Ziprasidone

The Last Psychiatrist - February 6, 2007

If one more person tells me ziprasidone "doesn't do anything," I'm going to choke them with the capsules. If it's never worked in your practice, how do you explain the numerous efficacy studies? All flukes? All of them? It couldn't be you?

Probably everyone has heard ziprasidone must be taken with food. But that's not to prevent nausea or protect the stomach lining, it's to get the drug to be absorbed.

You'll have to take my word for it right now that 120mg is the a base dose. (120mg ziprasidone=10mg olanzapine=3mg risperidone.) This is amazingly hard for psychiatrists to appreciate ("there are equivalences? And those are the doses??") But it's even harder to get them to understand the relationship to food: ziprasidone needs fat to be absorbed.

80mg on an empty stomach (blue line) gets you the equivalent of 40mg if taken with food. That's half the dose. In other words, if you dose your ziprasidone "all at night" (no food) then you're getting about half of what you thought you were. (In chronic dosing this will be less of a problem, but 30-50% increased absorption with food is a good guideline.)

Hospitals: they dose BID, which means morning and night, which means no food either time. Guess what happens (or doesn't).

BTW, crackers won't do it. The graph above is with 800 calories, 400 calories of fat. That's a meal, not juice.

If your doctor gives you less than 120mg and then gives up, he doesn't understand the proper dosing of ziprasidone. If he doesn't know about the importance of food, then you're in big trouble. Forget about reading journals, he's not even listening to the reps. (I know: because they're biased.)

I bring this up partly as a public service message, but also to explore the curious observation that even though many doctors know this already, they still don't dose with food. I can't imagine laziness is the answer. There is some weird thinking that this isn't relevant in the "real world" because food is weaker than medication. Drug-drug interactions matter; drug-food couldn't be important. And if it was really important, someone e would have mentioned it.

Everyone complains about diabetes and weight gain; here's a drug that likely doesn't have these problems. But because it doesn't have those toxicities, it therefore can't be "strong," or effective.

I'm not trying to advocate for ziprasidone. I'm pointing out that much of our perception of a treatment's efficacy can come simply from our mishandling of it; and to alert humanity to the inherent bias in ourselves. If we've never gotten ziprasidone to work, then not only do we think it doesn't work, but we think everyone who says it does work is a Pfizer schill.

Quetiapine had this problem, too. Six years ago, no one used quetiapine. Now everyone uses it. Did they improve it? No. It's marketing, but in reverse: Astra Zeneca didn't delude everyone into thinking it works when it doesn't; we deluded ourselves into thinking it didn't, when it did. So whose fault is that? Depakote: six years ago Depakote was untouchable, it was the king of bipolar treatment. Now? Did we get new data saying don't bother? Did they make the drug weaker? This is the key: the data that brings us today's conclusions is the exact same data that gave us the past's, opposite, conclusions. In other words, no one actually read the data; they based their conclusions on something else. Clinical experience? No.

The bias goes well beyond "Pfizer paid that doctor off"-- it comes from a belief system ("meds are life savers" vs. "meds are band-aids"; nature vs. nurture; your own race/gender; your family history of mental illness/drug abuse (or lack of it); your desire to be a "real doctor" etc, etc) that is much deeper and exerts a much stronger control over your thinking. To the exclusion of any new information.

And, of course, it's so much a part of you that you don't see it as a bias. And other people (patients) don't know it's there, so they're at the mercy of your unexamined assumptions.

The solution is exhausting, and no one will like it: constant critical re-evaluation of your beliefs. Both the science (as much of it as there is) and countertransference. And, most importantly, long looks at your own identity. How did you come up with it? Because, in fact, you did.

Can An Antipsychotic be an Antidepressant?

November 3, 2006
The Charade is Revealed-- We Are Doomed

Here's a question: can an antipsychotic be an antidepressant? Why, or why not?

The correct answer is that the question is invalid, because there is no such thing as an "antipsychotic" or an "antidepressant." We (should) define them based on what they do, not what they are. Therefore, Wellbutrin and Effexor are both antidepressants if and only if they both treat depression-- not because of some element of their pharmacologies, which are anyway different. Strattera, on the other hand-- which has a pharmacology (in some ways) similar to Effexor-- is not an antidepressant, only because it doesn't treat depression.

Following, just because something is called an antidepressant, or antihypertensive, it doesn't necessarily take on all the other properties or side effects of the others in its "class." Not all "antidepressants" have withdrawal syndromes (only SSRIs do). Not all antihypertensives cause urination (only diuretics do.) You wouldn't dare put a "class labeling" on "antihypertensives" of "diuresis."

So you see where I'm going with this-- except you don't.

I've previously yelled about the inanity of "antipsychotic induced diabetes" or "antidepressant induced mania" when they ignore pharmacologies, doses, and, of course, actual data.

But today I saw something that I now understand to be one of the signs of the Apocalypse. It is the new package insert of Seroquel, which just got a new indication for the treatment of bipolar depression. The new PI reads:

Suicidality in children and adolescents - antidepressants increased the risk of suicidal thinking and behavior (4% vs 2% for placebo) in short-term studies of 9 antidepressant drugs in children and adolescents with major depressive disorder and other psychiatric disorders. Patients started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. SEROQUEL® is not approved for use in pediatric patients. (see Boxed Warning)

Stating the obvious: in none of these 9 studies was any patient actually ever on Seroquel; Seroquel itself is not associated with a risk of suicide; it's not even been tested for major depressive disorder; and, well, this isn't very rigorous science, is it?

Just because a is now called an antidepressant, it carries the same risk as the SSRIs? (Whether even SSRIs have this risk is besides the point.) Isn't that, well, racist?

This is not really about preventing suicide. If we were worried about suicide, really, then why 24 hours before the FDA posted this warning, no one cared about Seroquel's doubling of the suicide rate? Oh, because it doesn't actually double the suicide rate? Die.

So the game is clearly not about science, it's about politics, it's about liability, it's about money.

If this was honestly about about protecting children from suicide, we'd shrug our shoulders and say, "well, they're just very, very cautious, so we'll be careful and keep going." But that's not what this is. What this is factually inaccurate, misleading, and therefore more dangerous, more harmful. In a simple example, this warning protects no one for a risk of suicide-- no potentially suicidal patient is going to look at this and say, "well, crap, I'm not taking this." But it may prevent someone from taking it when they could actually benefit. See?

This is Structuralism gone very badly awry, Saussure just bought a pick axe and he's come looking for us all.

Antipsychotics: Global Buckets of Money

Wednesday, June 04, 2008

From Clinical Psychology & Psychiatry

Antipsychotics were the sixth best selling class of medications globally in 2007, according to IMS Health. They raked in a cool $20.7 billion, an increase of 10.7% from 2006. Thank God we are doing a better job of overrecognizing, er, appropriately treating bipolar disorder. Antidepressants were #7, at $19.7 billion, down nearly seven percent. This does not appear to be due to declining prescriptions. Blame generics, not decreased prescriptions for the lower numbers. With Cymbalta, Lilly has shown that new antidepressants don't have to be anything special, so it would behoove other companies to release other run of the mill antidepressants, attach a comical, er, highly educational marketing campaign such as Depression Hurts, then watch the money roll in. Just some free advice.

How about the top 10 drugs? Three of them were antipsychotics. No, I'm not kidding. Most surprisingly, Zyprexa had the best figures worldwide, which was interesting given the flat U.S. sales in 2007. Seroquel outsold Zyprexa in the U.S., but Zyprexa had a better run globally. Who knows what tricks are being used to sell Zyprexa internationally? Never mind, it's not like Lilly would do anything sly to market Zyprexa.

The new era of antipsychotics for everything appears to be in full swing.

CATIE

April 16, 2006

CATIE: Sigh

1. You know, if you're going to be rigorous about BID dosing schedules because the FDA requires it, why so liberal with total dosing for Zyprexa? A mean dose of Zyprexa is 20.8 is way (150%) above FDA guidelines. For comparison, that would have meant dosing Geodon at 240mg, Seroquel at 1000mg, and Risperdal at 6mg. BTW: a mean of 20.8mg means that a lot of people were dosed with MORE than 20.8mg (max=30mg).

2. The miracle here isn't that Zyprexa won, but that Zyprexa 20mg barely won against Geodon 114mg.

3. Why Trilafon (perphenazine)? Originally you thought all conventionals were the same; so why not Haldol? Or Mellaril? You say it's because it had lower rates of EPS and TD, which is fine, but then why exclude TD patients from that arm?

4. So you excluded patients with tardive dyskinesia from the perphenazine group (fine) but then had the nerve to say people tolerated it as well as other meds? Do you think maybe people who have TD may have different tolerances to meds? Different EPS? Different max doses? That they're just different?

5. You can't generalize from an obviously slanted "typical" arm to all other typicals. If you chose Trilafon over Haldol because of better tolerability a priori, you can't now say that "typicals" have equal tolerability to atypicals. Why not pick two typicals of differing potencies (like Mellaril and Haldol) and infer from there?

6. Do you actually believe-- does anyone believe-- that any of these patients are compliant with BID regimens? Especially with sedating meds like Seroquel?


The secret to understanding CATIE 2 is to understand that there are two CATIE 2s.

CATIE2-Efficacy: People who dropped out of CATIE 1 because their med didn't work were randomized to Clozail, Zyprexa, Risperdal or Seroquel. On average, new Clozaril switches stayed on 10 months, everyone else only 3. 44% of Clozaril stayed on for the whole 18 month study; only 18% of the others completed the study.

CATIE2-Tolerability: People who dropped out of CATIE 1 because of side effects (not efficacy) were randomized to Zyprexza, Risperdal, Seroquel, and Geodon (not Clozaril.) Risperdal patients stayed on for 7 months, Zyprexa for 6, Seroquel for 4 and Geodon for 3.

CATIE2-Efficacy is fair. If you fail a drug, you're likely to do better on Clozaril than anything else.

CATIE2-Tolerabilty makes no sense at all. The reason Geodon was used is because it has "very different" side effects. Hmm. How? "In particular, ziprasidone [Geodon] was known not to cause weight gain." But this assumes that the intolerability of the first antipsychotic was its weight gain.

Most importantly is this: if a patient couldn't tolerate their first antipsychotic, how likely is it that it was effective? In other words, if it wasn't tolerable, it wasn't efficacious-- these patients could have been in CATIE2-Effectiveness study. So how did they choose?

Easy: they gave the patient the choice: Geodon or Clozaril? Out of 1052, half left altogether. 99 went into the Clozaril study (CATIE2-Effectiveness) and 444 went into Geodon (CATIE2-Tolerability.) Of the 444 in the Tolerability trial, 41% were actually labeled first drug non-responders. 38% were labeled as not tolerating their first drug, but of those, who knows how many were also nonresponders?

And 74% dropped out again.

If you take the 444 in the Tolerability study and divide them into two groups:

• those who left CATIE1 because of lack of efficacy: then switching to Zyprexa or Risperdal kept them on their meds longer. (Which makes no sense again: this is the same thing as the CATIE2-Effectiveness, where (except for Clozaril) there was no difference between Seroquel, Zyprexa and Risperdal.)
• those who left CATIE 1 because of lack of tolerability, then it made no difference what you switched to.

Sigh.

And what's with the blinding? In every other study with a clozapine arm, you equalize the weekly blood draws by making everyone have to submit to them. But in this case, they unblinded clozapine so as not to have to subject all these people to blood sticks. Except they were subjecting them already-- they were checking blood levels.

And where was perphenazine? "[CATIE1] did not anticipate this unexpected result [that perphenazine would be as efficacious] that challenged the widely accepted (but never proven) belief that the newer atypical antipsychotic medications are better than all older antipsychotic medications" and so was not considered for CATIE2. Apart from the fact that it is simply untrue that anyone thought the atypicals were more efficacious than the typicals, it is furthermore untrue that that the authors did not "anticipate this unexpected result." In 2003, after basically doing Medline meta-analysis, they found that "not all of them were substantially different from conventionals such as perphenazine."

What's funny about these guys is how they conveniently lump all typicals together but arguing for differential effects of individual atypicals; then argue typicals are different from each other to justify picking Trilafon; and then say atypicals are different from each other ("not all of them were different") but typicals are all pretty much the same ("conventionals such as perphenazine.")

Bottom line:

The stated purpose of CATIE2 was to help clinicians decide which drug to switch to if patients a) failed their first drug; b) couldn't tolerate their first drug.

The divorce rate in America is 40-50%. Say you get divorced, and a friend says, I have two women for you, Jane and Mary. If the problem with your first wife was that she didn't turn you on, you should marry Jane. If the problem with your ex was that she was annoying, you should marry Mary.

What's going to happen here is that your second marriage, to either girl, is doomed. Certainly more than the national average of 50%. How long is it going to take before your second wife doesn't turn you on either? How long before you find stuff intolerable about her? The answer is, more likely than your first marriage-- say, 75%-- because the problem isn't your wives, it's you. You've framed the question in an idiotic and arbitrary manner. You don't get married to get turned on OR to be with someone who isn't annoying. You want the marriage to have both simultaneously, and much more. These things are not separable. This is CATIE2. A meaningless dichotomy-- efficacy and tolerability are not separate, let alone opposites-- used to create a false paradigm of medication selection.

April 17, 2006

CATIE Reloaded

And enough with the notion that medication compliance is a good proxy for overall efficacy.

All of these horrible psychiatry studies-- CATIE, Lamictal and Depakote maintenance trials, etc-- keep telling us how long patients stay on medications, because they say this means the drugs are working. The authors think that if a drug is working, they patient will stay on it. But you would think this only if you didn't actually treat many patients. I can make a similar argument that staying on a medication is inversely related to efficacy-- because when a patient feels better, they simply stop taking their meds.

Think about antibiotics. People don't finish the full 14 day course, precisely because they feel well. If they felt sick, they would probably take them longer than 14 days. In fact, people overuse these antibiotics even when its a virus, despite the antibiotic having no efficacy at all. They will demand an antibiotic even though know that it shouldn't be doing anything.

Same with pain meds. Oh, that's an acute problem? How about the chronic problems of diabetes and hypertension. People will skip/miss/forget doses when they feel asymptomatic, and will be more compliant when they have symptoms associated with these illnesses (e.g. headache, dizziness, etc.)

Look, I'm not telling you that compliance and efficacy aren't related. I am saying that if you want to measure efficacy, don't use compliance as a proxy-- go measure actual efficacy. And don't tell me it's too hard. You got $67 million for this study. Find a way.

Are Antipsychotics Overprescribed in Kids?

From The Last Psychiatrist - May 3, 2006

According to USA Today, 2.5 million antipsychotic prescriptions a year are written for kids under 18. The rate for privately insured kids is 6.5 in 1000-- it has to be easily ten times that for Medicaid kids.

The FDA database has 45 deaths; 6 from diabetes, the rest from CV disease, liver failure, suicide, etc. There were 41 pediatric NMS cases.

According to the article, 13% of antipsychotic prescriptions are for bipolar disorder.

So are antipsychotics being overprescribed? The answer is yes, but not for the reasons cited in the article.

The article, indeed, all articles about pediatric psychiatry, make a special point about how these medicines are not FDA approved for kids. This is absolutely meaningless. FDA approval requires two double blind, placebo controlled studies. These studies are universally taken on by the drug companies. No drug company would ever assume the massive risk of such a study-- let a lone two-- in kids. How do you recruit the study subjects? What parent is going to allow it? Rich parents? No chance. So it will have to be Medicaid parents-- and thus will come the Tuskegee-like charges, dripping with the obvious social and racial implications of pharma testing on poor minorities. Pharma is already loathed; they're not going to take any risks for the sake of a medal from the FDA. So there will not be any new pediatric indications for psych meds. Not in this climate. Think this hurts Pharma? It's your kids that suffer.

But don't be confused by crypto-socialist hysterics who say that Pharma will do anything for a profit, including peddle drugs to kids. Drug companies do not market these antipsychotics for kids. They are paranoid to a fault about doing this; they know everyone is scrutinizing them, especially lawyers. If you are a child psychiatrist who sees no adults, reps cannot even call on you. And if they call on you for other things, they cannot mention the use in kids. In the past five years, it has never-- never-- happened that a rep detailed me about their use in kids.

The only two reasons these drugs are used in kids is because psychiatrists give them, and parents demand them.

First, the parents. They don't come looking for antipsychotics, specifically. But my experience is that they are unrealistic about what is going on with their kids; in near denial about the family dynamics impacting on the kid's behavior; and virtually devoid of insight into relatively obvious, though procedurally difficult, maneuvers that could improve the situation. If your kid doesn't sleep enough, and consistently-- if your five year old doesn't nap-- you cannot tell me your kid has ADHD. Period. Parents demand a diagnosis of bipolar disorder for their kids because it means the divorce had nothing to do with it. They demand another medication when the first one fails to get the kid to do math homework instead of playing Xbox all day. And their kids' marijuana and alcohol abuse can't possibly have anything to do with their own marijuana and alcohol abuse. Parents: don't flame me. Your situation is different, I know. I know.

Second, psychiatrists prescribe them because of the pressure to do something, in the face of consistent failure. They don't start with antispychotics-- they end up with them. They prescribe them out of desperation. This is why, in every story about a child getting sick from one of these medicines, they are, in fact, on several medicines. First they start with Ritalin. If Ritalin doesn't help, or there is a side effect, or they can't sleep-- then a second drug is added. Maybe this helps, but after a while something else happens-- and another drug is added to this. That's why psychiatry's current obssession with the detection of underdiagnosed "bipolar disorder" is so important. This diagnosis justifies, and encourages, polypharmacy.

It is psychiatry's ridiculously dangerous, and ultimately doomed, paradigm: if you are not doing well on a medication, you must be so sick that you require two medications. It seems to have occurred to no one in psychiatry that failure on a medication could mean that it was the wrong medication.

The reason this polypharmacy madness is even possible is psychiatry's obsession with diagnosis, labels-- with semiotics.

What makes a drug an antipsychotic? Well, it treats psychosis. Fine-- but does that exclude its efficacy for something else? If it is later found to be efficacious in, say, depression, then what do you call it? Is the drug an antipsychotic that's also good for depression, or an antidepressant that's also good for psychosis?

There's no value in the label "antipsychotic" or "antidepressant" except what we give it. It's a drug that treats psychosis and depression, not an antipsychotic that treats depression (or the other way around). If you can't see the difference, stop reading now and go back to watching American Idol.

For example, why are antipsychotics viewed as "off label" for kids? The word "antipsychotic" is meaningless. Antipsychotics are tested against a scale, like the Brief Psychatric Rating Scale. But these scales measure a lot of things, like depression, and not just psychosis.

And at what point did we start making a distinction between psychosis and "dementia related psychosis?" Or bipolar depression and regular depression? Why do we need separate FDA approvals? Does someone know something about the physiology of these disorders that I don't? Do we need to start approvals for "diabetes related depression?"

Saying an antipsychotic is worse than an antidepressant for depression is a valueless statement, especially in the absence of data on this question. You are actually better off asking, "which is better for depression, blocking the serotonin transporter or blocking 5HT2a receptors?" See? Put this way the distinction seems less obvious. And even that question is valueless, as there is nothing (that we know of at this time) that allows us to say what effect either pharmacologic maneuver actually has. 5HT2A blockade does what again? Really? Do you have any evidence for that at all? And no more post hoc ergo propter hoc nonsense. David Hume laughs at you.

A Simpson's reference is helpful here:

Homer: Not a bear in sight. The Bear Patrol must be working like a
charm.
Lisa: That's spacious reasoning, Dad.
Homer: Thank you, dear.
Lisa: By your logic I could claim that this rock keeps tigers away.
Homer: Oh, how does it work?
Lisa: It doesn't work.
Homer: Uh-huh.
Lisa: It's just a stupid rock.
Homer: Uh-huh.
Lisa: But I don't see any tigers around, do you?
[Homer thinks of this, then pulls out some money]
Homer: Lisa, I want to buy your rock.

I know. The FDA, the Scientologists, socialists, the parents at the end of their ropes- the easy thing to do is blame Pharma. I'm in the strange position of having to be a Pharma apologist, to be the only doctor willing to defend Pharma. There are plenty things I don't like about the way Pharma conducts business, but I can't voice these complaints because I have to use the time countering these inane attacks. I know what will happen if the Pharma critics get their way.

You think Pharma should have no sales contact with physicians? Fine. Now deal with the consequences.

Antipsychotics and Diabetes

May 10, 2006

Glucose Transport

Glucose is absorbed through the small intestine into the blood.

All glucose is taken into cells via hexose transporters: this is facilitated diffusion (no ATP). Facilitated diffusion is passive diffusion through a channel made by a transmembrane protein; the proteins are able to open and close this channel. There are many ways channels can be opened/closed: ligand gated (i.e. neurotransmitter receptors), voltage gated (neurons), or, in the case of hydrophilic molecules such as glucose, mechanically gated: the channel is shaped like a closed "V". Glucose goes to the bottom of the V, causes a conformational change and the "V" opens, but closes at the top (makes an upside down "V".) Glucose can pass, and the V recloses. All diffusion is down a concentration gradient.

The hexose transporters are called, randomly, "Glucose transporters 1-5" (GLUT1-5).

GLUT4 is the main transporter in muscle, fat, and the heart. GLUT4 is insulin-sensitive (though it can also be activated by muscle contraction-- go figure.) In the absence of insulin, GLUT4s are stored in cytomplasmic vesicles floating around in the cytosol. If insulin binds to the insulin receptor (an ATP dependent tyrosine kinase receptor-- NOT the GLUT4), a signal cascade is activated that causes the cytpolasmic vesicle to go to and bind to the plasma membrane and lodge the GLUT4 there. The GLUT4 then allows glucose to diffuse through. When insulin disappears, the insulin receptor reconforms, the signal cascade stops, and the GLUT4 pinches off (by clathrin and other contracting proteins in the cell membrane) into a vesicle again (pinocytosis).

Thus, if there is no insulin: even if there is much glucose, there is no signal for the vesicle to go to the plasma membrane and lodge the GLUT4, so there will be no transport of glucose into the cell; so glucose stays high in the blood. Thus we have Type 1 diabetes.

Insulin also stimulates the creation of glycogen in the liver and muscle. [Insulin activates hexokinase (1st enzyme in glycolysis) as well as phosphofructokinase and glycogen synthase) and inhibits glucose-6-phosphatase ((opposite direction of hexokinase, same reaction) gluconeogenesis).]

Insulin promotes fatty acid synthesis.
Once glycogen synthesis has maxed out (i.e. about 30g, about 20% of the carbohydrate part of a studied meal, max in 4-6hrs,) then fatty acid synthesis IN THE LIVER takes over. Glucose is converted to free fatty acids (FFAs) and dumped back into the blood as lipoproteins-- which are then broken up into FFAs.

FFAs go into the adipose cells of the body. Glucose also goes into adipose cells-- via GLUT-- and are converted into glycerols. Glycerol+FFAs= triglycerides.

Thus, insulin's role is to store fat and/or oxidize glucose. Too little insulin will also trigger protein catabolism.

GLUT1 and GLUT3 account for 95% of the glucose transport to the brain. GLUT1 is for the blood brain barrier (the tight junctuions of the BBB are what require these channels), and GLUT3 is in the neurons. (pic here) GLUT1 is also found in muscle.

These are not insulin dependent (like GLUT4 is) so the brain can continue to get its energy. Not only does the distribution of GLUT 1 and 3 mirror capillary density and areas of relative glucose utilization, the GLUT1/3 densities can change depending on chronically increased (or decreased) need for glucose. Interestingly, nicotine, which increases brain glucose utilization, increases GLUT1/3 but not capillary density.

GLUT2 and 7 are in the liver. GLUT2 can also carry D-fructose.

GLUT5 is in the intestine, and some glial cells of the brain.

Type II diabetes is insulin resistance, not lack of insulin. There is not, at least initially, a problem with the pancreas's secretion of insulin in response to high glucose. The problem is at the level of the insulin receptor and/or GLUT, which become insensitive to the effects of insulin-- because there has been so much of it for so long. (For more info, see: News Physiol Sci. 2001 Apr;16:71-6.

Antipsychotics and Diabetes

The Last Psychiatrist
May 10, 2006

Atypicals and Diabetes: Glucose Transport

Glucose is absorbed through the small intestine into the blood.

All glucose is taken into cells via hexose transporters: this is facilitated diffusion (no ATP). Facilitated diffusion is passive diffusion through a channel made by a transmembrane protein; the proteins are able to open and close this channel. There are many ways channels can be opened/closed: ligand gated (i.e. neurotransmitter receptors), voltage gated (neurons), or, in the case of hydrophilic molecules such as glucose, mechanically gated: the channel is shaped like a closed "V". Glucose goes to the bottom of the V, causes a conformational change and the "V" opens, but closes at the top (makes an upside down "V".) Glucose can pass, and the V recloses. All diffusion is down a concentration gradient.

The hexose transporters are called, randomly, "Glucose transporters 1-5" (GLUT1-5).

GLUT4 is the main transporter in muscle, fat, and the heart. GLUT4 is insulin-sensitive (though it can also be activated by muscle contraction-- go figure.) In the absence of insulin, GLUT4s are stored in cytomplasmic vesicles floating around in the cytosol. If insulin binds to the insulin receptor (an ATP dependent tyrosine kinase receptor-- NOT the GLUT4), a signal cascade is activated that causes the cytpolasmic vesicle to go to and bind to the plasma membrane and lodge the GLUT4 there. The GLUT4 then allows glucose to diffuse through. When insulin disappears, the insulin receptor reconforms, the signal cascade stops, and the GLUT4 pinches off (by clathrin and other contracting proteins in the cell membrane) into a vesicle again (pinocytosis).

Thus, if there is no insulin: even if there is much glucose, there is no signal for the vesicle to go to the plasma membrane and lodge the GLUT4, so there will be no transport of glucose into the cell; so glucose stays high in the blood. Thus we have Type 1 diabetes.


Insulin also stimulates the creation of glycogen in the liver and muscle. [Insulin activates hexokinase (1st enzyme in glycolysis) as well as phosphofructokinase and glycogen synthase) and inhibits glucose-6-phosphatase ((opposite direction of hexokinase, same reaction) gluconeogenesis).]

Insulin promotes fatty acid synthesis.
Once glycogen synthesis has maxed out (i.e. about 30g, about 20% of the carbohydrate part of a studied meal, max in 4-6hrs,) then fatty acid synthesis IN THE LIVER takes over. Glucose is converted to free fatty acids (FFAs) and dumped back into the blood as lipoproteins-- which are then broken up into FFAs.

FFAs go into the adipose cells of the body. Glucose also goes into adipose cells-- via GLUT-- and are converted into glycerols. Glycerol+FFAs= triglycerides.

Thus, insulin's role is to store fat and/or oxidize glucose. Too little insulin will also trigger protein catabolism.

GLUT1 and GLUT3 account for 95% of the glucose transport to the brain. GLUT1 is for the blood brain barrier (the tight junctuions of the BBB are what require these channels), and GLUT3 is in the neurons. (pic here) GLUT1 is also found in muscle.

These are not insulin dependent (like GLUT4 is) so the brain can continue to get its energy. Not only does the distribution of GLUT 1 and 3 mirror capillary density and areas of relative glucose utilization, the GLUT1/3 densities can change depending on chronically increased (or decreased) need for glucose. Interestingly, nicotine, which increases brain glucose utilization, increases GLUT1/3 but not capillary density.


GLUT2 and 7 are in the liver. GLUT2 can also carry D-fructose.

GLUT5 is in the intestine, and some glial cells of the brain.

Type II diabetes is insulin resistance, not lack of insulin. There is not, at least initially, a problem with the pancreas's secretion of insulin in response to high glucose. The problem is at the level of the insulin receptor and/or GLUT, which become insensitive to the effects of insulin-- because there has been so much of it for so long. (For more info, see: News Physiol Sci. 2001 Apr;16:71-6.

Next up: how do antipsychotics affect glucose/insulin/transporters?

From The Last Psychiatrist - May 10, 2006

How Do Antipsychotics Cause Weight Gain?

In order for this post-- and any discussion on antipsychotic induced weight gain-- to make sense, you have to understand one thing: each antipsychotic seems to cause weight gain by a different mechanism, not varying degrees of the same mechanism. Because let me tell you right off the bat: researchers here are far from agreed.

A review of some articles:

In rat pancreatic beta cells, neither clozapine nor haloperidol had any effect on basal insulin release. In the presence of high glucose, haloperidol had no effect on the normal insulin surge, but clozapine inhibited this effect by 40%. How it did this is not clear, as clozapine, in the presence of glucose, completely suppressed electrical activity by hyperpolarizing the membrane potential (i.e. increased K+ conductance.) Haloperidol depolarized (inhibited K+ conductance). Thus, by completely suppressing electrical activity, it should have completely suppressed insulin release-- but it only inhibited 40%. Similarly, haloperidol should have increased insulin release (via depolarization) but it didn't have any effect. We don't know what would have happened if the study had been continued for a year; but note here that the effect on insulin is dependent on the presence or absence of glucose, not the other way around.

Most studies focus on the changes in serum parameters (triglyceride, cholesterol, insulin, etc) and not the mechanism for these changes.

For example, in 112 schizophrenics on meds for 8 weeks, olanzapine, clozapine, risperidone, sulpiride all increased insulin and C reactive peptide, as well as insulin resistance; but only clozapine and olanzapine increased triglycerides and cholesterol, and had a greater impact on insulin, insulin resistance, and C-peptide. What you can't tell is when this happened and what came first: did the insulin go up as a direct effect of the med, and consequently so did cholesterol, or did insulin resistance happen first, etc?

In the first study looking at the drugs' effects on GLUT1-5 mRNA, it was found that mirtazapine increases GLUT4 (muscle/fat) and 5(intestine) mRNA, and haloperidol and olanzapine increase GLUT5. No effect on GLUT1-3. (Contrast with clozapine and risperidone, below.)

The authors propose something interesting about mirtazapine: "Therefore, the increasing effects of mirtazapine on GLUT4 mRNA levels in our study might lead to a decrease in blood glucose levels and to an increase in cellular fat deposition, leading to intermittent or continuous lowering of blood glucose levels with a subsequent increased uptake of carbohydrates and other types of nutrients." In other words, better glucose uptake into cells means more fat inside cells, and less glucose outside cells (hypoglycemia)-- which is a stimulus to eat more.

This is important, so I'll repeat it: the hyperglycemia seen with olanzapine and haloperidol is here proposed to be due to the acute lowering of blood glucose (because of increased transport), and thus an increase in eating and fat deposition, and consequently insulin resistance and hyperglycemia; not a direct affect on glucose metabolism.

(Consistent with olanzapine's effect on GLUT5 (and not on carbohydrate metabolism, per se), metformin did not prevent weight gain in 40 people on 10mg olanzapine (all gained 5-6kg in 14 weeks.)

In (male C57) mice, over a 6 month period, clozapine, chlorpromazine and quetiapine induced hyperglycemia via effects on glucose transport. haloperidol and amisulpiride have little effect on GLUT, and were found not to induce hyperglycemia. Risperidone had a medium effect on hyperglycemia, but at the lower doses.

Using rat pheochromocytoma cells, clozapine and risperidone both inhibited glucose transport (i.e. GLUT3).

Desmethylclozapine (a metabolite) was an even more potent inhibitor, while clozapine-N-oxide, the other metabolite, had no effect on glucose transport. Clozapine and fluphenazine also inhibited glucose transport in (rat) muscle cells. The drugs block glucose transport in a non-competitive (i.e. allosteric) manner (and tricyclics appear to work in the same way.) What is interesting about this is that different people metabolize clozapine differently, and perhaps those who create more desmethylclozapine get more hyperglycemia than those who make less (and/or more clozapine-N-oxide.

A follow-up study tried to correlate the toxicity of these drugs to cells to their inhibition of glucose transport.

They found that clozapine, desmethylclozapine, quetiapine and fluphenazine were toxic to cells; risperidone was minimally toxic; and olanzapine actually promoted cell growth.

Quetiapine, olanzapine and clozapine all inhibited glucose transport about the same amount, and in a dose dependent manner. (Remember: haloperidol and sulpiride don't.)

However, if the cells were exposed to drug for a longer time, fluphenazine greatly inhibited glucose uptake, clozapine had no effect, and olanzapine increased glucose uptake. In other words, the toxic typicals only need a sort exposure to kill a cell, while less toxic atypicals need prolonged exposure. Also, fluphenazine increased GLUT3, and the atypicals had little or no effect (as found above.)

Olanzapine was found not to affect either the basal or the insulin stimulated glucose transport via GLUT1 or 4. (Fun fact: bovine serum albumin (or impurities therein), used to replicate the fact that olanzapine is highly (93%) protein bound, actually increased basal glucose transport, making suspicious all studies previosuly done with BSA.) This contradicts the findins of the Dwyer articles, above, where antipsychotics had inhibitory effects on glucose transport. A possible explanation could be dosing: this study used doses comparable to 20mg, while others used 20x that amount.

Another study, in humans, found that neither olanzapine nor risperidone affected acute (3 week) insulin sensitivity. Again, what happens after you get heavy is up for debate.

So what we have here is confusion, but:

1. acute, high dose in vitro studies indicate that typicals>atypicals inhibit glucose transport, but haloperidol does not.

1b. Typicals are toxic to cells, atypicals less so, and olanzapine promotes cell proliferation.

2. Normal dose and human studies show no effect on insulin dependent glucose transport (i.e. GLUT4) but there are effects on small intestine absorption (GLUT5) with olanzapine and haloperidol.

3. Clozapine inhibits insulin release in the presence of glucose, but haloperidol doesn't.

4. Acute effects may be different than chronic. i.e. even though antipsychotics may not directly affect insluin resistance or glucose transport, if they make you hungry or increase fat over time, this could result in later insulin resistance, hyperglycemia, etc.

Weight Gain & Olanzapine

From The Last Psychiatrist - May 14, 2006

Olanzapine's Weight Gain: Does What You Eat Matter More Than How Much?

The authors of this article have an interesting hypothesis, upon which I speculate wildly. But it is fascinating:

GLUT5, is found primarily in the small intestine (though also in muscle and kidneys.) What's interesting about it is that it transports fructose, which in turn directly stimulates additional GLUT5 mRNA expression. You eat fructose, this increases the expression of GLUT5 in the intestinal villi, which increases the transport of fructose. So the more fructose you eat, the more readily you can absorb it.

Now fructose doesn't stimulate insulin secretion. Since insulin regulates leptin, fructose actually reduces leptin. Fructose increases ghrelin. So you get hungry. Fructose goes to the liver and is metabilized to acyl glycerols, and consequently result in increased triglycerides.

So you have a situation in which Remeron and olanzapine (and high dose Haldol) cause an increase in GLUT5 expression; if they are also eating fructose (read: high fructose corn syrup) this is causing an additional expression in GLUT5, and hunger, and increased triglycerides... if one wants to conduct a useful experiment, find out if the people who gain the most weight on olanzapine are those who consume the most high fructose corn syrup (and not just those who eat the most.) In other words, can you gain weight on olanzapine if you are eating Atkins?

(NB: there are many who want to believe that olanzapine causes weight gain by increasing leptin; and so fructose and GLUT5 lowering leptin seems confusing. olanzapine, as shown above, actually decreases leptin, acutely. (And clozaril has either no effect, or minimal lowering.) Letpin only increases with increased fat-- i.e. as a consequence of fat, not as the cause of fat. Those who have found increases in serum leptin do so only after chronic administration, and resultant weight gain (for example, in a study of 13 schizophrenics on olanzapine who showed a small increase in leptin after 4 weeks-- and after a 2 kg weight gain; or 6 week animal study finding increased fat and leptin. The question, as noted by the authors, is whether the acute hypoleptinemia and hypoglycemia is what triggers hunger and an ultimate increase in fat, leptin, glucose and insulin. )

From The Last Psychiatrist - August 2, 2007

Aren't Two Antipsychotics Better Than One?

MY PSYCHIATRIST WANTS TO GIVE ME TWO ANTIPSYCHOTICS AT THE SAME TIME. WHAT SHOULD I DO?

Undoubtedly, your first impulse will be to punch him in the testicles, but as you know, the Kellogg-Briand pact (1928) expressly forbids this. However, it is notably silent on the issue of voodoo/ shark attacks, which can be used with discretion.

Antipsychotics exhibit their antipsychotic effect through D2 blockade. (1) Got it?

Take a look at the following figure again, showing % blockade of receptors (serotonin or dopamine) as a function of dose.



So you'll observe a few things.

First, these antipsychotics will have equivalences in dosage. If you use 10mg olanzapine as a baseline, how much dopamine does it block? 70%. How much risperidone does it take to block the same amount? 3mg. Therefore, 10mg olanzapine = 3mg risperidone. If you look at the graphs for the other antipsychotics (not shown-- sheer laziness), you get the following conversion for antipsychotic effects:

10mg olanzapine = 3mg risperidone= 500mg quetiapine= 120mg ziprasidone

Interestingly, most comparator trials done-- which look at symptom responses-- show these same equivalences. For example, ZEUS ziprasidone vs. olanzapine trial: 126mg ziprasidone=11mg olanzapine. This shouldn't be surprising since THAT'S HOW THE DRUGS ARE WORKING.

Second, no drug company can claim their drug has superior efficacy, because, again, they're all working through the same mechanism. Certainly, people tolerate each drug differently, but that's not efficacy, is it? Certainly an individual might respond to one better, but you have no way of predicting that. You simply cannot tell, by looking at someone, which drug will work and which won't. I'll show you: which drug will work best for this guy?

It's a trick question: the correct answer is penicillin.

The only way a drug company or study could claim to find superiority is if they don't use comparable dosages. "We found that risperidone 6mg was significantly more effective than 100mg of quetiapine." Really? Bite me.

Third, and this is really a math question: Since there are a finite number of D2 receptors in your skull, if you are on 6mg or risperidone-- which blocks 90% of them, and the doctor decides to augment with some olanzapine, where's the olanzapine going to go? Answer: your thighs.

Tom recognized her instantly despite the red anonymity bar

It's not going to D2 receptors, because they're all already blocked with risperidone. So it's just going to go around to other receptors-- H1, a1, M1, etc-- all of which have nothing to do with bipolar or psychosis. Issues of tolerability aside, mixing two antipychotics is no different than giving more of just one antipsychotic.

"Abiliquel"-- taking Abilify and adding quetiapine-- is sheer idiocy of such magnitude that even Eli Roth is repulsed. The first time someone told me what Abiliquel was, the room became filled with the sounds of six guys screaming in horrific pain, and that was because I was punching them in the testicles. Why not just give him Motrin + Advil? Oh: "But I use it cleverly: I give 15mg of Abilify and 25mg of quetiapine. See?" I see. I see that you're bleeding from the testicles. Guess why. You give 15mg Abilify-- that's acting as a D2 blocker. 25mg quetiapine isn't even a D2 blocker, it's an H1 blocker, you're paying for an antipsychotic and getting Benadryl. You say, "well, I know," (liar), "but I'm using the Abilify as an antipsychotic and quetiapine as a sedative." But, Gwyneth, you could have gotten the exact same effect by giving Abilify and Benadryl+trazodone-- which would be cheaper, and safer; or giving simply 500mg quetiapine alone, which would have gotten you both antipsychotic effect and sedative effect, thus reducing the cost by half, etc, etc. Remember that scene in the movie Hostel where Matthew McConaughey gets bitten by a radioactive lab rat and transforms into an immortal superhero?

Matthew McConaughey (Owen Wilson) proves there can be only one.

No? Do you know why? Because you knew better than to see that celluloid atrocity. How come you didn't know better than to prescribe two antipsychotics at once? You don't mix Zoloft and Paxil together, do you? Haldol and Prolixin? Seriously, do you just make crap up as you go along, or do you have pharmacological non-sequitors prepared in your Moleskine?

The same, by the way, goes for all you nutboxes who work in hospitals. If you have a patient on, say, 10,000mg of quetiapine, and he goes into an ER and gets indignant and flips a table over, and you inject him with 5mg of Haldol (90% blockade), you think that 10,000mg of quetiapine is doing him any good as an antipsychotic? I gots news for youse all: every time you prn (emergency dose) someone with Haldol, their brain is only on Haldol. Any other antipsychotic you give them that day is strictly a monetary gift to Big Pharma; you may as well PayPal them $180 and spare the patient the exposure.

On second thought, you may as well PayPal me.

-------------------

1. There may come a day where a drug is invented that works through some other mechanism, maybe glutamate, but as of right now, all the available antipsychotics work through D2 blockade. Everything else is irrelevant. Now, these other receptors might be relevant for other effects (reducing anxiety, antidepression, etc) but let's try to focus on the specific problem and not get all Andrew Weil here.

Understanding Atypical Antipsychotics

From The Last Psychiatrist - July 10, 2007

Let's begin with a simple drive down a country road, say, I10.

The Three Problems of Psychiatry:

You know those white dashed lines separating the lanes in a highway? How long are they? Answer: _____________ Most people I ask say 3 feet. The real answer is 10 feet. Surprised? And that’s the first problem in psychiatry: perspective. Your perspective is always driving at 60mph, so they look 3 feet long. Unless you change your perspective, you never get to see the truth. Worse, much worse, you go through life confident they are three feet.

Which brings us to the second problem: closed mindedness. Even though I’ve told you the truth, you still don’t believe it—that’s how powerful your perspective is. “He must be talking about some other lines, maybe in France?” Unless you change your perspective, you will never be open to the truth, to the discovery that what you have thought, for your entire life, is wrong. Unless you get out of your car and measure those lines, you’ll never accept the truth.

Which brings us to the third problem: if you do try and change your perspective, get out and measure those lines, you will be quickly dispatched by a minivan to the face for your lack of faith.

The irony of it all was not lost on Paris. Or was it coincidence? Irony?

Here is a picture of a molecule of Seroquel:

It’s a single molecule. Count them.


Seroquel, like all atypical antipsychotics, binds to multiple receptor types. Seroquel blocks, with varying affinity, histamine (H1), alpha 1 (a1), dopamine (D2), etc, etc. You can imagine a molecule having different spokes to it, that each bind to different receptors. Here’s a graphical representation of this, made famous by Steven Stahl, MD, at the University of California, and formerly with Styx:

Consult your doctor if you are at risk for esophageal rupture

The other way this is often represented is with a pie chart:

From the video Serocool (Styx, 1981)

A typical understanding of this pie chart is that the various sizes represent “amounts” of blockade. So, here, Seroquel is very antihistaminergic—so it causes a lot of sedation. It is moderately an alpha1 blocker—which is what causes orthostasis (lightheadedness/dizziness/grogginess). And much less of a D2 blocker, which is what actually provides the antipsychotic effect. You can also see that Seroquel’s H1 section is bigger than Zyprexa’s, which explains why Seroquel is more sedating than Zyprexa. (1)

One molecule gets you H1, a1, 5HT2a, D2

Two molecules gets you twice as much H1, a1, 5HT2a, D2

So this is so easy to visualize that anyone can understand it. But unfortunately this representation is misleading, it leads you to think something that is not completely accurate, in the same way that looking at Nancy Pelosi makes you think of that guy in Raiders of the Lost Ark:

BUT HOW CAN COLOR PICTURES BE WRONG?

One of the central themes of the postmodern critique of our values is that aesthetics must trump truth as long as aesthetics remains undefined. That’s the semiotic conundrum, why psychiatry is politics: the truth is demanded only when it supports a preset ideology.

WHAT THE HELL ARE YOU TALKING ABOUT?

Nothing. Let’s move on.

The mistake is that those pie chart sections aren’t amounts, they are affinities. They are preferences. Here's a metaphor. Imagine you have only one molecule of Seroquel. Where does one single molecule prefer to go? It can’t go to four different places, right? It has to "choose." And most likely it chooses to go to H1. The spokes don't cause the effect-- the spokes fit into receptors-- the receptor causes the effect. So if it binds to H1 receptor, the other spokes remain unused.

Let’s say you are a gentleman, and as such prefer blondes by virtue of their fair hair, lithe contouring, and receptiveness to new ideas. If you’re in a room with 10 brunettes and two blondes, do you go to everyone, equally? (Assume for this gedankenexperiment you have only the one, non-mechanical penis.) No, you make a bee line for the blondes.

Tom was thankful he was sober enough to avoid the ugly one

WHAT IF ALL THE BLONDES ARE TAKEN?

This is a safe bet. Sadly, since not every blonde will support your ideas for a ménage, you’ll have to settle for the brunettes. Painful, I know. I can call you in a script for Viagra.

So one molecule goes to H1. What about two molecules? Or three? Or 13 gazillion?

Think how sedating 25mg of Seroquel is (trust me, it's sedating.) Why isn't 32 times more-- 800mg-- lethal? Certainly 32mg of Xanax is more than a short nap, so what's the difference?

Instead of thinking that the drug binds to all receptors simultaneously, a better analogy would be a champagne fountain, like at a wedding. Except I hate champagne, so pretend it is a rum fountain. Rum fills the top level, overflows into the second level, then that overflows into the third, etc. You can't get anything into level 3 until you fill levels 1 and 2. And, once you've filled level 1, you can't put anything more into it.

Get it? So level one can be labeled H1, level two is alpha 1, and level 3 is D2. (2)

So you can see that, at some dose, there is no more increasing sedation with Seroquel. You've filled up level 1-- the H1 section. Going from 25mg to 50mg is a big jump in sedation (level 1), but going from 400mg (level 3) to 800mg is not felt to be an increase in sedation. It's the same amount of sedation, because by the time you hit 400mg, you were all full up. (3)

But there’s a dark side to my analogy, and it isn’t the rum fits. Here’s the thing: if one molecule of Seroquel goes to H1, and not to D2, then can it have any antipsychotic effect? No. One molecule binds to H1, so it isn't an antipsychotic, it's an antihistamine.

DOESN’T THE BOX CLEARLY SAY ANTIPSYCHOTIC?
Yes, it does. Weird, isn’t it?

Until this drug is blocking a significant number of D2 receptors, it is not functioning as an antipsychotic. Important: the antipsychotic effect of one molecule of Seroquel isn't so weak you just can't see it-- it is exactly and precisely zero.

The drug can't be called an antipsychotic unless it is behaving as an antipsychotic, regardless of the product labeling.

ARE YOU SAYING THE FDA ARE A BUNCH OF UNSCIENTIFIC ASS-MONKEYS?

What?

At some amount of D2 blockade, these things will be antipsychotics. What amount? Theories abound, but look at it this way: 10mg of Zyprexa blocks a certain number of D2 receptors. How much Seroquel, Risperdal, or Geodon does it take to block the same number? Answer:

10mg Zyprexa = 500mg Seroquel = 3mg Risperdal= 120mg Geodon. (4)

This is the problem so many doctors have. “I tried him on Seroquel, it didn’t work.” Really? At what dose? Because higher doses aren’t stronger—they are completely different. The behavior of Seroquel at 100mg is completely different than the behavior and effects at 500mg. 500mg is an antipsychotic; 100mg is not an antipsychotic. I know it looks like it’s five times more, but it’s not—it’s the addition of a completely new level. It's like adding a new “drug.” Just because the FDA calls it an antipsychotic, and that word is printed on the box, doesn't mean it is.

DOES THAT MEAN 5mg ZYPREXA = 250mg SEROQUEL?

So you weren’t listening.

Reducing these doses by half pretty much extinguishes the D2 blockade. Reducing the dose puts you into a different "level." They’re not half as good as they were, they’re completely different.

The drug isn't a tease. It doesn’t give you a little bit of efficacy at a low dose, “oh, it’s working a little bit—he must be a Seroquel responder—I’ll just increase the dose to get more efficacy.” Another way of saying it is this: the absence of efficacy at 250mg is in no way predictive of what might happen at 500mg, because the two doses are working at different receptors.

So, yes, 5mg Zyprexa is equal to 250mg Seroquel for psychosis, in the same way that an academic psychiatrist is like a certain Congresswoman from California: they all do nothing. ZING! (5)

Next up: Oh, No, Not Effexor, Too?

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1. The pie chart is wrong, wrong in the same way that Pamela Anderson is wrong, i.e. right in many ways. This is an in vitro pie chart, derived from affinities of receptors ripped out of the cadaverous remains of former tax attorneys. It may not represent what happens in an actual human body when confronted with unequal distribution of drug and receptors, number, and subtypes of receptors. It also doesn’t account for competition from other endogenous chemicals, drugs, or ice picks in the skull. All this notwithstanding, they are still usefully inaccurate. And all this is just a metaphor anyway.

2. This is not technically accurate. Receptor systems don’t fill up, i.e. become saturated, before the next system is impacted. More accurately, there exists a certain level of binding at one receptor such that it then becomes equally likely that it goes elsewhere. So my rum fountain should be more accurately labeled “the effects from H1 blockade” and “the effects from alpha 1 blockade.” Those effects do “max out.” Also, a drug’s maximal effect can occur well before 100% saturation of a system; for example, 10% H1 blockade may be all that is necessary to get maximal sedation, such that increasing binding to 20% doesn’t get you more effect. Nor might a drug be able to bind to more than 10%. So while binding saturation is often used interchangeably with maximal effect, they are not the same.

3. Drugs bind to specific receptors, but also nonspecifically (i.e. everywhere else.)

Note that binding is related to the rates of the binding (Kd=Koff/kon)

If you want a real world example, look at Zyprexa, below-- a real human in a real PET scanner eating real Zyprexa:





If you increase the dose from 5mg to 30mg, serotonin binding increases from 95% to 100%. Do you expect to “feel” much difference? But D2 binding goes from 55% to 85%. That you’ll feel.)

4. Be careful: these are the equivalents for D2 blockade—for antipsychosis. If you are using Zyprexa for, say, anxiety, then maybe D2 isn’t the relevant system. Maybe it’s the serotonin that’s relevant. (I have no idea; NO ONE HAS ANY IDEA.) So the conversion doesn’t hold. Do you understand? If you are using 10mg Zyprexa tablets to clog a toilet in some heroin fueled Consumer Reports product test down at the American Standard offices, you don’t need 500mg Seroquels to get the same clogging action. Ok?

5. Actually, this isn’t true either. 250mg Seroquel has trivial D2 blockade, but Zyprexa 5mg still has some (55%). So 5mg Zyprexa is more likely to treat psychosis than 250mg Seroquel. The equivalences are really to be used the other direction: if you needed 15mg of Zypexa, you will likely need more than 600mg Seroquel…