Viibryd and dopamine

[Caddy]

Hey all,

I'm curious about the pharmacology of Viibryd. I know the 5HT1 activation is what makes it special. According to Wikipedia, it has "clinically unimportant" activity at the DAT and NET.

Wikipedia also says something similar about Zoloft, but the consensus here on this forum seems to be that Zoloft's dopamine inhibition DOES contribute to it's effects. Can somebody explain the following excerpt from Zoloft's Wikipedia page?

Quote

sertraline showed the highest affinity of them all for the DAT, even higher than the norepinephrine–dopamine reuptake inhibitors (NDRIs) nomifensine (K_i = 56 nM) and bupropion (K_i = 520 nM).^[99][110] Sertraline also has similar affinity for the DAT as the NDRI methylphenidate (K_i = 24 nM)

I don't understand what those numbers mean, especially since the number for bupropion is so much higher than the rest. Wikipedia lists Viibryd at 37 nM.

Thanks,

Caddy

Edited October 2, 2019 by Caddy

[argh]

.

Edited September 20, 2020 by argh

[Caddy]

2 minutes ago, argh said:

Those numbers represent the affinity of the drugs to bind to the receptors. What matters is the intrinsic activies at said receptors.

But it says that sertraline has a higher affinity than bupropion, despite listing sertraline at 25 nM and bupropion at 520 nM.

[argh]

.

Edited September 20, 2020 by argh

[mikl_pls]

3 hours ago, Caddy said:

But it says that sertraline has a higher affinity than bupropion, despite listing sertraline at 25 nM and bupropion at 520 nM.

What matters is the relative affinity for the serotonin transporter. While Zoloft may have similar affinity for the DAT as methylphenidate, it has much, much higher affinity for the SERT. So in order to get any clinically relevant effect at dopamine reuptake inhibition with Zoloft, it would either need to have less affinity for the SERT so that the affinities are closer to each other, allowing for clinically relevant DRI and SRI, or you would need high doses (possibly even supratherapeutic doses) to have relevant DRI what with the relatively high affinity for the SERT. Same with Prozac and the 5-HT2C antagonism—the SERT affinity is so much higher than 5-HT2C affinity, it's questionable as to whether it is really clinically relevant.

As for bupropion, it has active metabolites that have higher affinity for the DAT and one higher for the NET than bupropion itself.

As for Viibryd, it does have an effect on dopamine release via 5-HT1A partial agonism (postsynaptic). The presynpatic 5-HT1A partial agonism initially decreases serotonin release, but once they are downregulated by chronic stimulation, both by direct partial agonism and via increased serotonin levels form SERT inhibition, serotonin release will be disinhibited.

[Caddy]

This is another thing that confused me:

Quote

However, sertraline is highly protein-bound in plasma, with a bound fraction of 98.5%.^[7] Hence, only 1.5% is free and theoretically bioactive.^[7] Based on this percentage, free concentrations of sertraline would be 2.49 ng/mL (8.13 nM) at the very most, which is only about one-third of the K_i value that Tatsumi et al. found with sertraline at the DAT.^[99] A very high dosage of sertraline of 400 mg/day has been found to produce peak plasma concentrations of about 250 ng/mL (816 nM).^[7] This can be estimated to result in a free concentration of 3.75 ng/mL (12.2 nM), which is still only about half of the K_i of sertraline for the DAT.^[99]

That is from the Zoloft wiki page again. This made me think that a larger number was better.

Edited October 3, 2019 by Caddy

[mikl_pls]

4 hours ago, Caddy said:

This is another thing that confused me:

 

 

That is from the Zoloft wiki page again. This made me think that a larger number was better.

 

The Ki (inhibition constant) describes affinity to a receptor or transporter. Lower numbers describe a tighter binding, while higher numbers describe either looser or negligible binding (AKA practically no affinity at all). For the sake of most receptors and transporters, it is measured in nanomoles (nM). Affinities that are "subnanomolar" (< 1 nM) are very tight and generally the most relevant. 10,000 nM or above is describing practically negligible affinity. Ki is completely different from IC50 (half maximal inhibitory concentration), which is the concentration of a substance to inhibit an endogenous activity by half (such as the serotonin transporter taking serotonin out of the synapse). This is also different from the concept of intrinsic activity, which is the ability of a substance binding to a receptor to either stimulate a receptor (IA = 100%, called an full agonist or just agonist), partially stimulate or "regulate" activity of a receptor (0% > IA > 100%, "partial agonist"), neutralize the activity of the receptor (IA = 0%, antagonist, or reverse the activity of the receptor (IA < 0%, inverse agonist). A partial agonist's intrinsic activity can be low enough for it to behave like an antagonist; e.g., pindolol, a beta blocker, has affinity greater at the 5-HT1A receptor than serotonin itself (Ki = 15-81 nM) and has an intrinsic activity of 20-25%, and therefore acts as a "functional antagonist." Same with aripiprazole with the 5-HT2A receptor, having an affinity of Ki = 3.4-35 nM and an intrinsic activity of 12.7%, acting as a functional antagonist as well.

[Caddy]

Ah, okay.

So Viibryd is a pretty strong agonist of 5HT1A, since it binds tightly (0.2 nM) and significantly agonizes (60-70% IA), right? Would Viibryd also be the second most dopaminergic SSRI (37 nM at the DAT) behind Zoloft (25 nM at the DAT)? I don't see any IA or IC50 numbers for the transporters.

Thanks.

Edited October 3, 2019 by Caddy

[mikl_pls]

I would say Trintellix is even more potent a 5-HT1A agonist, having greater intrinsic activity than Viibryd.

As far as rating them in order of "dopaminergic-ness," I'm not sure enough to say, really.

[HydroCat]

There are many factors to take into account for really assessing the “dopaminergic-ness”, or activity on any other receptor for the matter. Intrinsic activity, selectivity etc... and we are not yet talking about metabolism.

However, looking at affinity Ki values alone, Sertraline has a 1:55 Serotonin:Dopamine Ki values, while Viibryd has a 1:370 ratio, so by this calculation, Sertraline has about 6.7-fold stronger activity on the DAT than Viibryd.

Professionals say that the DAT effect of Sertraline is questionable. From personal non-professional experience it definitely is not.

Edited October 6, 2019 by HydroCat

[browri]

I think with Viibryd, you don't ever go to the doses that would be necessary to produce any meaningful of inhibition of DAT. That being said, they are finding that for some people, doses higher than 40mg are useful, and it's possible that at those doses, you could achieve a level of DAT inhibition that may be significant......possibly, but even then it's kind of a stretch. It's very much the same though with Zoloft in the 150mg-200mg range. For some people like @HydroCat, there are noticeable energizing effects at those doses that are kind of hard to just write off as "initial serotonergic activation/agitation". Many people get by just fine though on 25-50mg of Zoloft, and those patients likely aren't experiencing any sort of DAT inhibition.

For what it's worth I don't think Viibryd's bioavilability is all that great to begin with so that could be problematic.