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Clozapine increased to 350mg--Mechanism of action


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@browri and i were literally just having this conversation funny enough. 

"Clozapine is regarded as the one atypical antipsychotic with the highest ratio of 5HT2A antagonism (5.35nM for clozapine and 10.9nM for norclozapine) to D2 antagonism (157nM and 101nM, respectively). Clozapine's affinity for dopamine receptors is actually piss poor in comparison to its affinity for 5HT2A receptors, and clozapine is an intermediate binder at dopamine receptors like olanzapine, quetiapine, and loxapine at lower doses. So it touches down, binds and blocks, then releases, theoretically allowing some normal physiological dopamine signaling because it doesn't remain bound the whole time like typical antipsychotics or some of the older atypicals like risperidone, which binds pretty tightly.

So with greater 5HT2A antagonism and this "touch-and-go" dopamine receptor binding, lower doses would indeed promote dopamine signaling, and this can have a very positive effect on mood. Only downside is clozapine is a pretty strong muscarinic acetylcholine antagonist, which can have a plethora of not-fun effects like drug-induced type 2 diabetes similar to olanzapine or cognitive dysfunction" 

This is browri's explanation which would be as good or better than mine 

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11 hours ago, Iceberg said:

@browri and i were literally just having this conversation funny enough. 

"Clozapine is regarded as the one atypical antipsychotic with the highest ratio of 5HT2A antagonism (5.35nM for clozapine and 10.9nM for norclozapine) to D2 antagonism (157nM and 101nM, respectively). Clozapine's affinity for dopamine receptors is actually piss poor in comparison to its affinity for 5HT2A receptors, and clozapine is an intermediate binder at dopamine receptors like olanzapine, quetiapine, and loxapine at lower doses. So it touches down, binds and blocks, then releases, theoretically allowing some normal physiological dopamine signaling because it doesn't remain bound the whole time like typical antipsychotics or some of the older atypicals like risperidone, which binds pretty tightly.

So with greater 5HT2A antagonism and this "touch-and-go" dopamine receptor binding, lower doses would indeed promote dopamine signaling, and this can have a very positive effect on mood. Only downside is clozapine is a pretty strong muscarinic acetylcholine antagonist, which can have a plethora of not-fun effects like drug-induced type 2 diabetes similar to olanzapine or cognitive dysfunction" 

This is browri's explanation which would be as good or better than mine 

Aww thanks, @Iceberg!

@the maze runner the above quote describes what makes clozapine unique relative to other atypical antipsychotics. AAPs are all unique from typical antipsychotics because of their serotonergic antagonism, particularly 5HT2A. Of the atypicals, clozapine's ratio of antagonism at 5HT2A to D2 activity is the greatest. This action at 5HT2A receptors is known to promote norepinephrine and dopamine signaling. So the theory is that the more we promote dopamine relative to how much we're blocking dopamine receptors, we should be able to improve mood issues in tandem with treating psychosis.

Combined with this is clozapine's binding profile at dopamine receptors. Quetiapine is known for some of the loosest binding in the atypicals. Olanzapine, loxapine, and clozapine share this intermediate binding profile with quetiapine, but they bind slightly more tightly to dopamine receptors. This binding potential to a degree is dose proportional. They will always release from dopamine receptors more readily than their typical AP cousins, and usually more than their atypical AP siblings. What's important though is the potential action this has. Dopamine receptors are present in the short-form (i.e. D2S), which is pre-synaptic and negatively controls dopamine outflow into the synapse. They are also present post-synaptic in the long-form (i.e. D2L). The post-synaptic receptors are where dopamine would mediate its effects in psychosis but also its ability to ease anhedonia in depression. By binding to both forms for a period of time and disassociating, dopamine signaling is promoted but modulated. By blocking the pre-synaptic receptors, dopamine is released from neurons into the synapse. Blocking post-synaptic receptors dulls some of this increased dopamine activity, but after a time, the antagonist disassociates and "normal" physiological dopamine signaling can proceed. I say "normal" because while the receptors are no longer blocked, by blocking the pre-synaptic receptors, the synapse now has an increased baseline level of dopamine, hence the antidepressant effect. Certain areas of the brain like the pre-frontal cortex don't contain any native dopamine transporter and rely upon the norepinephrine transporter to clear both norepinephrine and dopamine. Because blockade happens more so at night and receptors are less antagonized during the day, normal (but now slightly increased) dopamine signaling during the day, particularly in the pre-frontal cortex, should theoretically reduce things like akathisia and other kinds of EPS while also having an antidepressant effect. This may be why quetiapine and olanzapine in particular are known for their antidepressant utility. And clozapine's 5HT2A/D2 ratio being greater than any other AAP may underlie why it works where other things just don't for one reason or another.

Disclaimer: Caplyta (lumateperone) was just approved by the FDA last year as a new atypical antipsychotic. It is the first AAP to best clozapine's 5HT2A/D2 ratio. In addition to its extremely significant 5HT2A antagonism, it only seems to occupy dopamine receptors to about 30-40% at its standard dose of 42mg. Additionally, its dopamine receptor affinity matches its affinity for inhibition of the serotonin transporter (SERT).

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As a continuation and an aside to that, while the "-pines" are known for their intermediate binding, other AAPs accomplish increased dopamine signaling via other ways. For example, risperidone has a tight binding profile at dopamine receptors unlike clozapine. However, its affinity for the pre-synaptic short form of the dopamine receptors (D2S) is slightly greater than its affinity for the post-synaptic long form (D2L). At the usual antipsychotic doses >2mg/day, this doesn't matter because high levels of receptor occupancy occur regardless of receptor locus. However, in very small doses, this can be significant because risperidone has the potential to preferentially antagonize pre-synaptic receptors over post-synaptic ones. This means net positive dopamine signaling. So something like 0.25mg to 0.5mg at night added to an antidepressant can even be useful in major depressive disorder for some people. Despite low doses of risperidone rarely showing signs of EPS, pdocs still shy away from it sometimes because it still carries a fairly high rate of EPS overall for an AAP despite its significant 5HT2A antagonism, which is apparently insufficient to offset those movement-related side effects.

Lurasidone carries a similar rate of EPS and akathisia to risperidone, but for bipolar depression it is used at lower doses 20mg-60mg/day. You can go >60mg/day, but clinical trials showed on average that the higher doses didn't make a difference in depression. In lurasidone's case, it similarly has a greater affinity for pre-synaptic dopamine receptors than post-synaptic, like risperidone, and a somewhat intermediate binding profile at post-synaptic receptors as long as you keep the dose low, similar to the "-pines". Higher doses seem to block all dopamine receptors indiscriminately though, making it more like its "-done" siblings. So if you keep the dose between 20mg-40mg, you can actually cause a net increase in dopamine signaling with a dopamine antagonist. There is something to be said, however, for lurasidone's unparalleled antagonism of the 5HT7 receptors, which act as auto-receptors in a similar way to the D2S form dopamine receptors. Particularly this causes increased serotonin signaling in the hippocampus and some other brain regions. So it is suspected that some of lurasidone's antidepressant effect also comes from this 5HT7 antagonism.

Wow. Got off on a tangent. Hope some of this is useful to ya lol :wtf:

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