, or better than other second generation antipsychotics? According to the phase-3 studies, it depends on the dose (9):
For those who cannot see the image clearly, as the dose increases from 4-8mg/d to 20-24mg/d, the percentage of people experiencing severe adverse events rose from 09.% to 2.4%, which is similar to Haldo and Risperdal (2.4% & 2.0%). It's important to note that Haldol was dosed at 15mg/d, which is quite high (> 90% D-2 blockage) and Risperdal was dosed 4-8mg/d (70-90% blockage). Since no data are available for dosage of iloperidone and percentage of D-2 blockage, we have to guess. Since 20-24mg/d had a similar profile as the comparator drugs, we can hypothesize that 20-24mg of iloperidone blocks close to 80-90% of D-2 receptors.

Here are results from 3 efficacy studies (8) - Negative values indicate improvement:
Trial 1
Trial 2

Trial 3 (submitted to FDA)
Pooled data
What do you notices in all four charts? Both Haldol and Risperdal led to greater symptom reduction than iloperidone at all doses. Note that all P-values are versus placebo, so I have no idea if any inter-drug differences were statistically significant. Based on these data, iloperidone doesn't offer anything of value over what's already on the market. Weight gain was comparable to Risperdal. The 4-week study with ziprasidone produced similar results (also submitted to the FDA):

Both drugs were dosed at the upper limits (24mg/d & 160mg/d). Iloperidone also produced a larger change in QTc interval than ziprasidone (that's strike two). Overall, it appears that iloperidone produces results more slowly than other drugs. In long term (1 year) trials, rates of relapse were comparable to Haldol. Keep in mind that all of these studies are plagued by the same methodological problems I have spoken about before (17, 18).

Of course, none of this has to do with patient care or quality of life. If it did, Fanapt would have actually been a better drug. What this is about is money:

“Shares of Vanda Pharmaceuticals Inc. soared to a new 52-week high after the Rockville, Md.-based biotech drug maker reported early Thursday its schizophrenia treatment, iloperidone, was effective in a late-stage clinical trial. Vanda shares jumped $10.95, or 70.7 percent, to $26.45 in afternoon trading on 28 times their average volume. Shares, which reached a new year-high of $28.67 earlier in the session, had traded between $7.21 and $17 over the past 52 weeks” (19).

"Vanda's stock price reportedly exploded 824 percent higher in after hours trading" (20).

When the television commercials and journal ads begin rolling out, just remember this motto: "Fanapt! It's just like everything else!"



Potkin, S., Litman, R., Torres, R., & Wolfgang, C. (2008). Efficacy of Iloperidone in the Treatment of Schizophrenia Journal of Clinical Psychopharmacology, 28 (Suppl. 1) DOI: 10.1097/JCP.0b013e3181692787

Fat People Cause Global Warming

We all hate fat people. That's a given. But why do we hate fat people? (and by "we" I mean white, Anglo-Saxon, male researchers). The answer is simple: We're not allowed to hate black people. Don't believe me? Let's examine the stereotypes. "Black people are lazy" is now "fat people are lazy." First it was "black people like chicken." Now it's "fat people have a genetic condition that makes fried chicken taste delicious." There are also historical similarities between the two groups. There used to be a "poll tax" to stop black people from voting. Now we have a "twinkie tax"(1) to stop fat people from eating. Just like the "black codes" that stripped black people of their individual liberty, we now have "food codes"(2) that strip fat people of their dietary liberty. Then there was the "science" that proved "negro inferiority"(3). Now, we have the "science," which proves that fat people cause global warming (4). At least that's what a new article published in this April's International Journal of Epidemiology suggests (I like how the press release was published on Earth Day*).

So why are we allowed to hate fat people? Supposedly, it's unhealthy, "world-wide, over 1 billion adults are overweight and around 300 million are obese. The increasing global relevance of overweight and obesity has serious implications for health, increasing the risk of type 2 diabetes, cardiovascular disease, stroke, and some cancers."(4) As it turns out, "normal people" aren't that healthy either (5a, 5b, 5c). The other reasons that make it acceptable to hate fat people, they're unattractive and fat jokes are funny, were not examined in this study.

"There is some evidence that the entire population distribution of BMI may be shifting upwards, increasing the risks of disease for the whole population and not only for the most overweight in the upper tail-2"(4). In layman's terms, people are getting fatter. However, take a look at the title of the study cited, "Weight gain and its predictors in Chinese adults." Apparently, what happens to Chinese people can be generalized to the global population. This is another example of not appropriately supporting your statements.

So why should we direct our liberal rage at fat people? "The upward shift in the population distribution of BMI could also have important environmental consequences. Food production accounts for an estimated 20% of global greenhouse gas (GHG) emissions and food consumption is intimately linked to BMI." (I question that 20% figure; 6).

Here is the stated goal of study, "to estimate the impact on GHG emissions of increase in the population distribution of BMI." How can you do a study about fat people and global warming and not examine flatulence? According to angry liberals, cow flatulence is bad for the environment (cow). Since the fat equivalent of "jungle bunny" is "cow," it seems only natural to study this too.

Here's why it was not studied: NO people and their habits (or flatulence) were actaully studied. They assumed the characteristics of a "normal adult (30-59) population of 1 billion people with mean BMI of 24.5 kg/m2 and 3.5% obese, with a corresponding overweight population with mean BMI of 29.0 kg/m2 and 40% obese." While certain human characteristics such as height and weight are normally distributed, other examined behaviors in this study such as driving, walking, and flying are not normally distributed (or they could be, I just made that up). Other methodological problems can be seen here.

"Our normal population BMI distribution reflects the UK situation in the 1970s and our overweight population BMI distribution reflects that predicted for the UK in 2010." Here's something that has never been made clear to me; in research that includes obesity data collected before 1998, what definition is being used? The definition changed after 1998 (7, 8). Current estimates indicate that approximately 30% of Americans are obese (9). However, using the pre-1998 definition, approximately 12% of Americans are considered obese, when in 1980, 14% of Americans were considered obese (10). Has the prevalence of obesity increased or decreased?

The remainder of the paper is an exercise in statistical masturbation. They concluded that "compared with a normal population distribution of BMI, a population with 40% obese requires 19% more food energy for its total energy expenditure. Greenhouse gas emissions from food production and car travel due to increases in adiposity in a population of 1 billion are estimated to be between 0.4 Giga tonnes (GT) and 1.0 GT of carbon dioxide equivalents per year." Here's the Cliff's notes version (i.e., minus the soft bigotry of scientific jargon): fat people eat more, walk less, drive and fly more, and are affected by gravity more than "normal" people.

Although the authors acknowledge that all of their "assumptions" can "be questioned," (because there is no scientific rationale to that they're correct), they still state that "the assertion that increasing population adiposity (i.e., people are getting fatter) will result in an increase in GHG emissions is justifiable and provides further evidence of the link between human health and climate mitigation (i.e., global warming)."

Since these teabaggers are allowed to make wild assumptions in the name of science, I can do the same. Here is a picture of Al Gore when he was Vice President (11). He's thin. At 6'1" and 195lbs, his BMI was 25. Current standards classifies this as overweight. Here is Al Gore now (12). He's fat. I'm going to assume, based on these pictures, that he has gained a good 35 lbs. At 6'1" and 230 pounds, his current BMI is 30. That means that he's obese. Therefore, I can concluded that Al Gore's fat assedness (i.e., increased adiposity) is leading to an increase in GHG emissions, providing further evidence of the link between human health and global warming (i.e., climate mitigation). Perhaps I'll submit this to the International Journal of Epidemiology. If I'm lucky, they'll publish it on Earth Day next year.



Edwards, P., & Roberts, I. (2009). Population adiposity and climate change International Journal of Epidemiology DOI: 10.1093/ije/dyp172

They Should Have Seen This Coming

In the April 2009 issue of Mayo Clinic Proceedings (1), a research article titled, "Frequency of New-Onset Pathologic Compulsive Gambling or Hypersexuality After Drug Treatment of Idiopathic Parkinson Disease" was published. More specifically, the authors looked at two dopamine agonist drugs (i.e., pramipexole & ropinirole). There are many other dopamine agonist on the market (e.g., bromocriptine, apomorphine), but since those drugs are old (and cheaper), they are not prescribed as widely as the newer (and more expensive) drugs. Pramipexole (Mirapex) and ropinirole (Requip) are prescribed for Parkinson's disease, but are heavily advertised for the bogus condition, restless leg syndrome* (RLS; 2, 3).

Here's what they found. "Among the study patients with PD, new-onset compulsive gambling or hypersexuality was documented in 7 (18.4%) of 38 patients taking therapeutic doses of dopamine agonists but was not found among untreated patients, those taking subtherapeutic agonist doses, or those taking carbidopa/levodopa alone. Behaviors abated with discontinuation of agonist therapy or dose reduction."

Anyway, don't you think that compulsive gambling and hypersexuality are pretty weird "side effects?" (Binge eating is another common side effect).

As it turns out, not all dopamine agonist are created alike. Typically, they fall into two categories, ergot derivatives and non-ergot derivatives (apomorphine is a morphine derivative). Ergot is a substance produced by the parasitic fungus Claviceps purpurea (common in rye and wheat). LSD is synthesized from ergot (which is good stuff by the way). Pramipexole and ropinirole are non-ergot derivatives, while bromocriptine is an ergot derivative.

The dopaminergic system is comprised of 5 different dopamine receptors (D1-5). D2 agonism is the primary method of treating Parkinson's disease and RLS. Pramipexole and ropinirole have affinities (i.e., chemical attraction) for the D3 receptor, and then the D2 receptor. Bromocriptine primarily has a high affinity for the D2 receptor, and apomorphine has a high affinity for the D1 receptor, followed by the D2 receptor. As the late, great, last psychiatrist discussed (4), if a drug has multiple affinities (e.g., D3 & D2), that specific receptor system will need to be saturated before the other receptors are affected. It other words, with Pramipexole and ropinirole, the majority of the D3 receptors in the brain will become stimulated before the D2 receptors.

Here is where this story gets interesting (that's if you find this shit interesting): The D3 receptor is primarily found in the nucleus accumbens. This is the part of the limbic system that helps to modulate emotional behavior and also plays an important role in the rewarding and reinforcing effects of many abused drugs (and other behaviors such as eating and sex). Moreover, the D3 receptor is the most sensitive to stimulation, requiring less dopamine to generate action potentials.

To the best of my knowledge, it's only the dopamine agonist that stimulate D3 that have the associated "side effects" of compulsive gambling, hypersexuality, and binge eating. I have not seen any reports that bromocriptine and apomorphine have these side effects (5, 6, 7 , 8).

What we have, is a situation where people with a legit disease (i.e., Parkinson's disease) are getting treatment from a drug that, before the therapeutic receptor is stimulated, the behavioral reinforcing receptor gets stimulated and saturated first.

Bromocriptine and apomorhpine are older drugs and have been used on Parkinson's patients for a quite a while. Pramipexole and ropinirole are newer and are the only drugs in the US approved for the specter that is RLS. As is the pattern, when docs start prescribing a drug for one condition, they will prescribe it for other conditions as well (any psychiatric drug fits this model). By pushing these drugs for RLS (a vague and amorphous condition), docs will, by extension, prescribe these drugs for Parkinson's disease too, while the older drugs are prescribed less often.

A months supply (drugstore.com 60 tablets) of pramipexole (1mg for twice a day) costs approximately $170. A month's supply of ropinirole (3mg twice a day) cost approximately $180 (the drug recently went generic, so it should be cheaper soon). A month's supply of bromocriptine (5mg once a day) costs $130. Apomorphine is mainly administered by injection or pump, so a price cannot be provided.

I know what you're thinking, $40 or $50 is not a huge difference. Except, when you realize that some of the patients who developed compulsive gambling lost close to $60,000. A large price to pay for a drug that's probably no more effective than what's already been on the market for years.

I have not been able to find any comparator trials for bromocriptine, apomorphine, pramipexole, and ropinirole. So, why prescribe the newer drugs when nothing seems to be wrong with the older drugs? The side effects of compulsive gambling and hypersexuality arose after the new drugs had gone to market. Docs were prescribing the drugs without knowing the true risks (as is the case with any new drug). This is a common practice; out with old, in the new. It doesn't seem to matter that no evidence exist to indicate that new drugs are more effective than old drugs.

Here is my main point: I'm an idiot (not my main point); if I can look up the affinities of these two drugs on wikipedia (9, 10), and then deduce how they can cause these "side effects," the people who developed these drugs should have seen this controversy coming (that's my main point). It appears as if marketing, not science, was the prevailing force here, once again.

Micro-Rant:
Here's another crime against the sick: The FDA (The Federal Douche-bags of America) recently approved tetrabenazine-TBZ (Xenazine) for the treatment of chorea associated with Huntington's disease (Was that the drug 13 was on?). This drug has been available in other countries for decades (which means it should be cheap). "A years' supply of TBZ at a dose of 50mg/day will cost about $40,000" (11). Fuck! The pharmaceutical industry is the largest single lobbying sector in Washington DC (12). As a result, not only do Americans pay more money for their medications than other nations; we also cannot import drugs produced in other countries, or re-import drugs that were originally manufactured in this country. The cocksuckers!

* To people diagnosed with RLS, I have two things to say: Firstly, it was not my intention to diminish your suffering, as I acknowledge that it is real suffering; and secondly, fuck you!

To people diagnosed with chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivities, toxic mold and sick building syndrome, and Persian gulf war syndrome; the above applies to you too.

(image credit: Anthony Flores)



1. J. Michael Bostwick, MD,, 2. Kathleen A. Hecksel, MD,, 3. Susanna R. Stevens, MS,, 4. James H. Bower, MD and, & 5. J. Eric Ahlskog, MD, PhD (2009). Frequency of New-Onset Pathologic Compulsive Gambling or Hypersexuality After Drug Treatment of Idiopathic Parkinson Disease Mayo Clinic Proceedings

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Topiramate Does Not Treat Alcohol Dependence: Part 2

Remember that, in my first post (1), I pointed out that the primary outcome measure for the study was useless? In this second paper (2), the authors admit how unimportant their primary measure was, "...its extensive secondary physical and psychosocial consequences (alcohol dependence) are what make the burden of the disease so devastating. This realization is enshrined in practice in that no commonly used diagnostic scheme for alcoholism or alcohol dependence (i.e., DSM & ICD) includes a quantification of drinking behavior-only its physical and psychosocial sequelae." It's the disability caused by the behavior that is considered the illness, not the behavior itself.

Then, just like H.M., the authors forgot what they had stated 20 seconds prior, "Topiramate, a sulfamate-substituted fructopyranose derivative, (I still don't know what the hell that means) has been shown to decrease the primary aberration of excessive drinking by reducing the reinforcing effects of alcohol."

Two more points: First, the word "aberration" means straying from the norm, which does not distinguish between something being inherently "bad" from being perceived as "bad." Context is important. Second, It's not proven that topiramate reduces the reinforcing effects of alcohol. The paper they site for that (3), is a theoretical work, not scientific in nature. (Many patients that I have seen say that mixing topiramate and alcohol makes them sick).

Remember that effect size that the authors didn't calculate in the previous study? In a situation that is reminiscent to CL psych's critique of Seroquel's BOLDER study (4), the authors finally calculated one: 0.52 (that's medium). The effect size that I calculated was a Cohen d (0.20, small), which is the standard in the field. The authors didn't state the method used to make their calculation. And why are they providing the effect size in a different paper as opposed to the original paper? Transparency People!

"Topiramate appears to be a promising medication for the treatment of alcohol dependence" This is just plain fucking stupid. Binge drinkers (the actual group studied), represents a minority of people with alcohol dependence (23% in men and 9% in women). And again, drinking behavior is not apart of the definition of alcohol dependence, so you can't say the drug treats alcohol dependence.

"Topiramate's therapeutic effect on drink outcomes appears to be the largest reported for a medication in a multisite alcoholism trial." Can you guess what paper the authors reference for that statement?

"A meta-analysis comparing topiramate, disulfiram, and acomprosate?"

Ted Stevens: "No!"

It's the same study that I wrote about in my previous post, the same study they used to suck more data from to write this second paper. It's a clinical trial, not a comparator trial.

Enough dwelling on the past, in this new paper, the authors discuss how topiramate "treats" certain physical and psychosocial consequences of alcohol dependence.

"Topiramate administration was associated with improvements in physical health in 3 domains of total cholesterol level, hepatic function, and hemodynamic cardiovascular status (that's blood pressure to the non-pretentious).

This appears in the discussion section: "long-term heavy drinking has been associated with elevated lipid levels and the development of fatty liver disease." Then a study is referenced.

This needs to be said: When writing a research paper, all the references cited should be in the introduction/literature review, not in the discussion section (or at least cited in the introduction first). The introduction builds the case for why the study needs to be done and why you're looking for what you are (the introduction to this paper is mostly spent stroking the chemical cock of topiramate). Instead, the authors use the scientific literature to build their case in the discussion section, the last, and sometimes only part people read. This makes the paper more persuasive rhetorically (i.e., not based on substance). But I digress...

Anyway, topiramate beat placebo in lowering total cholesterol level. Cholesterol was lowered by 12 points. That's not close to the nearly 60 point drop you see in LDL-C with high dose statins, but hey, at $210 for one month's supply (topiramate's cost), you pay $17.50 for every point dropped as opposed to $1.30 per point with Lipitor.

I know what you're thinking, "you made that comparison because the drug actually did something you can't refute!"

Actually, I made that comparisons to refute this statement instead, topiramate, by reducing cholesterol "adds considerably to its general medical utility in treating alcohol-dependent individuals." I'd like to point out that high cholesterol is an American problem (and primarily age and diet dependent), not just an alcoholic problem. But in the context created by this study, one might believe that this effect actually has a clinical significance. It doesn't.

"Topiramate administration was associated with a significant decrease in liver enzyme levels, probably due to the reduction in heavy drinking." The liver enzymes were AST, ALT, and GGT. In the first study, they used those enzymes as an objective measure of alcohol consumption; now they are using the same data to say it's an improvement in liver function. Watch how that prestidigitation works:

Tompirate has been shown to reduce the number of drinks consumed (1) and improve liver functioning (2). I just referred to the same data, which was used in two different papers; however, it appears as if I cited two entirely different research experiments.

Here is some more magical thinking, "Taken together with the lowered lipid levels and the consequent reduced risk of fatty liver degeneration (did they test for that disease? NO!), the propensity toward progressive liver disease and eventual cirrhosis could, perhaps, be diminished if alcohol-dependence individuals were treated with topiramate."

The mean difference in AST and ALT from placebo is 4.70 and 6.74 U/L. Both mean levels before and after were within the normal range. I stress "normal range" because AST and ALT lack sensitivity in the diagnosis of chronic liver disease. 33% of the time, AST and ALT are normal, even when the liver is not (Don't these people watch House?). Even the authors attribute the drop in liver enzymes to the reduction of drinking.

"But wasn't the reduction of alcohol consumption do to the drug?"

Recall from my first post that the data are skewed, which makes any attributable effect hard to determine.

"But the data for AST and ALT changes aren't skewed you asshole!"

Here's why: The ranking of organs that carry AST and ALT 1) liver 2) heart 3)skeletal muscles 4) pancreas 5)kidney 6)brain 7)lung 8)white blood cells 9)red blood cells. The enzymes are not specific to liver function or decline.

Also, ALT levels can vary as much as 30% from one day to the next (10% for AST). ALT is lowered by 20% after exercise (something that wasn't controlled for in this study).

Right now, I can make a pretty good argument for why a cheap generic statin and group CBT are better at treating alcohol dependence than topiramate. Also, a combined statin and group therapy are cheaper than a month's supply of topiramate.

Now we're onto blood pressure. Topiramate lowered systolic blood pressure by 9% and diastolic blood pressure by 10%. Not bad. Hydrochlorothiazide could cause a 12% reduction for $26 a month (statin + diuretic + group CBT = still cheaper than topiramate). Moreover, the people in this study didn't have hypertension, although some had "prehypertension." Oh here we go again. First there was prehypertension. Then there was prediabetes. You know what I tell these people? Why don't you pre-suck my genital situation! Sorry, I was channeling George Carlin for a moment.

"Excessive alcohol consumption is generally a risk factory for obesity." They cite one study from 1997. As it turns out, there's not a lot of research on this topic. What I can say is that, of the identified risk factors for obesity, alcohol consumption barely ranks.

So why mention it? Because you can't have a study with topiramate without the obligatory shout-out for it's weight loss proprieties. They knew the answer going in, so why not include it. The mean BMI (which is a pointless measure by the way) was reduced by 1 point, which was statistically significant. Yippee!

Now we get the the so-called psychsocial factors. On the Obsessive Compulsive Drinking Scale (OCDS), at week 14, the mean score for topiramate was 7.67 (SD 6.793). Remember what I said about a large SD? The data here are skewed toward the right. Two other measures: Clinical Global Impression scales for improvement and severity (CGI & CGI-S), also have skewed data (to the right naturally). On the last measure to show a statistically significant difference, Drinker Inventory of Consequences scale, Recent Consequences (DfInC-2R), the SD (20.14) is larger than the mean (17.98). That's more skewed data.

Here's how to tell if data are skewed: 1) round the mean and SD to whole numbers 2) multiply the SD by two 3) subtract or add the result of step 2 from the mean. If the result of step 3 is lower than the lowest possible score (which is usually 0), the distribution is skewed to the right. If the result is higher than the highest possible score, the distribution is highly skewed to the left. Of course, this is only possible is the SD (or SE) are provided. If you pay attention, you'll discover that it's quite common for articles to not list the SD, which makes this little trick difficult to perform.

"In summary, our findings demonstrate that topiramet appears to be a generally effective treatment for alcohol dependence because it improves not only the 'symptom' of drinking but also its physical and psychosocial sequelae. " Morons, idiots, or imbeciles. You chose the descriptive term that best describes the authors of that last sentence.



Bankole A. Johnson, DSc, MD, PhD, MPhil, FRCPsych; Norman Rosenthal, MD; Julie A. Capece, BA; Frank Wiegand, MD; Lian Mao, PhD; Karen Beyers, MS; Amy McKay, PharmD; Nassima Ait-Daoud, MD; Giovanni Addolorato, MD; Raymond F. Anton, MD; Domenic A. Ciraulo (2009). Improvement of Physical Health and Quality of Life of Alcohol-Dependent Individuals With Topiramate Treatment Archives of Internal Medicine

Happiness Is A Mental Illness

Since bipolar I disorder had been softened to bipolar II disorder, which has subsequently been fractionated into the bipolar spectrum, we now have terms like "subthreshold hypomania" floating around in the literature (1). This satirical piece by the Onion doesn't seem so satirical anymore...

Is It Still Considered Off-Label?

The FDA (Federal Douche Association), approved the barely prescribed Symbyax (1) for treatment resistant depression (TRD). You'll notice that the press release says that Symbyax is the "First Medication" approved for TRD.

This is pure marketing. Current standard of care for depression is extremely lame. Instead of acknowledging that, people spin it, creating this beast we now call treatment resistant depression.

Other's have already written about this drug (2, 3). So, I'm not going to rehash what's already been said. Many of the studies submitted to the FDA have not been published (shocker!). Here is a link to two studies that were pooled together as "supporting data" for the FDA (4). There is nothing new here to really criticise. These two studies have the same flaws as all other antidepressant studies.

Here is what I take away from the FDA approval: Zyprexa can now be advertised and prescribed for major depression without that being considered off-label. Lilly has been in a lot of trouble for pushing Zyprexa for off-label uses (5).

Symbyax has been around for a few years. Originally indicated for bipolar depression, it has not been prescribed a lot. One reason is that it is cheaper to prescribe the two drugs separately. It also gives the prescribing doctor more freedom to tweak the doses of individual drugs as opposed to the approved combination doses. Moreover, the data that is provided show that olanzapine alone was almost equal to fluoxetine alone. I'm pretty sure there are many docs out there who will use that as an excuse to prescribe Zyprexa alone for depression (they already do by the way).

Here are some questions I never hear asked: Assuming the drug actually does something, what does that say about the biological mechanism of depression? Zyprexa is a dirty drug, it kind of hits up all the major neurotransmitter systems. Does that mean no more monoamine hypothesis of depression? Has the research over the last 30 years been crap? Are bipolar depression and unipolar depression no longer distinct biological entities since they respond to the same treatment? Is the bipolar/unipolar distinction another marketing gimmick? I don't know what to believe anymore, I don't know what's black and what's white, what's right and what's wrong...I'm lost, I'm lost...

Topiramate Does Not Treat Alcohol Dependnece: Part 1

Since I'm fresh out of rehab (I'm addicted to placebos), I decided to set my sights on the drug topiramate (Topamax), where in which certain peeps (i.e., employees of Jassen) are trying to get approval for the treatment of alcohol dependence (1).

Originally, I was going to list each researcher attached to this study (there are 14), and expose the ones that are paid employees of Janssen, and blah, blah, blah..., but then I read the study, and I decided that it was not necessary to that. The study is total crap.

How do I know the study is total crap? The short answer is that it was published in JAMA.

Here's my long answer:

The introduction begins with with this, "Hypothetically, topiramate, a sulfamate-substituted fructopyranose derivative, can decrease alcohol reinforcement and the propensity to drink."

"What the hell is a 'sulfamate-substituted fructopyranose derivative?'" Fuck if I know.

What I do know is this, it makes you forget that the article started with the word "hypothetically." See if you can detect the difference in meaning between these two sentences:

Topiramate...can decrease alcohol reinforcement and the propensity to drink, and

Hypothetically, topiramate...can decrease alcohol reinforcement and the propensity to drink.

The first sentence states what the drug is able to do, while the second sentence states what the drug may be able to do in the make-believe world of Candyland.

The study enrolled 371 men and women diagnosed with alcohol dependence according the DSM-IV-TR-LMNOP-XXX-666. For those of you who forgot, the diagnosis of alcohol dependence requires >/= 3 of the following criteria: tolerance, withdrawal, use of more alcohol than intended (this criterion is stupid by the way), unsuccessful effort to cut down on alcohol use, spending much time obtaining, using, or recovering from the effects of alcohol, reduction in social, occupational, or recreational activities, and continued use despite the presence of persistent physical or psychological problems.

But that's not all folks, this study has some more inclusion criteria for these people to meet: men had to consume 35 or more drinks per week (28 or more for women). That means these were heavy drinking people with alcohol dependence. (Important Note: The majority of people with alcohol dependence are NOT heavy drinkers, AKA binge drinking). The researchers also included 16 exclusion criteria (to read more on the effects of this, see 2, 3). Bottom line: This sample is not representative of people with alcohol dependence or those we see in clinical practice (not even in the ball park).

The primary outcome measure was a reduction in the "percentage of heavy drinking days." Do you remember the DSM criteria for alcohol dependence that I listed? You'll notice that the amount of alcohol consumed is not a criterion. Unlike with cigarettes, we don't have that nice curve to demonstrate that reduced alcohol consumption is related to reduced morbidity and mortality.

"Surely we can assume that though, right?"

No. Sorry.

Here's the bottom line: The primary result of this study is NOT IMPORTANT. It has nothing to do with alcohol dependence. If something reduces the amount of days that a person drinks 5 or more drinks in a day, does that mean the person no longer meets the criteria for alcohol dependence? To quote former Alaskan senator Ted Stevens, "NO!"

What other DSM condition is there, that this is considered an acceptable practice? What if the condition were depression? And what if we gave depressed people a pill that made them spend less time in bed? Can I conclude that this drug is an effective treatment for depression? "NO!" So why can these douche bags make the same conclusion about topiramate?

Here's another problem: If a participant tested positive for opiates, cocaine, amphetamines, antidepressants, propoxyphenes, and barbiturates at the time of randomization and before the beginning of the double-blind period, he or she was excluded from the study. If they tested positive for benzodiazepines in the week prior to randomization, they could be enrolled if they had a negative test 7 days later. After that, they could resume consumption of benzos without the knowledge of the experimenters (addicts can be sneaky that way). Hypothetically, participants could have increased their benzo consumption while they reduced their alcohol consumption (both are sedatives).

WARNING: STATISTICS 101
The results obtained from the useless primary measure are this: from baseline to week 14, there was a change from a mean of 81.91% [SD 20.04%] to 43.81% [SD 40.43%] for topiramate, and a change from a mean of 81.97% [SD 19.92%] to 51.76% [SD 37.43%] for placebo. The mean difference between the two was 8.44%.

Pop quiz: What's wrong with these numbers?

Answer: The standard deviations are big.

"What does that mean?"

This means (no pun intended) that the individual data points don't cluster around the mean (i.e., average). They are all over the place. Instead of creating a nice bell curve, they create a flat mound. A large standard deviation means that the data are volatile and hard to analyze. You cannot make good predictions from this kind of data.

Pop quiz: Instead of providing the mean difference (8.44%), which is meaningless, what number should the authors have provided?

Answer: the effect size.

The effect size will tell you whether the drug had a small, moderate, or large impact (i.e., does it actually do something). Luckily, I know how to calculate the effect size. It comes out to be 0.2. (actually 0.204061) That's small folks. Even antidepressants work better than that.

For any psychiatrists who might be reading, here's a problem for you folks. The average dose of topiramate of 171.4 mg (SD 107.6). Again, we have a huge SD. So, what is the optimal dose for these binge drinkers? You don't know? Well, neither do the researchers.

Here's the dirty secret with using significance tests in drug research: The populations studied are not selected randomly. Significance tests are designed to assess only sampling error (i.e., errors due to random sampling). There are no significance tests (strictly speaking) appropriate for testing differences when nonrandom samples are used. Results should always be viewed as tenuous. However, since these tests are all we have, we pretend that significant results actually mean something. It doesn't matter what you call it, psychiatry, psychology, we're all frauds.

Trivia: Many patients call Topamax, "Dopamax."Here's why - side effects that affected more than 10% of subjects in this study include: paresthesia (numbness or tingling, 51%), taste perversion (23%), anorexia (20%), pruritus (10%), difficulty with memory (13%), and difficulty with concentration and attention (15%).

Here's a nit-pick: the study ended after 14 weeks with no follow-up. Alcoholism tends to be a life-long condition for most people.

When you take 14 doctors (i.e., the researchers of the article), and you put their great minds together, you get these pearls of stupidity:

"Plausibly, individuals with certain subtypes of alcoholism might benefit the most from treatment with topiramate." There is not one bit of information in the article to support this claim.

"Our study had 3 limitations." Bullshit.

"Our finding in this study that topiramate is a safe and consistently efficacious medication for treating alcohol dependence is scientifically and clinically important." Horse shit.

I'm assigning homework to you people. This study was published less than two-years ago. It has been cited in other research papers 31 times (4). How many of those studies come close to providing a critique like this one? If this is how the peer-review process works, then my peers are morons.



Johnson, B., Rosenthal, N., Capece, J., Wiegand, F., Mao, L., Beyers, K., McKay, A., Ait-Daoud, N., Anton, R., Ciraulo, D., Kranzler, H., Mann, K., O'Malley, S., Swift, R., & , . (2007). Topiramate for Treating Alcohol Dependence: A Randomized Controlled Trial JAMA: The Journal of the American Medical Association, 298 (14), 1641-1651 DOI: 10.1001/jama.298.14.1641

My Blog Caused the Jonas Brothers' Movie to Flop

Two weeks ago, I published this post (1), which revealed that the "screaming young girls" lust for the Jonas Brothers is the result of classical conditioning and not innate animalistic urges. That following Wednesday, these chicks (2), put a link to that post on their site, which caused a large increase in the "screaming young girls" demographic on this site. Today, I came across this news article (3), "Jonas Brothers hit flat note at box office (Reuters)."

According to the logic of the authors I mention in this post (4), regarding their article on treatment emergent mania, the close temporal association (within 10 weeks) between my post and the release of the Jonas Brothers movie proves that my blog caused the Jonas Brothers movie to flop.

To all those people, who I helped save $10 and 1 hour and 15 minutes of your life, you can thank me by going to Furious Seasons (5) and donating that $10 to help him reach his spring fundraiser goal of $4000.00. Then, come back to this site and say "thank you" in the comments section of this post.

Treatment-Emergent Mania Is A Myth

Let's say that you're at your buddy's house. You're watching a crappy prime-time network program (the episode where Jack Bauer goes down on Madam President). Suddenly, your friend stands up, goes to the fridge, and takes out a diet-coke in a black can (d-bags call it Coke Zero). Before opening the can, he methodically taps his index and middle fingers on top of the can.

When you hear the tapping, you casually turn your head toward your friend and ask, "Are you retarded?"

"No," says your soon to be former friend, "I'm knocking loose the bubbles from the bottom of the can so they float to the top, so it won't foam when opened."

If you haven't tried this technique, you have certainly seen someone do it, despite the fact that it doesn't work (1). It's simply just not true, yet people all over the world perform this little trick and proudly profess their discovery to others, who then spread this good news to even more people. After enough time, a myth is transformed into a fact.

Another myth that has been accepted as fact is antidepressant induced mania, which is the topic of study in this pointless investigation (2). The study is titled, "Correlates of Treatment-Emergent Mania Associated With Antidepressant Treatment in Bipolar Depression." The stated goal of the study is to examine "the correlates associated with treatment-emergent mania in patients receiving adjunctive antidepressant treatment for bipolar depression."

Hidden beneath these words is the assumption that antidepressant induced mania is a real phenomenon with legitimate scientific backing. Moreover, it means the authors (all 13 of them) cited research studies that support this assumption.

"While antidepressants may be effective in some individuals with bipolar disorder, they can precipitate a rapid mood switch from depression to mania (8, 14, 15), a phenomenon also known as treatment-emergent mania." (2). According to this sentence, studies 8, 14, 15 are studies that utilize the scientific method to provide nearly conclusive evidences that "treatment-emergent mania" is a real phenomenon.

Reference 8 is a letter to the editor (3). It's in reference to a study published in 2005, in which antidepressants were found not to induce mania. I'll repeat that, because it sounds mildly important. The study found that antidepressants did not induce mania, yet, this letter was referenced as evidence in support of antidepressant induced mania. Drater spelled backwards is what?

Reference 14 is titled, "A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression" (4). First, modafinil is an arousal promoting agent (that's pharma speak for stimulant), not an antidepressant*. Secondly, the study found this, "there was no difference between groups in treatment-emergent hypomania or mania." They're 0 for 2.

Reference 15 is here (5). This study actually looked at the phenomenon of treatment emergent mania; however, it was a meta-analysis that found this, "In bipolar depressives, manic switch occurs substantially more often with TCAs (11.2%) than with SSRIs (3.7%) or placebo (4.2%)". The SSRI rate was lower than the placebo rate. Since this study (2) looked at the antidepressants sertraline, venlafaxine, and bupropion (SSRI, SNRI, & DNRI) and not TCAs**, that's strike three.

I vaguely recall myself complaining about not reading references before citing them (6, 7). What exactly to peer reviewers do anyway?

I had to re-read this study. When I found out that the authors cited 3 studies in support of their assertion that countered their assertion, I blacked out, only to wake-up 7 days later in Butte, Montana digging for copper in a pair of crotchless panties.

However, I should have stayed in Butte. When I picked-up where I left off, I read this, "more than 40% of patients enrolled in STEP-BD self-reported manic or hypomanic switch associated with antidepressant use." Self-reported? Parents self-reported that vaccines caused autism in their children. I'm suppose to accept patient self-reports as proof when patients cannot remember if they were hospitalized for a mood episode (8, I know the book has 1,200 pages; I'm too lazy to find the reference, but trust me it's in there, somewhere, I think..., don't quote me on that).

Here is where the researchers exhibit that special kind of stupid that I mentioned briefly in this post (9). The study found "that minimal manic symptoms at baseline coexisting with otherwise full syndromal bipolar depression are associated with antidepressant treatment-emergent mania or hypomania." Some could argue that the switch (as evidence by minimal manic symptoms) was already in progress, before the antidepressant was on board. Bipolar disorder is, after all, a highly recurrent disorder.

I could say more about this study, but my head hurts. I may have just popped an aneurysm. You can read more about this study and still learn nothing by going here (10).

You can read more about antidepressant induced mania here (11).

* Technically, "antidepressant" is a meaningless term. The FDA regulates what drug companies can advertise their drugs as treating. There are many classes of drugs (e.g., TCA, SSRI, NASSA), all of which have different mechanisms of action and are all equal in efficacy (roughly). A drug can have antidepressant properties and not be labeled as an antidepressant. Just because one subclass of antidepressant might increase switch rates does not mean all antidepressants increase switch rates. Modafinil works by stimulating the tuberomammillary nucleus of the hypothalamus, thus increasing arousal (in case you cared to know).

** Although the proposed mechanism of action for TCAs is through serotonin-norepinephrine re-uptake (SNRI), they are dirty drugs. They also block histamine receptors, muscarine receptors, and alpha adrenergic receptors. Those additional properties might explain the differences between TCA and SSRI in that one study.



M. A. Frye, G. Helleman, S. L. McElroy, L. L. Altshuler, D. O. Black, P. E. Keck, W. A. Nolen, R. Kupka, G. S. Leverich, H. Grunze, J. Mintz, R. M. Post, T. Suppes (2009). Correlates of Treatment-Emergent Mania Associated With Antidepressant Treatment in Bipolar Depression American Journal of Psychiatry, 166 (2), 164-172 DOI: 10.1176/appi.ajp.2008.08030322

I Need a Pill to Erase Stupid People

**WARNING: SCIENTIFIC CONTENT**

In this month's issue of Nature Neuroscience (1), there is an article titled "Beyond extinction: erasing human fear responses and preventing the return of fear." Anyone who has taken a general psych course knows that the term "extinction" refers to the process of unpairing a conditioned response from a conditioned stimulus. It's a component of classical conditioning.

"I'm bored." Wait, it gets better...

It works like this: You have an - unconditioned response-UR (e.g., hardened nipples), which is evoked reflexibly by the unconditioned stimulus-US (ice cubes). When you pair the US with a neutral stimulus that does not cause hardened nipples (e.g., Jonas Brothers), this is called the conditioned stimulus-CS. After the US, which leads to the UR, has been paired repeatedly with the CS, then the CS alone will elicit the same response, this is called the conditioned response-CR. Finally, when the CS is presented in the absence of the US repeatedly, the CR frequency is reduced, thus rendering the Jonas Brother incapable of hardening nipples; this is referred to as extinction.

This study (1) used a paradigm known as fear conditioning. It's identical to the process-above, except the CS is usually a noxious stimulus (e.g., Fall Out Boys). This form of memory is a type of implicit (i.e., unconscious) memory and primarily involves a subcortical structure called the amygdala. Take note of the word unconscious, because it will reveal how big an idiot you are, if you work for a print media outlet.

The study found "that oral administration of the beta-adrenergic receptor antagonist propranolol before memory reactivation in humans erased the behavioral expression of the fear memory 24h later and prevented the return of fear. Disrupting reconsolidation of fear memory opens up new avenues for providing a long-term cure for patients with emotional disorders." (1).

In response to these findings, which are not new (2), the following headlines were generated: "Beta-Blocker Erases Bad Memories" (3), "Pill Could Erase Bad Memories" (4), and my favorite, "Pill to erase bad memories: Ethical furore over drugs 'that threaten human identity'"(5). In that last article, an expert in "biological" ethics (the ethics caused by a chemical imbalance) opines, "It is obviously up to the individual whether or not she wishes to risk the possible effects, including psychological discontinuity, of erasing unpleasant memories. An interesting complexity is the possibility that victims, say of violence, might wish to erase the painful memory and with it their ability to give evidence against assailants. Similarly criminals and witnesses to crime may, under the guise of erasing a painful memory, render themselves unable to give evidence." Wow, he's a special kind of stupid.

The type of memory this cognitively retarded individual is discussing is called declarative memory, the knowledge to which we have conscious access (e.g., events and facts). Implicit memory, in contrast, is the knowledge to which we typically have no conscious access (e.g., motor skills, fear responses). Typically, I'd go easy on someone who lacks neuroscience training; however, if you read the damn article, it says, in black-and-white print, that propranolol (which suppresses the activity of the sympathetic nervous system) reduced the conditioned fear response, while leaving the "declarative memory for the acquired contingency between the conditioned and unconditioned stimulus intact" (1).

First, the authors should not have used the word "erased." Media types jump all over stuff that evokes images (a conditioned response) of 1930's science-fiction movies. Secondly, blink-rate was the behavior measured. No other behavioral measure of fear was studied. Thus, it is inconclusive that the fear response was completely erased. Moreover, in the body of the article, the authors state, "...that the fear memory may either be erased (storage theory) or may be unavailable as a result of retrieval failure (retrieval theory). Note that no behavioral procedure is currently available that differentiates between these two views of amnesia." They don't even know which process it is, or if it's either process. Personally, I throw my support behind a connectionist model of memory.

"What's that?"

Look! Midgets! (6).

Just like all other researchers who lack clinical experience and want to make their results seem more important than they are, they threw in this whopper, "disrupting the reconsolidation of fear memory opens up new avenues for providing a long-term cure for patients with emotional disorders." The disorder they specifically mention is post-traumatic stress disorder (PTSD).

The specific memory process they are trying to disrupt is called "reconsolidation," the process by which a memory (either declarative or implicit), after encoding and consolidation, is strengthened when recalled. This is actually a more efficient way of learning than through repetition alone (that's why flashcards are better than reading notes, 7). Their hypothesis is that the administration of a drug that partially suppresses the sympathetic nervous system (SNS) when a conditioned fear response is cued (i.e., recalled) supposedly disrupts reconsolidation, and the fear response is dampened (i.e., not strengthened).

The reason why this won't be a "long-term cure" for emotional disorders, especially PTSD, is due to the fact that "bad" memories are both declarative (i.e., hippocampus-dependent) and implicit (i.e., amygdala-dependent). The two memory systems are separate (known as double dissociation) and can function independently. This is the reason why the fear response was suppressed, but the memory for the conditioning events were intact. At the same time, this does not mean that one system cannot influence the other.

For example, amygdala activity (e.g., fear) has been shown to strengthen the consolidation (as opposed to reconsolidation) of memories. This happens through enhancement of hippocampal functioning (8). Moreover, amygdala activity can interact directly with the hippocampus during the initial encoding phase of an experience, which also positively affects long-term consolidation.
In other words, amydala activity can modulate declarative memory at multiple stages (encoding, consolidation, and reconsolidation) leading to a net effect of enhanced retention. IMPORTANT POINT: the more intense the stimulus (e.g., severe trauma), the better consolidated the memories will be (both declarative and implicit).

People (such as soldiers) who experience severe trauma, have very vivid declarative memories and intense emotional memories of their trauma. Both unconscious and conscious stimuli can provoke intense emotional and cognitive reactions (e.g., autonomic arousal, flashbacks). A soldier, who was a patient where I work, reported that s/he witnessed 19 of his/her fellow soldiers being killed (2 by suicide). That's a little more intense than a gentle electric shock or pictures of spiders. Do you think propranolol (half life of 3.4-6 hrs) will "erase" his/her fear response? I don't.

Cognitive-behavioral therapists will tell you that in addition to emotions leading to certain thoughts, thoughts can lead to experiencing emotions. Since the emotional memory process (amygdala-dependent) can enhance declarative memories during encoding, consolidation, and reconsolidation; administration of a beta-blocker before the reconsolidation phase (which was done in this study) could be too late. To truly help these people, you would have to prevent initial consolidation. This means people would have to be treated prophylatically (i.e., give people the drug before the trauma). The problem for a soldier is that propranolol reduces reaction times, something that could mean life or death for a soldier (plus there is no evidence that it prevents fear conditioning).

As it relates to memory reconsolidation, propranolol produces results similar to sedatives (i.e., benzodiazepines, 9, 10), which are commonly prescribed to people with PTSD and only manage anxiety (i.e., not a cure). I'm failing to see the scientific breakthrough here. If you really want to help our veterans, be sure to blow smoke in faces of the children they hardly ever see (11).



Merel Kindt, Marieke Soeter, Bram Vervliet (2009). Beyond extinction: erasing human fear responses and preventing the return of fear Nature Neuroscience DOI: 10.1038/nn.2271

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Smokers Give Their Partners Dementia

Adding to the exhaustive list of societal ills supposedly caused by smokers (e.g., heart disease, diabetes, J. Geils Band), is this article published in the British Medical Journal (1).

To be quite honest, as far as studies of second hand smoke (SHS) go, this is quite good. But then again, Hillary Clinton looks good next to a bloated and naked Alan Schatzberg.

One thing this study included that most studies of SHS didn't was an actual objective measure of nicotine exposure (cotinine). Typically, study participants are given questionnaires in which they are asked to remember past exposure to SHS during the earlier decades of life. That's not what I would call "scientific."

First the results: "Participants who did not smoke, use nicotine products, or have salivary cotinine concentrations of 14.1 ng/ml or more were divided into four equal size groups on the basis of cotinine concentrations. Compared with the lowest fourth of cotinine concentration (0.0-0.1 ng/ml) the odds ratios (95% confidence intervals) for cognitive impairment in the second (0.2-0.3 ng/ml), third (0.4-0.7 ng/ml), and highest fourths (0.8-13.5 ng/ml) were 1.08 (0.78 to 1.48), 1.13 (0.81 to 1.56), and 1.44 (1.07 to 1.94; P for trend 0.02), after adjustment for a wide range of established risk factors for cognitive impairment."

While the authors did control for known risk factors for cognitive impairment, they didn't control for known factors associated with elevated cotinine (other than SHS).

Once nicotine is in the body, between 70-80% is converted to the metabolite cotinine by the P450 liver enzyme CYP2A6. The remainder is converted into nicotine-N-oxide, nornicotine, and norcotinite. All of which are excreted in urine. Cotinine usually sticks around in your system for 20-25 hours after exposure to nicotine. What its presence does not indicate, is how one came in contact with nicotine.

Therefore, "Cotinine is a marker of exposure to many risk factors other than tobacco smoke. These correlations could confound studies of the health effects of smoking, especially passive smoking." (2).

Here are some of the known factors that are associated with increased levels of cotinine in nonsmokers: low education, low SES, high alcohol consumption, low fruit or vegetable consumption, high fried food consumption, and low breakfast cereal consumption. These are just the factors significant at the p<0.001 level and doesn't include factors at levels 0.01 and 0.05.

Lastly, some people, due to genetic variation, have low CYP2A6 activity, which reduces the rate of nicotine metabolism. These people are more likely to be nonsmokers (3).

Since none of the above-mentioned factors were taken into consideration, what the BMJ study is actually examining is the association between cotinine level and cognitive impairment, not SHS exposure per se.

I'm still not convinced by this apparent association either. The highest level of cotinine was 13.5ng/ml. In this study (2), the amount of cotinine is actual smokers ranged from 80.9ng/ml to 389.4 ng/ml, while nonsmokes ranged from 0.6 ng/ml to 0.8 ng/ml.

If nicotine exposure in small amounts can lead to cognitive impairments (as the study suggests), then smokers should be developing dementia at rates similar to people with Down syndrome (4). Since less than a quarter of the population are smokers (5, there are more ex-smokers than smokers now), a decline in the rate of dementia should be on the horizon.

That's about as likely to happen as electing an Arab US president (Obama doesn't count, he's only half Arab).

I know people love to hate smokers and like to pretend SHS exposes people to nearly equal amounts of toxic chemicals and increased health risks as actual smokers (read this idiot's rant, 6), but that's just not the reality of the situation (7, 8).

Besides, SHS is so 1990's. Today, we are faced with a new threat to our health: Third-Hand Smoke (9). I shit you not. Go ahead, read the article while I have a smoke...

Did you read it? Are you afraid for your child's health and safety? Well, I hope you are, because that was the entire point. I'm actually feeling guilty for blowing smoke in the faces of all those babies at that Romanian orphanage. Excuse me while light-up another one...



David J Llewellyn, Iain A Lang, Kenneth M Langa, Felix Naughton, & Fiona E Matthews (2009). Exposure to secondhand smoke and cognitive impairment in non-smokers: national cross sectional study with cotinine measurement BMJ

Good News for Rat Psychiatry

"Nicotine Exposure During Adolescence Induces a Depression-like State in Adulthood" is the title of a study published by Bolanos et al (the fruity looking guy to the right, 1).

The summary over at Sciencedaily is titled "Teen Smoking Could Lead To Adult Depression, Study Says" (2).

As you can see in the picture, Ms..err..Mr. Bolanos is pictured with a group of rats and not with Jonas Brothers. However, the title of his study, plus the conclusions he and his colleagues draw, lead you to believe that they are referring to actual people.

"Carlos Bolanos and a team of researchers found that nicotine given to adolescent rats induced a depression-like state characterized by a lack of pleasure and heightened sensitivity to stress in their adult lives. The findings suggest that the same may be true for humans." Actually, nothing in this study suggests that same may be true for humans.

Why is that? Because they studied rats.

You mean Harry Reid and Nancy Pelosi?

No, I mean members of the genus Rattus; Reid and Pelosi are members of Desmodus rotundus (3).

The rats were injected with "either nicotine or saline for 15 days. After the treatment period ended, they subjected the rats to several experiments designed to find out how they would react to stressful situations as well as how they would respond to the offering of rewards."

The said stressful situations included: running in an open field, running in a maze, and forced swimming. The reward paradigm was the administration of sucrose. Clearly, this screams ecological validity.

"The rats that were exposed to nicotine engaged in behaviors symptomatic of depression and anxiety."

Adding, "the researchers were able to alleviate the rats' symptoms with antidepressant drugs or, ironically, more nicotine." Okay, that last sentence was just plain stupid. Perhaps these people need a primer on the neurobiology of nicotine.

The average cigarette contains approximately 6-11mg of nicotine. However, when smoked, only 1-3mg reaches the circulation (the rats were given .32mg/kg twice-a-day, which seems excessive for an animal that weighs 250g. Studies I have read usually dose rats with 10 μg/kg). The half-life (amount of time it takes for half of the drug to be excreted) is typically around 2 hours. Because of the short-half life, a characteristic withdrawal syndrome (e.g., anxiety) begins rather quickly.

Here's the rub, when nicotine is re-administered, those symptoms disappear. There is nothing ironic about it. Secondly, the antidepressnat used in the study (bupropion) is a dopamine (DA) reuptake inhibitor. As fate would have it, nicotine leads to a transient increase in DA. I think these researchers were treating withdrawal, not a "depression-like state."

I know the withdrawal syndrome can be characterized as a "depression-like state," but they are passing this off as if its actual depression, which it's not.

Why isn't it? Two words: animal model.

Here's the problem with animal models of depression (or any other psychiatric disorder). Whereas many diseases can be considered at a molecular level, mental illnesses lack such pathophysiological understanding and are reliant upon lame and nonspecific syndromal classifications (e.g., DSM-IV-TR), which renders animal models as less valid.

For those not in the know, construct validity (as it relates to animal models) is "the accuracy with which the model replicates the key abnormalities or phenomena under study within the clinical condition" (4). Another important aspect of depression animal models is its predictive validity, the "given model's ability to correctly identify effective antidepressant treatments, usually drugs." Clearly, that hasn't happened yet (4, 5, 6).

As it relates to our good ol' friend agent 296.3 ( AKA Major Depressive Disorder), "there are no symptoms, nor any other clinical features, that are pathognomonic for depression. Assumed 'core' psychopathological phenomena such as a blunting, or absence of the capacity to experience pleasure (anhedonia), can also present as a common clinical feature in substance misuse and schizophrenia" (4).

Here is what the "depression-like state" in those rats looked like, "repetitive grooming, decreased consumption of rewards offered in the form of sugary drinks (supposedly an analogue to anhedonia), and becoming immobile in stressful situations instead of engaging in typical escape-like behaviors."

It's very similar to human depression as you can see. Also, the authors admitted that "the effect size of nicotine on sucrose preference (the anhedonia analogue), though statistically significant, is small, and that nicotine did not influence total sucrose intake" (1).

As should be obvious, many of the symptoms of depression are quite difficult to model in animals (e.g., suicidal ideation). What is suppose to be science is actually an exercise in logic, "arguments for the validity of animal models rely on Causal Analogical Models (CAMs)" (4).

What!?

"These CAMs are underpinned by Casual Analogical Reasoning."

WTF!?

I have no idea either; but I think I made my point.

The reasoning goes like this: 1) Animal A is similar to animal B, with regards to properties 1, 2, and 3; 2) Animal A has property 4; 3) Therefore, animal B has property 4.

As it relates to depression, part 1 assumes that rats and humans are identical, which we are not, therefore assumptions 2 and 3 don't hold.

So why did Ms. Bolanos conclude his interview with this, "The message to young people of course is don't smoke and don't even try it, if they do smoke, they need to be aware of the potentially long-term effects that recreational or even occasional cigarette smoking can have on their systems."

Answer: He's an idiot.

By "long-term", he means one month, which is apparently how long it takes an adolescent rat to become an adult rat? (not my area of expertise). What I do know is this: Smoking cigarettes actually acts as an inhibitor monoamine oxidase A and B (7). This effect is not produced by the administration of pure nicotine, it's caused by other compounds in cigarette smoke. This means that cigarettes are actually MAOI's, which can be used to treat depression. If nicotine causes a "depression-like state," then cigarettes can counteract that "depression-like state."

So my message to young people of course is do smoke or at least try it. And while you're at it, blow smoke in a baby's face (8).



Sergio D Iñiguez, Brandon L Warren, Eric M Parise, Lyonna F Alcantara, Brittney Schuh, Melissa L Maffeo, Zarko Manojlovic, Carlos A Bolaños-Guzmán (2008). Nicotine Exposure During Adolescence Induces a Depression-Like State in Adulthood Neuropsychopharmacology DOI: 10.1038/npp.2008.220

Pimp My Product

In the January issue of Archives of General Psychiatry, there is an article (1) titled "Influence of Cognitive Status, Age, and APOE-4 Genetic Risk on Brain FDDNP Positron-Emission Tomography Imaging in Persons Without Dementia." The purpose of this study was to determine if the above-mentioned variables are associated "with increased cerebral FDDNP-Pet binding." What is FDDNP? it stands for 2-(1-{6-[(2-[F-18]fluoroethyl)methyl)amino]-2-naphthyl}ethylidene)malononitrile. Kind of just roles off the toungue doesn't it.

The researchers of this article and this other article (2) are responsible for developing this molecule, which binds to both amyloid plaques and tau tangles, the neuropathological hallmarks of Alzheimer's disease (AD is actually more than just the presence of these two abnormalities, but I'll get into at a later date). In their most recent study, they demonstrated that cognitive status, age, and APOE status were all associated with increased cerebral FDDNP uptake, which means that the above-mentioned variables are associated with increased deposition of amyloid plaques and tau tangles. As the authors state, "the results are consistent with our hypothesis and with previous clinical and postmortem studies demonstrating a relationship between such risk factors and amyloid plaque and tau tangle formation in the brain." The objective of this study was not add to this specific literature (pathology), but to demonstrate that their molecule worked, which it apparently did.

If you read the piece over at Sciencedaily.com (3), you would think the objective was something else. I know I piss on this site frequently, but it's a good barometer for how the media (mis)represents science news. Their piece is titled, "Scientists See Brain Aging Before Symptoms Appear." Sounds way cooler than the journal title. However, that was not the aim of study; determining if their tracer worked was the real aim. Remember, all of the findings regarding pathology were already known. The researchers even cite that research in their article.

So why the hyperbole? This stuff is only interesting to a select group of people (e.g., radiologists). Why try to make the uninteresting, interesting? Marketing, "UCLA scientists have used innovative brain-scan technology developed at UCLA, along with patient-specific information on Alzheimer's disease risk, to help diagnose brain aging, often before symptoms appear." I guess before this "innovative brain-scan technology," diagnosing presymptomatic brain ageing was difficult, right? Not really, (4, 5, 6, 7, 8, 9, 10). Again, the purpose of the study was to demonstrate the utility of the tracer.

In the journal article's financial disclosure section it says, "The University of California, Los Angeles, owns a US patent (6,274,119) titled 'Methods for Labeling B-Amyloid Plaques and Neurofibrillary Tangles...Drs Small, Huang, Cole, and Barrio reported that they are among the inventors, have received royalties, and will receive royalties on future sales." They're pimping their invention. Nothing wrong with that. But is all the BS necessary? Even the lead researcher joins in on the BS game, "Combining key patient information with a brain scan may give us better predictive power in targeting those who may benefit from early interventions, as well as help test how well treatments are working...this type of scan offers an opportunity to see what is really going on in the brain." The picture included with post is a FDDNP-PET image. Clear as mud, right? Not to be a nit-pick, but the study wasn't designed to determine if the stated variables can be utilized to predict onset, course, impairment, etc.

Here is more subtle advertising:

"Eventually, this imaging method, together with patient information like age, cognitive status and genetics, may help us better manage brain aging"

"PET, combined with the FDDNP probe, is the only imaging technology that offers a full profile of neurodegeneration that includes measures of both plaques and tangles"

This one is my favorite, "According to Small, in the future (cue music from Sagan's Cosmos), brain aging may be controlled similarly to high cholesterol or high blood pressure. Patients would receive a brain scan and perhaps a genetic test to predict their risk. Medications and other interventions could be prescribed, if necessary, to prevent or delay future neurodegeneration, allowing doctors to protect a healthy brain before extensive damage occurs. The brain scans may also prove helpful in tracking the effectiveness of treatments." What a prognosticator. Granted Dr. Small's utopia is a cliche and a bit hackneyed, but I still get this warm and fuzzy feeling inside the cockles of my heart.

Once again, the purpose of this study was "to determine if impaired cognitive status, older age, apolipoprotein E-4 (APOE-4) genetic risk for Alzheimer disease, family history of dementia, and less education are associated with increased regional cerebral FDDNP-PET binding." This is one of those study where the researchers knew the answer before going in (2, 11). The subjects involved were the same subjects involved in their previous study (2).

Hey, did any know that people want to revise the diagnostic criteria for Alzheimer's disease? These researchers sure did, "these criteria (referring to the revised criteria) include the presence of...1 or more abnormal biomarkers such as molecular neuroimaging with PET...FDDNP-PET might be a useful tool in applying such revised research diagnostic criteria."

I'm not faulting these people for pimping their product. That's expected. Just don't pretend that you're doing something otherwise.

Do You Hate Your Grandparents?

Are you tired of receiving birthday and Christmas cards with only five bucks inside? Do you wish that grandma and grandpa would die so you can get your share of the inheritance? If you answered "yes" to any of the above questions, then I have the product you're looking for. Antipsychotic medication. Yes, that's right folks, the same drugs you use to sedate your annoying children can be use to kill your grandparents. And the best part is, it's completely legal.

A new article published in the January 9th issue of the Lancet Neurology (1) gives the details. "The study involved 165 Alzheimer’s patients in care homes who were being prescribed antipsychotics. 83 continued treatment and the remaining 82 had it withdrawn and were instead given oral placebos. Findings showed a significant increase in risk of death for patients who continued taking antipsychotic medication. The difference between the two groups became more pronounced over time, with 24-month survival rates for antipsychotic-treated patients falling to 46% versus 71% on the placebo and at 36 months it was 30% versus 59%. It means that after three years, less than a third of people on antipsychotics were alive compared to nearly two thirds using the dummy drug."

Just imagine, in three short years you will no longer need to listen to your grandmother as she goes on and on about how lonely she is and how much she hates the nursing home you put her in. You can finally live a guilt free existence.

For whatever reason, these results came as a surprise to some people, "Rebecca Wood, Chief Executive of the Alzheimer’s Research Trust, said: 'The findings of this research are a real wake-up call and underline the danger of prescribing antipsychotics long-term for anything other than exceptional circumstances. We must avoid the use of these drugs as a potentially dangerous "chemical cosh" to patients who would be better off without it. The study also highlights the urgent need to develop better treatments as Alzheimer’s patients have few options available to them.'" "Wake-up call?" "Highlights the urgent need?" I guess she's not aware of all this research (2, 3, 4, 5, 6, 7).

However, if history is any indicator, this "new" research won't change a damn thing (8).

And the Award Goes To...

It's common practice on web logs to hand out specialized awards. Because I am both a narcissist and a conformist, I too have my own award to hand out: The Silver Douche Award. I chose the name in honor of comedian George Carlin, who frequently referred to Barbara Bush as a silver douche.

Since I am the only committee member on the board to nominate douche bags for excellence in douche baggery, the first Silver Douche Award (The Douchey) is awarded to Dr. Alan Schatzberg.

His credits include the following: 1, 2, 3, 4, 5, 6.

Congrats Dr. Alan Schatzberg! You're A Douche.

Neuropsychology Research is Lame

Admittedly, I'm biased. I've taken many cheap shots at psychiatry and, to a lesser extent, clinical psychology. However, my training is in neuropsychology, which is the study of the relations between brain function and behavior. I have yet to bite the hand that feeds me. Since it's a new year, I figured I'd begin by doing just that.

In the January 2009 issue Neuropsychology (1), an article titled "Exploring Effects of Type 2 Diabetes on Cognitive Functioning in Older Adults" was published. First, let's identify the assumption in this title: Type 2 diabetes affects cognitive functioning. The article is summarized over at Sciencedaily.com (2). As usual, the article begins with hyperbole, "Adults with diabetes experience a slowdown in several types of mental processing, which appears early in the disease and persists into old age, according to new research." Now, when I looked up the definition for the word "several," the definition I found was this, "more than two but fewer than many." In the actual study, of all the administered neuropsychological tests, only two statistically significant differences were found. According to my own new research, the opening sentence of the Sciencedaily article is nonsense.

However, there's more. The Sciencedaily article incorrectly summarizes the results, "Healthy adults performed significantly better than adults with diabetes on two of the five domains tested: executive functioning, with significant differences across four different tests, and speed, with significant differences or trends across five different tests. There were no significant differences on tests of episodic and semantic memory, verbal fluency, reaction time and perceptual speed."

Actually, out of the four tests of executive functioning, healthy controls performed significantly better than the diabetes group on one test only. Also, heed attention to this phrase, "...and speed [referring to processing speed], with significant differences or trends across five different tests. " [my emphasis]. Buyer beware when you come across the word "trend" in research articles. The term is not interchangeable with statistical significance. To say "significant differences or trends" is misleading. When a difference is statistically significant, we believe that it's likely the result didn't happen by chance. When that the difference was "close" to being statistically significant (i.e., it could have occurred by chance), we use to term trend instead. Trends do have heuristic value. They can identify areas that need further research or closer scrutiny; however, to include the phrase in a popular article is sloppy. It makes the results seem more significant than they are. It's akin to reporting response rates as opposed to remission rates in antidepressant research (e.g., 70% response rate, 25% remission rate). It's semantics, not science. In the actual study, only one test yielded significant results, not five.

What we have is a study that found two significant results (and 19 negative results), and the conclusion is that people with type 2 diabetes experience a slowdown in executive functioning and processing speed. There are a few problems that the researchers don't address. First, the more neuropsychological tests an individual is administered, the probability of having an abnormal test result increases. Second, all this study shows is that there were differences between two groups, not that the scores obtained were abnormal.

In neuropsychology, we categorize performance based on standard scores and percentiles. The line between normal and abnormal varies depending on the cut off point (typically a cut off of one standard deviation is used). Nowhere in this study do the authors state that the type 2 diabetes group had abnormal scores (i.e., below one standard deviation). They're just different from the control group. Also, the diabetes group had 41 subjects while the control group had 424 subjects. Again, we have a problem with external validity (3).

I would have an impromptu visit from a proctologist if a patient performed poorly on a single test and then I concluded that they had an impairment. The reason we give multiple tests for each domain of functioning (e.g., executive, language, visual-spatial, memory, somatosensory, processing speed, and olfaction), is to look for patterns of deficits, not just deficits. It's the patterns of deficits that lead us to a diagnosis.

Getting back to the actual study, the following domains were assessed: verbal memory (they incorrectly called this episodic memory, which is different), semantic memory (i.e., crystallized intelligence to you CHC fans out there), verbal fluency, executive functioning, and processing speed (they used the fancy term neurocognitive speed).

They improperly assessed memory, and the data they reported makes no sense. The results they listed deal with proactive and retroactive interference, which is source memory, not the ability to learn, encode, and to retain information.

They used a form of verbal fluency that isn't widely used clinically.

The tests they used to assess so-called executive functioning, the Hayling Sentence Completion Test and the Brixton Spatial Anticipation Test, don't even crack the top 40 tests used by neuropsychologists (4). The tests have only been around since 1997, and they are poorly normed.

The tests used to assess processing speed (excuse me, neurocognitive speed) are not used clinically.

I question whether these researchers know what they are doing. I understand that the more widely used neuropsychological instruments are expensive, but they still could have used tests that have clinical relevance (at least ones that crack the top 40). Secondly, identifying group differences without indicating if results are abnormal (e.g., mild deficit or moderate deficit) is clinically meaningless (in this case). I can administer IQ tests to high school graduates and college graduates. Will there be group differences. Very likely. Does that mean those differences are abnormal and require clinical intervention? NO! They're just different. Somehow, that didn't stop one of the co-authors from suggesting public health policy, "...public health programs could check the cognitive status of people with more advanced or severe cases [of diabetes]; ensure that diet and medications are effectively employed in all early diagnosed cases; and enact possible cognitive monitoring or training programs for people with diabetes." If they are normal, what's the point?

At least the last paragraph in the Sciencedaily article has shades of rationalism (I'm being ironic here), "Diabetes is a known risk factor for late-life neurodegenerative diseases such as Alzheimer's [current research suggests it doubles the risk]. Although the deficits [when were these identified as deficits? How about differences] detected in the current sample were not clinically significant [duh!], they appear (according to subsequent research by the authors [where's the reference to this research?]) to foreshadow additional deficits [differences]. Only further study would reveal whether it's possible to "connect the dots" between mild early deficits [differences] in speed and executive function, and later signs of a progressive cognitive impairment." Based on this study, many (as opposed to several) additional studies are needed.

So, getting back to the assumption implied by the article's title, does type 2 diabetes affect cognitive functioning? If this was the only article I read on the matter, I would have no idea.

Me Too Drug Marketing

In the December 8 issue of the holy journal known as the Lancet (1), an article was published regarding the sassy cousin of ramelteon, tasimelteon. Ramelteon selectively binds to the melatonin receptors in the suprachiasmatic nuclei of the hypothalamus (m1 & m2 specifically). At present the drug is FDA approved for the treatment of primary insomnia.

Enter tasimelteon, which is in phase III clinical trials and is being studied for circadian rhythm sleep disorders (jet-lag and shift-work being the most common). I don't know a lot about the pharmacological properties of tasimelteon, but as far as I can tell, it offers no advantage over ramelteon since they affect the same brain receptors and have a similar half-life (I believe ramelteon is more potent).

Just like all the SSRI's that followed Prozac, this drug appears to offer nothing in the way of improved effectiveness or safety over ramelteon, however, I am making the prediction that when the drug does hit the market, it will cost a pretty penny (2, 3).

Here is what the Medical Letter had to say about ramelteon when it was released, "Ramelteon (Rozerem), a melatonin receptor agonist, is not a controlled substance and apparently has no potential for abuse, but its hypnotic effect is not impressive. In clinical trials, it produced small, statistically significant improvements in sleep latency, but had little effect on sleep maintenance." You can substitute the name tasimelteon for ramelteon and the Medical Letter statement still holds true.

The study published in the Lancet was funded by Vanda Pharmaceuticals Inc., the company responsible for the development of tasimelteon. Sure the article talks about safety and tolerability, how it beat placebo, and blah blah blah (placebo actually did pretty well too), but this article is a simple marketing ploy, nothing more. Think of it as a movie trailer, which is released months before the actual movie, in order to generate buzz, because the actual product has no substance (e.g., Valkyrie). The cool part is, the articles that talk about this drug, act as if ramelteon does not exist. Tasimelteon is portrayed as a break through drug (4, 5), which it's not.

So, should this drug actually make it to market, it will be advertised for circadian rhythm sleep disorders. I might be as bold as to say it will be advertised as the first drug approved for these types of sleep disorders, even though there are already many effective ways to managed these sleep problems.

Gosh, I Didn't See That Elephant In The Room

In the December issue of Pharmacotherapy (1), a group of researchers pointed out the obvious, which was that "widely prescribed medications" are "most urgently in need of additional study to determine how effective and safe they are for their off-label uses." Naturally, 9 of those 14 drugs are "antidepressants and antipsychotics," which "have high levels of off-label use without good scientific backing."

Ranking number 1 in terms of off-label use is our good friend quetiapine (Seroquel), which is used to sooth all that ails you. To be honest, I thought olanzapine (Zyprexa) would have at least broke the top 5, but since olanzapine is about as healthy as being exposed to asbestos (2, 3), perhaps landing at unlucky number 13 is appropriate.

Explaining why quetiapine was number 1, one researcher said, "this drug lead all others in its high rate of off-label uses with limited evidence (76 percent of all uses of the drug), it also had features that raised additional concerns, including its high cost at $207 per prescription, heavy marketing and the presence of a 'black-box' warning from the FDA." Personally, I don't think black-box warnings mean anything anymore. They're all the rage now. They're happenin'. A drug truly hasn't made it until it has its own black-box warning. It's the pharmacological equivalent of the iphone.

In the highly ambiguous field of mental health, there are many fads (e.g., Premenstrual Dysphoric Disorder, brought to you by Prozac; Social Anxiety Disorder, brought to you by Paxil). So what's all the rage these days? Bipolar disorder of course, "the most common off-label use for six of the 14 drugs on the list was for bipolar disorder." The principal cause of these fads is another elephant in the room, "when the volume of off-label use of any drug reaches the magnitude that we're documenting, it suggests a role of the pharmaceutical industry in facilitating these types of uses." (Plot twist).

"Although companies are largely prohibited from marketing off-label uses to physicians and consumers, they make use of exceptions or may market drugs illegally...several recent lawsuits have identified systematic plans on the part of some companies to market their products for off-label uses." This has been well-documented at clinpsych (4).

There is, however, one elephant in the room that these researchers neglected to mention. Namely, that much of the research for the uses of these drugs is abysmal (5, 6, 7, 8, 9, 10). The current system is broke. We are just circling the drain at this point. These people can call for all the new research they want, but when the only thing that is produced is garbage, then that's all you're going to get. Garbage in, garbage out.

Update (01/07/09): I like his article more than mine (Last Psychiatrist).

Can You Guess Which One Is The Dummy?

I have been very busy the last few weeks; however, I should have a new post on either Saturday or Sunday. In the mean time, I came across this picture of our new Veep and was struck by the similarity he has with one of my favorite comedians. Can you tell which one is the real dummy?

News Flash: This Just In: Breaking News...

Welcome to the 6 o'clock news, I'm your anchor, Woodrow Butdonthaveapaddle. This just in...

Jaak Panksepp, a researcher at Bowling Green State University in Ohio (1), say's he has discovered that rats respond to tickling with actual laughter.

Upon hearing these findings, university officials took away the researcher's pot and told him to stop being such a crazy jagoff.