You may have seen the advertisements on TV:  "if you've taken Zyprexa and have diabetes, call us, the legal team at..."

Before you take your patients off of Zyprexa in a misguided attempt at warding off litigation, consider the following:

1.  You can't be sued if there's no damage. In other words, you can't be sued because of the risk of diabetes, you can only be sued for diabetes.  No damage, no lawsuit.  If a patient gets diabetes, you catch it and act appropriately, you can't be sued.  If you take reasonable care (note the weight every, say, 6 months; follow blood sugars every, say, year-- more frequently if there is weight gain), not only have you shown above standard-of-care practice, but you're going to catch the problem and fix it-- so no lawsuit.

2.  The lawyers in these ads are trying for a class action-- against the company.  Class actions are not about the severity of drug side effects.  The class action requires  that the company (Lilly) knew about the risks, but purposefully hid these risks from doctors and the public.  (This is why there are no class actions against chemotherapy makers.)   But if the company hid the info, then the doctor couldn't be responsible for the diabetes, because the risk was hidden.  So the class action actually protects the doctor, in a sense.

3.  Here's a puzzler: consider the following by-product of these advertisements.  By soliciting patients who have taken Zyprexa and gotten diabetes, they are, essentially, telling people about the risk.  So a patient who develops diabetes sometime in the future may not be able to claim he didn't know about the risk, as the risks have now entered the public discourse.

Stop worrying about lawyers.  Worry about loose practice.

As a final point on selegiline, it has long been thought that its efficacy in Parkinson's is due to the inhibition of the metabolism of dopamine.  Which is true, but there may be more to it than that.

A summary of this fascinating article: 

Apoptosis  is different from necrosis in a fundamental way: it is signaled, rather than directly caused.  In necrosis, the cell rapidly dies, the plasma membrane ruptures (with resultant irreversible ion shifts),  but DNA stays intact.  In apoptosis, the plasma membrane stays intact, but the cell shrinks, chromatin condenses and the DNA fragments.

Signaling is important: the genes p53, bad and bax induce apoptosis, while the Bcl family of genes promotes survival.  It is now thought that apoptosis mediates substantia nigra neuronal death.

So anything that delays or stops apoptosis could be neuroprotective.

Selegiline seems to be such a drug.  Since it inhibits the metabolism of dopamine, it will also prevent the formation of free radicals associated with this metabolism.  But, through a mechanism totally independent of MAO-B inhibition, it  protects dopamine neurons from MPTP and its metabolite MPP+.  (This is a double effect: MAO-B inhibition prevents the metabolism of MPTP to the toxic MPP+; and then selegiline's other unexplained mechanism protects neurons from MPP+.) Its metabolite desmethylselegiline is actually a more potent neuroprotector; and  P450 inhibitors which block the metabolism of selegiline to desmethylselegiline, also inhibit the overall neuroprotection.

The anti-apoptotic mechanism of selegiline (and the even more powerful irreversible MAO-B inhibitor rasagiline) is via glyceraldehyde-3-phosphate dehydrogenase (GAPDH).  GAPDH is usually in a dimer with a stem-loop of RNA in the cytoplasm.  In mitochondrial oxidation, NAD+ levels rise and then knock off the GAPDH, which then floats to the nucleus.  There, GAPDH inhibits the formation of of anti-apoptotic molecules, and thus causes apoptosis.  Propargylamines insert themselves into the RNA dimer and obstruct GAPDH from dislocating-- thus it cannot go to the nucleus and cause apoptosis.

Additionally, rasagiline upregulates Bcl-2 and Bcl-xl, among other anti-apoptotic molecules.

The study goes on to describe some clincial trials.  Indeed, the entire May 2006 supplement in Neurology is about neuroprotection in Parkinson's-- definitely worth the read.  We'll have more on this topic after some research. 

The title says it all:  Ictal eye closure is a reliable indicator for psychogenic nonepileptic seizures.

First, the bottom line: 

50/52 patients with pseudoseizures closed their eyes during their "seizure," while 152/156 of actual epileptics opened their eyes during their seizures.  That's a sensitivity of 96% and a specificity of 98%.  That's gold.

Now, the details: 

The authors took 234 consecutive "seizure" patients, hooked them up to video EEGs and stopped their medications.  There were 938 total ictal events in 221 patients.  52 (23%) had pseudoseizures, and 156 (70%) had eplieptic seizures.   There was a 3:1 female predominance in the pseudoseizures, no difference in epileptics.

In the epileptics, there was rhythmic eye blinking during tonic-clonic activity, and the eyes closed after theseizure was finished. 

An interesting corollary to this is when pseudoseizures occur in an actual epileptic: quoting the authors, "the simple question of eye opening or closure can help differentiate between the two types of events. One previous study found that patients with both types of events tended to have their eyes closed during PNES and open during ES.(6)"

Outstanding. 

Of course, this is isn't going to mean much to psychiatrists, apparently.

A questionnaire was put to neurologists (N=39) and psychiatrists (N=75) about the utility of video EEG in diagnosing pseudoseizures. 70% of the neurologists, but only 18% of the psychiatrists, thought that video-EEG was accurate "most of the time" in diagnosing pseudoseizures.  12% of the psychiatrists (no neurologists) said it is accurate "almost never."  (3% of the psychiatrists gave no clear response.  Why doesn't that surprise me?)

So here are some other differentiating symptoms:

In seizure patients, there is a crescendo-decrescendo quality to the spike-wave frequencies on EEG.  In pseudoseizure patients, however, the frequency is the same from beginning to end, and it comes on suddenly as if a switch was flicked.  The spike-wave on EEG is actually motion artifact, and typically runs around 4 Hz, while epileptics have frequencies that vary between 4-25 Hz.

In a study of 40 pseudoseizure vs. 40 matched normal controls,  the pseudoseizure group had more left handers, reduced strength and speed in both dominant and non-dominant hands, and reduction in the dominant hand advantage in strength and speed (i.e. both hands performed equally badly-- the dominant hand wasn't a little better.)  Interestingly and importantly, the authors did not think this was due to faking or psychological factors, but felt that it was due to actual neurologic impariment in bilateral pathways: 65% had had a closed head injury, 27% had had physical abuse, and 17% had had a history of substance abuse.  40% had an IQ less than 90!

A study in epileptics vs. pseudoseizure patients trying to determine how long after admission to a video EEG unit it takes for patients to have events (answer: 88% had it on day 1) also found that urinary incontinence, focal neurologic exams, and tongue biting were about the same in both groups.  But more epileptics had events less than one minute, and more pseudoseizures lasted > 5 minutes (and very few (13%) lasted less than one minute.)

Slightly different results were found in another study:  11/28 pseudoseizure patients had them  on day 1, but 9/28 needed an average of 5 days.  19/28 had an induced pseudoseizure to IV saline challenge within 3-7 minutes.  But still-- 3 days should be enough for most patients.

And alexithymia is of no value. It is found more often in epileptics and pseudoseizure patients equally, though still more than expected in the community. A larger, controlled trial had found a similar inability for alexithymia to differentiate: alexithymia was very common in epileptics (76%) and pseudoseizures (90%).  Thus, it is likely that alexithymia is a coping strategy, and not an independent trait.

Addendum 11/5/06: I did find an interesting (Greek) study finding an excess of seizures on full moons (34% vs. about 21% for the other phases.)   Importantly (and in contrast to suggestions by other studies) these were not pseudoseizures, because all patients were monitored.  The authors speculate either electromagnetic/gravitational effects (hey, it could happen) or an interaction between the intrinsic seizure threshold and the environment (i.e. you can change you rown threshold.)

Ironically, while selegiline can't be mixed with cheese or Prozac, it can be mixed with methamphetamine and cocaine.  A small placebo controlled study found that concomittant administration of methamphetamine (15 or 30mg) with selegiline (oral) caused no EKG, lab, or vital sign changes.  The clearance and half-life of methamphetamine was also unchanged.  Similarly, 10mg PO can be safely mixed with up to 40mg cocaine, should you be into that.  An earlier study found that 10mg/d could reduce the high of cocaine and reduced the activity of the amygdala (as defined as glucose utilization on PET scan) and not caus any negative interactions.

If that's not good enough for you, a study using the selegiline patch 20mg/d in 12 cocaine addicts found that heart rate and blood pressure were lower on selegiline at baseline, and were increased less after 40mg cocaine IV.  It  caused a slightly less subjective feeling of highness.  In case this is not amazing to you, let me point out that as an MAO-B inhibitor, selegiline should increase dopamine levels-- and you should feel more high.  But the opposite happened.  (Why?  Because selegiline already raises dopamine, so the effect of cocaine is less (because there's less dopamine left to increase) and so it feels less fun?)

It had no effect on cocaine pharmcokinetics or dynamics, and did not alter cocaine's effect on prolactin (suppression) or growth hormone (increase.)

A larger, 300 person double blind trial of patch versus placebo (done by the same authors) found no difference for the treatment of cocaine dependence-- but, importantly, there weren't any adverse effects of mixing the two, either.

While not recommended, it appears the patch is at least safe with your addict populations.

You've probably already read quite a bit about the selegiline (L-deprenyl) patch (right?), but these four (five) points may frame the information more usefully.

1a.  All the oral MAOIs you are used to (phenelzine, moclobemide, trancylpromine, etc) are either nonselective (both MAO-A and MAO-B inhibitors) or are selective MAO-A inhibitors. 

1b.  MAO-A inhibition is needed for antidepressant effect.

2.  MAO-A metabolizes serotonin, norepinephrine, dopamine, and tyramine.

3.  MAO-A in the gut is what metabolizes tyramine.  Inhibition of the gut MAO-A allows tyramine to enter the circulation unmetabolized-- thus releasing norepinephrine and causing hypertensive crises.

4.  Oral selegiline (pill) is an MAO-B inhibitor at doses less than 10mg/d.

In other words, a) selegiline requires no dietary restriction below 10mg/d (because it doesn't affect MAO-A in the gut) and b) it doesn't work below 10mg/d (for depression; MAO-B metabolizes dopmaine, so selegiline will still be good for Parkinson's at small doses.)

5.  Above 10mg/d, selegiline is nonselective (thus MAO-A and B inhibition).  Thus, a) it should work; b) it will require dietary restrictions.

One interesting point: selegiline is rapidly metabolized (first pass) to desmethylselegiline, l-amphetamine, and l-methamphetamine. (1)

The point of the patch is that it bypasses the first pass metabolism (you don't eat it) so you get much higher concentrations of drug into the CNS and few metabolites.  Also, much less goes to the intestinal MAOs, so you get both MAO-A and B inhibition in the brain, but less of the MAO-A in the intestine.  So even if you use doses greater than 10mg/d, you (probably) don't need dietary restrictions. (NB: even though I can't find any studies clearly linking the risk (most find it safe up to 20mg) the PI still says to avoid tyamine foods above 9mg/d.)



Part 2:  Efficacy

Above, I made the outrageous statement, "it doesn't work below 10mg/d."  What's really outrageous is that I couldn't find any evidence that it worked above 10mg/d, either.

Here's a typical example: a 2003 study of 289 patients, double blinded, placebo controlled, of selegiline patch 20mg/d (keep in mind, the starting dose is 6mg/d) vs. placebo patch.  Though the paper finds "statistical superiority" of the patch over placebo, it took 8 weeks to get a 2-3 point difference on the MADRS or HAMD-28.  (For context: the HAMD-28 has 28 questions with ratings from 0-4.  So three points difference could be three points on one question, or one point on three questions...)  It never beat placebo on the HAMD-17.  (To the author's credit, he does not hide this and is upfront that these were "modest" differences.)

Contrast that with the first clinical trial of the selegiline patch (done, astonishingly, by the same author): superior efficacy on all three scales.  But, of course, even at 20mg/d, it's really not that superior:

Maybe 2-4 points, max?  I grant more people responded to the patch (as defined by reduction of 50% on the HAM score)-- but it was 15% more people, and, well, come on on...

Just to make the point, a 67 person, multicenter, double blind, placebo controlled study tested oral selegiline's efficacy in schizophrenics, and found  improvement vs. placebo in "negative symptoms," as defined by the Scale for the Assessment of Negative Symptoms (SANS).   Troublingly, "improvement" means one point difference:

And not much happened for depression (HAM-D) either.

Someone, somewhere is going to accuse me of only showing weak studies and omitting all the studies that showed it worked well.  Okay.  Here is the last known study:

The only other patch study was a 321 person, 1 year long placebo controlled study, found that while twice as many people dropped out for side effects (13.2% vs. 6.7%), twice as many on placebo relapsed at 6 months (16.8% selegiline relapse vs. 29.4% placebo).  Interestingly, at one year the relapse rates for both drug and placebo were identical-- in other words, all relapses occurred in the first 6 months, none in the second 6 months.

That's it.