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Re: Prozac+Zyprexa Special for Treatment Resistence

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




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