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OCDme

150 zoloft vs 200?

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Hi, i have a pharmacology question about SSRIs and in this instance lets take Zoloft as an example-

Once you get past 100 mg of zoloft, lets say 150 mg don't you basically occupy SERT transporter as much as it will go  therefore 

 

Is there really any subjective difference going up to 200? If so, how come?

This can apply to all high dose SSRIs

I'm confused by the principle of the matter

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6 hours ago, OCDme said:

Hi, i have a pharmacology question about SSRIs and in this instance lets take Zoloft as an example-

Once you get past 100 mg of zoloft, lets say 150 mg don't you basically occupy SERT transporter as much as it will go  therefore 

 

Is there really any subjective difference going up to 200? If so, how come?

This can apply to all high dose SSRIs

I'm confused by the principle of the matter

 

https://ils.unc.edu/bmh/neoref/nrschizophrenia/jsp/review/tmp/352.pdf

there is a TON of research on this, and many researchers have posed this exact question. Although zoloft is a bit tricky, because some sources will tell you that it has a slight effect on dopamine as you get to higher doses. My only theory: Supposedly, by mid range does the occupancy is at almost 80% and at high range 80-85% (see linked paper, i didnt read the whole thing just abstract and results.) So it seems like the effect is exponential somehow. it takes almost 80% to get any effect, but at higher doses where many people see benefit it is only a 5% increase. That would account for the benefit of 200 over 150 (I guess) cuz even really small changes in the occupancy seem to have effect once you hit the threshold of whatever number that paper gave. 

@browri is good at these things 

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On 10/21/2020 at 6:56 PM, Iceberg said:

 

https://ils.unc.edu/bmh/neoref/nrschizophrenia/jsp/review/tmp/352.pdf

there is a TON of research on this, and many researchers have posed this exact question. Although zoloft is a bit tricky, because some sources will tell you that it has a slight effect on dopamine as you get to higher doses. My only theory: Supposedly, by mid range does the occupancy is at almost 80% and at high range 80-85% (see linked paper, i didnt read the whole thing just abstract and results.) So it seems like the effect is exponential somehow. it takes almost 80% to get any effect, but at higher doses where many people see benefit it is only a 5% increase. That would account for the benefit of 200 over 150 (I guess) cuz even really small changes in the occupancy seem to have effect once you hit the threshold of whatever number that paper gave. 

@browri is good at these things 

thanks @Iceberg 😉

As far as I know without doing too much digging, sertraline is fairly selective for serotonin at 25mg to 100mg. Above 100mg, it starts to occupy the dopamine transporter as well. Generally speaking, for an SSRI, 80% SERT occupancy is necessary for antidepressant effect, but an atypical antidepressant like Trintellix only inhibits the serotonin transporter to about 55% at a dose of 10mg, yet the serotonin levels in the brain are much higher than would be expected of 55% SERT occupancy and significant antidepressant effect is achieved despite the consensus that 60% SERT occupancy is the bare minimum for antidepressant effect.

So basically, you have to take that SERT occupancy together with everything else. If you achieved 80-90% SERT occupancy but also had some inhibition of DAT, then it would certainly be a different effect. Initially the increase in serotonin from SERT inhibition would cause an increase in dopamine signaling, but long-term desensitization would result in a net reduction in dopamine signaling. So adding that DAT inhibition to prop up dopamine certainly could have an effect for a small subset of patients. And the dopamine desensitization in tandem with serotonin desensitization could have a potential for a stabilizing effect in some patients with mood cycling disorders.

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