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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 10 of 10. This is the beginning of the thread.
Posted by JohnL on October 25, 2000, at 17:22:21
Hi all. I was doing a little research at www.mentalhealth.com and stumbled onto this interesting study. Just thought I would pass it on. It seemed interesting and intriguing. It's amazing how different each medicine is. Anyway, it seems Prozac + Zyprexa have some unique synergy that isn't duplicated with Zoloft or other antipsychotics. Something unique about this combo. For whoever's interested.
John1: Neuropsychopharmacology 2000 Sep;23(3):250-62
Related Articles, Books,
LinkOut
Synergistic effects of olanzapine and other
antipsychotic agents in combination with fluoxetine on
norepinephrine and dopamine release in rat prefrontal
cortex.Zhang W, Perry KW, Wong DT, Potts BD, Bao J, Tollefson GD,
Bymaster FPNeuroscience Research Division, Lilly Research Laboratories, Lilly
Corporate Center, Indianapolis, IN 46285-0510, USA.To understand the mechanism of the clinical efficacy of olanzapine and
fluoxetine combination therapy for treatment-resistant depression (TRD),
we studied the effects of olanzapine and other antipsychotics in
combination with the selective serotonin uptake inhibitors fluoxetine or
sertraline on neurotransmitter release in rat prefrontal cortex (PFC) using
microdialysis. The combination of olanzapine and fluoxetine produced
robust, sustained increases of extracellular levels of dopamine ([DA](ex))
and norepinephrine ([NE](ex)) up to 361 +/- 28% and 272 +/- 16% of the
baseline, respectively, which were significantly greater than either drug
alone. This combination produced a slightly smaller increase of serotonin
([5-HT](ex)) than fluoxetine alone. The combination of clozapine or
risperidone with fluoxetine produced less robust and persistent increases
of [DA](ex) and [NE](ex). The combination of haloperidol or MDL
100907 with fluoxetine did not increase the monoamines more than
fluoxetine alone. Olanzapine plus sertraline combination increased only
[DA](ex). Therefore, the large, sustained increase of [DA](ex),
[NE](ex), and [5-HT](ex) in PFC after olanzapine-fluoxetine treatment
was unique and may contribute to the profound antidepressive effect of
the olanzapine and fluoxetine therapy in TR
Posted by SLS on October 25, 2000, at 21:38:56
In reply to Prozac+Zyprexa Special for Treatment Resistence, posted by JohnL on October 25, 2000, at 17:22:21
John,
There have been clinical trials of Prozac + Zyprexa for about a year now. I don't know if there is anything particularly special about Prozac specifically when combined with Zyprexa, except that both drugs are sold by Eli Lilly. Lilly has sponsored these studies. I doubt the synergy of Prozac with Zyprexa is unique among SSRIs.
- Scott
> Hi all. I was doing a little research at www.mentalhealth.com and stumbled onto this interesting study. Just thought I would pass it on. It seemed interesting and intriguing. It's amazing how different each medicine is. Anyway, it seems Prozac + Zyprexa have some unique synergy that isn't duplicated with Zoloft or other antipsychotics. Something unique about this combo. For whoever's interested.
> John
>
>
>
> 1: Neuropsychopharmacology 2000 Sep;23(3):250-62
> Related Articles, Books,
> LinkOut
>
>
> Synergistic effects of olanzapine and other
> antipsychotic agents in combination with fluoxetine on
> norepinephrine and dopamine release in rat prefrontal
> cortex.
>
> Zhang W, Perry KW, Wong DT, Potts BD, Bao J, Tollefson GD,
> Bymaster FP
>
> Neuroscience Research Division, Lilly Research Laboratories, Lilly
> Corporate Center, Indianapolis, IN 46285-0510, USA.
>
> To understand the mechanism of the clinical efficacy of olanzapine and
> fluoxetine combination therapy for treatment-resistant depression (TRD),
> we studied the effects of olanzapine and other antipsychotics in
> combination with the selective serotonin uptake inhibitors fluoxetine or
> sertraline on neurotransmitter release in rat prefrontal cortex (PFC) using
> microdialysis. The combination of olanzapine and fluoxetine produced
> robust, sustained increases of extracellular levels of dopamine ([DA](ex))
> and norepinephrine ([NE](ex)) up to 361 +/- 28% and 272 +/- 16% of the
> baseline, respectively, which were significantly greater than either drug
> alone. This combination produced a slightly smaller increase of serotonin
> ([5-HT](ex)) than fluoxetine alone. The combination of clozapine or
> risperidone with fluoxetine produced less robust and persistent increases
> of [DA](ex) and [NE](ex). The combination of haloperidol or MDL
> 100907 with fluoxetine did not increase the monoamines more than
> fluoxetine alone. Olanzapine plus sertraline combination increased only
> [DA](ex). Therefore, the large, sustained increase of [DA](ex),
> [NE](ex), and [5-HT](ex) in PFC after olanzapine-fluoxetine treatment
> was unique and may contribute to the profound antidepressive effect of
> the olanzapine and fluoxetine therapy in TR
Posted by JohnL on October 26, 2000, at 6:29:25
In reply to Re: Prozac+Zyprexa Special for Treatment Resistence, posted by SLS on October 25, 2000, at 21:38:56
> John,
>
>I don't know if there is anything particularly special about Prozac specifically when combined with Zyprexa, except that both drugs are sold by Eli Lilly. Lilly has sponsored these studies.Scott,
That's what I found interesting. You would think they would have appeared less biased if they had some other laboratory test their drugs in blind fashion.
John
Posted by AndrewB on October 28, 2000, at 2:54:09
In reply to Re: Prozac+Zyprexa Special for Treatment Resistence, posted by JohnL on October 26, 2000, at 6:29:25
Thank for the info., I found this abstract provocative. I would be curious to see the whole article. What was the suspected underlying mechanism for this underlying synergy? All the antipsychotics they listed effect certain serotonin receptors as well as dopamine receptors. Also, were the antipsychotics used at low dosages at which they would be presumably acting on dopamine autoreceptors. I wonder if this article sheds any light on whether SSRIs can be effectively combined with sulpiride or amisulpride, dopamine specific antipsychotics.
AndrewB
Posted by anita on October 29, 2000, at 19:03:06
In reply to Re: Prozac+Zyprexa Special for Treatment Resistence, posted by AndrewB on October 28, 2000, at 2:54:09
Hi Andrew,
Zyprexa and Risperdal are supposed to further boost serotonin levels in ppl who are already taking SSRIs by antagonizing the 5HT2A receptor, which adds to the SSRI effect on 5HT1A receptors, and it also increases dopamine in an area of the prefrontal cortex. Then again, some say the antipsychotics work simply because they increase the blood level of the SSRI or make it work more effectively. This might be the case for the special synergy with prozac, as prozac is a relatively messy drug and can increase norepinephrine and dopamine as well as serotonin. This could also be why Zoloft only increased dopamine levels, since zoloft only affects serotonin and dopamine.
I don't know if low doses of Zyprexa and Risperdal increase dopamine other than thru their 5HT2A antagonism.
anita
> Thank for the info., I found this abstract provocative. I would be curious to see the whole article. What was the suspected underlying mechanism for this underlying synergy? All the antipsychotics they listed effect certain serotonin receptors as well as dopamine receptors. Also, were the antipsychotics used at low dosages at which they would be presumably acting on dopamine autoreceptors. I wonder if this article sheds any light on whether SSRIs can be effectively combined with sulpiride or amisulpride, dopamine specific antipsychotics.
>
> AndrewB
Posted by SLS on October 29, 2000, at 21:25:03
In reply to Re: Prozac+Zyprexa Special for Treatment Resistence » AndrewB, posted by anita on October 29, 2000, at 19:03:06
> Hi Andrew,
Zyprexa and Risperdal are supposed to further boost serotonin levels in ppl who are already taking SSRIs by antagonizing the 5HT2A receptor, which adds to the SSRI effect on 5HT1A receptors, and it also increases dopamine in an area of the prefrontal cortex. Then again, some say the antipsychotics work simply because they increase the blood level of the SSRI or make it work more effectively. This might be the case for the special synergy with prozac, as prozac is a relatively messy drug and can increase norepinephrine and dopamine as well as serotonin. This could also be why Zoloft only increased dopamine levels, since zoloft only affects serotonin and dopamine.> I don't know if low doses of Zyprexa and Risperdal increase dopamine other than thru their 5HT2A antagonism.
> anita
I am confused. I thought 5-HTa and 5-HTc receptors were excitatory upon serotonergic neurons and that 5-HT1a was inhibitory.Maybe this system is more complicated than I understand.
It would seem to me that blockade of 5-HT2 receptors would inhibit rather than increase serotonin activity. A decrease in the serotoninergic inhibitory input upon DA pathays in the prefrontal cortex would result in a "freeing-up" of DA neurons and thus an increase in DA activity there. As for postsynaptic 5-HT1a receptors, stimulation of these autoreceptors would have the same net effect as blockade of 5-HT2a/c receptors to reduce 5-HT activity.
I should think that it is the antagonism of 5-HT2 receptors that helps keep in check the potential overactivity of 5-HT neurons to help prevent some of the SSRI side effects that might involve DA activity, e.g. apathy and loss of libido. I thought this was how Serzone worked to treat sexual side effects of SSRIs.
The drug that most excites me at the moment is ziprasidone (Zeldox). Not only is this atypical antipsychotic a potent 5-HT2a antagonist, but, unlike the others currently available, it is also a potent agonist at the 5-HT1a. In addition, the ratio of 5-HT2 to DA blockade is very high, possibly reducing the risk of EPS to levels less than risperidone and comparable to olanzapine. I don't know, but maybe the lower the affinity for DA receptors, the more likely the possibility that DA autoreceptor blockade would yield pro-dopaminergic effects.
Ziprasidone might be sort of like a hybrid of sulpiride, nefazodone (better, ketanserin), and pindolol.
Does anyone know when ziprasidone / Zeldox is due to reach the pharmacist's shelves?
Oh yeah. Anita might be right about a synergy specific with Prozac, possibly involving its noradrenergic activity. It may be that a possibly important property of the atypicals is being overlooked. They are relatively effective antagonists of NE alpha-1 receptors.
Anita, please un-confuse me for what I am probably misunderstanding about serotonin.
- Scott
Posted by chdurie2 on October 29, 2000, at 23:51:10
In reply to Re: Prozac+Zyprexa Special for Treatment Resistence, posted by SLS on October 29, 2000, at 21:25:03
> > Hi Andrew,
> Zyprexa and Risperdal are supposed to further boost serotonin levels in ppl who are already taking SSRIs by antagonizing the 5HT2A receptor, which adds to the SSRI effect on 5HT1A receptors, and it also increases dopamine in an area of the prefrontal cortex. Then again, some say the antipsychotics work simply because they increase the blood level of the SSRI or make it work more effectively. This might be the case for the special synergy with prozac, as prozac is a relatively messy drug and can increase norepinephrine and dopamine as well as serotonin. This could also be why Zoloft only increased dopamine levels, since zoloft only affects serotonin and dopamine.
>
> > I don't know if low doses of Zyprexa and Risperdal increase dopamine other than thru their 5HT2A antagonism.
>
> > anita
>
>
> I am confused. I thought 5-HTa and 5-HTc receptors were excitatory upon serotonergic neurons and that 5-HT1a was inhibitory.
>
> Maybe this system is more complicated than I understand.
>
> It would seem to me that blockade of 5-HT2 receptors would inhibit rather than increase serotonin activity. A decrease in the serotoninergic inhibitory input upon DA pathays in the prefrontal cortex would result in a "freeing-up" of DA neurons and thus an increase in DA activity there. As for postsynaptic 5-HT1a receptors, stimulation of these autoreceptors would have the same net effect as blockade of 5-HT2a/c receptors to reduce 5-HT activity.
>
> I should think that it is the antagonism of 5-HT2 receptors that helps keep in check the potential overactivity of 5-HT neurons to help prevent some of the SSRI side effects that might involve DA activity, e.g. apathy and loss of libido. I thought this was how Serzone worked to treat sexual side effects of SSRIs.
>
> The drug that most excites me at the moment is ziprasidone (Zeldox). Not only is this atypical antipsychotic a potent 5-HT2a antagonist, but, unlike the others currently available, it is also a potent agonist at the 5-HT1a. In addition, the ratio of 5-HT2 to DA blockade is very high, possibly reducing the risk of EPS to levels less than risperidone and comparable to olanzapine. I don't know, but maybe the lower the affinity for DA receptors, the more likely the possibility that DA autoreceptor blockade would yield pro-dopaminergic effects.
>
> Ziprasidone might be sort of like a hybrid of sulpiride, nefazodone (better, ketanserin), and pindolol.
>
> Does anyone know when ziprasidone / Zeldox is due to reach the pharmacist's shelves?
>
> Oh yeah. Anita might be right about a synergy specific with Prozac, possibly involving its noradrenergic activity. It may be that a possibly important property of the atypicals is being overlooked. They are relatively effective antagonists of NE alpha-1 receptors.
>
> Anita, please un-confuse me for what I am probably misunderstanding about serotonin.
>
>
> - Scott
Posted by ChrisK on October 30, 2000, at 6:29:35
In reply to Re: Prozac+Zyprexa Special for Treatment Resistence, posted by SLS on October 29, 2000, at 21:25:03
> Does anyone know when ziprasidone / Zeldox is due to reach the pharmacist's shelves?
>Zeldox has been approved by the FDA and my pdoc hopes that it will be on the shelf around the first of the year.
Posted by Sunnely on October 30, 2000, at 21:25:49
In reply to Re: Prozac+Zyprexa Special for Treatment Resistence » SLS, posted by ChrisK on October 30, 2000, at 6:29:35
> > Does anyone know when ziprasidone / Zeldox is due to reach the pharmacist's shelves?
> >
>
> Zeldox has been approved by the FDA and my pdoc hopes that it will be on the shelf around the first of the year.
Hi Chris,Please pardon me, if my info is up-to-date, I don't believe Zeldox has been approved by the FDA, yet. Pfizer (maker of Zeldox) received an "approvable" letter from the FDA a few months ago. Pfizer is still trying to "iron out" some kinks with the FDA regarding Zeldox's effect on the electrocardiogram (ECG). The FDA will most likely require Pfizer to include some form of information alerting physicians about the risk of cardiac rhythm disturbances associated with the drug's use. The exact nature of the wording has not yet been worked out. It is not known, for example, whether electrocardiograms (ECG) or other forms of monitoring for heart rhythm disturbances will be recommended or required.
Posted by anita on October 30, 2000, at 22:24:14
In reply to Re: Prozac+Zyprexa Special for Treatment Resistence, posted by SLS on October 29, 2000, at 21:25:03
Hi Scott,
Sorry, didn't mean to be confusing. Sometimes I think in shorthand.
I meant that in combination with an SSRI, 5HT2A antagonism would stimulate the 5HT1A receptors already stimulated by the SSRI. The increase in 5HT by SSRIs causes, over time, the desensitization of 5HT1A autoreceptors. Once this occurs, 5HT can no longer effectively inhibit its own release. Stimulation of 5HT2A receptors by 5HT reduces the actions of 5HT at 5HT1A receptors. Separately, antagonizing 5HT2A receptors (i.e., decreasing serotonin) in the mesocortical prefrontal cortex increases dopamine activity there.
I too am very interested in Ziprasidone. I called the company and they said that if the FDA formally approves it without any hitches, it will probably be available in spring.
BTW, did you get my email? I started risperidone a few days ago, going well so far.
anita
> > Hi Andrew,
> Zyprexa and Risperdal are supposed to further boost serotonin levels in ppl who are already taking SSRIs by antagonizing the 5HT2A receptor, which adds to the SSRI effect on 5HT1A receptors, and it also increases dopamine in an area of the prefrontal cortex. Then again, some say the antipsychotics work simply because they increase the blood level of the SSRI or make it work more effectively. This might be the case for the special synergy with prozac, as prozac is a relatively messy drug and can increase norepinephrine and dopamine as well as serotonin. This could also be why Zoloft only increased dopamine levels, since zoloft only affects serotonin and dopamine.
>
> > I don't know if low doses of Zyprexa and Risperdal increase dopamine other than thru their 5HT2A antagonism.
>
> > anita
>
>
> I am confused. I thought 5-HTa and 5-HTc receptors were excitatory upon serotonergic neurons and that 5-HT1a was inhibitory.
>
> Maybe this system is more complicated than I understand.
>
> It would seem to me that blockade of 5-HT2 receptors would inhibit rather than increase serotonin activity. A decrease in the serotoninergic inhibitory input upon DA pathays in the prefrontal cortex would result in a "freeing-up" of DA neurons and thus an increase in DA activity there. As for postsynaptic 5-HT1a receptors, stimulation of these autoreceptors would have the same net effect as blockade of 5-HT2a/c receptors to reduce 5-HT activity.
>
> I should think that it is the antagonism of 5-HT2 receptors that helps keep in check the potential overactivity of 5-HT neurons to help prevent some of the SSRI side effects that might involve DA activity, e.g. apathy and loss of libido. I thought this was how Serzone worked to treat sexual side effects of SSRIs.
>
> The drug that most excites me at the moment is ziprasidone (Zeldox). Not only is this atypical antipsychotic a potent 5-HT2a antagonist, but, unlike the others currently available, it is also a potent agonist at the 5-HT1a. In addition, the ratio of 5-HT2 to DA blockade is very high, possibly reducing the risk of EPS to levels less than risperidone and comparable to olanzapine. I don't know, but maybe the lower the affinity for DA receptors, the more likely the possibility that DA autoreceptor blockade would yield pro-dopaminergic effects.
>
> Ziprasidone might be sort of like a hybrid of sulpiride, nefazodone (better, ketanserin), and pindolol.
>
> Does anyone know when ziprasidone / Zeldox is due to reach the pharmacist's shelves?
>
> Oh yeah. Anita might be right about a synergy specific with Prozac, possibly involving its noradrenergic activity. It may be that a possibly important property of the atypicals is being overlooked. They are relatively effective antagonists of NE alpha-1 receptors.
>
> Anita, please un-confuse me for what I am probably misunderstanding about serotonin.
>
>
> - Scott
This is the end of the thread.
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