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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 9 of 9. This is the beginning of the thread.
Posted by SLS on February 6, 2001, at 10:03:19
Monday February 5 5:46 PM ET
FDA Approves Pfizer Schizophrenia Drug
WASHINGTON (Reuters) - U.S. regulators on Monday approved Pfizer Inc.'s (NYSE:PFE - news) schizophrenia treatment Zeldox, setting the stage for a high-stakes marketing battle with two treatments that already boast blockbuster sales.A Food and Drug Administration spokeswoman said regulators cleared the drug, known generically as ziprasidone, for sale in the United States. Schizophrenia is a psychosis believed to affect about one percent of the world's population, in which people have delusions and hallucinations, often hearing voices.
The FDA had declined to approve Zeldox in 1998 over concern that some patients taking it in clinical trials had ``QT prolongation,'' a heartbeat irregularity linked to an increased risk of rare but potentially fatal heart-rhythm disturbances.
But a panel of outside experts concluded last July that the drug's effectiveness outweighed any risks.
The FDA has required that the Zeldox package insert label warn patients and doctors about QT prolongation and risk of sudden death.
But the agency did not require that a severe ``black-box'' warning be placed on the label, a safeguard the agency reserves for drugs deemed to have especially worrisome side effects.
Analysts said Zeldox had advantages that could make it a
strong competitor to two top-selling schizophrenia drugs, Eli Lilly and Co.'s (NYSE:LLY - news) Zyprexa and Johnson & Johnson's (NYSE:JNJ - news) Risperdal.
``The real long-term question is whether Zeldox demonstrates equal efficacy to Zyprexa. That really is a question mark in the minds of leading physicians,'' said Barbara Ryan, a Deutsche Banc Alex. Brown drug analyst.
Studies have shown that Zeldox relieved schizophrenia symptoms with little or no weight gain. Other anti-psychotic drugs can cause weight gain of up to 20 pounds a year, a side effect that leads some patients to stop taking the medications regularly.
``Patients on Zeldox don't have the weight gains'' or have higher risk of developing type II diabetes, side effects that are both seen with Zyprexa, said Banc of America Securities analyst Len Yaffe.
``But Zyprexa has the advantage of being dosed just once a day, versus twice a day for Zeldox, and is not associated with the potential to cause irregular heartbeat,'' Yaffe added.
Yaffe said Zyprexa had global sales of almost $2.4 billion in 2000 and that they are expected to rise to $2.9 billion this year. Risperdal had global sales of $1.6 billion in 2000, including $1.1 billion in the United States.
The FDA approval was announced late on Monday, shortly before the close of stock trading. On the New York Stock Exchange, Pfizer shares closed up 85 cents at $45.75, while Lilly fell $2 to $79.90 and Johnson & Johnson fell $1.17 to $93.93.
Posted by Craig on February 7, 2001, at 2:25:55
In reply to Ziprasidone (Zeldox) Approved !, posted by SLS on February 6, 2001, at 10:03:19
Pfizer's press release adds that it "expects to introduce ziprasidone in the US in 20 mg, 40 mg, 60 mg and 80 mg capsules in March." http://www.pfizer.com/pfizerinc/about/press/ziprasidone.html
***********************************
> Monday February 5 5:46 PM ET
> FDA Approves Pfizer Schizophrenia Drug
>
>
> WASHINGTON (Reuters) - U.S. regulators on Monday approved Pfizer Inc.'s (NYSE:PFE - news) schizophrenia treatment Zeldox, setting the stage for a high-stakes marketing battle with two treatments that already boast blockbuster sales.
Posted by JohnL on February 8, 2001, at 4:40:42
In reply to Ziprasidone (Zeldox) Approved !, posted by SLS on February 6, 2001, at 10:03:19
Hi Scott,
I was just curious. Since I respond well to antipsychotics in general, I am curious in learning more about Zeldox. Beyond the known benefits of fewer side effects, do you know how Zeldox differs from Zyprexa?For example, while Zyprexa works on both serotonin and dopamine receptors, it is actually weighted proportionately a little stronger toward the serotonin side. I wonder if Zeldox is weighted the same, or whether it is stronger on dopamine. And what about the antihistimine part of it? Same as Zyprexa? Different? Sedating or not? Any idea if Zeldox blocks presynaptic dopamine, postsynaptic, both, or differing depending on dose size?
I'm just curious at how Zeldox and Zyprexa differ in mechanism, on paper anyway.
Thanks in advance!
John
Posted by SLS on February 8, 2001, at 9:20:04
In reply to Re: Ziprasidone (Zeldox) Approved ! - SLS, posted by JohnL on February 8, 2001, at 4:40:42
Hi John.
The easiest way to descibe ziprasidone is to consider it to be olanzapine but without the weight gain. Like olanzapine, it more potently binds to and antagonizes (blocks) the serotonin 5-HT2a receptor than it does to the dopamine D2 receptor. It is this ratio of receptor blockade that seems to be responsible for the potential of these atypical neuroleptics to treat the negative symptoms of schizophrenia while reducing the emergence of EPS or TD. 5-HT2a blockade probably plays a prominent role in the ability of these drugs to potentiate antidepressants in cases of depression.
What I find most intriguing about ziprasidone is that it is the first atypical neuroleptic that binds potently to and agonizes (stimulates) the serotonin 5-HT1a receptor. It is very much like buspirone in this way, and I am hoping that this will potentiate the antidepressant properties that the atypicals seem to have. Ziprasidone is a “cleaner” drug than the others as it does not bind appreciably to histamine H1 or muscranic acetylcholine receptors. However, cleaner is not always better.
I may petition my doctor to give ziprasidone a try in the spring.
This all sounds very exciting, but it must still be evaluated in the arena of long-term clinical usage.
- Scott
Posted by Chris A. on February 9, 2001, at 0:19:19
In reply to Re: Ziprasidone (Zeldox) Approved ! - SLS, posted by SLS on February 8, 2001, at 9:20:04
Scott,
Thanks for the refresher course re: zpiprasidone's mode of action. My university consultant pDoc recommended eighteen months ago that I try it as soon as it became available. Needless to say, that has seemed like a very long time. Ironically, today was the day for my long awaited appt. with him. After driving ninety miles in blowing snow, I found I-70 to be closed through the Rockies, so had to return home. Olanzapine gives me a lead-dead feeling at tiny doses and actually increses my depression. Do you know if ziprasidone is different enough in it's chemical structure to not cause that side effect? I was concerned about NMS. Tardive dyskinesia is also a concern since I've developed it even with small doses of neuroleptics. Respiradone or olanzapine may have been the culprits. There were so many questions I wanted to ask Dr. Dubovsky, so since I couldn't see him I'm asking you:)!
Please get to feeling better soon. It's been so long since I've been able to log onto babble.Blessings,
Chris A.
Posted by Eric on February 9, 2001, at 14:41:47
In reply to Ziprasidone (Zeldox) Approved !, posted by SLS on February 6, 2001, at 10:03:19
The reason to get a little excited about Zeldox is not due to the fact it is another new anti-psychotic. The reason to get a little excited about this new medication is due to the fact it is the ONLY neuroleptic on the market in the USA which has automatic built in antidepressant properties.
Zeldox is reported to have built in, moderate serotonin and norephinephrine reuptake properties in addition to its anti-psychotic properties. What this means is that this drug could possibly be used all by itself to treat some cases of depression. None of the other anti-psychotics have serotonin or norephinephrine reuptake capability built into them. Thus, none of the other anti-psychotics used in the USA have any significant anti-depressant properties.
Because Zeldox has this unique, automatic built in serotonin/norephinephrine reuptake capability, it might possibly be useful used all by itself in some cases of refractory depression and psychotic depression. Usually the thing that is done is to "augment" an SSRI or Effexor with an atypical anti-psychotic, usually Zyprexa or Seroquel. With Zeldox this augmentation may not be necessary because the drug comes with both qualities...anti-psychotic and antidepressant...automatically built into it.
Posted by SLS on February 9, 2001, at 17:02:06
In reply to re: , posted by Eric on February 9, 2001, at 14:41:47
Hi Eric.
> The reason to get a little excited about Zeldox is not due to the fact it is another new anti-psychotic. The reason to get a little excited about this new medication is due to the fact it is the ONLY neuroleptic on the market in the USA which has automatic built in antidepressant properties.
>
> Zeldox is reported to have built in, moderate serotonin and norephinephrine reuptake properties in addition to its anti-psychotic properties. What this means is that this drug could possibly be used all by itself to treat some cases of depression. None of the other anti-psychotics have serotonin or norephinephrine reuptake capability built into them. Thus, none of the other anti-psychotics used in the USA have any significant anti-depressant properties.I am excited for the same reasons as are you. However, I never considered the possibility that ziprasidone would be consistently and robustly effective as an antidepressant. I guess we'll see.
Where did you get your information regarding the effects of ziprasidone on the reuptake of the monoamines? Is it a reuptake inhibitor? Is the effect at the transporter relavent at clinical dosages?
Perhaps just as important is that ziprasidone does produce increases in extracellular levels of dopamine. I found one study that indicated that ziprasidone did not influence the reuptake of norepinephrine. However, zotepine did. Regarding serotonin, ziprasidone stimulates 5-HT1a somato-dendritic autoreceptors which *inhibit* the firing of serotonergic neurons. It is my opinion at this point that some depressions are actually the result of *too much* serotonergic activity. By inhibiting serotonergic neuron firings by both 5-HT2a antagonism and 5-HT1a agonism, ziprasidone may produce a synergy to inhibit those serotonergic neurons that would otherwise inhibit dopaminergic pathways in meso-cortical and pre-frontal cortical areas of the brain; those which seem to be involved with mood. The result might be an increase in mood elevating dopaminergic activity. (Or perhaps better put, a return to normal mood). This is presumed to occur as the result of an increase in the *release* of dopamine. Increases in extracellular norepinephrine might occur the same way. Neither of these properties are exclusive to ziprasidone. It is zotepine that seems to be unique in its ability to bind to norepinephrine transporter. Ziprazidone will probably show itself to be superior to the other neuroleptics for treating the negative symptoms of schizophrenia.
Olanzapine (Zyprexa) by itself has produced potent antidepressant responses in some people. However, I don't know as to how long this improvement tends to last.
- Scott--------------------------------------------
Neuropharmacology 1998 Jul;37(7):937-44 Related Articles, Books
Elevation of extracellular cortical noradrenaline may contribute to the antidepressant activity of zotepine: an in vivo microdialysis study in freely moving rats.Rowley HL, Kilpatrick IC, Needham PL, Heal DJ
CNS Biology, Knoll Pharmaceuticals Research and Development, Nottingham, UK. Helen.Rowley@knoll.co.uk
The antipsychotic, zotepine, as well as possessing affinity for dopamine D1- and D2-1ike receptors, has high affinity for the noradrenaline (NA) transporter and inhibits [3H]NA uptake by rat frontal cortex synaptosomes, in vitro. The present studies investigated the effects of zotepine on extracellular NA in the frontal cortex of freely moving rats using in vivo microdialysis. Removal of calcium from the perfusate reduced extracellular NA by 70.5% and prevented the 50 mM KCl-stimulated increase in NA levels. Zotepine (0.5-1.5 mg kg(-1) i.p.), evoked biphasic, dose-dependent rises in extracellular NA with maximal increases observed at 60 min (+ 171.0%) and 240 min (+ 211.5%) post-treatment. The increases in NA levels were sustained for up to 100 min post-dosing. Clozapine (10.0 mg kg(-1) i.p.), resulted in a smaller, transient increase in NA levels (+ 72.0%) which lasted for 20 min post-treatment. Neither ziprasidone (3.0 mg kg(-1) i.p.) nor olanzapine (1.0 mg kg(-1) i.p.) influenced extracellular NA. Systemic treatment with the antidepressant desipramine (0.3 mg kg(-1) i.p.) resulted in a prolonged elevation of NA levels over 240 min (maximal increase of + 354.3%), whilst local infusion of nisoxetine (1-100 microM) through the dialysis probe increased NA levels in a concentration-dependent manner (up to 587.8% of control values). These data suggest that the inhibition of NA uptake by zotepine and its subsequent prolonged elevation of extracellular cortical NA may underlie the reported antidepressant properties of zotepine in schizophrenic patients.
PMID: 9776389
Posted by Eric on February 9, 2001, at 23:05:11
In reply to Re: Ziprasidone (Zeldox) an antidepressant ?, posted by SLS on February 9, 2001, at 17:02:06
I read it a long time ago when I first read about Zeldox. Zeldox has what could be described as moderate serotonin and norephinephrine REUPTAKE properties automatically built into it. This is in addition to its primary function as an anti-psychotic. Do a search on it and you will pull up some stuff and can see it for yourself.
Zeldox=atypical anti-psychotic PLUS has moderate serotonin/norephinephrine reuptake AKA "antidepressant properties"
Posted by JohnX on February 11, 2001, at 5:17:01
In reply to Re: Ziprasidone (Zeldox) an antidepressant ?, posted by SLS on February 9, 2001, at 17:02:06
> Hi Eric.
>
>
> > The reason to get a little excited about Zeldox is not due to the fact it is another new anti-psychotic. The reason to get a little excited about this new medication is due to the fact it is the ONLY neuroleptic on the market in the USA which has automatic built in antidepressant properties.
> >
> > Zeldox is reported to have built in, moderate serotonin and norephinephrine reuptake properties in addition to its anti-psychotic properties. What this means is that this drug could possibly be used all by itself to treat some cases of depression. None of the other anti-psychotics have serotonin or norephinephrine reuptake capability built into them. Thus, none of the other anti-psychotics used in the USA have any significant anti-depressant properties.
>
>
>
> I am excited for the same reasons as are you. However, I never considered the possibility that ziprasidone would be consistently and robustly effective as an antidepressant. I guess we'll see.
>
> Where did you get your information regarding the effects of ziprasidone on the reuptake of the monoamines? Is it a reuptake inhibitor? Is the effect at the transporter relavent at clinical dosages?
>
> Perhaps just as important is that ziprasidone does produce increases in extracellular levels of dopamine. I found one study that indicated that ziprasidone did not influence the reuptake of norepinephrine. However, zotepine did. Regarding serotonin, ziprasidone stimulates 5-HT1a somato-dendritic autoreceptors which *inhibit* the firing of serotonergic neurons. It is my opinion at this point that some depressions are actually the result of *too much* serotonergic activity. By inhibiting serotonergic neuron firings by both 5-HT2a antagonism and 5-HT1a agonism, ziprasidone may produce a synergy to inhibit those serotonergic neurons that would otherwise inhibit dopaminergic pathways in meso-cortical and pre-frontal cortical areas of the brain; those which seem to be involved with mood. The result might be an increase in mood elevating dopaminergic activity. (Or perhaps better put, a return to normal mood). This is presumed to occur as the result of an increase in the *release* of dopamine. Increases in extracellular norepinephrine might occur the same way. Neither of these properties are exclusive to ziprasidone. It is zotepine that seems to be unique in its ability to bind to norepinephrine transporter. Ziprazidone will probably show itself to be superior to the other neuroleptics for treating the negative symptoms of schizophrenia.
>
> Olanzapine (Zyprexa) by itself has produced potent antidepressant responses in some people. However, I don't know as to how long this improvement tends to last.
>
>
> - Scott
>
> --------------------------------------------
>
>
> Neuropharmacology 1998 Jul;37(7):937-44 Related Articles, Books
>
>
> Elevation of extracellular cortical noradrenaline may contribute to the antidepressant activity of zotepine: an in vivo microdialysis study in freely moving rats.
>
> Rowley HL, Kilpatrick IC, Needham PL, Heal DJ
>
> CNS Biology, Knoll Pharmaceuticals Research and Development, Nottingham, UK. Helen.Rowley@knoll.co.uk
>
> The antipsychotic, zotepine, as well as possessing affinity for dopamine D1- and D2-1ike receptors, has high affinity for the noradrenaline (NA) transporter and inhibits [3H]NA uptake by rat frontal cortex synaptosomes, in vitro. The present studies investigated the effects of zotepine on extracellular NA in the frontal cortex of freely moving rats using in vivo microdialysis. Removal of calcium from the perfusate reduced extracellular NA by 70.5% and prevented the 50 mM KCl-stimulated increase in NA levels. Zotepine (0.5-1.5 mg kg(-1) i.p.), evoked biphasic, dose-dependent rises in extracellular NA with maximal increases observed at 60 min (+ 171.0%) and 240 min (+ 211.5%) post-treatment. The increases in NA levels were sustained for up to 100 min post-dosing. Clozapine (10.0 mg kg(-1) i.p.), resulted in a smaller, transient increase in NA levels (+ 72.0%) which lasted for 20 min post-treatment. Neither ziprasidone (3.0 mg kg(-1) i.p.) nor olanzapine (1.0 mg kg(-1) i.p.) influenced extracellular NA. Systemic treatment with the antidepressant desipramine (0.3 mg kg(-1) i.p.) resulted in a prolonged elevation of NA levels over 240 min (maximal increase of + 354.3%), whilst local infusion of nisoxetine (1-100 microM) through the dialysis probe increased NA levels in a concentration-dependent manner (up to 587.8% of control values). These data suggest that the inhibition of NA uptake by zotepine and its subsequent prolonged elevation of extracellular cortical NA may underlie the reported antidepressant properties of zotepine in schizophrenic patients.
>
> PMID: 9776389I just heard of this anti-psychotic recently and
believe that it may be my best bet, I'm wondering
what you all think. I haven't done much research
here. I haven't tried the other anti-psychotics like zyprexa
etc. I believe that their weight gain property is attributable
to alpha-1 antagonism and possible histamine binding.It seems the chemical structure used to achieve
the 5ht-2 antagonism results in the same side
effects for most of the latest anti-psychotics
as well as serzone. I tried serzone for 2 months
and it made me so drowsy that I crashed my car,
so I'm very much afraid to try Zyprexa and friends.
I have pretty bad anhedonia, and chronic tension
headache and bruxism. From my research I know
almost with certainty that both
a reduction in raphe serotonergic firing and
5ht-2 antagonism will likely relieve all of my
major problems. If this drug doesn't cause weight
gain, can I assume it's not antagonizing alpha-1
receptors ? I.e. will it not make me dizzy and
drowsy and crash my car (or cause the 20 pounds
of weight gain like serzone) ?Thanks for any feedback,
-john
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