Dear Ariela:

Your questions get more difficult.

> #1.
> it's been my experience that in spite of the studies -- DATATOP and the
> subsequent, controversial british PDRG-UK (which concluded that selegiline
> was responsible for a 57% increase in a patient's mortality odds over
> those who received levodopa only) -- the medical establishment opts for
> selegiline as soon as pd is suspected.

I am not sure that it is true that the medical establishment opts for
selegiline as soon as PD is suspected.  Most of the neurologists I know
hardly ever use it.

> my PWP was prescribed the drug first by a (very) general neurologist,
> and then by a succession of better and finer-tuned movement disorder
> specialists.  i hope i'm not being indiscreet when I say dr. fahn of
> columbia-presbyterian recommends selegiline together with a dopamine
> agonist as the initial line of defense, then maintains this basic regimen
> for as long as one's symptoms are manageable.

I recognize that Dr. Fahn is a very highly respected movement disorder
specialist.  However, I disagree with that approach.  I do not know what his
rationale for using selegiline like that may be.

> which makes me wonder -- if selegiline does not extend the effect of
> dopamine agonists, does not delay the need for starting levodopa (or
> its effect once it's started), and does not slow neuron degeneration,
> does it really matter if it "only" relieves the symptoms of pd?  for
> an incurable, difficult disease, I'd say this ain't too shabby..

The question of whether selegiline has any intrinsic antiparkinsonian
activity, separate from its putative (and disproven) neuroprotective effect,
its antidepressant effect, or its ability to extend the duration of levodopa
by slowing down the metabolism of dopamine, has been debated heavily.
Although I am unaware of any studies to show that it has significant
antiparkinsonian effect, theoretically it might by slowing down the
metabolism of endogenous dopamine (whatever little of it is left, since it
has been estimated that by the time PWP develop symptoms more than 75% of
their dopaminergic neurons are already gone).

> #3.
> when faced with a "just in case" scenario, I think I become a lemming
> - just count me in!  it seems to me that the controversy over how long
> can levodopa be administered without causing or accelerating dyskinesia
> is inherently unsolvable.  as with cancer studies, it would be impossible
> to design a model where the natural progression of the disease could
> be factored in as a constant, finite variable.  now if the received
perception
> is that of a limited treatment-period (I understand 5 to 10 years before
> levodopa's effectiveness begins to fail and side effects become
intolerable),
> then why not err on the side of caution, especially if a patient is doing
> all right?

As I read your comments, I fear that you echo the propaganda that the drug
companies have used to promote the agonists.  The studies that purport to
show that early treatment with agonists is less likely to result in late
dyskinesias are biased studies.  The design of those studies (ropinirole,
pramipexole, and cabergoline) compared early levodopa against early agonist
treatment.  The second step of the study allowed supplementation with
levodopa for both arms of the study.  Certainly, if you supplement levodopa
with more levodopa, then you will get side effects.  These studies should
have had an arm in which levodopa was later supplemented with agonist.  In
my opinion, the failure to include that arm makes the studies incomplete,
inconclusive, and biased.

In my opinion, when levodopa is judiciously used, the levodopa dyskinesias
can be avoided by keeping the dose of levodopa lower than in those studies,
and supplementing with agonist.  This was the way the agonists were
initially used.  The duration of treatment with levodopa alone often exceeds
five years, and is  longer than the period in which agonist is sufficient
alone.  Eventually, almost all PWP end up using two drugs - an agonist and
levodopa.

> #4.
> oops, my mistake.  Of course there are many ANTI depressants that are
> reuptake inhibitors (not the least of which is the SSRI group...).
however,
> i'm afraid that error made my query rather unclear.  i should have asked
> two separate questions: a) do all dopamine agonists have depressant-
> or barbituate-like properties? and b) if so, would they not, when combined
> with selegeline (an MAO-B inhibitor), cause a "shock" reaction similar
> to that of prozac (SSRI) when given with selegiline?

I do not know that the agonists have depressant activity.  They do cause
some sedation.  I have not encountered any difficulties using
antidepressants in PWP.

> #5.
> and last but not least, speaking of selegiline being such an 'iffy' drug
> (even as a simple anti-oxidant), how do you explain the great popularity
> and following it has among anti-aging enthusiasts?

In my opinion, such popularity is unfounded, and based on wishful thinking.
The hope that antioxidants may retard the aging process is widespread, but
there is not an iota of data to show that it is true.  Snake oil was also at
one time very popular.

Some of the above answers are based on my opinions.  I fully recognize that
other opinions may differ.


Jorge A. Romero, MD

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