The MacGuffin

Al Sharpton is an Idiot

2012-01-27T12:09:00.000-08:00

America's Panacea for racial Freudian slips, Al Sharpton, had a "heated clash" with a Republican congressman whose identity isn't important since, if he actually agreed with Sharpton, he wouldn't have been on his program in the first place.

What caused Sharpton to contort his face in such unnatural manner was the following exchange: Sharpton: "Is it fair that billionaires pay a lower tax rate than their own secretaries?" To which the Republican replied, "Well they actually don't, according to the IRS."

Now, if two reasonable people were having this discussion, the conversation might proceed like this, Sharpton: "Will you please show me the IRS data about which you speak? So I may correct myself"; Republican: "Sure Al; and would you like some motherfucking ice tea?"

Reality turn out differently, "Sharpton started to raise his voice and asked the question again. 'Is it fair? Is it fair?' Huelskamp continued to deny the accuracy of Sharpton's question. 'It's not true, Al.' Sharpton then said 'on the basis of the report—if the report is inaccurate, fine, you stipulate that—I'm asking you, is it fair? Is the arrangement fair, in your opinion?'"

There is only one answer that Sharpton is willing to hear: NO! He's not interested in facts; notice how he continues to seek an answer even after granting that the statement "billionaires pay less than their secretaries" might be false.

1. Warren Buffet's "secretary" is an idiot. Some time ago, Mr. Buffet claimed that his secretary made $60,000 and paid a 30% tax rate. Here's the problem with that: our income tax system is progressive, meaning that we pay higher tax rates as our income gets higher. As the table below shows, there are six tax brackets.

Let's say our income (husband and wife jointly filing) is $112,000. This would put us in the 25% bracket. If the U.S. had a flat rate tax system (and no deduction), we would pay 25 percent of $112,000 in income tax, or $28,000 (a common misunderstanding of how the tax system functions). Under our tax system we pay 10 percent on the first $17,000, or $1,700. We then pay 15 percent on the next band of income up to $69,000, or $7,800. We then pay 25 percent on the marginal amount over $69,000, for another $10,750 in taxes. When we total the taxes paid on these three bands of income it comes to $20,250, for an average (or effective) tax rate of 18.8 percent. The national average is 11% (Note that effective tax rate is what was actually paid. It will always be lower than the marginal tax rate).

Effective Tax Rates by Income (2009)

According to the bracket for single filers (let's assume Mr. Buffet's "secretary" is single), she would have paid $830 on the first $8,300 of her income (10%) and then she would have paid $3,255 for the remaining $21,700 of her income ($30,000 - $8,300). A total of $4,085 would have been paid for an effective tax rate of 13.6% (This does not include deductions and credits, which would have likely lowered her rate to 7%). Clearly Mr. Buffet needs to educate his "secretary" on how to file tax returns; after which, he should fire her.

2. Who decides what is fair?

How Much Should the Top 1% Pay Before It's Considered Fair?

The top 1% of income earners (those with incomes of $343,927 in 2009) paid a larger percentage of the income tax (36.73%) than the bottom 90% combined (29.5%). Also in 2009, the top 1% earned 16.9% of the adjusted gross income (that's down from 20% before the recession).

On the other side of the coin are the non-payers. A non-payer tax return is one filed by an individual or couple who, thanks to legal credits and deductions, owes nothing. In 2009, a record number of individuals (58 million) paid no income tax. That is, 42% of tax filers were non-payers. Only 0.3% (2009 data, table 1.1) of those non-payers earn more than $100,000.

I'll repeat that since it's mildly important: 42% of the bottom 85% of income earners (i.e., <$100,000) paid no income tax.

Moreover, many of these non-payers also receive "refundable" tax credits even though they have no income tax liability. For millions of these non-payers, these refundable credits exceed their total payroll tax (i.e., social security, medicare, unemployment) contributions. In 2008, more than a third of all tax returns resulted in complete nonpayment; that is, people got back every dollar that was withheld from their paychecks during the year.

3. Raising Taxes on Wealthy Won't Fix Anything

Earlier, congress wanted to impose a 5.6% surtax on those with incomes above $1,000,000. According to the CBO, that tax would raise $450 billion over the next 10 years. That's 45 billion a year. Last year's deficit (fiscal year 2011) was 1.3 trillion, the second largest deficit of any nation in the history of the world. After you subtract 450 billion from 1.3 trillion you get 850 billion. If you cut out all non-defense discretionary spending you save $530 billion, leaving our deficit at $320 billion. Only after halving securing spending, will last year's deficit go away.

4. Stop Blaming the Bush Tax Cuts

The CBO, broke "down the major components of the $11.8 trillion swing from surpluses to deficits over the ten year period 2002 to 2011." Higher spending turns out to be the largest factor erasing those surplus projections.

As the chart above shows, the Bush Tax cuts have been declining in significance as a contributing factor to the annual deficits while increased spending and recent tax cuts (e.g., payroll tax cut) are larger contributing factors to annual deficits.

5. The Elephant in the Room

Mandatory spending is consumes 60% of the annual budget. That Social Security (761 billion), Medicare (468 billion), and Medicaid (269 billion). And last*, but certainly not least is Defense spending ($660 billion), which is not actually mandatory spending, although it should be since no one wants to touch it.

Until people start focusing on reforming these programs and these programs alone, all other talk is a waist of time.

The information is out there, all you have to do is let it in...

*All other mandatory spending programs combined (e.g., food stamps, unemployment) total over 600 billion.

Koo Koo for Four Loko

2011-01-07T12:41:00.000-08:00

Next time you watch your local news, remember this: News Media = Misses the Entire Point.

If you have not seen the news about the drink Four Loko being banned, I will bring you up to speed.

According to various we-have-nothing-else-to-report news organizations, the drink Four Loko is to some, a "blackout in a can" and to others, it is "cocaine in a can." Four Loko, through its "witch brew" mixture of alcohol and caffeine can, according to research (1a), cause a person to become a "wide-awake drunk," and thus impair a person's ability to judge his or her level of intoxication. The negative effects of this drink, which has predominately affected college students, are "spreading like a plague across the country." (1b, 1c).

In all, Michigan, Oklahoma, Washington, Utah, and New York have banned the drink. The FDA evaluated the situation and said that caffeine is an "unsafe food additive" (2). Because of this negative publicity, Fusion Projects has removed the caffeine content from their Four Loko brand.

However, even the removal of caffeine is not enough according to some experts (3). For some strange reason, all of these "experts" reside at Rutgers University:

"When consulted about the combination of caffeine and alcohol in one 24.5 oz. can, Rutgers U. nutritionist and registered dietitian Peggy Policastro explained the concoction’s effects on the body. 'The natural response of the body to alcohol is sleepiness and fatigue,' she said. 'When a stimulant such as caffeine is added, this response is blocked, allowing for the consumer to engage is riskier behavior for longer.'"

Here is an example of how the news covered this "controversy":

I've transcribed the more hyperbolic parts:

The created context is about the dangers of Four Loko (i.e., don't blame irresponsible teenage behavior)

Anchor: "Well, four teens are hospitalized in White Plains, and police say it's all because of a beverage that looks like an energy drink."

Exaggerate the affects of the this witch brew (i.e., It's PCP in a can )

Field Reporter: "Cops and kids say just one can of Four Loko can make you do crazy things."

Cue ~~expert~~, er, teenager who can attest to the affects of Four Loko

Dumb Teen: "I've seen people have half of it, and they're gone...and if you have a whole one, you're...way gone."

Cue inappropriate comparison to another beverage

Field Reporter: "That's because just one can of it has an alcohol content of 12% while the average mixed drink or beer has just 5%."(Note: Wine also has a 12% alcohol content)

Cue Morgan Rolland, a responsible teenager who has never drank Four Loko because "she's 19, and she's diabetic" (I bet she's a virgin too). Also note at the 50 second mark that there is a bunch of alcohol just behind her chair.

Dumb Teen: "I've seen a man get very drunk off just one, and he's like a hundred and like 95 pounds and he was gone."

Cue stupidity

Field Reporter: "What's more scary is that you can pretty much buy this anywhere, and in some stores, it's not even listed in the beer section."

Just the Facts:

Four Loko is an alcoholic-energy drink marketed by Phusion Projects which contains alcohol, caffeine, taurine (which has no proven energetic affect), and guarana (a rich source of caffeine). In all, Four Loko has the equivalent of 80mg of caffeine (i.e., average cup of coffee). Depending on state law, Four Loko contains either 6%ABV (the equivalent of a Molson beer) or 12%ABV (equivalent to wine, 4). It comes in a 24.5 oz. can (the equivalent of a bottle of wine).

The Problem is Teenagers, Not Four Loko:

"The NIAAA states that approximately 599,000 college students in the United States get accidental alcohol-related injuries, such as alcohol poisoning. Half of them are under the legal drinking age of 21" (5).

"There are 1,742,887 drug-related ED visits nationwide and 7 percent involved alcohol only in individuals under the age of 21." (6).

"About four in five of all college students drink, including nearly 60 percent of students age 18 to 20."

"Approximately two of every five college students of all ages—more than 40 percent—have reported engaging in binge drinking at least once during the past 2 weeks. However, colleges vary widely in their binge drinking rates—from 1 percent to more than 70 percent."

"It is estimated that more than 696,000 students between the ages of 18 and 24 are assaulted by another student who has been drinking each year (430,000 of them by a college student under 21)."

"About 11 percent of college student drinkers report that they have damaged property while under the influence of alcohol."

"It is estimated that more than 97,000 students between the ages of 18 and 24 are victims of alcohol-related sexual assault or date rape each year (about half among students under 21)."

"It is estimated that more than 400,000 students between the ages of 18 and 24 had unprotected sex as a result of their drinking and more than 100,000 students between the ages of 18 and 24 report having been too intoxicated to know if they consented to having sex each year" (7).

Fact of the Day: One's Belief that Alcohol Will Produce Relaxation, Sexual Desire, or Aggression Has More Effect on the Individual's Behavior than the Pharmacological Effects of the Drug (8, 9, 10).

How to Use a Journal Article to Advertise Your Product

2010-08-26T16:43:00.000-07:00

From this Month's JAMA (1) "Cognitive Behavioral Therapy vs Relaxation With Educational Support for Medication-Treated Adults With ADHD and Persistent Symptoms" by Safren et al.

In order to use an article to advertise your product, first you'll need to chose a topic about which people are fairly ignorant and make yourself an expert on it:

“Approximately 4.4% of adults in the United States have attention-deficit/hyperactivity disorder (ADHD).”

Writing Style Recommendation: If you use the word “approximately,” which means “near or around,” then don’t use a number with a decimal. That’s too much precision. Just say “approximately 4% of adults.”

The lead author is Steven Safren, Ph.D., ABPP. In case you’re wondering, those initials mean people have to refer to him as “doctor” and believe that he actually knows what he is talking about. Although adult ADHD is rather amorphous, Safren et al. have extensively researched CBT with adult ADHD. This gives Safren et al. a posteriori authority on the topic.

Second, you'll need to concoct a reason why you're conducting research:

“…Medications have been the primary treatment; however, many adults with ADHD cannot or will not take medications while others show a poor medication response. Furthermore, those considered responders to medications may continue to experience significant and impairing symptoms. Thus, there is a need for alternative and next step strategies.”

Reader Advisory: Don’t be fooled by this “need.” It’s not a real need, it’s a constructed need (hey look at this huge hole in the ground I created! It needs to be filled!). These authors are using the construct of ADHD and the failure of medication (to treat an arbitrary construct) to accomplish their own goal.

You can read the results in the abstract here (1) as they are only of secondary importance.

Here is the real importance of this article: “Cognitive behavioral therapy was delivered consistent with our manuals.”

The authors of this article are also the authors of these two books (2, 3). This journal article will serve as a marketing device for these manuals.

It works like this: First, they will give “talks” touting the results of this research.

“I am going to show you a bunch of statistics that have no real world relevance…”

Second, they will conclude that pointless discussion with…

“Our manual is available in the literature section located in the lobby.”

Unfortunately, those manuals don’t contain actual cognitive and behavioral material. Sure, they use the jargon, but it’s not actual CBT.

Writing Style Recommendation: Add words to mundane terms, thus making them appear more important than they actually are.

“Sessions were designed specifically to meet the needs of ADHD patients and included things like starting and maintaining calendar and task list systems”

Anybody can use a calendar or task list, but only “doctors” can provide instruction on how to use a calendar system or a task list system.

Here's a beauty...

“The first module focused on psycho-education about ADHD…”

What’s the difference between psycho-education and regular education you ask?

If you read an ADHD article on webMD, that’s “education.” When a psychologist prints out that webMD article and hands it to you, that’s “psycho-education.”

Study CBT protocol (i.e., the important one)

Study Relaxation protocol (i.e., the unimportant one)

Other cutting edge cognitive behavioral techniques include “setting priorities” and “breaking large tasks into manageable steps.” Oh snap!

I argue that this is not CBT but rather a collection of common sense solutions to everyday organizational needs. However, Safren et al. refer to this as a particular “type of cognitive behavioral therapy,” which was successfully documented to be useful “as a next-step strategy for patients with ADHD…”

So you better go buy those books!

Safren SA, Sprich S, Mimiaga MJ, Surman C, Knouse L, Groves M, & Otto MW (2010). Cognitive Behavioral Therapy vs Relaxation With Educational Support for Medication-Treated Adults With ADHD and Persistent Symptoms: A Randomized Controlled Trial. JAMA : the journal of the American Medical Association, 304 (8), 875-80 PMID: 20736471

Cerebellar Agenesis: Life without a Cerebellum

2010-05-28T15:53:00.000-07:00

Many people are familiar with the famous patient H.M., the man who, in an attempt to control his intractable epilepsy, underwent surgical resection of both his medial temporal lobes.

There is another patient who is less famous, known the by initials H.C. He died in 1939 when H.M. was just entering adolescence. Unlike H.M., this patient did not undergo radical resection surgery. In fact, he never underwent brain surgery at all. His contribution to neurology did not begin until after his death at the age of 76.

In what was supposed to have been a routine autopsy, H.C. was discovered to have had no cerebellum (see pictured brain above). H.C. had a very rare neurological condition known as cerebellar agenesis. When I was in graduate school, I was taught that the neuroplasticity of the brain was so remarkable, that even a child born without his or her cerebellum could grow-up to have no deficits and live a normal life. As it turns out, that was only partly true. H.C. was in fact, not without deficits. His tale is recounted briefly in two articles from the March 2010 issue of Brain:

"It was clear that there were indeed clinical signs included right external strabismus (i.e., misaligned eyes), slow and slurred articulation and an unsteady gait." (1)

However, he did live a "normal life":

H.C. "had employment, that he was able to work in a manual job and that his working life was not curtailed by his cerebellar agenesis." (1)

What is interesting about H.C. compared to H.M., is that H.C.'s agenesis was discovered only after he died. Very little clinical history about his life exists, making this story a great neurological detective case. Most of what is known about H.C. comes from hospital notes during his last years of life, just before he developed dementia:

"The social history describes him as 'single.' The notes contained a record of his assessment by a neurologist, Dr. Jacobson, who described him as 'a simple man with some hearing loss and slow slurred speech; he has a fair memory for recent and remote events concerning himself, but with limited general knowledge. There is no hallucination or delusions nor emotional defect. He is clean in his habits and able to attend to his person. He is able to get around unassisted." (1)

The human brain is estimated to have approximately 85 billion neurons (2). The cerebellum, which is typically 1/4 the size of the rest of brain, contains a full 50% of all our neurons. If you pay close attention to the image above, you will notice that, in addition to not having a cerebellum, H.C. was also missing his pons, the bulbous structure that is typically adjacent to the cerebellum and is responsible for arousal and alertness.

Many of the patients I have seen with cerebellar strokes typically have severe and irreversible deficits. While H.C. did have some cognitive and functional deficits, that he lived a full and functional life is nothing less than remarkable. His case is an example of how extraordinary the human brain actually is.

I encourage you to read more about the mysterious case of H.C. here.

Boyd, C. (2009). Cerebellar agenesis revisited Brain, 133 (3), 941-944 DOI: 10.1093/brain/awp265

Lemon, R., & Edgley, S. (2010). Life without a cerebellum Brain, 133 (3), 652-654 DOI: 10.1093/brain/awq030

Detroit SWAT Team Kill 7 Year-Old Girl

2010-05-16T22:51:00.000-07:00

There has to be a better way to do this....full story here.

UPDATE: As luck would have it, this particular raid was being filmed for a reality show known as "The First 48." Base on the footage, the family lawyer is alleging a cover up (1).

Draw Muh...er...Comedy Central Executives Day

2010-05-14T17:43:00.000-07:00

May 20th has been declared "Everybody Draw Muhammad Day" (1). By now, many should be aware of the controversy surrounding South Park's 200th and 201st episodes.

Shortly after the airing of episode 200, a group known as Revolution Muslim posted the following message on their site:

"We have to warn Matt and Trey that what they are doing is stupid and they will probably wind up like Theo Van Gogh for airing this show...this is not a threat, but a warning of the reality of what will likely happen to them." (2).

Thereafter, the media got wind of this post and ran with it. All major news networks and outlets had something to say about this "controversy". A week later, the 201st episode aired. It was, against the wishes of Matt Stone and Trey Parker, heavily edited by the douche bags at Comedy Central/Viacom.

As a result of the ignorant and spineless actions by the douche bags at Comedy Central/Viacom, a self-proclaimed idiot (3) and artist, Molly Norris, declared May 20th to be "Everybody Draw Muhammad Day." She had created a poster showing many objects, such as a tea cup, claiming to be the likeness of Muhammad. She sent this poster to different media outlets, who took it seriously, and then it went viral.

Ms. Norris has since distanced her self from "Draw Muhammad Day" and suggested that we should draw Al Gore instead (4).

After reading and listening to the media, I decided to do some research. To me, all this "controversy" seemed a bit contrived. After all, this was nothing like the Danish cartoon hysteria. If you were paying attention at all, it appears that this "controversy" had fallen on deaf ears in the Muslim world (5).

The true extent of Muslim hysteria was this: one post, by one Islamic group, Revolution Muslim.

I read about the group on Wikipedia (6). It turned out to be an interesting read:

"The group of 5-10 members....run by Yousef al-Khattab, born Joseph Cohen, an American Jew who converted to Islam in 2000 after living in Israel and attending an orthodox rabbinical school."

More about Joseph Cohen from LoonWatch.com :

"He was born and raised in the United States as a Jew, and holds both American and Israeli citizenship. In the late eighties, Cohen embraced an ultra-orthodox interpretation of Judaism, and began attending a yeshiva (rabbinical school). In 1998, Cohen hearkened to the Zionist call, and packed up his bags to relocate to the Israeli Occupied Territories where he became an Israeli settler. As an ardent and extreme Zionist, Joseph Cohen fell in with the Jewish fundamentalist group Shas, an extreme right-wing political party that believes in flouting international law based on their religious beliefs. Less than three years later, Cohen 'converted' to Islam, moved back to the United States, and founded the most radical Islamic group in the country." (7, 8)

A radical in one religion will be a radical in another religion.

Maybe, just maybe, it was not the Muslims who were over reacting, but rather, the American Media. Now many people across this country are angry, and on May 20th, people will take pencil to paper and draw the Prophet Muhammad.

Perhaps this anger is misplaced. After all, it was Comedy Central/Viacom that censored the cartoon. It was also Comedy Central/Viacom that censored people who criticized their spineless behavior (9). Perhaps the true enemies of free speech are the people responsible for actual censorship: the executives/lawyers at Comedy Central/Viacom.

Woman Hospitalized Following Botched Raid

2010-05-13T09:25:00.000-07:00

How many armed, anonymous, men does it take to give an old woman a heart attack? The answer:

"An elderly Polk County woman is hospitalized in critical condition after suffering a heart attack when drug agents swarm the wrong house. Machelle Holl tells WSB her 76-year-old mother, Helen Pruett, who lives alone, was at home when nearly a DOZEN local and federal agents swarmed her house, thinking they were about to arrest suspected drug dealers." (1)

There Are 40,000 of These Each Year

2010-05-05T14:21:00.000-07:00

Here's what happened (1):

"SWAT team breaks into home, fires seven rounds at family's pit bull and corgi (?!) as a seven-year-old looks on.

They found a "small amount" of marijuana, enough for a misdemeanor charge. The parents were then charged with child endangerment.

So smoking pot = "child endangerment." Storming a home with guns, then firing bullets into the family pets as a child looks on = necessary police procedures to ensure everyone's safety.

Just so we're clear."

Transcranial Magnetic Stimulation: Does it Live Up to the Hype?

2010-05-05T11:49:00.000-07:00

Repetitive Transcranial Magnetic Stimulation (rTMS) is a treatment for depression that was approved by the FDA in October of 2008 (1). Repetitive TMS involves a device (pictured right), which is noninvasive, that excites the neurons in the brain. When this done over the left dorsolateral prefrontal cortex (an area of the brain supposedly less active in depressed patients), brain activity increases. The major selling point is that it has very few side-effects compared to standard antidepressant treatment (most common effects are headache and tingling at the stimulation site).

The FDA approval of this device has been controversial (2). The initial study submitted to the FDA was rejected. The folks at Neurostar (the manufacturers of the device) did a post-hoc analysis of that data. They discovered that patients, who failed to respond to only 1 antidepressant, subsequently responded to rTMS greater than sham (27.3% versus 10.5%). Based on this analysis, the FDA approved rTMS for the treatment of MDD in patients who have failed only 1 antidepressant trial.

In this month's Archives of General Psychiatry, is an article titled "Daily Left Prefrontal Transcranial Magnetic Stimulation Therapy for Major Depressive Disorder" (3). This study was funded by the NIMH and is the first nonindustry funded multisite study of rTMS (though some of the researchers are paid consultants of the TMS manufacturer). It involved 190 people.

What supposedly separates this study from all others, is the sham treatment. One major criticism of the previous TMS research is that the sham treatment was not convincing enough to prevent unblinding (for example, sham did not cause scalp irritation or facial twitching). The researchers went to great lengths to develop a sham treatment which produced the similar physical sensations of rTMS to prevent unblinding.

(Click to Enlarge)

Unfortunately, approximately 50% of the active treatment group correctly guessed which treatment condition they were in. A full 66% of placebo participants correctly guessed their condition. In truth, the level of unblinding is not a whole lot different from standard antidepressant drug trials (since placebos are inactive). The patients, on average, were similar to the patients in the Neurostar post-hoc analysis. The participants failed 1.51 antidepressant trials.

The primary outcome was remission, defined as a score of 3 or less on the HAM-D or 2 consecutive HAM-D scores less than 10 during phase 1 of the study. Phase 1 was three weeks in duration. Patients received rTMS once a day for 50 minutes (5 days a week).

(Click to Enlarge)

Unfortunately, the results were negative. During the three week period (the right side of the chart) only 6 patients (11%) met criteria for remission. The average drop in HAM-D score for active treatment was only 5 points (26 to 21). The researchers then extended the the length of phase 1 by two weeks. The number of patients who went into remission during this extension phase was 13 (14%). By increasing the length of the phase 1, they obtained statical significance. Sounds fishy to me, but at least they provide all the data.

Similar to the Neurostar analysis, those who did remit were less treatment resistance (i.e., failed only 1 antidepressant trial). The number needed to treat (NNT) was 12. That means, 12 people will need to be treated with rTMS before another person, who otherwise would have not remitted without intervention, finally does remit. That's not very good. However, that number is not far off from standard antidepressant drug trials.

Does rTMS have any practical value as a future treatment for depression? Based on these results, one will need to attend a 50 minutes session everyday (excluding weekends) for 3-5 weeks to see some sort of result. That is in stark contrast to attending psychotherapy 1-2 times a week or visiting a psychiatrist once every 4-6 weeks. As Daniel Carlat points out in his monthly report (1), each treatment session would cost approximately $400. Insurance companies do not currently cover this treatment (and probably never will). Moreover, the group of patients who did remit (i.e., those who failed only 1 antidepressant trial) is not very marketable. Odds are they will try a second antidepressant instead. According to the Star-D results, the odds of improvement are 30% on a second antidepressant compared to 14% of rTMS. Presently, rTMS just does not make economic sense.

George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, Anderson B, Nahas Z, Bulow P, Zarkowski P, Holtzheimer PE 3rd, Schwartz T, & Sackeim HA (2010). Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Archives of general psychiatry, 67 (5), 507-16 PMID: 20439832

Psychosis Among Substance Users

2010-05-04T17:36:00.000-07:00

Psychosis among drug users is quite common. Often, it is difficult to determine which came first, substance use or psychosis. Frequently, they co-occur. In cases where drugs are causally related (i.e., substance-induced psychosis), the condition is typically transient with a duration of 1 month or less. In rare cases, the length of psychosis can last longer. And in even rarer cases, symptoms such as hallucinations can be permanent.

Psychosis can be associated with the use many legal (e.g., alcohol) or illicit substance such as stimulants (amphetamines and cocaine), cannabis, and hallucinogens. An article by Thirthalli and Benegal (1) reviews the evidence that these drugs can cause psychosis in nonpsychotic persons.

Alcohol

The neurochemical effects of alcohol are complex. "Common knowledge" states that alcohol acts in a similar fashion to other sedatives (e.g., diazepam). In other words, it is an agonist of GABA receptors. In reality, the alcohol molecule is very simple. It has the ability to cross cell membranes (e.g., blood-brain barrier) easily and can exert its effects on the brain within minutes. Alcohol also influences the phospholipid bilayer that make up cell membranes. This ability has a widespread impact on normal cell functions and also enables alcohol to modify the action of many neurotransmitter systems, such glutamate, dopamine, and norepinephrine in addition to GABA.

Alcohol-induced psychosis can occur during different drug states such intoxication or withdrawal (e.g., delirium tremens, alcoholic hallucinosis). In general, the risk of psychosis is two-fold greater than in the general adult population.

Stimulants (click to enlarge picture; 2)
Cocaine and Amphetamines are widely known to lead to psychosis. The psychosis produced by both cocaine and amphetamines is similar to schizophrenia. The risk of psychosis from amphetamine use is quite high; greater than 70% in chronic users. Users who develop first episode psychosis use an average of 20 times years. Psychosis typically lasts for the duration the drug is in the system. However, it can last more than a month in more severe cases.

For cocaine, typically 50% of chronic users experience paranoia and hallucinations. Cocaine-induced psychosis has a stereotypical form; Users believe that their drug use is being watched and that they are being followed. This paranoia is typically accompanied by hallucinations. Cocaine-induced psychosis also shows sensitization; that is, psychosis becomes more severe and occurs more rapidly with continued use. Unlike amphetamine-induced psychosis, cocaine induced-persistent psychosis is very rare.

Cocaine has the highest affinity and binds most strongly to the serotonin (5HT)reuptake pump, followed by the dopamine (DA) reuptake pump, then the norepinephrine (NE) reuptake pump (FYI-Effexor is cocaine with a PG-rating; effexor's affinities are for serotonin, then NE, and then DA). Contrary to popular belief, amphetamines do not act by blocking the dopamine reuptake pump. Amphetamines are indirect agnonist of the catecholaminergic systems (i.e., dopamine and norepinephrine). First, amphetamines go inside the neuron and release both DA and NE from their vesicles into the cell cytoplasm (i.e., catecholamins are released inside the neurone). Second, The catecholamines are subsequently transported outside of the neuron by a reversal of the reuptake pumps. This results in a MASSIVE increase in synaptic DA and NE. Lastly, at higher doses, amphetamines inhibit catecholamine metabolism, leading to even higher concentrations in the synapse.

Cannabis
There has been a boom in the current research of cannabis and psychosis. There appears to be a temporal correlation between early cannabis use and onset of schizophrenia. This association is stronger than for any other substance. Why the association exists is unclear. In general, cannabis has the same risk of inducing psychosis as alcohol (i.e., two-fold).

There are two cannabinoid receptors in the human body: CB1 and CB2. The CB2 receptor is not expressed in the brain, and is primarily found in the immune system. The CB1 receptor is typically found in the basal ganglia, cerebellum, hippocampus, and the cortex. CB1 receptors exist on the axon terminal instead of the post-synaptic cell. In others words, CB1 receptors are autoreceptors that can inhibit the release of many different neurotransmitters.

Hallucinogens
Many different drugs fall under this category: mushrooms, peyote buttons, and LSD, for example. Many hallucinogenic drugs are either synthesized by plants or are based on plant-derived compounds. The main active compound in peyote is mescaline, while psilocin in found mushrooms. LSD is actually a synthetic compound, but is based on a fungal alkaloid taken from ergot.

Hallucinogenic compounds have a catecholamine-like structure (most are similar in shape to serotonin). Hallucinogens are primarily 5-HT2a receptor agonists. While these drugs do not lead to dependence, withdrawal, or cravings, they still can lead to serious problems for some users. Some people experience acute anxiety or panic attacks in responses to the drugs' hallucinogenic effects. There is a disorder known as hallucinogen persisting perception disorder (HPPD), which is the fancy name for "flashbacks." The most severe reactions, of course, are psychotic breakdowns. However, similar to the above mentioned drugs, psychosis is typically transient. Most prolonged episodes of hallucinogen-induced psychosis involve individuals who have already been diagnosed with a psychotic disorder or who have manifested prepsychotic (e.g., prodromal) symptoms before taking these drugs.

Treatment
In most cases, substance induced psychosis does not need medical treatment per se. It usually disappears when the drug's affects are gone. However, there are cases when treatment is necessary. Alcohol dependent individuals in withdrawal do need medical treatment because alcohol withdrawal can be lethal. Typically, sedatives (benzodiazepines) are the drugs of choice. For either cocaine or amphetamine induced psychosis, first or second generation antipsychotics are the drugs of choice because of their potent D2 receptor antagonism. In general, it is common for anyone presenting with psychotic symptoms to be prescribed antipsychotics. Occasionally, patients who are addicted to amphetamines will be prescribed antipsychotics in hopes that they will reduce the risk of subsequent psychosis or reduce euphoria, making the drug less reinforcing. Drugs that antagonize the 5HT2a receptor such as risperidone (or any second generation antipsychotic), ketanserin, and ritanserin have been shown to reverse hallucinogenic-induced psychosis.

In rare cases when psychosis persists, there are a few things to consider, such as, is their another cause for the psychosis? For example, does the person have schizophrenia or is there a physical cause for the psychosis (e.g., tumor, metabolic, etc)? Often times, doctors not knowing what to do, will double down on the antipsychotics. This is unlikely to work because the mechanism of action (D2 or 5HT2a blockade) does not necessarily increase with the addition of a second drug. Simply upping the does of the current drug should suffice. Side effects, however, are always additive. Antipsychotics with higher affinities for both D2 and 5HT2a receptors are preferable (e.g., risperidone).

Risk Factors
The risk factors for substance-induced psychosis are similar across all substances. Pre-morbid psychiatric history or a family history of schizophrenia put an individual at risk. Also, the longer a substance is consumed and the larger the quantities consumed are also risk factors. Polysubstance use or consuming drugs that contain other compounds increases the risk of psychosis too. Unfortunately, the research into the neurobiological and genetic underpinnings is substance-related psychosis are quite poor. A useful theory for substance-related psychosis which could lead to better acute treatment is lacking.

Thirthalli, J & Benegal, V. (2006). Psychosis Among Substance Users Current Opinion in Psychiatry

"Anatomy of an Epidemic" or The Same Story Told Over and Over Again

2010-05-03T14:09:00.000-07:00

On Salon.com, there is an interview with Robert Whitaker, the author of Mad in America, about his new book titled "Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America."

The article/interview at Salon is devoid of any context:

"In the past few months, the perennial controversy over psychiatric drug use has been growing considerably more heated. A January study showed a negligible difference between antidepressants and placebos in treating all but the severest cases of depression. The study became the subject of a Newsweek cover story, and the value of psychiatric drugs has recently been debated in the pages of the New Yorker, the New York Times and Salon...The timing of Robert Whitaker’s "Anatomy of an Epidemic," a comprehensive and highly readable history of psychiatry in the United States, couldn’t be better."

That study in JAMA is hardly a first (1, 2, 3), nor is Mr. Whitaker's book a first (4, 5, 6, and anything written by Peter Breggin). Timing couldn't be better? Sure, if by timing you mean, when can one cash in on anti-psychiatry sentiment.

I have not read this book. I did read his previous book, Mad in America, which surveyed the history of the treatment of mental illness in American and the rise of psychiatric drugs. Based on that book, which was sensationalistic and misrepresented research, I think I know what to expect in his new book. My focus, instead, will be on his interview. Comments in red.

"Psychiatric drug use is a notoriously tough subject for writers, because of all the contradictory research. Why wade into it? In 1998, I was writing a series for the Boston Globe on abuse of psychiatric patients in research settings. I came across the World Health Organization’s outcomes study for schizophrenia patients, and found that outcomes were better for poor countries of the world -- like India, Colombia, Nigeria -- than for the rich countries. And I was startled to find that only a small percentage of patients in those countries were medicated. I also discovered that the number of people on disability for mental illness in this country has tripled over the last 20 years..."

He doesn't provide an actual number for "only a small percentage of patients." However, according to the Worldwide-Schizophrenia Outpatient Health Outcomes (W-SOHO;7), which surveyed Europe, Asia, Africa, and Latin America, it revealed that a not so small 40% of patients where on antipsychotic medications. The real differences between rich and poor counties is that patients in developing countries were primarily on first generation antipsychotics (60%) and on monotherapy (75%). The reasons for outcome differences are many.

"...If our psychiatric drugs are effective at preventing mental illness, I thought, why are we getting so many people unable to work?"

I don't think anyone of real importance claimed that psychiatric drugs were aimed at "preventing mental illness." Again, there is no context. For example, one explanation for the increase of those on disability is that entitlement programs have increased their coverage over the years to include those with mental illnesses.

"What's so risky about Ritalin? For one, a significant percentage -- between 10 and 25 percent -- of kids prescribed medication for ADHD will have a manic episode or psychotic episode and deteriorate in such a way that they’re diagnosed with bipolar disorder..."

He is misrepresenting the data. That study (8), examined the comorbidity of ADHD and mania, not the association of stimulant medication use and risk of mania. It's quite possible that those who eventually develop bipolar disorder have an ADHD appearance during childhood.

"But if these studies are so groundbreaking, why have they gone unreported in the media? Because the NIMH didn’t announce it. Just as they didn’t announce the 2007 outcome study for schizophrenia patients. In that study, the recovery rate was 40 percent for those off meds, but only 5 percent for those on meds. I checked all the NIMH press releases for 2007, and found no release on this study. I found no announcement of it in any American Psychiatric Association publication or textbook. Not a single newspaper published an account of the study. And that’s because the psychiatric establishment -- the NIMH, the APA, even the National Alliance on Mental Illness, an advocacy organization -- did not put out any press release about it or try to alert the media in any way."

Either he's lying or had a lobotomy. I have reviewed that study as well as it's follow-up (9). Here is what the researchers actually discovered :

"Looking at it from a different viewpoint, the data suggests that schizophrenia patients with good prognostic features, with better premorbid developmental achievements and with more favorable personality characteristics are the subgroup more likely to stay off antipsychotics for a prolonged period"

That's why the NIMH, APA, and NAMI didn't sound the alarm about that supposed discovery. Here's another way to highlight the absurdity of his conclusion: Two women have been diagnosed with breast cancer. One has a strong family history of breast cancer and tested positive for the BRCA gene (i.e., she has a poor prognosis). The other woman has no family history nor the BRCA gene. Both were treated with chemo. One recovered quickly stopped treatment. The other woman, while still being treated, died. The chemotherapy killed her, right?

I could continue, but what's the point. His book has one intended audience: People who already hate psychiatry. If one cares to fully fact check the entire interview, you'll find one misleading statement after another. Whitaker is biased and has no scruples about misrepresenting facts and data to suit his narrative.

He is no different than the very industry that he is attacking.

R-Rated Movies Aren't Bad for Your Kids...R They?

2010-04-27T16:01:00.000-07:00

In the May issue of the Journal of Studies on Alcohol and Drugs is an article titled "Parental R-Rated Movie Restriction and Early-Onset Alcohol Use." (1) Without reading the study, one can guess the reported result : the more R-rated movies that youths watch, the higher the frequency of early-onset alcohol use.

This study was funded by the National Cancer Institute and National Institute on Alcohol Abuse and Alcoholism. Remember what the Last Psychiatrist says: What do researchers want to be true?

First comes the filter that will aid our interpretation of the results:

"TODAY’S YOUTH HAVE UNPRECEDENTED ACCESS to entertainment media (Roberts et al., 2005), and longitudinal research has linked various forms of entertainment media with aggressive behavior (Bushman and Anderson, 2001), sexual behavior (Collins et al., 2004), and tobacco use (Sargent, 2005). Indeed, the available research evidence has led the National Cancer Institute (2008) to declare a causal relation between exposure to movie smoking and youth smoking initiation."

In the words of Mr. Mackey, "Mm..R-rated movies are bad...mmkay."

The study was done by survey. 3,577 youths where chosen out of 4,655 (grades 5-8) because they reported to never have drunken alcohol without the knowledge of their parents. Also at baseline assessment the youths rated how restrictive their parents were in allowing them to view R-rate movies.

Statistics 101: Very boring, but very important to interpret these results.

This study is correlational. This results are known as the standardized coefficient. This can vary from +1 (indicating a perfect positive relationship), to zero (indicating no relationship), all the way down to -1 (indicating a perfect negative relationship, that is, when the frequency of a factor goes up, the other factor goes down). As a rule of thumb, standardized coefficients between .00 and .30 are considered weak, between .30 and .70 are moderate, and between .70 and 1.00 are considered strong.

The primary meaning of standardized coefficients lies in the amount of variation in one variable that is accounted for by the variable with which it is correlated. To obtain this information, you square the standardized coefficient (e.g., .30 x.30). This number is called the coefficient of determination. Then you multiply the coefficient by determination 100. This proportion of variance indicates the percentage of variance. The coefficient of determination is the primary information measure. Correlation coefficients of .30 account for about 10 percent of the variance (.30x.30 =.90x100= 9%).

Here are the results as reported in the abstract, that is, the information they want you to know:

"The sample included 2,406 baseline never-drinkers who were surveyed at follow-up, of whom 14.8% had initiated alcohol use. At baseline, 20% reported never being allowed to watch R movies, and 21% reported being allowed all the time. Adolescents allowed to watch R-rated movies had higher rates of alcohol initiation (2.9% initiation among never allowed, 12.5% once in a while, 18.8% sometimes, and 24.4% all the time). Controlling for sociodemographics, personality characteristics, and authoritative parenting style, the adjusted odds ratios for initiating alcohol use were 3.0 (95% CI [1.7-5.1]) for those once in a while allowed, 3.3 [1.9, 5.6] for those sometimes allowed, and 3.5 [2.0, 6.0] for those always allowed to watch R-rated movies. Alcohol initiation was more likely if R-rated movie restriction relaxed over time; tightening of restriction had a protective effect (p < .001)."

With odds-ratios, 1.0 represent the prevalence of something (e.g., drinking behavior) that already exists in the population. Anything above that represents an increase in prevalence. For example, in the study, it's reported that youths who have peers who drink have an OR of 5.7, meaning that there is over a 400% increase in the incidence of early on-set drinking when one's peers start drinking early (peer pressure). Kids allowed to view R-rated content once in a while showed a 200% increase, those allowed sometimes saw a 230% increase, and those allowed all the time saw a 250% increase.

While these numbers are quite high, this tells us nothing about the relationship strength. Remember multiple variables can lead to this result. Here is a graph of the correlation coefficients:

Exposure to R-rate movies has a standardized coefficient of 0.10. This relationship is weak. Using the formula above, the amount of variance in behavior attributed to viewing R-rated content is only 1%.

So why are youths, who are exposed to R-rated content, 2 times more likely to try alcohol at an earlier age?

Here is how the authors explain it:

"Youth who say that their parents allow them to watch R movies see more R movies and, therefore, more depictions of alcohol use...thus, the mechanism could be social influence via modeling of positive depictions of alcohol use."

Wrong!

Exposure to R-rated movies various with onset of early alcohol use by 1%. That means 99% of the variance is explained by other reasons (e.g., peer pressure!) While it is true that this tiny relationship is statistically significant, it has no practical significance what so ever.

But who cares about the actual science, politicians and other nanny state advocates have their sound bite,

"The research to date suggests that keeping kids from R-rated movies can help keep them from drinking, smoking and doing a lot of other things that parents don't want them to do, Sargent said." (2)

If only it were that simple.

Tanski SE, Cin SD, Stoolmiller M, & Sargent JD (2010). Parental R-rated movie restriction and early-onset alcohol use. Journal of studies on alcohol and drugs, 71 (3), 452-9 PMID: 20409440

Do Antidepressants Enhance Stroke Recovery?

2010-04-22T16:40:00.000-07:00

A few months ago, in the February issue of Archives of General Psychiatry appeared this study (1) title, "Escitalopram and Enhancement of Cognitive Recovery Following Stroke."

The design was simple: a placebo group, an escitalopram group, and a problem solving therapy group (a manual based therapy to treat depression in the medically ill). No patients in this group met diagnostic criteria for Major Depression (so why the PST group?) according to the Hamilton Scale for Depression (HAM-D). Patients were administered the following neuropsychological tests at baseline and post-treatment:

"-The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). This 25- to 30-minute battery assesses functioning in 5 domains (immediate memory, visuospatial/constructional, language, attention, and delayed memory). These domains are evaluated by 12 individual subtests, including List Learning, List Recall, List Recognition, Story Memory, Story Recall, Figure Copy, Figure Recall, Line Orientation, Picture Naming, Semantic Fluency, Digit Span, and Coding. This battery provides age-corrected norms for overall performance (total scale score) and scores in each domain."

(Number of Subjects in Each Treatment Group)

Here is what the researchers discovered: "We found a difference among the 3 treatment groups in change in RBANS total score (P<.01) and RBANS delayed memory score (P<.01)." They also found a significant result for immediate memory too, but for reasons beyond my knowledge (crack-cocaine?) they neglected to report this result. Test scores are below.

(Click to Enlarge)

The authors then engaged in a trite discussion about how escitalopram led to an improvement in memory and how serotonin theoretically affects memory, and blah, blah, blah.

On the surface, it does appear that escitalopram led to better outcomes: For the Total Score (a global measure of cognition) the escitalopram improved by 9.1 points compared to 5.7 for placebo; for delayed memory the escitalopram group improved by 12.4 points versus 5.9 for placebo, and for immediate memory (i.e., learning) the escitalopram group improved by 11.7 points versus 7.4 versus placebo.

However, look at the post-treatment final scores for both groups: total score: 89.8 (escitalopram) versus 91 (placebo); delayed memory 96.6 (escitalopram) versus 94.2 (placebo); and immediate memory 95.1 (escitalopram) versus 98.5 (placebo). Essentially, both groups post-treatment performance was nearly identical. The reason why the escitalopram group showed a larger magnitude in change was because that group had lower baseline scores.

The authors did point out that there was not statistical different between any of the baseline scores; however, that's irrelevant. Neuropsychological test performance scores are classified as either average, low average, mild deficit, moderate deficit, or severe deficit. Many of the escitalopram group baseline scores where in the mild-deficit range while the placebo group scores were in the low-average range. Functionally, that kind of difference is significant*.

Another factor not discussed is the rate of recovery in stroke patients. There is a pretty well delineated recovery curve for patients with mild-to-moderate strokes. Most recovery occurs in the first 6 months, followed by a slower recovery over the next 1-2 years. Those with more severe deficits will show greater initial recovery and then plateau at a level similar to the less sever group. This is why the groups matched on post-treatment assessment scores.

*It's actually more complicated than that. Scores actually fall within a certain range. So a person could perform in the mild-deficit range at point then in the low-average range at another point. So it's quite possible that these results reflect the error in the psychological instrument rather than a benefit from escitalopram.

Either way, I'm skeptical that escitalopram actually helped these people.

Jorge RE, Acion L, Moser D, Adams HP Jr, & Robinson RG (2010). Escitalopram and enhancement of cognitive recovery following stroke. Archives of general psychiatry, 67 (2), 187-96 PMID: 20124118

Health Care the Squeakquel: A Requiem in Two Parts

2010-04-21T17:11:00.000-07:00

An interesting read over at the New York Times

"In a new report, the Congressional Research Service says the law may have significant unintended consequences for the 'personal health insurance coverage' of senators, representatives and their staff members. For example, it says, the law may 'remove members of Congress and Congressional staff' from their current coverage, in the Federal Employees Health Benefits Program, before any alternatives are available." (1)

I guess that's the problem when you "pass the bill so that you can find out what is in it" (2).

"The confusion raises the inevitable question: If they did not know exactly what they were doing to themselves, did lawmakers who wrote and passed the bill fully grasp the details of how it would influence the lives of other Americans?"

As Ted Stevens likes to yell "NO!" (3)

One major selling point of the new health care bill was that it will reduce the deficit by $138 billion over the 2010–2019 period (4). That estimate was made by the nonpartisan Congressional Budget Office (CBO). The problem, however, is in how the CBO makes their estimates: they assume every provision in the bill will be carried out (e.g., cuts to medicare). In reality, congress never follows through with anything. For example, cuts to medicare have been delayed 5 times over the last 10 years (3 times by Republicans and 2 times by Democrats). A former CBO director wrote an article that details some of ways that this bill could contribute to the deficit rather than reduce it (5).

Last point about the deficit: if the debt is currently $12, 875, 520, 291, 623, 42 (6), what percentage is $138 billion? I tried to put that into my calculator, and all I got was this "60 2 4377".

Remember when Obama said this during the campaign: "One thing we have not done is raise income taxes on families making less than $250,000. That's another promise we've kept." (7).

Actually, that is what he said during his most recent radio address. Here is what he said during the campaign "I can make a firm pledge: Under my plan, no family making less than $250,000 will see their taxes increase—not your income taxes, not your payroll taxes, not your capital gains taxes, not any of your taxes." (8)

Needless to say, he's broken that promise more times than Tiger Woods cheated on his wife. According to Americans for Tax Reform (ATR), you can add 7 more tax hikes for that below $250,000 tax group (9), four of which affect income, thus also nullifying his revised statement about income tax increases. Here is a list of more taxes being implemented as well (10). The upshot of this is that congress will be taxed too, though, through their own stupidity (11).

In an earlier post (12), I lamented that this was a health insurance bill, not a health care bill. I might have been wrong with that assertion, since it is quite possible that actual health care will be affected. You see, we have a microcosm that can act as a crystal ball to see our future. It's the state of Massachusetts. When that ~~Moron~~ Mormon Mitt Romney was governor of Massachusetts, he passed a health care reform bill for the state. It was the model after which the Democrats constructed their health care bill.

Here is the current state of things is Massachusetts:

"People seeking to buy health insurance for the first time, or customers looking to change policies, found they could not do so." (13)

The state rejected of 235 of 274 proposed health insurance rate increases. That decision will cost insurance companies a lot of money (rendering them profitless). A judge ruled that the companies must comply with those rate rejections (14). That decision lead some insurers to do this:

"Health insurers are starting to sell policies that largely bar consumers from receiving medical care at popular but expensive hospitals such as Massachusetts General and Brigham and Women’s — a once radical idea that is gaining traction as a way to control soaring health care costs." (15)

Even the Massachusetts Treasurer (a recently former Democrat) has warned us of the things to come

"The Massachusetts treasurer said Tuesday that Congress will 'threaten to wipe out the American economy within four years' if it adopts a health-care overhaul modeled after the Bay State’s. " (16)

I think history is about to repeat itself. In the Senate:

"Fearing that health insurance premiums may shoot up in the next few years...Mr. Harkin praised a bill introduced by Senator Dianne Feinstein, Democrat of California, that would give the secretary of health and human services the power to review premiums and block 'any rate increase found to be unreasonable.' Under the bill, the federal government could regulate rates in states where state officials did not have 'sufficient authority and capability' to do so." (17)

We're fucked.

UPDATE: Oops! Heath Care bill costs $251 billion more than originally thought (that's larger than $138 billion right?). From the Obama Administration's Health and Human Services Administration Department (pdf; 18).

"Medicare cuts could drive about 15 percent of hospitals and other institutional providers into the red, 'possibly jeopardizing access' to care for seniors."(19).

UPDATE: Double oops! "CBO: Medicare Payment 'Doc Fix' Is More Expensive Than Expected." (20)

UPDATE: The Health Insurance Trade-Off Game (22)

UPDATE: It just keeps going up, up, up. New CBO report say that an additional $115 billion in discretionary spending will be needed (23)

FYI: To all you conservatives out there, don't think the Republicans are going to "repeal the bill" either. (21)

And please, do not nominate this guy...

(part 1 here)

Sexual Addiction or It's Not My Fault That My Penis Fell Into Her Vagina

2010-04-01T17:31:00.000-07:00

David Duchovny, Tiger Woods, Steve Phillips, and now Jesse James. All men, all self-diagnosed sex addicts, and all victims of their disorder. Well, that's how they want to be betrayed in the media. To most people, sexual addiction appears to be a "get out of jail free" card for sleazy douche bags. So this begs the question, is it a real disorder?

Like any other complex human behavior, it all depends on who you ask.

There appear to be four main camps: those who liken the condition to a chemical dependency disorder, those who view it as a disorder similar to obsessive-compulsive disorder, and those who believe it to be an impulse control disorder. The fourth group believes that the other three groups are full of shit.

Even though many people are diagnosed with, and treated for sexual addiction every year (estimated 3-6% of US population), there is no actual disorder in any of the previous versions of the DSM. A new disorder is being considered for the DSM-V, which is termed "Hypersexual Disorder."

Here of some examples of proposed diagnostic criteria:
1) A maladaptive pattern of behavior, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12-month period:

A) tolerance, as defined by either of the following:
-a need for markedly increased amount or intensity of the behavior to achieve the desired effect
-markedly diminished effect with continued involvement in the behavior at the same level or intensity

B) withdrawal, as manifested by either of the following:
-characteristic psychophysiological withdrawal syndrome of physiologically described changes and/or psychologically described changes upon discontinuation of the behavior
-the same (or a closely related) behavior is engaged in to relieve or avoid withdrawal symptoms
-the behavior is often engaged in over a longer period, in greater quantity, or at a higher intensity than was intended

C) there is a persistent desire or unsuccessful efforts to cut down or control the behavior
D) a great deal of time spent in activities necessary to prepare for the behavior, to engage in the behavior, or to recover from its effects
E) important social, occupational, or recreational activities are given up or reduced because of the behavior
F) the behavior continues despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the behavior

I'd argue that these criteria adhere too closely to the substance dependence model and fail the capture the essence of human sexual behavior. Moreover, I don't know think "blue balls" would technically count as a withdrawal symptom.

From the DSM-V
A. Over a period of at least six months, recurrent and intense sexual fantasies, sexual urges, and sexual behavior in association with four or more of the following five criteria:(1) A great deal of time is consumed by sexual fantasies and urges, and by planning for and engaging in sexual behavior.
(2) Repetitively engaging in these sexual fantasies, urges, and behavior in response to dysphoric mood states (e.g., anxiety, depression, boredom, irritability).
(3) Repetitively engaging in sexual fantasies, urges, and behavior in response to stressful life events.
(4) Repetitive but unsuccessful efforts to control or significantly reduce these sexual fantasies, urges, and behavior.
(5) Repetitively engaging in sexual behavior while disregarding the risk for physical or emotional harm to self or others. B. There is clinically significant personal distress or impairment in social, occupational or other important areas of functioning associated with the frequency and intensity of these sexual fantasies, urges, and behavior.
C. These sexual fantasies, urges, and behavior are not due to the direct physiological effect of an exogenous substance (e.g., a drug of abuse or a medication).

There are some similarities between substance dependence, OCD, and impulse control disorders: impulsivity, obsessions, and compulsions.

Impulsive behaviors are by done without any forethought, spur of the moment.
Obsessions are intrusive thoughts that an individual does not want to have, but has them anyway.
Compulsive behaviors are behaviors that people do, but they do not want to do them.

There is another feature that ties all these disorders together: the addiction, obsession, or compulsion is the central organizing principle of that individual's life. The crack addict lives his life around obtaining and using crack, the patient with OCD is so fearful of contamination that she washes her hands so many times that she has blisters, someone with trichotillomania is completely bald because they cannot stop pulling their hair out. These people do not live happy lives. Their disorder rules their life; they are disabled. These people are doing something that they most certainly do not want to do.

Jesse James had an 11 month affair and Tiger Woods had a 2 year affair (plus other alleged affairs). David Duckovny banged his tennis partner. Steven Phillips is a misogynist. Sounds more like these were guys who got caught cheating and are now doing major damage control.

One more thought. If true addicts cannot use the substance to which they were addicted, are sex addicts not allowed to have sex anymore? If Jesse James porks Sandra again, did he relapse?

Discuss amongst yourselves.

Health Care: A Requiem In Two Parts

2010-03-30T16:16:00.000-07:00

I need to take a drug holiday from my usual concoction of Valium, Restoril, Ambien CR, and Benadryl to sleep at night. Apparently, I slept through an important change in human ethical thought. No longer does society have a moral obligation to provide health care, but rather, it's health insurance which we have the "moral imperative" to provide (1).

I find that really odd, since insurance, as I've come to know it, is defined as the "equitable transfer of the risk of a loss, from one entity to another, in exchange for a premium, and can be thought of as a guaranteed and known small loss to prevent a large, possibly devastating loss" (2). Perhaps all that moral imperative stuff is found in the new revelation of Jesus Christ found in the Book of ~~Moron~~ Mormon. I'll have to look into that...

With health insurance, the "risk" that is being transferred is that of incurring medical expenses. As it turns out, there are a lot people in this country who do not have health insurance and therefore, are at risk for incurring medical expenses. The oft quoted (and inflated) statistic of people who do not have health insurance is 47 million (3). Even after the bill's passage, some 23 million still will not be covered.

But, who is to blame to for this high number?

"It's the insurance companies dummy!" was the implied message I got from one reader, who opined:

"I have no idea why everyone is defending the insurance companies who have been raping consumers' wallets for years and padding the pockets of politicians to keep antitrust laws from applying to them (thankfully, no more)."

Wow. Those companies sound really awful. I love my wallet. I would never let any harm come to it, sexual or otherwise. I guess a big "Thank You Mr. President Obama" is in order (and if you come into the oval office, a nice sloppy blow job too).

Obama sure screwed those wallet raping insurance companies (4): no more excluding people with pre-existing conditions, and no more setting rates based on a person's health status.

“In addition, a weak economy is causing younger, healthier individuals to drop their insurance. As healthy people forego health insurance, the rates for those Americans who need coverage increases. That is why going into 2009 we advocated for robust insurance market reforms, including guaranteed coverage with no pre-existing condition exclusions or health status rating paired with an effective personal coverage requirement to get everyone covered." (5)

The above quote is not from an Obama speech. It's from America’s Health Insurance Plans (AHIP) President and CEO Karen Ignagni (i.e., the evil insurance lobby, dun, dun, dun...).

If the insurance industry actually supports those provisions in the bill, how exactly did Obama screw them?

The real question to ask is why the insurance industry supports those provisions. The answer: national health insurance mandate (i.e., "personal coverage requirement"). The health insurance industry is happy to drop those practices as long as they have a nice pool of "younger, healthier individuals" to be conscripted. Since unhealthy individuals can no longer be charged higher premiums, it's healthier individuals who will see their premiums go up by as little as 10-13% or as high as 27-30%, depending on varying sets of circumstances (6).

We never learn from our mistakes. Many states have experimented with banning certain insurance practices such as the exclusion practice. This essentially kills any incentive to obtain insurance until you're actually sick. This ends up costing insurance providers a lot of money. The federal government's solution? Coerce their citizens to buy insurance. That's it, problem solved right?

Not exactly. Even with the mandate, there is still no incentive for healthy people to buy insurance. The average cost for an individual policy is $5,500 (7). The fine for not purchasing insurance ranges from $95 (1% of income) the first year to $695 (or 2% of income) after that. Would you rather pay $700 or $5000? Even if you're eligible for federal subsidies, $2,300 is still more expensive than $700. It's for this reason, the health insurance industry does not support this bill. The fines are too small (and currently, not enforceable).

We can predict what will happen next. It's known as a "death spiral." When premiums rise for those healthy people who already have policies (since unhealthy people can no longer be charged higher rates), more and more healthy people will drop their insurance. This will create an insurance pool of primarily of high cost, sick people (8). Many insurance companies will not be able to stay in business under these sets of circumstances. More and more health care dollars will become the responsibility of the government, which of course, is funded by taxing it citizens.

So in this sense, Obama has screwed the insurance companies. And us along with them.

(FYI: Those pesky anti-trust laws still don't apply to the health insurance companies).

(Coming soon: Will the health care bill reduce the deficit?)

The Dumbest Study I've Ever Read

2010-03-23T19:57:00.000-07:00

This study has nothing to do with drugs, psychotherapy, or even neuroscience. It's about Jesus' head; more specifically, it's about Jesus' head in relation to the size of the main course in 52 different depictions of the Last Supper.

I know what you're all thinking, it's barely past noon, and I've hit the scotch too hard this time. From the International Journal of Obesity:

"Portion sizes of foods have been noticably increasing in recent years, but when did this trend begin? If art imitates life and if food portions have been generally increasing with time, we might expect this trend to be reflected in paintings that depict food. Perhaps the most commonly painted meal has been that of Jesus Christ's Last Supper, chronicled in the New Testament of the Bible. A CAD–CAM analysis of the relative food-to-head ratio in 52 representative paintings of the Last Supper showed that the relative sizes of the main dish, bread, and plates have linearly increased over the past millennium."

First, it's spelled noticeably, not noticably. No need to thank me, I'm just here to help.

Lead author, Brian Wansink, proudly displayed his virginity by saying, "I think people assume that increased serving sizes, or ‘portion distortion,’ is a recent phenomenon, but this research indicates that it’s a general trend for at least the last millennium."

His brother Craig Wansink, proving that mental illness does run in their family added, "As the most famously depicted dinner of all time, the Last Supper is ideally suited for review."

Here is a graph showing some of the data that will one day lead to a vaccination for jock itch.

I am posting another graph below because I hate all of you.

What they found was that "the main courses depicted in the paintings grew by 69%, plate size by 66%, and bread size by 23%" over the course of 1000 years.

I've lost precious minutes from my life. I've created this post to waste your time as well.

Be careful everyone. Stupid can kill...

B Wansink and C S Wansink (2010). The largest Last Supper: depictions of food portions and plate size increased over the millennium International Journal of Obesity, 37

UPDATE: It just got worse...

"54% of Voters Oppose the Health Care Plan"

2010-03-23T10:03:00.000-07:00

So why are these people so fucking proud of themselves?
I don't care what people or other media say (1), this is not a "health care reform bill," it's a (really expensive) health insurance bill. It doesn't matter whether you have medicare or private coverage. Insurance does not equal actual health care (Nor quality of care either).

Update: Reader comment:

"Anonymous said...

You claim to have some background in psychology and science, yet your title is a rather emphatic and dubious conclusion based on a source that provides absolutely no information regarding the methodology employed. There is nothing easier in the world than to obtain a skewed polling result based simply upon the wording of a question. Yet, we do not know what questions were asked, the order in which they were asked, etc. From what I can see from their site Rasmussen is about as objective as Fox News and leans in the same direction."

(Click to Enlarge)

From realclearpolitics (1). You'll notice ALL of the polls show lack of support. Douche.

Update Too:

"a source that provides absolutely no information regarding the methodology employed. There is nothing easier in the world than to obtain a skewed polling result based simply upon the wording of a question. Yet, we do not know what questions were asked, the order in which they were asked, etc. From what I can see from their site Rasmussen is about as objective as Fox News and leans in the same direction."

Methodology located at the bottom of the article page (2) "This national telephone survey of 1,000 Likely Voters was conducted by Rasmussen Reports March 19-20, 2010. The margin of sampling error for the survey is +/- 3 percentage points with a 95% level of confidence (see methodology)."

Amazingly, this right-wing whack job website also lists the questions and the order in which they were asked too (3).

WARNING: Chantix Causes Suicide, Herpes, and Nocturnal Vaginal Itch Syndrome

2010-03-15T16:30:00.000-07:00

Here is a brief tale of an American dream deferred...

"Tina Hurst is a suburban mother and a manager at a Fortune 500 company. Her life was great, but she had one dark secret...'I was a closet smoker,' Hurst said."

Here is where the plot thickens...

"Her doctor prescribed a drug called Chantix to help her quit. Seven million Americans have taken it. Hurst says she took Chantix for two months and it worked great."

Then, tragedy struck...

"But when she stopped, 'I totally went off the deep end,' she said. Hurst says she started walking around the house in circles, crying and hallucinating. 'I thought somebody died. And I was freaked out,' Hurst said."

But, it wasn't over just yet...

"An ambulance rushed Hurst to a hospital where records indicate she was very agitated and had to be restrained. She spent four days in a psych unit. Prior to this, Hurst said she never had a history of anxiety, depression or any mental problems. She thinks it was caused by Chantix. Her doctor's diagnosis? "Substance-induced psychotic disorder." (1)

No, this isn't the plot of Gothika (2), this is an account of a woman who claims that she was adversely affected by Pfizer's anti-smoking drug Chantix (varenicline). Stories like this are common place now. Since the drug has come to market, it has racked up some 10,102 reports in the FDA's adverse events database (3).

Normally, I'm all for psychoactive drugs causing harm to people. However, I think a skeptical approach should be taken when it comes to this drug.

The most widely heard side-effect of Chantix is that it causes suicidality. For the sake of argument, let's forget that suicidality is a very complex and multifaceted human condition; we're going to pretend that this little pill can lead an otherwise normal and healthy person to want to kill himself (4).

First, let's examine the neurobiological reasons why this might happen...oh, wait a minute, there are no widely accepted (or proposed?) mechanisms of how this happens, just like there is no proposed mechanism for the supposed anti-depressant induced mania phenomenon (5) or the anti-depressant induced suicidality phenomenon.

What we do have is a temporal association (6). That is, event B happens around, near by, within some sort of proximity of event A. Once that happens, our minds automatically link events A and B together, and we have causation! No need for scientific investigation. Just turn on your computer, sign onto word press and start blogging about how "Chantix Causes Traffic Accident, Passengers Almost Die."

Here's why I am skeptical of the Chantix-suicidality link: smoking is associated with psychiatric illness (8, 9, 10). Specifically, individuals who smoke and have a comorbid psychiatric (i.e., Axis I or II) disorder make up 7% of the population, yet they consume 34% of all cigarettes smoked in the United States. Moreover, cigarette use is associated with most major psychiatric disorders. This means that 7% of 45 million smokers are mentally ill. That's a lot of people who are already at risk for suicide, regardless of whether they use Chantix or not.

Here is another interesting piece of research:

"This study examined the relation between smoking and suicide, controlling for various confounders...We found a positive, dose-related association between smoking and suicide among White men. Although inference about causality is not justified, our findings indicate that the smoking-suicide connection is not entirely due to the greater tendency among smokers to be unmarried, to be sedentary, to drink heavily, or to develop cancers." (11)

I almost forgot about this study:

RESULTS: Current daily smoking, but not past smoking, predicted the subsequent occurrence of suicidal thoughts or attempt, independent of prior depression and substance use disorders (adjusted odds ratio, 1.82; 95% confidence interval, 1.22-2.69). Additionally, current daily smoking, but not past smoking, predicted the subsequent occurrence of suicidal thoughts or attempt, adjusting for suicidal predisposition, indicated by prior suicidality, and controlling for prior psychiatric disorders (adjusted odds ratio, 1.74; 95% confidence interval, 1.17-2.54). (12)

Anybody ever abruptly stop their anti-depressant medication? Bad stuff happens, right? Here is a pretty picture from a study in the September 2003 issues of ~~PENIS~~ er, PNAS (13).

Here is a comparison of a smoker and nonsmoker and the amount of monoamine oxidase throughout their bodies. Smoking lowers the amount of this enzyme, which breaks down the catecholamines (5HT, DA, NE). Without this enzyme, the levels of these neurotransmitters rises. This is how the class of anti-depressants known as monoamine oxidase inhibitors are supposed to work.

Here are the instructions for how a patient is supposed to use Chantix:

That is, they quit smoking one week after starting Chantix. Since Chantix is a partial-nicotinic agonist and not an MAOI, this could have the same effect as abruptly stopping your anti-depressant medication.

What if the instructions read like this instead. "Patients should be instructed to set a date to quit smoking and to stop their antidepressant medication and to initiate CHANTIX treatment one week before the quit date." Would you still take it?

Earlier, I mentioned the FDA's adverse events database. This is a system, where if an adverse reaction to a drug is suspected, it can be reported.

Here is a link (14) to the FDA's adverse events database on those who quit smoking cold turkey.

You'll notice that there is no real link because there is no actual database for this. The data that is collected by the FDA's actual database is biased, there are too many confounds that are not accounted for.

What about actual research? If you search PubMed for the terms "varenicline" and "suicide" you get 19 hits. Only three are actual prospective studies that looked at the matter (15, 16). The first study only had 1 suicide, but the patent's psychiatric background is unknown since the study is not complete. In the second study,

"There was no evidence that varenicline was associated with an increased risk of depression or suicidal thoughts."

The third study uses an adverse events reporting paradigm (17):

"All patients with suicidal events either had a past medical history of psychiatric illness prior to starting varenicline and/or a precipitating factor for the event. Clinicians should closely monitor patients with pre-existing psychiatric illness who are taking varenicline."

I'm not defending Chantix or Pfizer; over 10,000 reported adverse events for a drug that has been on the market for less that 4 years is a lot. Also, I have no explanation for how seemingly normal people such as Ms. Hurst have such horrible reactions. But, let's not always play the "drug companies are evil" card either. Chantix is the most effective smoking cessation drug on the market. It actually has helped 2 or 3 people.

Just remember, things are not always as they seem; do your own research; and don't trust the shit you read on blogs!

Is the Clinical Significance Criterion Significant?

2010-02-25T16:41:00.000-08:00

The draft version of DSM-V: Revenge of the Fallen has been online for a few weeks (1) and much has already been written about it (1, 2, 3, 4). Much focus has been on what is "new" and what is "gone." One feature that is shared by the majority of DSM diagnoses, the "clinical significance" criterion, might be on its way out. Typically this criterion reads "The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning." The general rule being, if the person does not satisfy this criterion, a diagnosis probably should not be made.

This criterion is unique to the DSM-IV and is not found in the earlier versions of the text. The stated reason for adding it to the DSM was to

"establish the threshold for the diagnosis of a disorder in those situations in which the symptomatic presentation by itself (particularly in its milder forms) is not inherently pathological and may be encountered in individuals for whom a diagnosis of mental disorder would be inappropriate."

Since mental health disorders are made by subjective analysis (often referred to as clinical judgment), does the addition of this criterion aid in the diagnostic process?

Not according to Wakefield et. al who published an article in the January 2010 issue of the American Journal of Psychiatry (5). In the article, titled, "Does the DSM-IV Clinical Significance Criterion for Major Depression Reduce False Positives? Evidence From the National Comorbidity Survey Replication," the authors' reason why the criterion is ineffective, is because it is redundant.

Wakefield argues that "distress is common to both normal reactions (e.g., acute grief) and disordered conditions, 'since most of these symptoms are either intrinsically distressing or are almost invariably accompanied by distress about having the symptom."

In other words, it's highly unlikely that an individual will satisfy full diagnostic criteria for a disorder and not be distressed or impaired.

(Click to Enlarge)

In the results reproduced above, out 2,071 respondents who reported episodes of sadness, 1,254 (60.5%) met diagnostic criteria for major depressive disorder (MDD). Of those who did not meet full criteria for MDD (n=817 or 39.5%), 93.5% did satisfy the "clinically significant distress or impairment" criterion. This suggests that the criterion is a poor indicator of diagnostic status. This result agrees with other research (6).

It's unlikely that any modification of this criterion, other than its deletion, will resolve this issue of redundancy. If the definition is narrowed, there will be more false negatives; if the definition is broadened, there will be more false positives. Actually, the whole idea of false negatives/positives for already highly arbitrary (i.e. not valid) diagnoses is quite humorous, but I digress...

Wakefield, J., Schmitz, M., & Baer, J. (2010). Does the DSM-IV Clinical Significance Criterion for Major Depression Reduce False Positives? Evidence From the National Comorbidity Survey Replication American Journal of Psychiatry DOI: 10.1176/appi.ajp.2009.09040553

Women: Know Your Limits!

2010-02-25T00:01:00.000-08:00

A Public Service Announcement.

A Tale of Two Studies: Voxel-Based Lesion-Symptom Mapping

2010-02-24T16:54:00.000-08:00

Brain imaging has contributed greatly to our understanding of the functional neuroataomy of the human brain. A lot these contributions have been blogged about by my bestest buddy Neuroskeptic (why don't you return my phone calls anymore!?). One of the more popular methods used to capture brain function is the functional magnetic resonance (fMRI). However, the results of fMRI studies are correlational and do not represent causation. There is another method, however, that "can identify regions, including white matter tracts, playing a causal role in a particular cognitive domain." This method is known as voxel-based lesion-symptom mapping (VLSM). A voxel is the three-dimensional analog of a pixel, and represents a volume of about 1 cubic millimeter. This method produces pretty images such as this one below.

A team of researchers from various important sounding universities published a study in this month's Proceedings of the National Academy of Sciences (PNAS; 1). In this issue of PNAS (pronounced penis), is an article titled "Distributed Neural System for General Intelligence Revealed by Lesion Mapping." The researchers created 3-D representations of the lesions of 241 subjects who had "single, focal, stable, chronic lesions of the brain." The subjects also had undergone neuropsychological testing, which included either the WAIS-R/WAIS-III.

The researchers were trying to discover where in the brain is general intelligence (often designated as "g"). Specifically,

"we address the question of whether g draws upon specific brain regions, as opposed to being correlated with global brain properties (such as total brain volume). Identifying such brain regions would help shed light on how g contributes to information processing and open the door to further exploration of its biological underpinnings, such as its emergence through evolution and development, and its alteration through psychiatric or neurological disease."

If "g" sounds like a highly abstract to concept to you, that's because it is. It's actually a really controversial concept within the field (2, 3). Below are the "g" loadings from this study.

The closer the color is to red, the closer that particular subtest loaded onto one of three g-related functions (i.e., verbal, spatial, working memory). The statistics of this study are admittedly over my head, since calculating g loadings require factor analysis. Since "g" is an abstraction, no actual number is presented for "g." Only how well a specific test loads onto "g" is provided.

What the researchers discovered should not be surprising to any biped mammal with working frontal lobes,

"One of the main findings that really struck us was that there was a distributed system here. Several brain regions, and the connections between them, were what was most important to general intelligence." (4)

More specifically,

"Statistically significant associations were found between g and damage to a remarkably circumscribed albeit distributed network in frontal and parietal cortex, critically including white matter association tracts and frontopolar cortex. We suggest that general intelligence draws on connections between regions that integrate verbal, visuospatial, working memory, and executive processes." (1)

"Statistically significant associations" is not same as "causal role." It's correlational. Still, nice sleight of hand.

What this group of geniuses is saying is that different brain functions are located in different parts of the brain, and when everything works in harmony, you have general intelligence.

"The researchers say the findings will open the door to further investigations about how the brain, intelligence, and environment all interact."

Open doors? That would mean that this research is original and ground breaking. It's not. In fact, in the March 2009 issue of Neuron (5) appeared this study, "Lesion Mapping of Cognitive Abilities Linked to Intelligence." Here is the press release (6). In this study, there were 241 patients with "single, focal, stable, chronic lesions of the brain," who had their lesions mapped and were also administered either the WAIS-R/WAIS-III. Also, the researchers are the same in both studies.

This study also found that performance on these (same) tests mapped primarily onto the frontal and parietal lobes.

The main difference is that the former study examined the anatomical location of intelligence in general, while the latter examine the anatomical location of general intelligence.

"So, what's the difference smart ass!?"

It depends on who you ask. Some say there is no difference, while others say there is a difference. At this point in the debate, however, we're engaging in mental masturbation (which is equally satisfying, plus people don't stare when you do it on the bus).

What I've been trying to figure out is if this counts as a duplicate publication? Sure, this doesn't have the far reaching consequences of these douche baggers (7, 8). There is a slight theoretical difference, the results are essentially identical. ~~Curiously, in the most recent study, there is no citation to the other study. You'd think that the researchers want other people to read both of their studies~~.

Perhaps I'm looking too much into this. Or, perhaps I just enjoy mental masturbation...

Gläscher J, Rudrauf D, Colom R, Paul LK, Tranel D, Damasio H, & Adolphs R (2010). Distributed neural system for general intelligence revealed by lesion mapping. Proceedings of the National Academy of Sciences of the United States of America PMID: 20176936

Gläscher J, Tranel D, Paul LK, Rudrauf D, Rorden C, Hornaday A, Grabowski T, Damasio H, & Adolphs R (2009). Lesion mapping of cognitive abilities linked to intelligence. Neuron, 61 (5), 681-91 PMID: 19285465

Brodmann's Map 100 Years Later

2010-02-03T12:58:00.000-08:00

Brodmann's map. Anyone who has taken a course in basic neuroanatomy has been exposed to his roadmap of the cerebral cortex.

In this month's Nature Reviews Neuroscience, Zilles and Amunts (1) dedicated an article to Korbinian Brodmann and his map, celebrating its 100th anniversary (Brodmann's original work was published in 1909).

First, a little background. Brodmann's original map contains 52 areas; however, areas 12-16 and 48-51 are only found in nonhuman primate brains, so only 43 areas are actually labeled. How Brodmann constructed his "map" is quite complicated. He made numerous razor thin, horizontal slices of human brains. He then stained the cell bodies within those slices and attributed a number to an area if it was cytoarchitectonically distinct from its neighboring areas of the cortex.

Many others followed Brodmann's work with maps of their own. According to the article,

"During the next three decades, Otfried Foerster, Alfred Walter Campbell, Grafton Elliott Smith, Constantin Freiherr von Economo and Georg N. Koskinas argued for localizable anatomical and functional correlation and the segregation of cortical entities"

Many of those names may be new to you, which highlight how influential Brodmann's work has been. The reason there are many different "maps" is because brain mapping is not an exact science. Trying to differentiate the cortex based on brain architecture can produce profoundly different results, depending on the staining technique that is used and on the researcher's subjectivity.

"The Vogts used myelin-stained histological sections to study brain architecture (that is, myeloarchitecture). Their myeloarchitectonic map has many more areas (a total of 200) than that of Brodmann, because the Vogts further subdivided the Brodmann areas on the basis of the regionally more differentiated architecture of intracortical nerve fibres."

Below is a comparison of the various "maps" that have been produced since Brodmann's work in 1909.

(click to enlarge)

Differences between all these brain maps are apparent. However, there is also considerable overlap, suggesting that there is some degree of observer independence, reproducibility, and objectivity to the process.

A little historical note for anyone who was forced to memorize all those Brodmann areas, but was hampered by its apparent lack of logic (areas 1,2,3, start in the mid-lateral areas, while the remaining numbers are distributed in a quasi-random order). Each area number was assigned based on the order in which he prepared a slide, hence the apparent randomness of number assignment.

In his time, testing whether each "area" was correlated to a specific function was quite difficult. Over time, as other "maps" were published and his original became criticized for lack of objectivity, his map fell out of fashion. That is until the 1980's, when various brain imaging techniques were developed. Being able to image a live human during the performance of a specific task, it became possible to associate functional data with cytoarchitectual data. It was Brodmann's map that become apart of many of the first software and sterotaxic atlases for these machines.

Brodmann's work helped to revolutionize modern neuroscience. While many other maps have followed Brodmann's, and even though contemporary research has shown that "his map is incomplete or even wrong in some of the brain regions," many of the areas do correlate very well with various functional areas of the cortex, which is why his work still has relevance 100 years later.

Zilles K, & Amunts K (2010). Centenary of Brodmann's map - conception and fate. Nature reviews. Neuroscience, 11 (2), 139-45 PMID: 20046193

Cognitive Impairment and Schizophrenia

2010-02-02T17:19:00.000-08:00

Time to act like a big boy again...

When you hear the word "schizophrenia," what comes to mind? Frequently, people imagine someone who has auditory hallucinations (e.g., a voice keeping a running commentary on the person's behavior) or bizarre delusions, such as having thoughts broadcasted to others.

When mental health professionals discuss the disorder, the most common phrases used are "positive symptoms" (e.g., hallucinations, delusions) and "negative symptoms" (e.g., flat affect, alogia). Current medical treatments almost exclusively focus on treating the positive symptoms. Increasingly, there is more discussion about medications treating the negative symptoms as well; however, most medications do a piss poor job of this (1).

What is also "known" about this disorder, is that individuals who have it often have pervasive cognitive deficits as well. There are some who argue that it is the cognitive symptoms that are a main reason for disability and dysfunction (2).

In this month's American Journal of Psychiatry (3), a group of researchers reported on a 30-year longitudinal study of cognition in individuals who eventually go on to develop schizophrenia.

What they wanted to know, is if cognitive impairment is present from early childhood and if those impairments remain stable throughout a lifetime (the developmental deficit hypothesis); whether future schizophrenia subjects lag behind healthy people in their cognitive development (developmental lag hypothesis); or whether they have a decline in cognitive functioning just prior to illness onset or as a result of psychosis (developmental deterioration hypothesis).

The authors of this study followed a cohort from birth to age 32. The children were initially assessed at age 2, with follow-up assessments occurring at ages 5, 7, 9, 11, and 13.

The children's cognitive abilities were assessed with the Wechsler Intelligence Scale for Children - Revised (WISC-R), which was originally published in 1974 (the WISC is currently in its 4 edition).

Scores are generated from this battery by taking the raw score and converting it to an age-match scaled score (SS). In lay terms, an individual's performance is compared to other individuals who are of a similar age cohort. This way, you can tell how someone's performance compares to other people of the same age. The primary score generated by the WISC is a full-scale IQ. If you read my older post on IQ scores (4), you'll recall that IQ can be a meaningless number as it obscures the variability in an individual's performance. In order to compensate for this, the researchers mainly focused on the composite scores of the WISC: verbal comprehension (information, vocabulary, and similarities; see subtest descriptions below), perceptual organization (block design, picture completion, and object assembly), and freedom from distractibility (arithmetic and digit symbol coding).

(click the below image to enlarge)

The researchers found support for both the developmental deficit and lag hypotheses but not the developmental deterioration hypothesis. This is consistent with other research, which suggests that cognitive deficits in people diagnosed with schizophrenia remain stable over time (5, 6, 7). As the authors described,

"For all eight cognitive tests, the linear slopes of the growth curves were positive and significant (all p values <0.001), indicating that on average, future case subjects, similar to healthy comparison subjects, showed developmental increases in their cognitive functions between ages 7 and 13 years."

For the developmental deficit hypothesis, the authors noted,

"future schizophrenic case subjects exhibited early and static cognitive deficits on the following four cognitive tests: information, similarities, vocabulary, and picture completion...future schizophrenia subjects had significantly lower [performance] values than healthy comparison subjects."

And for the developmental lag hypothesis,

"on three cognitive tests (block design, arithmetic, and digit symbol)...future schizophrenia case subjects had lower linear slope values than healthy comparison subjects, indicating that their growth on tests measure freedome from distractibility and visual-spatial problem solving skills was developmentally slower."

(click to enlarge)

The researchers concluded,

"The neurodevelopmental model of schizophrenia posits the existence of deviations in cognitive development many years prior to the emergence of overt clinical symptoms of adult schizophrenia. Findings from this study add to what is known about the neurodevelopmental model in three ways. First, our findings point to both cognitive developmental deficits and cognitive developmental lags during childhood in individuals who will go on to develop schizophrenia as an adult. Second, different cognitive functions appear to follow different developmental courses from childhood to early adolescence. The developmental deficit model appears to apply to verbal and visual knowledge acquisition, reasoning, and conceptualization abilities. The developmental lag model appears to apply to freedom from distractibility and visual-spatial problem solving abilities. Third, these patterns of cognitive deviations from childhood to early adolescence in schizophrenia are not shared in recurrent depression."

By this point you may be asking yourself, "what the hell does all this psychobabble mean?"

In short, these results don't mean much for clinical practice. They've reconfirmed that future schizophrenia subjects have baseline cognitive deficits, and their neurodevelopment is slower than healthy people.

Here are the average IQs of the different groups pooled together:

The authors of this study made it sound as if all future schizophrenia subjects had cognitive deficits. They didn't. Future schizophrenia subjects had an average IQ score of 94, while healthy subjects had an IQ of 101. Both of these scores fall in the average range (90-110). 7 points is not a big difference.

Above, are two bell curves I constructed to illustrate my point. IQ is a normally distributed score. The purple curve represents normal subjects (mean IQ 101) and the pink curve represents the future schizophrenia subjects (mean IQ 94).

A standard deviation (i.e., a measure of performance variability) for IQ scores is 15 points. A score of 85 (1 SD below the mean) is considered impaired. As you can see, there is considerable overlap between the schizophrenia bell curve and the normal subject bell curve. Nearly two/thirds of the schizophrenia population will have an IQ in the normal range or better; however, the maximum IQ for most schizophrenia subjects will be caped (i.e., rarely above 115), although there are notable exceptions (e.g., John Nash).

Another important point to note is that while a difference in IQ of 7 points (94 versus 101) is statistically significant, it is not clinically significant. You need a difference between 1 to 1-1/2 standard deviations to achieve clinical significance. Based on the bell curve, only 15% of future schizophrenia subjects will have an IQ that low.

The second problem with this study is that the cognitive assessments were not neurodiagnostic.

"the model posits that there is insult to the brain acquired or inherited in early development" and therefore "the developmental deficit model for the etiology of schizophrenia is supported by our data."

What the data indicate is that some, but not all, future schizophrenia subjects had difficulty on some, but not all, of these tests (remember, performance was lower on average). One of the major criticisms of cognitive tests is that performance is influenced by factors outside of the individual. The only factor that is controlled for by the WISC-R is age. But other factors, such as quality of education, region of habitation, ethnicity, medications, and gender are not controlled. In order to determine if a problem is brain based, one needs to control for those other variables, which is why neuropsychologists should use demographically correct norms when possible.

Here's an example: Future schizophrenia subjects tend to be isolated, are viewed by others as weird, and are stigmatized by their peers. These factors can contribute to poor self esteem, stereotype threat, poor school performance, and most importantly, poor motivation to perform well. Of course a person with this social history will perform poorly on cognitive tests (people with recurrent depression also have lower IQ scores on average, see above).

Here's another problem: let's assume that differences in IQ are brain based. The IQ test results do not pinpoint were the problem actually is. Below is a pyramid that illustrates what brain/neurocognitive functions need to be intact in order for the higher order functions (e.g., IQ) to be accurately assessed.

For example, if a person performs poorly on the WISC-R Vocabulary subtest, you then want to know why that person performed poorly. He or she could of had a poor educational background, the person could have a memory retrieval problem, or an expressive speech problem, or a hearing problem.

For anyone who has undergone neuropsychological testing, you'll recall that we administer a butt-load of tests (between 20-30), which takes between 3-6 hours to complete. We do this so we can accurately pinpoint why a person performed poorly and so we can make useful recommendations. If the problem was educational, a tutor will help, if the problem was memory retrieval, cueing will be helpful, if the problem was hearing, a aid will be helpful.

There are many other problems with this study. However, the take home message is that future schizophrenia subjects, on average, perform poorly on some cognitive tests, but that poor performance difference is not huge. Why some perform poorly while others do not is still unknown. This study and its press release (8) do not help resolve this debate, it only muddies the waters.

Reichenberg, A., Caspi, A., Harrington, H., Houts, R., Keefe, R., Murray, R., Poulton, R., & Moffitt, T. (2010). Static and Dynamic Cognitive Deficits in Childhood Preceding Adult Schizophrenia: A 30-Year Study American Journal of Psychiatry, 167 (2), 160-169 DOI: 10.1176/appi.ajp.2009.09040574

Cock Goes Here...

2010-02-01T18:16:00.000-08:00

and here...

I expect to lose readers over this...

Does Schizophrenia Need to Be Treated?

2010-01-28T18:41:00.000-08:00

The short answer is "Yes."

However, the dogma about the illness is one of chronicity, that is, schizophrenia is an illness of unremitting symptoms even with the best of treatments.

Is this depiction accurate?

Not entirely, according to Harrow et. al, who set out to answer this question (and many more) in the Schizophrenia Bulletin article "Do Patients with Schizophrenia Ever Show Periods of Recovery? A 15-year Multifollow-Up Study."

The authors wanted to answer 4 questions:

1. Do some or even a large percentage of patients with schizophrenia show periods of recovery? If so, what percentage?

2. Do patients with schizophreniform disorders show more favorable courses and outcomes than patients with schizophrenia? (Yes)

3. Is schizophrenia associated with slower recovery than other psychotic disorders? (Yes)

4. Is psychosis in nonschizophrenia patients a risk factor for subsequent poor outcome? (Maybe)

Since the focus of this post is on the answer to that first question, I've provided the answers to the other questions for brevity (the article is available for free).

Methodology and Study Outcomes:
The study consisted of 274 DSM-III diagnosed patients (64 of whom had schizophrenia) who were studied at 5 different intervals over 15 years. The total diagnostic breakdown and numbers of patients within each diagnosis assessed during each follow-up period are listed below:

Patients were assessed at 2 years, 4.5 years, 7.5 years, 10 years, and 15 years post-initial hospitalization.

Other schizophrenia patient demographics are listed below:

Recovery was defined rather strictly:

1. the absence of major symptoms throughout the follow-up year (i.e., absence of psychotic activity and absence of negative symptoms).

2. adequate psychosocial functioning, including instrumental (or paid) work half-time or more during the follow-up year.

3. the absence of a very poor social activity level.

4. no psychiatric rehospitalizations during the follow-up year.

The data provided include, "(a) percentage of patients with schizophrenia in recovery at any follow-up year and (b) the cumulative percentage of schizophrenia patients who, over 15 years, ever show the potential for an interval or period of recovery." In other words,the number of patients with schizophrenia who had at least one interval of recovery during the 15 year period.

Results:
Here are the percentages of patients that were in recovery during each follow-up interval for each diagnostic group:

On average, during any given follow-up period, approximately 19-22% of schizophrenia patients (out of 64 total) were in remission. All patients groups had their lowest period of recovery during the first two years after hospitalization. The schizophrenia group had the lowest frequency of patient recovery during all follow-up periods.

Here are the cumulative percentages of the patients that had at least one interval of recovery during the entire study period:

As time progressed, the number of patients who experienced at least 1 interval of recovery in each diagnostic group increased. Again, the schizophrenia group had the lowest cumulative number of patients who achieve recovery; 3 out of every 5 schizophrenia patients did not achieve remission.

Here is where it gets interesting:

The majority of the schizophrenia patients, who had at least one interval of recovery, were not being treated with any medications. In the authors' words, "very poor outcome patients with schizophrenia are more likely to be on antipsychotic medications."

One can generate many different hypotheses based on this result. For example, you could argue that psychotropic medications in general, and antipsychotic medications specifically, are dangerous drugs that cause more harm than good.

That's just how two individuals chose to spin this result:

Indeed, these findings indicate that not receiving treatment works better than pharmaceutical intervention. Similarly, University of Illinois researchers recently found that only 5 percent of medicated schizophrenia patients recover, but 40 percent of non-medicated patients recover (Harrow, Grossman, Jobe, and Herbener 2005; also see Harrow and Jobe 2007). In other words, schizophrenia patients are eight times more likely to recover if they are not on medications!(1)

Quick! Somebody notify the APA! We need to start revising all those treatment algorithms, STAT!.

Unfortunately, the authors of that piece, which appeared in the September/October 2008 edition of Skeptical Inquirer, are full of shit (excuse my French, but to call them liars would be considered libel).

Harrow and Thomas, with the same patient cohort, did another study: Factors Involved in Outcome and Recovery in Schizophrenia Patients Not on Antipsychotic Medications - A 15-Year Multifollow-Up Study.

One goal of this study was to examine the "clues on whether the better functioning of the subgroup of unmedicated patients with schizophrenia versus those on antipsychotics at the 15-year follow-up was a function of their current medication status" or "other long-term characteristics marked them off as different types of patients."

They answered this question by comparing the two groups on various premorbid and prognostic factors that were assessed near the beginning of the study.

In the figure above, we see that unmedicated patients scored better on indices of "favorable prognosis." In the figure below, we also see that unmedicated patients had better scores on "premorbid achievement" measures as well. Keep in mind that these two factors (i.e., favorable prognosis and premorbid achievement) were assessed near the beginning of the study, and not afterward. This means that being on antipsychotics was not a major factor in patient outcomes, suggesting that the better overall recovery of the unmedicated patients was mainly due to long-term patient characteristics.

In the discussion section, the authors summarize their main findings:

"Looking at from a different viewpoint, the data suggests that schizophrenia patients with good prognostic features, with better premorbid developmental achievements and with more favorable personality characteristics are the subgroup more likely to stay off antipsychotics for a prolonged period."

What was identified is a small subset of patients who are able to experience episodes of recovery in the absence of antipsychotics. According to the authors, those patients "who go off antipsychotics are a different type of patient."

There are many things to keep in mind regarding these two research papers. First, the sample is rather small (64 cases of schizophrenia). Of those diagnosed, the majority never did achieved remission. At the end of the study, only 12/64 (19%) patients had been in remission the previous study year. Of those who did achieve remission, many eventually relapsed. And, overall, the schizophrenia patients had significantly poorer outcomes when compared to all other clinical groups...Oh screw it, who wants pie?

Harrow M, Grossman LS, Jobe TH, & Herbener ES (2005). Do patients with schizophrenia ever show periods of recovery? A 15-year multi-follow-up study. Schizophrenia bulletin, 31 (3), 723-34 PMID: 16020553

Harrow M, & Jobe TH (2007). Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year multifollow-up study. The Journal of nervous and mental disease, 195 (5), 406-14 PMID: 17502806

Now That's Change I Can Believe In!

2010-01-27T13:26:00.000-08:00

In this week's issue of the Medical Letter (1), a brief review regarding medical marijuana is included, which concluded that,

"Medical marijuana may be effective for treatment of nausea, anorexia, pain and some other conditions, but published data supporting its efficacy for treating patients with intractable cancer pain are limited, dosage is not well standardized, and cannabis is often poorly tolerated, especially by older patients. " (Jan 25 issues, 2010)

This conclusion was based on a review of the three forms in which marijuana is usually consumed: botanical, oral synthetic, and oromucosal. As it relates to the botanical form (most popular among the 18-34 demographic), the Medical Letter stated that for nausea, pain, anorexia, asthma, glaucoma and spasticity,

"It appears to be modestly effective, depending on the dose, for some of these disorders, but well-controlled studies large enough to be convincing are lacking, and non-standardization of dosage makes the available data difficult to interpret." (my emphasis)

Let's forget about the controversy surrounding marijuana as a medicinal agent or as an illicit schedule I controlled substance (i.e., high abuse potential; no legitimate medical use). Just focus on the reason why, this drug, which is legal for medicinal use in 14 states, lacks "well-controlled studies large enough to be convincing" as a medicinal agent: the federal government has a monopoly on the supply of marijuana for large scale, FDA approved study:

"DEA's final ruling rejecting the application of UMass Amherst Professor Lyle Craker for a license to cultivate research marijuana for use by scientists in FDA-approved research. The ruling, which contradicts the recommendation of DEA Administrative Law Judge Mary Ellen Bittner, maintains the unique government monopoly over the supply of marijuana available for FDA-approved research." (2)

Here's the back story: Professor Craker and the Multidisciplinary Association for Psychedelic Studies (MAPS) applied for that license 7 years ago. A DEA administrative judge, Ms. Ellen, recommended the license because "competition with NIDA would be in the public interest." Still the DEA rejected the application.

Marijuana must be a very, very dangerous drug because every other Schedule I drug (e.g., cocaine) can be produced by government-licensed independent laboratories.

The only organization that conducts research on marijuana in large scale studies is the National Institute on Drug Abuse (NIDA). (3) As the name of the organization betrays, their interest lie in showing how bad marijuana can be. Since the Institute on Drug Abuse is a federal organization, the research produced there is used to produce legislation. (4) This lack of competition is what prevents real discoveries and innovations, which can be a benefit to the public, from being made.

The individual responsible for making this final DEA ruling is Michele Leonhart, whom Obama just nominated as the new head of the DEA. (5) I vaguely remember Obama promising some sort of Change as it relates to marijuana policy (i.e., no more raids). (6) However, raids on marijuana clinics still continued. In response to this apparent hypocrisy, Mr. Obama's White House said that,

"It expects those kinds of raids to end once Mr. Obama nominates someone to take charge of DEA, which is still run by Bush administration holdovers."

Mr. Leonhart is one of those Bush holdovers. Now that's Change!

Medical Letter, Inc. (2010). Medical Marijuana The Medical Letter, 52 (1330)

Schizophrenia Treatment: The Future

2010-01-22T01:55:00.000-08:00

A reader request:

"I know you wrote that you're frustrated with reading clinical drug research but I was wondering if you could dedicate a post to explaining the barrier of entry for new antipsychotics that are *different* from the "new" antipsychotics. Also, I do not understand why you've stated the old antipsychotics are better (for whatever reasons) than the new antipsychotics. My husband has been on Risperdal for years and it works. I'm vigilant about exercise and diet so as to try to curb the potential diabetes side-effect. The fear on both our parts of psychotic episodes and the potential destruction that one could cause, is far outweighed by the benefits of risperidone. That is our choice, but I'm hopeful breakthroughs will occur in drug research that improve beyond the current "new" drugs that are simply more of the same.

I love your blog and plan to visit frequently."

I cannot say that there is just one "barrier of entry" for new drugs to treat psychosis. Many new chemicals go through a very lengthy developmental process that takes years of preparation before testing human subjects is possible. Only a minority of drugs make it that far, and an even smaller percentage actually make it to market. As I do not work in this particular field, I cannot comment beyond this.

Both the first and second generation antipsychotics are thought to treat psychosis through blockade of D2 dopamine receptors. This is know as the dopamine hypothesis of schizophrenia.

The third wave of antipsychotics that are currently under development are driven by the glutamate hypothesis of schizophrenia. In order to explain how these newer agents might work, I first need to give an overview of the glutamate system.

Organization of the Glutamatergic System: (Very BORING, but necessary to understand how these compounds work)

Glutamate is the primary excitatory neurotransmitter of the nervous system. It is composed of both metabotropic and ionotropic receptors, the latter of which produce fast postsynaptic reactions. Because glutamate neurons are present throughout the brain (as opposed to specific, concentrated nuclei such as the median raphe and substantia nigra), its role in specific behaviors and other brain functions is difficult to determine. For sure, however, its major functions discovered so far include synaptic plasticity, and learning/new memory (especially long-term potentiation).

Glutamate Synthesis, Release, and Inactivation:
Glutamate can be synthesized by many different chemical processes. It is primarily made by the breakdown of glucose. The primary precursor to glutamate is known as glutamine (which is located in glial cells as well as glutamate neurons), which is converted into glutamate via an enzyme called glutaminase (located in glutamate neurons). The process works like this: after a neuron releases glutamate, in will be transported back either into the nerve terminal or into glial cells (astrocytes in this case) and is then converted into glutamine by the enzyme glutamine synthetase. Glutamaine can be later released again by astrocytes and taken up by neurons that converted it back into glutamate by the enzyme glutaminase.

Ionotropic Glutamate Receptors:
There are three subtypes of glutamate ionotropic receptors. The three receptors are AMPA, Kainate, and NMDA (see the image above). Most fast excitatory responses to glutamate are mediated by activation of the AMPA receptor (even though the NMDA receptors gets all the press these days).

For both the AMPA and kainate receptors, the effect of depolarization is mainly caused by the influx of sodium (Na+) ions into the cell. NMDA activation is very different. These receptors allow sodium AND calcium (Ca++) into the cell. Calcium is responsible for activation of various second messenger systems.

Similar to the nicotinic receptor described in this post, recall that the complete receptor contains five separate subunits that come together to form the receptor channel. The other feature that distinguishes the NMDA receptor from the AMPA and kainate receptors is that it requires TWO different neurotransmitters to cause depolarization. Glutamate is the first neurotransmitter required. The other neurotransmitter is the amino acid glycine (see below).

If glycine is not binding to its specific site along with glutamate, the receptor channel remains closed. Another amino acid, d-serine, can also bind to this site in place of glycine. Glycine and d-serine are considered co-agonists. There are two additional binding sites on the NMDA receptor that affects its function. One site is within the cell that binds to magnesium (Mg++) ions. The magnesium ions block the flow of sodium and calcium until it is released from the receptor. Here is where it gets complicated: the presence of both glutamate and glycine at their respective sites is not enough to release the magnesium ion from within the cell. The cell must be depolarized first by either the AMPA or kainate receptors, in addition to glutamate and glycine latching onto their NMDA receptors, which then frees the magnesium ion from within the cell allowing sodium and calcium to flow inside, thereby activating a second messenger system (phew!).

You'll also notice from the above image that there is a site for the illicit drug phencyclidine (PCP) and also ketamine (AKA special K). Both PCP and ketamine, when binding to their receptor site, act as an antagonist. As it turns out, the behavioral effects of both of these drugs produce a syndrome very similar to schizophrenia, which is why the NMDA receptor is a new target for treatment in schizophrenia.

Metabotropic Glutamate Receptors:
In all, there are eight metabotropic glutamate receptors. They have the designations of mGluR1-mGluR8 (metabotropic Glutamate Receptor #). Similar to other metabotropic receptors, some are excitatory while others are inhibitory. Some are also located on neuronal terminals, where they act as presynaptic autoreceptors that inhibit glutamate release.

Third Generation Antipsychotics:
Most of what you are about to read is from Essential Pharmacology by Stephen Stahl (1). There will not be the usual links to research studies for two reasons: I am too lazy to look them up, and Stephen Stahl doesn't cite shit (thus, making his opinions suspect).

Glutamate Antagonist and Agonist
Currently, there is a split in the field as to whether glutamate agonists or antagonists will be effective treatments. Some feel that excessive glutamate activity, which leads to excitotoxicity, occurs at the beginning of schizophrenia, thus making an antagonist a reasonable choice for treatment (by preventing cell death). However, if you recall from the above section, certain drugs that are glutamate antagonists (e.g., PCP) lead to a syndrome very similar to schizophrenia. Finding a drug that is "just right" will be difficult (memantine is a current candidate). Also proposed are drugs that stimulate the glutamate autoreceptors (see section below), which have the benefit of not causing psychosis. Lamotrigine has been proposed as a possible treatment option.

Others theorize that the glutamate system is hypofunctional and needs a little boost (the theory being that if glutamate blockade leads to psychotic symptoms, then reactivation will treat the illness). One class of drugs being researched to achieve this goal is glycine agonists. If you recall, glycine is a co-agonist that is integral for the depolarization of the NMDA cell. The amino acids which bind to this receptor site (i.e., glycine, d-serine, & d-cycloserine) all "have been tested in schizophrenia, with evidence that they can reduce negative and/or cognitive symptoms" (pg. 441).

GlyT1 inhibitors
This is a class of drugs that inhibit the reuptake of glycine into glial cells. The theory is that glycine levels in the brain are lower than normal. In this sense, they would work like SSRI antidepressants and increase the amount of glycine available. According to Stahl, "several GlyT1 inhibitors are now in testing" and have been "shown to improve negative, cognitive, and depressive symptoms, including symptoms such as alogia and blunted affect" (pg. 442). Possible agents include: sarcosine, SSR 504734, SSR 241586, JNJ17305600, and Org25935.

mGluR2/3 presynaptic agonist
These are the autoreceptors that I mentioned earlier. Current compounds include LY404039, LY35470, LY379268, and MSG0028. LY404039 has been tested through its prodrug version (allows for better absorption) LY2140023, which is eventually converted into LY404039. It has demonstrated "significant improvement of positive and negative symptoms of schizophrenia compared to placebo" possibly making it the "first example of an antipsychotic agent that does not directly block dopamine 2 receptors." These results should be viewed with caution (2). The Last Psychiatrist reviewed this study briefly:

"One side effect the authors did not discuss is the 4% rate of increased CPK. CPK increases from antipsychotics indicate that excess muscle rigidity is causing muscle breakdown; muscle proteins then clog up your kidneys, leading to death, a disorder called, neuroleptic malignant syndrome (NMS). In this study, placebo and Zyprexa did not cause increased CPK."

AMPA-kines
Recall that AMPA (or kainate) activation is required for the NMDA receptor to depolarize. This class of compound focuses on increasing activity at the AMPA receptor. One drug that has been tested, CX 516, produced results that have been characterized as "disappointing." Still, other similar compounds are being developed: CX 546, CX619/Org 24448, Org 25573, Org 24292, Org 25501, and LY 293558.

Other Compounds
Many other compounds are also being tested, which have nothing to do with glutamate. These include: 5HT2A antagonist/agonist, 5HT1A/2C/6/7 agonist/antagonists, D3 antagonists, D1 agonists, nicotinic agonists, muscarinic agonists, cannabinoid antagonits, and many, mamy more.

Conclusion:
Glutamate is currently the neurotransmitter du jour. Any novel antipsychotic that hits the market will likely manipulate this particular system. If you trust Stahl (which I don't) there is a lot of promise here. My opinion is that everything is still in the gestational phase, and a major break through could happen or it could not. Moreover, I believe that it is unlikely that any one drug alone will treat all the symptom domains of schizophrenia. More likely, a polypharmacoligic approach will be needed. However, side-effects are always additive, so finding the right combination of drugs will be difficult. But hopefully, with the advent of new classes of drugs, that combination will be more effective than currently available treatments.

P.S. I do not specifically recall stating that first generation antipsychotics are "better" than second generation antipsychotics. Both appear to be equal in efficacy. Where they differ is side-effect profile (e.g., tardive dyskinesia versus metabolic syndrome).

Great Acts of Stupidity or How Science Shouldn't Work

2010-01-08T13:09:00.000-08:00

Has anyone read the book Freakonomics? I have. And by "have," I mean that I read the first page of the table of contents (1). What I learned from that brief, yet informative passage is that "conventional wisdom is so often wrong."

Here's an example. "Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder" (2).

For reasons of brevity, articles are worded so that certain assumptions are implied (implicit), while the main aim of the article can be stated explicitly.

What is the implicit assumption in this introduction?

It's this: Valproate (Depakote) and lithium are reasonably effective maintenance therapies. How do we know this? Because both drugs are recommended as monotherapy for the prevention of relapse in bipolar disorder.

Here is where it gets interesting (or pathetically sad). Lithium has over four decades of research supporting its efficacy. If we define a mood stabilizer as a drug that treats acute mania, acute depression, and prevents relapse into either mood episode, then lithium is the only drug on the market that meets those criteria (3). Valproate, on the other hand, has evidence to support its efficacy as an anti-manic agent. It meets only 1 out 3 criteria for a mood stabilizer.

"Then why is it recommended as a maintenance treatment?" Because of this study (4), which found that "divalproex...did not differ significantly from the placebo group in time to any mood episode."

If you are exceedingly sharp, you'll notice that it's a negative study. Yet valproate has managed to become a recommended monotherapy. To read more about this, check out this post (5).

This article, released online ahead of print, is known as the BALANCE study. (BALANCE is a backronym that stands for Bipolar Affective disorder Lithium/ANticonvulsant Evaluation). Here is the saddest fact of this study: Most of the mental effort that when into it was for creating the backronym. It goes down hill after that.

Here are the results: "For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy."

It other words, lithium monotherapy or lithium with valproate adjunctive therapy is more effective at preventing relapse than valproate alone. The difference between lithium and the combination treatment was not statistically significant.

Here is where it gets really sad (6): "Welcome back lithium. After losing its luster because of concerns over potentially serious adverse effects, this drug is drawing increasing respect...This study, along with other recent research, goes a long way toward putting lithium back on top as the preferred treatment for bipolar disorder, said lead study author John R. Geddes, MD...We’ve got more evidence purporting the lithium efficacy, safety, and its antisuicidal effects than we’ve ever had before," Dr. Geddes told Medscape Psychiatry. "So don’t throw lithium away; it’s a highly effective treatment, and if people can tolerate it, then it’s worth trying."

"don't throw lithium away!?" Exactly, what study suggested that? Some of you might be thinking that atypicals have replaced lithium since they too are effective as anti-manic and maintenance treatments, but lithium's efficacy was compared to valproate, not an atypical.

In other words, lithium was more effective than a drug that is no more effective than placebo. Why is this a major finding? Why was this study done?

"Although the study could not confirm a benefit of the valproate-lithium combination therapy over lithium alone, its findings should challenge current clinical guidelines that recommend valproate monotherapy as a first-line option for long-term treatment of bipolar disorder."

There is one study, ONE! on maintenance treatment. It's NEGATIVE! That alone should have prevented valproate from becoming a first-line option.

Here is a special kind of stupid: "In an accompanying editorial (7), Rasmus W. Licht, MD, Mood Disorders Research Unit, Aarhus University Hospital, Risskov, Denmark, praised the BALANCE study, describing it as 'outstanding work' and 'an impressive example of international collaboration.'

He said that even without a placebo group*, the study 'confirms the long-term efficacy of lithium, not only for the prevention of mania but also for prevention of depression.'

On the basis of the study’s results, 'the BALANCE group rightly challenges the recommendation by present clinical guidelines that valproate monotherapy is a first-line option for long-term treatment."

Make sure you read the above carefully. I highlighted the parts that celebrate acts of stupidity. This "outstanding work" took an "international collaboration" to "confirm the long-term efficacy of lithium," which "rightly challenge" clinical guidelines.

Lithium has been the most empirically supported bipolar drug to date. It's the only drug that meets all three defining criteria for a mood stabilizer. Valproate has proven efficacy as an anti-manic only. This study, along with the accompanying editorial, and subsequent press releases should not exist. This is just plain fucking stupid!

A few years ago, articles, based on data that has been around for 20 years, stated that that antidepressants were not as effective as initially stated.

Last year, research showed that vaccines didn't cause autism (even though no research showed that they did).

Now, research is showing us that lithium is effective (never disputed) when compared to a drug that was never shown to be effective.

This is science, telling us what we should already know!

* Just as a side note. The press releases for this study (8) are pushing the combination treatment as the preferred method of treatment. Here is my problem with that: I don't interpret these results as supporting polypharmacy as superior. Although there was a trend for the combination treatment over lithium alone, the difference was not statistically significant. Second, since valproate never had proven efficacy, I view it as an "active placebo," which could also explain the the better performance of the combination treatment. Sadly, the damage is done.

The BALANCE investigators and collaborators (2009). Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial The Lancent : doi:10.1016/S0140-6736(09)61828-6

One of These Beasts is Lindsay Lohan's Sister.

2010-01-05T21:39:00.000-08:00

Kanye West is still a Douche Bag

2009-12-28T16:42:00.001-08:00

In an attempt to counter his image as a professional douche bag, Mr. West "got into the Christmas spirit by making a surprise appearance at the Los Angeles Mission Saturday (Dec. 26). The Grammy winner, alongside longtime girlfriend Amber Rose, joined other volunteers and served lunch to the homeless, who greeted the Chicago native and took pictures. 'It's just important [to give back] when you're very blessed.'" (1).

"West showed up ready to work. He went straight for the kitchen, put on a apron and got on serving duty."

What Mr. West did not do, however, was go straight for his wallet to donate a tiny fraction of his fortune to the very organization that has to raise money to feed this segment of the population (2).

Stress Now, Mental Illness Later

2009-12-15T13:48:00.000-08:00

Routinely, I enjoy crapping on the common biological explanations of various mental illnesses (e.g., monoamine hypothesis). However, this does not mean that I do not believe in the importance biology plays in the development of mental illness.

To say that a specific mental illness is the result of a "chemical imbalance" or one "bad gene" is ridiculous. The problem with biological explanations of mental illness is that they neglect the psycho/social aspects of illness development (they are also poorly support by research too!).

Since I'm a psychologist, I pay attention to stress. I believe stress to the be the glue that binds biology and psychology together. This is because stress or more importantly, psychological stress, has a biological mechanism that has both short-term and long-term effects on the body and brain. Certain aspects of the physiology of stress act as "transcription factors," that is, they regulate gene expression. This means the effects of stress can be felt acutely (i.e., in the short-term) or many years later (e.g., the average time span between onset of sexual abuse and the development of clinical depression is 11.5 years, 1).

This poses an interesting question: can the age at which one experience "stress" predict both the onset and type of mental illness? That's what Lupien et al. (2) wanted to answer in an interesting paper that was published in Nature Reviews Neuroscience earlier this year.

Before I delve into their hypothesis, I am required by law to describe the hypothalamus-pituitary-adrenal (HPA) axis (see below).

This is how it works. You perceive a stressor (e.g., all the women with whom you were having extra-marital affairs, suddenly decide to tell their "stories" to TMZ), your hypothalamus releases corticotropin release hormone (CRH). CRH stimulates its neighbor, the pituitary gland, to release adrenocorticotropic hormone (ACTH), which finds its way down your blood stream and stimulates the adrenal glands to release glucocorticoids (steroids) as well as catecholamines (epinephrine and norepinephrine).

After this, many wonderful things occur: your wife attacks you with a golf club; your blood sugar spikes, blood pressure and heart rate increase, which delivers a rush of blood and oxygen to your thigh muscles. This enables you to run to your SUV, which you crash 5 feet from your drive way. Now the stressor is gone (i.e., you release a statement on your website indicating that you need to do some "soul searching"); the glucocorticoids bind to certain receptors (i.e., GRs & MRs), and the system shuts down and returns back to its homeostatic baseline.

Lupien et al. reviewed the relevant literature on the effects of stress (e.g., chronic stress, abuse, etc) and neurological development during the following life phases: prenatal, postnatal, adolescence, and adulthood. What they found is summarized below.

"How the effects of chronic or repeated exposure to stress (or a single exposure to severe stress) at different stages in life depend on the brain areas that are developing or declining at the time of the exposure."

(Paraphrased for simplicity) prenatal stress (defined as maternal stress or exogenous steroids during pregnancy) affects the development of many of the brain regions that are involved in regulating the HPA axis (i.e., hippocampus, frontal cortex, and amygdala).

"Postnatal stress has varying effects: exposure to maternal separation during childhood leads to increased secretion of glucocorticoids, whereas exposure to severe abuse is associated with decreased levels of glucocorticoids. Thus, glucocorticoid production during childhood differentiates as a function of the environment."

"From the prenatal period onwards...some areas undergo rapid growth during a particular period. From birth to 2 years of age the hippocampus is developing; it might therefore be the brain area that is most vulnerable to the effects of stress at this time. By contrast, exposure to stress from birth to late childhood might lead to changes in amygdala volume, as this brain region continues to develop until the late 20s. During adolescence...there is an important increase in frontal volume. Consequently, stress exposure during this period should have major effects on the frontal cortex."

"In adulthood and during aging the brain regions that undergo the most rapid decline as a result of aging (amygdala, frontal cortex, hippocampus) are highly vulnerable to the effects of stress hormones. Stress during these periods can lead to the manifestation of incubated effects of early adversity on the brain or to maintenance of chronic effects of stress."

What all that psychobabble means is this: certain brain regions (i.e., amygdala, hippocampus, & frontal cortex) are more vulnerable to stress during certain developmental stages (e.g., the hippocampus is most vulnerable before age two). What the authors are postulating is that these areas, when affected by stress, can be use to predict the nature of the psychopathology that will result from exposure to stress at different ages. Or in their words:

"Exposure to adversity at the time of hippocampal development could lead to hippocampus dependent emotional disorders, which would be different from disorders arising from exposure to adversity a times of frontal cortex development."

This sounds very interesting! Is there any evidence to support it? They list two studies (3, 4). "The first reported that women who experienced trauma before the age of 12 years had increased risk for major depression, whereas women who experienced trauma between 12 and 18 years of age more frequently developed PTSD. The second study reported that repeated episodes of sexual abuse were associated with reduced hippocampal volume if the abuse occurred early in childhood, but with reduced prefrontal cortex volume if the abuse occurred during adolescence."

This does seem to support their hypothesis. However, if you read those two studies, you'll find that it is not as clean cut as these authors suggest. Also, other variables were not discussed such as temperament and genetics, sex and gender, SES, and culture. The research is also murky on what constitutes a "prefrontal" disorder versus a "hippocampal" disorder (not to mention the many anatomical overlaps between psychiatric diagnoses). In spite of those limitations, it is an interesting hypothesis that is worth exploring.

To read an excellent book on this subject, check out Robert Sapolsky's Why Zebras Don't Get Ulcers.

Lupien, S., McEwen, B., Gunnar, M., & Heim, C. (2009). Effects of stress throughout the lifespan on the brain, behaviour and cognition Nature Reviews Neuroscience, 10 (6), 434-445 DOI: 10.1038/nrn2639

Ben Stein is a Moron (O'Reilly is too)

2009-12-14T15:42:00.000-08:00

This has been done to death, but I've been wanting to write about this for a long time. (Excerpt from the O'Reilly Factor back in October 2007, 1 .)

O'REILLY: In the unresolved problems segment tonight, how did life begin? Religious people believe a higher power created the universe; secular progressives say all kinds of things, but God is not in the equation. And some believe, those who subscribe to intelligent design; that is a deity created life; are being persecuted in America. Joining us now from Washington Ben Stein, who has put together a new documentary called “Expelled: No Intelligence Allowed.” The film set to open in theaters this February.

So, what's the issue in your mind?

STEIN: Well, the issue is that Darwinism, which was a brilliant theory and a great, great relic of the age of imperialism in the 19th century, basically said that mankind evolved from apes and monkeys and from cells and so forth. And that's a brilliant proposition; Darwin was a brilliant guy. But it didn't say how life began. It didn't say how the cell got to have hundreds of thousands of moving parts each of which has to work perfectly. It said maybe life was created by lightning striking a mud puddle. That has never struck me as convincing. And I thought there are a lot of gaps in Darwinism. Intelligent Design is an effort to try to fill in some of those gaps. It might be totally wrong, but at least it's an effort to try to fill in some very obvious gaps.

Amazingly, if you take half of O'Reilly's brain and half of Stein's brain and put them together, somehow, you end up with less than you started.

1. "how did life begin?" Evolution can not, does not, and will not explain how life began. Abiogenesis, a subfield of chemistry (not biology), is the study of how life on Earth could have arisen. Evolution is a mechanism of change. It does not explain the origins of life, it explains the diversity of life.

2. "those who subscribe to intelligent design; that is a deity created life" Intelligent design and creationism are not entirely interchangeable (actually they are, there are only semantic differences). Intelligent design holds that "certain features of the universe and of living things are best explained by an intelligent cause, not an undirected process such as natural selection" (2). For whatever reason, they refuse to define or operationalize that "intelligent cause" (i.e., God) and they seem to lack the curiosity to want to discover how this "intelligent cause" operates.

3. There is no such thing as "Darwinism." That's a term used by creationist to demean those who believe in the theory of evolution. What Mr. Stein should have said is that "Evolution is a brilliant theory" and then end the interview.

4. "mankind evolved from apes and monkeys and from cells and so forth." Apes are monkeys. Humans are apes. Humans are also monkeys. Humans did not evolve from apes and monkeys, humans share a common ancestor with apes and monkeys.

5. "But it didn't say how life began." Of course it doesn't. That's called abiogenesis.

6. "It didn't say how the cell got to have hundreds of thousands of moving parts each of which has to work perfectly." Once the cell was there (the living organism), evolution explains the diversity of those moving parts and how they function so well.

7. "life was created by lightning striking a mud puddle." No scientific theory that attempts to explain the origin of life on Earth postulates this. And again, evolution has nothing to do with this.

8. "Intelligent Design is an effort to try to fill in some of those gaps." Mr. Stein identified no gaps in evolution. He conflated two distinct theories from two different fields of science (chemistry and biology).

The Devolution of Psychotherapy

2009-12-14T12:12:00.001-08:00

Devolution: noun; retrograde evolution, degeneration.

I recently returned from the 6th Evolution of Psychotherapy Conference (1), the "world's largest psychotherapy conference!"

This conference is supposedly a who's who of the world of psychology and psychotherapy. The list of "keynote speakers" included luminaries such as Robert Sapolsky, Aaron Beck, and Philip Zimbardo. However, other people of questionable credentials (e.g., Daniel Amen and Francine Shapiro) and of questionable relevance (e.g., Andrew Weil and Deepak Chopra) were also featured.

Similar to all major conferences, it was expensive (2):$699 for the main conference, plus an additional $249 for the pre-conference, and $199 for the post-conference. In all there were over40 "prominent" people featured and over 200 presentations and workshops. With over 7,000 people in attendance, what where we paying for?

According to the syllabus it was this: "attendees will increase their therapeutic skills by learning: 1. the basic principles and techniques of contemporary schools of psychotherapy, 2. the commonalities that underlie successful clinical work, and 3. the historical development and future projections of psychotherapeutic disciplines."

Unfortunately, those goals were not accomplished.

What the fuck was that purveyors of pseudoscience, Daniel Amen, doing at this conference? And why was he reserved for $249 pre-conference? Jeffrey "I whistle when I talk" Zeig, the person who produces these conferences, is a star fucker. Here is why Amen should not have been there (3, 4, 5).

I will admit that I have never familiarized myself with the work of either Andrew Weil or Deepak Chopra. My bias automatically lumped them in with quacks (e.g., Amen). However, after viewing their addresses, I have a difference opinion of them. Both are vary good public speakers (especially Deepak). Weil has a fairly good conceptualization of the current state of health care, but his prescriptions involved way too much government intervention for my libertarian soul. Deepak prefers to stay in the realm of metaphysics (i.e., philosophy, logic), rather than hard science. There is nothing wrong with that, but the relevance of his speech (and Weil's) to psychotherapy is questionable.

Although she was not a keynote speaker, I have to mention my hatred for the work of Francine Shapiro. I know this will be unpopular, but eye movement desensitization and reprocessing (EMDR) is bunk (6) . Let me clarify that, the theory behind EMDR is bunk (7). I have wanted to dedicate a series of posts to Shapiro and her "therapy," but every time I begin reading the relevant literature, I get so over come with rage that all I want to do is travel to Rwanda and club a Tutsi to death.

In the main auditorium there were various booths promoting various high-tech fancy pants technology such as EEG Spectrum International's "neuro feedback" (8) for clinical practice (An over zealous rep claimed that neuro feedback can "cure" ADHD in just 6 short sessions!).

Sadly, many of the other great names (Barlow, Bandura, Kernberg) had poorly done presentations and workshops.

Now for the good: Robert Sapolsky is amazing. Unfortunately, I am so intimately familiar with his research that I didn't learn anything.

Aaron Beck was amazing. For someone who is pushing 90, he was sharp, spry, articulate, funny, and up-to-date with all the current research.

Zimbardo also gave a great speech. I have never been much of a fan of his, but his presentation altered my perception of him and his work (though I still question the validity of his prison study).

Overall, the conference was not as great as I had hoped. Many of the workshops were a let down. Very little evidence based material was presented (I didn't spend over $800 to meditate in a room full of strangers or express my needs through dance). This conference reminded me of a late night talk show. A lot of bad jokes (told primarily by host Jeff Zeig) and the guests were there only to push their latest products (new books, etc).

If this is the evolution of psychotherapy, I just might change my mind about biological psychiatry.

The Cholinergic Hypothesis of Depression?

2009-12-03T18:41:00.000-08:00

Come the year 2012 there could be a new antidepressant with a novel mechanism of action on the market in these United States (1). As the drug is still in development, it is known as "TC-5214."

According the the press release, TC-5214 is a "nicotinic channel blocker that is thought to treat depression by acting on neuronal nicotinic receptors, or NNRs, according to Targacept. Targacept says NNRs are found on nerve cells throughout the nervous system and regulate nervous system activity."

This is the first I've heard the term "neuronal nicotinic receptors." In all my texts they are referred to as nicotinic cholinergic receptors (nAChRs). In common parlance, they are simply referred to as "nicotinic receptors." My bias leads me to believe that this is the term that polled best in a focus group as being both "sciency" sounding and "catchy." But I digress...

In this abstract (2), this rationale is put forward, "based on the notion that the depressive states involve hypercholinergic tone, we have examined the potential palliative role of NNR antagonism in these disorders, using TC-5214" (my emphasis).

I have never heard this "cholinergic" hypothese of depression before.

They add, "TC-5214 demonstrated positive effects in a number of animal models of depression and anxiety... forced swim test, a classical depression model....behavioral despair test ... the social interaction paradigm, a model of generalized anxiety disorder...the light/dark chamber paradigm , a model of GAD and phobia."

Take this for what it is worth. I hold almost no faith in animal studies (3) since the animal models simply cannot mimic the complexities of human mental illness and that the majority of drugs that pass animal trials fail to generate positive result in humans.

And just like many other theories of depression, a complex mental illness can be boiled down to a single receptor, "the antidepressant and anxiolytic effects seen in these studies are likely attributable to antagonist effects at the α4β2."

Since so much has been written about serotonin, norepinephrine, and dopamine, I've decided to dedicate the rest of post to acetylcholilne, the proposed "cause" of depression that this new drug will treat. (NERD ALERT: If you find this kind of stuff boring, stop reading now!)

Acetylcholine (ACh) is synthesized in one step (as opposed to the multiple steps required for the catecholamines). As you can see in the above image, there are two precursors: choline and acetyl coenyzme A (acetyl CoA). Choline is primarily derived from the fat in our daily diets. Acetyl CoA is produced within the cell by way of fat and sugar metabolism. The synthesis of ACh is catalyzed by the enzyme choline acetyltransferase (ChAT), which does as the name implies, it transfers the acetyl from CoA to choline to form ACh. ChAT is present in the cytoplasm of neurons that use ACh as their neurotransmitter.

Acetylcholinesterase (pictured above) breaks down ACh into choline and acetic acid (the acid that gives vinegar its smell and taste, 4). AChE is found within the presynaptic cell to metabolize excess ACh, on the membrane of the postsynaptic cell to break down ACh released into the synaptic cleft. It's also found in the neuromuscular junction (where PNS nerves stimulate muscles).

Cholinergic neurons play important roles in both the central and peripheral nervous systems (CNS & PNS). ACh neurons modulate both the sympathetic branch and the parasympathetic branches of the PNS. In the brain, the main neuclei that produce ACh are clustered in only a few areas. The first major pathway originates in the dorsal tegmental areas and projects to the thalamus. This pathway is part of the "reticular activating system," which govern the arousal level and alertness. Next is the septal nucleus that projects to the fornix and terminates in the hippocampus (ACh plays a prominent role in long-term memory formation). Next is the "ACh forebrain complex," which includes three "bands," the largest being the nucleus basalis of Meynert. These projections go all through the cortex and amygdala, the olfactory bulbs and the vestibular-cochlear nerve (important in balance).

There are two acetylcholine receptor subtypes, muscarinic and nicotinic.

Nicotinic receptors are highly concentrated on muscle cells, ganglionic neurons in the PNS, and on certain brain neurons. They are ionotropic (made up of an ion channel). When ACh binds to this receptor, sodium (Na+) and calcium (Ca2+) rush into the cell, causing depolorization, and increasing the cell's excitability. These receptors also enhance the release of other neurotransmitters.

The nicotinic receptor (above) is comprised of five proteins that form a channel. The subunits are label with Greek letters: beta, gamma, sigma, and two alpha subunits (ACh needs to bind to both of these to open the channel up). The structure, however, of the brain nicotinic neurons and muscles neurons are different, leading to different pharmacological difference between the two (see below).

The drug TC-5214 reportedly binds to neuron type three at the alpha4, beta2 subunit. (Contrary to what Wikipedia says, 5, this drug has NOT been tested in MDD patients).

Muscarinic receptors, conversely, are metabotropic (similar to monoamine NTs). So far, 5 muscarinic receptors have been discovered (M1 to M5), with some being excitatory and others inhibitory. Receptors are widely distributed throughout the brain including the neocortex, hippocampus, thalamus, striatum, and the basal forebrain. Outside of the brain muscarinic receptors are found mainly in cardiac muscle and smooth muscle (such as those found in the bladder). This is the receptor system associated with "anticholinergic syndrome" (6).

ACh's exact role in mood and cognition is still not known. It's associated with long-term memory formation (e.g., Alzheimer's disease) and attention and arousal (e.g., focused attention). Will TC-5214 actually treat depression? I doubt it. It seems to me, as a nicotinic receptor antagonist, it is better suited for smoking cessation (Chantix loses patent protection in 2012). Either way, it will be interesting to see how this one develops.

Your IQ Means Nothing

2009-12-01T17:17:00.000-08:00

"The teenager accused of murdering a 21-year-old man in 2005 has a below-average level of intelligence, making it more likely he could be influenced by an older gang member, a psychologist testified Monday.

Dr. Rahn Minagawa testified that he performed an IQ test on defendant Josue Orozco, 19, in October and found Orozco scored an 81, indicating a much-lower-than-average intelligence but not mental retardation.

Minagawa, a San Diego-based psychologist who testified for the defense Monday, said Orozco's low intelligence would likely make him 'more vulnerable' to the influence of an 'original gangster.'" (1).

IQ is an antiquated concept. Many people, included the above-mentioned douchebag Dr. Minagawa, believe that IQ is a unitary construct. It's not. The number is useless.

First the basics. IQ or full-scale IQ (FSIQ) is a composite of separate, smaller composites. For example, the WAIS FSIQ is made up of the Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and the Processing Speed Index (PSI). The sub-composite scales convey more information than the FSIQ, but they too also obscure a lot of clinical information tool.

Here's how useless an IQ score is. The article notes that Orozco's IQ is 81. I recently had a patient (young male with similar demographic characteristics as Orozco). His FSIQ was also 81.

If I only told my patient that his IQ was 81, what could he do with that information? Other than believe that he is stupid, nothing. If I made treatment recommendations based his IQ, what could I suggest? Nothing.

My patient's full profile breaks down to this when he is compared to people of a similar age (Orozco's IQ is age based):

FSIQ = 81 (mild-deficit)
VCI = 90 (low average)
PRI = 76 (mild deficit)
WMI = 86 (low average)
PSI = 84 (mild deficit)

On the surface, his scores seem pretty poor.

Here's the rub, test performance is influence by other factors other than age. Factors like ethnicity, level of education, and gender also affect test performance.

Instead of comparing my patient's results to people of a similar age, let's look at what happens when I compare his results to a population with similar age, education, gender, and ethnic background.

FSIQ = 86 (low average)
VCI = 97 (average)
PRI = 79 (mild deficit)
WMI = 91 (average)
PSI = 91 (average)

His scores improved! Only his PRI is still in the mild-deficit range (he had a right-parietal lesion). Does this alter my interpretation? What about our murderer? Let's pretended that these are his test scores. If his age-matched IQ of 81 means that he is "more likely" to be influenced by an OG, does that mean his demo-corrected IQ makes him less gullible? Not even close.

Why not? Because IQ has nothing to do with social psychology. IQ cannot predict one's ability to make decisions. Even tests designed to assess decision making cannot predict one's ability to make decisions.

In this case, it's Orozco's position within the gang that makes him more likely to be influence by an older gang member. His age at the time of the crime (14) better explains his gullibility than his lousy IQ score. Bottom line: This psychologist is an idiot!

I use to take a combination of Ambien CR, diazepam, Restoril, diphenhydramine, and bourbon to sleep at night. I have an IQ of 140. Like I said, it's a useless number.

Sorry Philip, This Study Won't Change Anything

2009-11-20T14:59:00.000-08:00

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

2009-10-28T11:34:00.000-07:00

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

2009-10-27T23:57:00.000-07:00

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

2009-10-27T20:54:00.000-07:00

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"

2009-10-19T10:00:00.000-07:00

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

2009-10-12T16:02:00.001-07:00

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

Reader Requests

2009-10-08T15:45:00.001-07:00

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

2009-09-24T13:27:00.000-07:00

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?

2009-09-23T12:18:00.000-07:00

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

2009-09-11T00:20:00.001-07:00

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

Update: Asenapine and Iloperidone

2009-09-11T00:04:00.000-07:00

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

2009-09-10T20:51:00.001-07:00

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

2009-09-03T15:20:00.000-07:00

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

Update: (February 8, 2010) . The February 8th issue of the medial letter (Vol 52, Iss. 1331) they have a piece on Saphris

"ADVERSE EFFECTS — The most common adverse effects occurring in >5% of patients taking asenapine and at least twice as frequently as in those taking placebo were akathisia, oral hypoesthesia and somnolence in schizophrenia trials, and dizziness and extrapyramidal symptoms other than akathisia in bipolar trials. Weight gain in clinical trials was greater than with placebo, but less than with risperidone or olanzapine."

"DRUG INTERACTIONS — Asenapine serum concentrations may increase when the drug is taken with a strong inhibitor of CYP1A2 such as fluvoxamine (Luvox, and others). Asenapine is a weak inhibitor of CYP2D6; serum concentrations of paroxetine (Paxil, and others), which is both a substrate and inhibitor of CYP2D6, increased almost 2-fold when taken with asenapine."

"CONCLUSION — Asenapine (Saphris) is a new second-generation antipsychotic agent. Available data on its efficacy are not impressive. It can cause extrapyramidal symptoms and weight gain. Because it has poor bioavailability when swallowed, the drug must be administered sublingually to achieve therapeutic blood levels; whether schizophrenic or acutely manic patients will be able to adhere to this requirement is an additional concern."

I'm Back...Fresh Out of Rehab

2009-08-31T20:04:00.000-07:00

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

2009-05-11T19:35:00.000-07:00

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

Update: (February 22, 2010). The current issue of the medical letter (Vol. 52, Iss. 1332) has a piece on Fanapt.

"ADVERSE EFFECTS — Common adverse effects that have occurred in at least 5% of patients taking iloperidone and at least twice as often as with placebo include dizziness, dry mouth, somnolence, fatigue and nasal congestion (REF 8). In clinical trials, the incidence of extrapyramidal symptoms with iloperidone did not differ from those with placebo. At an iloperidone dose of 20-24 mg/d, 4.8% of subjects developed sustained orthostatic hypotension and the QT interval increased by a mean of 9.1 msec. In short-term studies, subjects treated with iloperidone gained a mean of 2.0 kg body weight; high-dose (24 mg/d) iloperidone produced >7% weight gain in 18% of subjects."

"DRUG INTERACTIONS — Strong inhibitors of CYP2D6, such as paroxetine (Paxil, and others), or of CYP3A4, such as clarithomycin (Biaxin, and others), increase serum levels of iloperidone and further increase the effect of the drug on the QT interval. The manufacturer recommends lowering the dose of iloperidone by half when taken with such drugs. Iloperidone should not be used with other drugs that prolong the QT interval."

"CONCLUSION — The efficacy of iloperidone (Fanapt) for treatment of schizophrenia appears to be similar to that of other second-generation antipsychotics. The risk of orthostatic hypotension requires gradual titration to an effective dose, and QTc prolongation is also a concern. Older drugs with longer records of efficacy and safety are preferred."