I am quoting Boann and starting a new thread on levodopa vs. agonists and
their role in obssessive-compulsive disorder or the newly named, dopa agonist blamed, ICD. Well, there is so much interesting stuff flying back and forth, I think it is getting lost in the original thread.

I think you ask the key question early on...

Why is levodopa always exonerated? It can't just be author bias; there are far too many studies isolating agonists so there must be a rigorous statistical measure being used (we can only hope).

I became curious as to how agonists fared in other treatments. It's used as a monotherapy in treating RLS and in 2007, The Mayo Clinic was the first to report correlation between compulsive behaviors and agonist treatment of RLS.

The newest study I could find further isolates:

Among the study patients with PD, new-onset compulsive gambling or hypersexuality was documented in 7 (18.4%) of 38 patients taking therapeutic doses of dopamine agonists but was not found among untreated patients, those taking subtherapeutic agonist doses, or those taking carbidopa/levodopa alone. Behaviors abated with discontinuation of agonist therapy or dose reduction.

from "Frequency of New-Onset Pathologic Compulsive Gambling or Hypersexuality After Drug Treatment of Idiopathic Parkinson Disease"
J. Michael Bostwick, MD, Kathleen A. Hecksel, MD, et al. MayoClinic Proceedings. April 2009.

I think the clincher is that stopping or reducing the agonist ended the behavior. I do wonder if the compulsive behavior problems are more prevalent in males (anecdotally, I hear more horror stories from them, but more men than women have PD) and what ages are prevalent when looking at many different studies? In the end, I think this goes along with the fact that some of us are more prone to addictive behaviors to begin with...drug addiction also center on dopamine transmission. If you think of how agonists work vs. straight levodopa, I'm not surprised that given the right environment an agonist can do more harm than good.

Laura

I agree Laura. I really don't know why we (on the other thread) are having the argument. We've all acknowledged that both carbo-levo-dopa and agonists elicit different side effects in different people. We each have our own stories about our own drug side effects. My experience doesn't negate another person's experience. What's true for one is not true for another.

That's a huge problem when it comes to treatment of PD. No one should be given a bottle of pills and told to come back in a year; yet that is often standard practice. Treating PD is an art that requires trial, error and patience.

Sinemet has its own set of problems that rarely are used as excuses to stop treatment. In fact, a whole area of research has grown around the question of how to treat Sinemet side effects.

It keeps coming back to the same conclusion for me - they, we, us - don't know exactly what we are dealing with. I hope I'm still around when they figure it out!

What other thread was there? I am at a loss for words, which is probably an improvement. So there has been, for a year, a warning that Levo-dopa causes the same destructive behavior as Mirapex does, but no one seems to have known about the warning, which comes 60 years after the drug was introduced? It required an Anuket to go and find out.
I don't know what is science and what is corporate game playing. Mirapex was under attack; what studies prompted Levo-dopa to quietly insert a new warning claiming that their product causes just as much damage as the one that has all the lawsuits for damages?
I used to think I understood the situation; now I can't make head nor tail of it.

Indigo,
you mention:
'a whole area of research has grown around the question of how to treat Sinemet side effects'

which reminded me of the last newsletter that came out of MJFF and the headline article was:

MJFF AWARDS $1 MILLION FOR CRITICAL STEP TOWARD NEW DYSKINESIA TREATMENTS.

I have to admit to doing a double take when I saw this, for exactly what you mention above, dyskinesia is not a symptom, it is a side-effect.

So the question that is going round my head is, just how much does this tell us about the state of play in the non-patient PD world......?

Combined with the new Merck/Schering Plow combo and their adoption of a matrix for diabetic tablet drugs and l-dopa that will extend delivery to nine hours........ there are no products as of yet, and we know what the timeline is from drug design to patient......

I have to admit being confused by what is going on in the wonderful world of levodopa, too.................

Laura, you raise some interesting issues on compulsive behaviours, I wonder if gambling and hypersexuality issues are less prevalent among women on agonists because of disposition, perhaps the compulsions that women are more prone to display are different, rather than occurring less - who for instance is documenting punding behaviours that people display in their homes, out of view, or perserverant behaviours that manifest in excessive anxiety which also come in on the compulsive spectrum, and have also been discussed over time on boards like this......and that can have equally devastating effects on day to day living.....

I agree, as yet none of us know what we are dealing with..... at the end of the day it is the patient who has to haul him/herself out of bed, and start another day living with PD...

Here's the link to the 4-page "discussion."
http://neurotalk.psychcentral.com/thread112146.html

Have fun!

Peg

Hi Laura

I wasn’t going to post anymore on this subject because it never seems to go well, but given your questions, I am going to post the briefest synopses I can of the most glaring problems of each gambling/ICD study I have ever read,

There will be at least six – I am going to post them as separate posts – they won’t be in chronological order.

The biggest lesson I have learned is that it is not enough to read just the abstract and the news coverage. One must read the actual study – and do it carefully – because abstracts and news coverage can be and are spun. The studies are, too, but it is harder to hide in the full study because more data must be provided.

the first three form the foundation upon which this idea that DAs cause these problems and they do so all by themselves rests.

[the above should read "stacy et al"]

Assertion
The authors cite a prevalence of pathological gambling (PG) of 0.3% to 1.3% in the general population and find a prevalence of 1.5% among those taking Mirapex. They conclude that there is an association between dopamine agonists and pathological gambling.

Problem
The fact that the authors put forward the two prevalences in the context of the assertion that there is an association between the drug and the behavior naturally implies that the difference between the two numbers is statistically significant such that it confirms their conclusion.

But the authors do not SAY it is statistically significant.

That could be because the difference between 0.4% to 1.3% and 1.5% is not statistically significant.

0.3% is the only portion of the range for the general population for which 1.5% represents a statistically significant difference. (calculations verified by a statistician)

I have looked around quite a bit and the absolute lowest prevalence I have found for PG in the general population is 0.4%, and that was in Canada. I would check the authors’ source, except they do not provide one.

This means not that the authors found an association, but that they failed to find one.

Also, in spite of the fact that all PGers were also taking levodopa, it is exonerated.

this study can be downloaded for free from The Archives of Neurology

Assertion
The authors put forward 11 cases in which people gambled pathologically while taking a DA as their evidence of a causal association.

Problem
The authors fail to convey “out of how many?” 11 out of 11 would be compelling, while 11 out of 10,000 would not.

It was impossible given the info presented for the authors to draw ANY conclusions about the presence *or absence* of an association. I can cite two subsequent papers that make the same observation about this study.

Also, in spite of the fact that eight out of 11 PGers were also taking levodopa, it is exonerated.

Assertion
The authors mined the FDA’s database of adverse drug events (AERS), which contains over 2.5 million voluntarily reported events dating back to 1968, for correlations between PG and drugs. They found an unusually high correlation between reports of PG and Mirapex.

Problem
The authors failed to reveal that, of the 39 reports linked to Mirapex, 38 came in after the publicizing of the 2003 study. If there were *really* an association, one would expect to see that reports had come in before the 2003 study was so heavily publicized – and then an uptick after the 2003 study – that there was only one between 1997, when it hit the market, and 2003 (there were three for levodopa in the same time period) increases the likelihood that the 38 that came in after the 2003 study were not really attributable to the drug.
***
Just to give you an idea what the AERS is like -- the way it works is that someone has an adverse experience… or two, or twenty (no joke). Whoever reports it (could be the doctor, patient, drug co., author of a study, etc.) to the AERS reports every adverse reaction the patient is experiencing, regardless of how many; reports all the medications the patient is on, and picks one as the primary suspect and another as the secondary suspect. So, scenarios like a report that lists diabetes mellitus and dyslexia, with mirapex as primary suspect, are not uncommon.

In other words, any report that attributes behavioral changes to mirapex could also attribute, say, dyslexia to it, or dermatitis, or diabetes – there is no evaluation of the existence of a relationship between any drug and the reported adverse events.

That is just an FYI – not really relevant to the problem cited above.

this study can be downloaded for free by clicking here.

Assertion
The authors claim to have found an 18.4% prevalence of new onset pathological gambling and pathological hypersexuality combined. (This one's little harder to put into a nutshell)

Problem

1. They include two people as hypersexual but designate them in the footnote “not clearly pathologic." These two also lacked any temporal information regarding the relationship between commencement/cessation of the drug and the behavior. On what basis are they included?
   
2. They include two people for whom the period between commencement of the drug and behavior onset is extremely long, i.e., one year, and 2 1/2 years. They provide no time frame for the cessation of behavior in relation to the cessation of the drug. If it was long as the period between beginning drug and onset of behavior, can it really be concluded that the drug was responsible? Without that info, on what basis are they included?
   
3. They exclude almost half of the participants from the total agonist population in their prevalence calculations with the rationale that less than 2mg of Mirapex per day is subtherapeutic – according to the Mirapex product label, the therapeutic benefit plateaus at 1.5mg/day, which would mean doses less than 2mg ARE therapeutic.

Upshot
if you include those who were excluded based on agonist dosage, and exclude the four people the basis of whose inclusion is unclear, the numbers change as follows:

Pathological gambling 4.5%
hypersexuality 1.5%
aggregated 6.0%

While the authors mention the DSM IV, they do not say they used its stringent criteria to identify PG. Rather, they say they used the DSM IV definition of “pathological.”

Utilizing the strict DSM IV criteria, Richard Kessler 2008 found a prevalence of PG of 0.6% in the general population – but he also found a *problem gambling” prevalence of 2.3% - “problem gambling” is defined as meeting one of the 10 possible DSM IV criteria for PG – Bostwick et al’s selection parameters were more along the lines of pathological AND problem gambling, for which Kessler finds the aggregated prevalence of 2.9%.

PG prevalence of 4.5% is a little bit on the high side, agreed, but it's a heck of a lot lower than 18.4%.

The hypersexuality prevalence is much lower than it is in the general population, where it is estimated to be 5-6%.

The aggregated total is lower than it would be for the general population.

Also, in spite of the fact that five out of seven PGers were also taking levodopa, is exonerated.

Finally, it should be noted that of the seven designated as agonist-related PGers in this study, three were also described in Dodd’s 2005 study summarized earlier.