Sorry Philip, This Study Won't Change Anything

This study (1) published in the British Journal of Psychiatry was first brought to my attention on the Furious Seasons blog (2).

This study recruited the following subjects, "Parents with bipolar disorder were identified from their involvement in a mood disorders subspecialty programme and/or genetic studies as previously described. Briefly, suitable families were identified through a proband who met DSM–IV criteria for bipolar disorder based on Schedule for Affective Disorders and Schizophrenia – Lifetime version (SADS–L) research interviews conducted by an experienced research psychiatrist. Final diagnosis was made on masked consensus review involving two additional research psychiatrists using all available clinical information

All consenting children (n = 207) from eligible families (n = 105) between the ages of 8–25 years were enrolled. The duration of the longitudinal study ranged from 1 to 15 years. Children completed Kiddie–SADS–PL (Present and Lifetime version) interviews conducted by a child and adolescent psychiatrist at enrolment, annually or at any time symptoms developed, up until their 30th birthday. DSM–IV diagnoses were made using all available clinical information on a masked consensus basis. 64% of all major episodes were prospectively captured. Any retrospective data used were based on participant and parent recall, and verified through a review of all available clinical documentation."

Here is a brief summary of the results: "Of the 207 participants, 67 met DSM-IV lifetime criteria for at least one major mood episode (i.e., depression, mania, hypomania, mixed). Their mean age at analysis was 24 (s.d.=5) years and 67% were females. in total, 16% had been admitted to hospital at least once in their lifetime and 18% had a lifetime history of psychotic symptoms in episodes. The mean age at onset of the first major mood episode was 17 (s.d.=4) years and no one experienced an onset prior to 12 years."

Overall, this study confirmed what is already known about bipolar disorder. Average age of onset was 17 (+/-4) years. First episode is typically depressive, as is the second episode. Average cycle length was 31 months. No mood episodes occurred before the age of 12. This is the typical information anyone can get by reading the DSM-IV.

Philip added this brief commentary on his site regarding these results, "Someone alert Joe "Agitation is Mania!" Biederman and CABF! Seriously, that's a pretty stunning finding and certainly confirms what other researchers elsewhere in the world have written."

Unfortunately, Joe Biederman probably didn't even read this study, since, from his point of view, it's completely wrong. It's wrong because these researchers were using the old rule book (i.e., DSM-IV). People like Biederman, Goodwin, and Akiskal et al have changed the official rule book (actually each one has their own rule book).

Biederman asserts that agitation is pathognomonic for pediatric bipolar. Others have created such ridiculous terms as "soft bipolar disorder," "subthreshold hymania," and the absurd "Bipolar III 1/2." Check out CLpsych's critique (3) of the "COBY-established criteria for BP-NOS" (4) for an example of how such rule changes can be misused.

Some say that we are simply adopting a dimensional paradigm of illness as opposed to the rigid traditional paradigm. What makes the dimensional view superior to the traditional paradigm? Is it because more people are eligible for a diagnosis? Is it that more people are eligible for prescription medications? The bipolar spectrum paradigm certainly allows more of the population to have mental health diagnoses, and it allows drug companies to get more bang for their advertising bucks.

Some mental health diagnoses seem undeniable (e.g., depression, bipolar I disorder). Come DSM-V, schizoaffective disorder, Apserger's, borderline personality disorder (which might be reduced to an axis I disorder), and narcissistic personality disorder might disappear from our vernacular all together.

Bottom line: We're making this shit up!



Duffy A, Alda M, Hajek T, & Grof P (2009). Early course of bipolar disorder in high-risk offspring: prospective study. The British journal of psychiatry : the journal of mental science, 195 (5), 457-8 PMID: 19880938

Valdoxan: The Ideal Anti-Depressant Part 3

You can read my previous posts on this drug here (1, 2).

The Research: Part 2

The second study published on the efficacy of agomelatine was by Kennedy and Emsley (2006, 3).

This was a 6-week, double-blind, randomized, placebo-controlled study involving 212 patients. Dosage ranged from 25-50mg/day (dose adjustment at week 2 for poor responders). No other active comparator (e.g., paroxetine) was used in this study. Similar to the previous study (Loo et al, 2002), the efficacy of agomelatine on a severely depressed subpopulation was examine too.

Surprise, surprise, agomelatine was shown to be superior to placebo (HAM-D total score 14.1 +/- 7.7 versus 16.5+/- 7.4). Plot twist: "The proportion of patients who were in remission by the end of the acute treatment period was not statistically different between the two treatment groups." Of course, that could be due to the short duration (6-weeks) of the study.

Remember this quote from the previous study I reviewed: "25mg of agomelatine was significantly better than placebo at 2 weeks..., whereas this significant advantage for paroxetine...did not emerge until 4 weeks." Here is the survival analysis for this study:
The difference did not occur until week 4, the same as paroxetine in the previous study. So this study failed to replicate the result of the first study.

Common side-effects reported include: "dizziness, nasopharyngitis and influenza were more common in the agomelatine group that placebo." Again, no sexual side-effects were reported (sorry, no fancy chart to show).

Part 3:

The third published study was by Olie and Kasper (2005, 4). This study is similar in design as the study mentioned-above. At the end of 6-weeks, there was a superior response for agomelatine compared to placebo (3.44 point difference).

Here is the survival analysis curve for time to first response:
Here, you can see a difference was noted at week 2 (replicating the original result), but then they merge at week 4 (difference was still significant) and then separate again thereafter. What is interesting about placebo temporarily merging with the active drug at week four, is that there was a dose adjustment from 25mg to 50mg for poor responders at week 2. Probably not the robust result they were looking for, but a reaction non-the-less.
Reported side-effects are similar to the previous studies:
Comment: Both of these study are extremely short (6-weeks). 2/3 of depressed patients usually do not respond to their first anti-depressant. Moreover, while response rates (50% reduction in symptoms) are usually robust, remissions rates a paltry (usually 1/5-1/3 remission). No long-term information can be gathered from these two short-term studies. There is long-term data, but it's unpublished.

Side-effect do appear mild. However, many SSRI antidepressant trials show mild side-effects. It's not until the drug is widely prescribe do common side-effects become evident.

All three studies were biased against placebo (i.e., 1 week placebo wash-out period).

Keep in mind that these are published studies of positive trials. There are negative trials that are simply not published (I'm shocked!).

The European Medicines Agency, the parallel to the FDA, initially rejected the drug in 2006 (5).
Here is what they said:
In case you cannot read the image, it says, "The major concern of the CHMP was that the effectiveness of Valdoxan/Thymanax had not been sufficiently shown. The long-term study (the unpublished data I mentioned) did not show that the medicine was effective. The short-term studies shown that the medicine has an effect, but the extent of this did not allow the Committee to draw a firm conclusion on the medicine's effectiveness."

The drug was finally approved in 2008 (6). In their report they list all the submitted trials.

Some highlights:

-In study CL3-22, which included a fluoxetine comparator. This study, which was a short-term with a long-term (1 year) extension found that both agomelatine and fluoxetine were not statistically superior to placebo. (oops!).

-In study CL3-23 agomelatine and paroxetine were not statistically superior to placebo over the short-and-long term. (whoops!).

-CL3-24, the results were identical to CL3-33. (strike three, you're out!).

-Study CL3-21 was a relapse prevention study against placebo. At the end of the trial, agomelatine had a relapse rate of 26% versus 24% for the placebo group (strike four! wait that's not right). They did a post-hoc analysis (i.e., statistical masturbation) and found that only for severely depressed patients there was a statistical difference. The proper thing to do at this point is to run a NEW study to test that intriguing hypothesis since the analysis was done after the fact. (It didn't happen, obviously).

-Efficacy in the elderly was not demonstrated

-Because of concerns over liver toxicity, liver monitoring is required. (do they require that for SSRI's)

Versus other Antidepressants

Much of the hoopla around this drug has been it's supposed superiority against fluoxetine (Prozac). If you head over to the official website, they tout the findings of a recent study (7). But is it really superior? The data submitted to the EMEA showed agomelatine to be equal to SSRI's (2 paroxetine studies, 2 fluoxetine studies, & 2 venlafaxine studies). With the exception of one study where superiority to sertraline (submitted later) was shown. Here's is what the EMEA had to say about the matter:
"magnitude appears less than the active comparators."So that's 2 studies out of 8 that showed a superior effect. There are many studies in the literature that show one antidepressant being superior to another (8). However, results like theses are the exception, not the rule.

The Hype

Based on my review of the data, I'm not seeing much in the way of a wonderful new addition to the anti-depressant family. Aside from liver toxicity, side-effect profile does seem favorable, which is certainly an advantage compared to SSRI's. However, efficacy does not appear any greater than currently available treatments (maybe less effective overall). Just like SSRI's, there are a number of negative trials, so the effect is certainly not consistent.

Furthermore, during my review, I found 6 review articles (see my first post), which rehash the same 3 primary studies over and over again. What's worse, these 6 articles were published within a 3 year period and all in the journals for which Montgomery is the editor. They also read like the democratic party's "talking points" on health care reform, meaning, they all stay on message. That message being "need for better antidepressants" "safety and tolerability" "unique mechanism of action." This strikes me as familiar to the recent trend in second generation antipsychotic articles (9, 10, 11). What I truly enjoyed, though, is the SSRI bashing that was going on in these studies. Last Psychiatrist discussed quite well last year (12, 13).

My Final Verdict

Slightly better side-effect profile, actual clinical efficacy is uncertain.



KENNEDY, S., & EMSLEY, R. (2006). Placebo-controlled trial of agomelatine in the treatment of major depressive disorder European Neuropsychopharmacology, 16 (2), 93-100 DOI: 10.1016/j.euroneuro.2005.09.002

Pierre Olié, J., & Kasper, S. (2007). Efficacy of agomelatine, a MT1/MT2 receptor agonist with 5-HT2C antagonistic properties, in major depressive disorder The International Journal of Neuropsychopharmacology, 10 (05) DOI: 10.1017/S1461145707007766

Valdoxan: The Ideal Anti-Depressant Part 2

If you have not read my first post on agomelatine, do so now (1).

This is my usual shtick wherein I review research articles and crap all over them. The main questions I am seeking to answer through the next series of posts are:

Is agomelatine superior to SSRI anti-depressants? And,

Does it have a more tolerable side-effect profile?

Before I address those questions through the available literature, I want to bring a certain bias to everyone's attention. The bias is not mine, but rather Stuart A. Montgomery's bias.

"Who's that?"

Have you heard of the Montgomery-Asberg Depression Rating Scale (MADRS, 2)? It's that Montgomery. Here is a brief biography (3). Here is the important part: "Dr Montgomery is editor of International Clinical Psychopharmacology and editor of European Neuropsychopharmacology. He also serves on the editorial board of 18 other scientific journals." I point this out because much of the published research (including his own research) on this drug just happen to be in the two journals for which he is the editor (4, 5, 6, 7, 8, 9, 10). A siginifcant portion of these articles were published in supplement issues (i.e., pharma sponsored). He is also a "consultant" for the company (Servier) that manufactures the drug. For you lay readers, this is our much cherished "peer-review process" at work.

The Research: Part 1

The first published study demonstrating general efficacy for major depressive disorder (MDD) was in 2002 by Loo et al (10). In this study different doses of agomelatine (1, 5, and 25mg once a day) were compared to paroxetine (20mg) and placebo in people with MDD for 8 weeks.

Here are the results:
There were more patients in remission on agomelatine 25mg and on paroxetine compared to placebo. No statistical comparisons were done between the two active drugs. Here is a finding I saw quoted in almost every article I read hereafter, "25mg of agomelatine was significantly better than placebo at 2 weeks..., whereas this significant advantage for paroxetine...did not emerge until 4 weeks." I've circled the area on the graph this is in reference to:
Here are the results for severely depressed patients:
Here are the common side-effects:
Overall, both drugs were superior to placebo. Compared to severely depressed patients (i.e., HAM-D score >25), only agomelatine was superior to placebo. Patients on agomelatine 25mg responded sooner than paroxetine. Paroxetine had more side-effects when compared to agomelatine and placebo, with a significant difference for nausea. Neither drug was associated with a high incidence of sexual dysfunction.

Comment: I'm not seeing anything here that I would call a major breakthrough. The HAM-D standard deviations are pretty large (+/- 8 points or more) so there is a lot of variability in individual patient performance (common in AD clinical trials), which limits the generalizability of the study results. I wonder how both drugs would have compared to an active placebo (11). There are not too many differences in reported side-effects except for nausea. I would have expected a far worse side-effect profile for paroxetine given agomelatine's short-half life compared to paroxetine's 24hr half-life (agomelatine patients supposedly will sleep through any acute side-effects).

This study had a one-week placebo wash-out period (which they refer to as "placebo run-in"), which biases the study against placebo. The patients (including the severely depressed patients) were not actually that severely depression, "mean duration of current episode before inclusion was 4.8 months." I can't remember the last time I saw a depressed patient with an episode duration that short.

During the study, two participants committed suicide (congrats to the researchers for reporting these data!); one on paroxetine after 11 days and one on agomelatine 25mg after 10 days. There were 7 suicide attempts: 1 on agomelatine 1mg, 3 on agomelatine 5mg, 1 on agomelatine 25mg, 2 on paroxetine, and NONE on placebo (does that mean there's no risk of not treating with AD's?).

"Among these, one was an overdose with agomelatine. A patient ingested 18 capsules of 5 mg (90mg) with an unknown quantity of alcohol." This is very important: One major downfall of the tricyclic anti-depressants (TCA's) is that patients could use them to commit suicide. Doctors use to prescribe one weeks amount at a time to prevent suicides. Overdose with SSRI's is extremely difficult. A drug with hypnotic properties, when consumed with alcohol (which is commonly abused in depressed people) might suggest that this drug is contraindicated in suicidal patients; however, there was no mention of this in the article.

Part 3 coming soon.



Loo, H., Hale, A., & D'haenen, H. (2002). Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT2C antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study International Clinical Psychopharmacology, 17 (5), 239-247 DOI: 10.1097/00004850-200209000-00004

Valdoxan: The Ideal Anti-Depressant Part 1

Have you heard the news? Not only is there a novel anti-depressant with a "unique" mechanism of action on the horizon, it is also more effective than Prozac and with none of the side-effects! (1) What is this new wonder drug? Is it truly the ideal anti-depressant? (2) The new drug is agomelatine (Valdoxan, 3). The questions that should be asked are, does it really live up to the hype? Or is the hype just a marketing ploy?

Pharmacology

First, the boring stuff.

Agomelatine is a potent agonist of melatonin receptors MT1 and MT2 (same as Rozerem). Moreover, it is an antagonist (i.e., blocker) of the serotonin 5HT-2c receptor. Agomelatine is metabolised by the liver and excreted mainly in urine. The drug's half-life (i.e., time it takes to eliminate half of the compound) is 2.3 hours.

The drug is theorized to work in two ways. First, its actions at the MT1 and MT2 receptors are supposed to help "reset" circadian rhythms and improve sleep architecture. That seems simple enough, as melatonin is freely bought at any drug store; however, whether people with depression have a true circadian rhythm disorder (e.g., delayed sleep phase syndrome) or if their insomnia (or hypersomnia) is connected to another biological mechanism (hyper-or-hypo-cortisolism) is a matter of debate (My bias is with the latter theory).

The second mechanism is antagonism of the 5HT-2c receptor. This particular serotonin receptor is a post-synaptic receptor that is mainly found in the choroid plexus (4), cerebral cortex (5), globus pallidus (6), substantia nigra (7), and spinal cord (8). Drugs that affect the 5HT-2c receptor represent a subclass of anti-depressant known as norepinephrine/dopamine disinhibitors (NDDI).

According to psychopharmacology god Stephen Stahl, "Serotonin action at 5HT-2c receptors inhibits both NE and DA release...Drugs that block 5HT-2c receptors have the opposite action and thus disinhibit both NE and DA release." Keep in mind that is has only been demonstrated in rats. It is much harder to prove in humans. Stahl also notes that, "...this action is generally activating and may be why many patients, even from the first dose, detect an energizing and fatigue-reducing effect."

Did anyone pick-up on the drug's paradoxical mechanism of action? It is both a sedative-hypnotic and activating-energizing. I'm not sure how that works out when the drug is supposed to be taken at night (Any patient testimonials?). Also, as Neuroskeptic pointed out to me, "it is also very rapidly metabolised so if you take it at night there's probably none left by the next day..." With a half-life of 2.3 hours, most (but not all of the drug) will have been excreted by the time you wake-up in the morning and almost completely gone by next dosing time.

All anti-depressants have pretty lengthy half-lives (minus paroxetine), and a steady-state blood level is required for the drug to have a consistent effect. Usually it is the rapid shift in blood levels that contribute to side-effect severity (hence paroxetine's problems). With such a short half-life, can this drug truly be more effective? Is our current paradigm of how previous anti-depressants work just plain wrong?

Sleep and Depression

Now, more boring stuff.

Will this drug's action at the MT1 and MT2 receptors contribute to its overall efficacy? I have not been able to find any published studies utilizing polysomnography to measure its effects. Why is it important to test this drug with a polysomnograph? Here are some of the sleep findings in pateints with depression:

Depression is associated with a relative increase in central cholinergic activity compared with monoaminergic activity (i.e., serotonin); cholinergic systems reduce short-wave sleep (SWS) and increase REM sleep.

Initial insomnia is inversely proportional to age: the young do not fall asleep easily and complain of initial insomnia; older adults have trouble with sleep maintenance and complain of early morning awakening.

REM sleep abnormalities may persist after successful treatment of depression; short REM latency and SWS deficits can be familial and are found in relatives of depressed patients who do not have depression. Also, depressed individuals have increased sleep fragmentation; their sleep is unstable.

You might think it wise to discover if the drug actually benefits depressed people by resolving at least some of these problems. We'll see if any of the research addresses these issues.

Another MT1 and MT2 agonist drug on the market, Rozerem (ramelteon) is not very effective. According to the medical letter: "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." The two drugs have similar melotonin properties and half-lives (2.3 hours versus 2.6 hours) Also, it should be noted that depression associated insomnia is distinct from primary insomnia (i.e., psychophysiological insomnia). Typically, people who have insomnia that is a manifestation of a primary psychiatric illness tend not to respond well to the hypnotic class of drugs. As mentioned-above, the drug is somehow both sedating and activating. It's hard to tell how that will affect sleep quality as well.

In the real world, it is unlikely this property (i.e., MT1 & MT2 agonism) will have a clinically meaningful effect.

Part 2.

"White House advisers say Fox News is not news"

News flash: If this is you're leading news story (CNN, 1), (MSNBC, 2), it's not a news organization either.

Six Biggest Myths about Psychology that Everyone Believes

This is by Angela Peterson (No idea who she is). She requested a plug. So here it is (1).

Reader Requests

Since this web log has been active, I have received requests from readers about certain topics about which to write. If there is a topic in which you are interested an would like me to create a post on that topic, just send me an e-mail with your suggestion: MacGuffin Blog.

This Is Not A Democracy

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

Answer: NO!

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

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

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

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

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

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

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

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

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

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

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

Congrats George Lakoff! You're a douche!

Would You Like Paper? Plastic? Or a Mexican?

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

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

Jack Kemp Is Not Dead

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

Update: Asenapine and Iloperidone

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

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

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

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

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

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

Lurasidone = Asenapine = Iloperidone

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

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

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

Here are some quotes from this press releases:

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

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

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

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

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

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

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

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

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

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

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

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

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

More Important Point: Akathisia and parkinsonism ARE extrapyramidal symptoms.

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

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

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

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

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

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

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

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

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



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

Saphris: It's Different without Actually Being Different

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

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

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

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

Here are the various receptor affinities for the drug:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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



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

I'm Back...Fresh Out of Rehab

In the Last Psychiatrist's post about Michael Jackson's death (1), he reports the time-line of drugs that Michael Jackson received on the day he died:

1:30 am: 10 mg Valium.
2 am: 2mg IV Ativan.
3 am: 2mg IV Versed.
5 am: 2mg of IV Ativan.
7:30 am: 2 mg of Versed.
10:40 am: 25 mg of propofol.

Here's what happened to me:

6am: Double shot of Knob Creek Bourbon.
6:01am: 1 mg Xanax.
6:05am: Crush two 5mg tablets of dextroamphetamine and snort it.
8am: Drop the kids off at school.
8:30am: Inject one 500mg vial of amobartial into the deep dorsal vein of my penis.
9am: Go to work at the hospital, so I can help others.
9:05am: Security card doesn't work, realize that I don't have kids and that I was fired from the hospital two months ago.
9:15am: Driving home, paranoid that the car in front of me is following me the long way around...need to lose him....
4am: Drove down to LA and back; that will keep that fucker busy.
4:05am: Take one 30mg capsul of Restoril, two 12.5mg tablets of Ambien CR, 10 mg Valium, 2g of diphenhydramine.
5am: Develop anticholinergic syndrome.

8am three days later: Wake up. Emptying my pockets. I come across a human finger, a wad of Turkish money, and a snapshot of a naked ex-convict named Dogmeat. The photo was inscribed, "To Dave, my new old lady."

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...