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