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    Comparing IC 50 values? 
    #1
    Two drugs in question:

    Atomoxetine = 0.36 nM


    Reboxetine = 8.2 nM


    Perhaps there are more accurate IC50 values out there though.


    Atomoxetine is dosed up to 100 mg

    Reboxetine to 10 mg max.


    Reboxetine supposedly failed clinical trials as an AD, but was approved anyways.


    Atomoxetine supposedly failed clinical trails as an AD, but was approved for ADHD.

    For myself - I've only ever responded to NE enhancing drugs so, I'm just looking for the most powerful one in that capacity.



    According to them IC50 values - that would be atomoxetine, right?
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    #2
    iC specifies potency of attaching to the target site, not telling efficacy.
    Ie. it may bind and be a partial agonist not exerting full effect, or jus bind and doesnt give effect at all (antagonist), or bind then give reversd effect(inverse agonist)

    I think what you are looking for is EC50 value, that determines the efficacy
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    #3
    EC50 values for them two meds are no where to be found.

    I had difficulty enough finding their IC50 values.

    Can anyone point me in a favourable direction??



    PS - is "racing thoughts" a symptom kind of, synonymous with depression?
    I was actually just reading that on drugs.com reviews for atomoxetine.
    Racing thoughts, to an extreme degree - apparently cause some people, chronic lethargy.
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    #4
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    Cotcha Yankinov's Avatar
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    These are reuptake inhibitors so there will be no EC50 to be found.

    RE: "racing thoughts", you may also think about the terms mania/hypomania and rumination, and the former is common in bipolar while the latter is very common in all depressions. Its possible that rumination plays a big role in the causality of depression, and many antidepressant treatments seem to address the hyperactivation of the "default mode network", a neural network linked to rumination and depression.

    ADHD medicines typically stimulate the executive control network - a network somewhat in opposition to the default mode network.
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    #5
    Quote Originally Posted by Cotcha Yankinov View Post
    These are reuptake inhibitors so there will be no EC50 to be found.

    RE: "racing thoughts", you may also think about the terms mania/hypomania and rumination, and the former is common in bipolar while the latter is very common in all depressions. Its possible that rumination plays a big role in the causality of depression, and many antidepressant treatments seem to address the hyperactivation of the "default mode network", a neural network linked to rumination and depression.

    ADHD medicines typically stimulate the executive control network - a network somewhat in opposition to the default mode network.
    Default mode network being relative to all monoamines?
    Predominantly serotonin perhaps?

    Executive function - similar to control I'm guessing: I read a clinical trial claiming the use of noradrenergic agents are specific to executive control.
    I haven't come across the term "default mode network" - any paper links on that?


    So - without EC50 values - in terms of kind of labelling which of the two would have greater potency at the NE transporter.

    In non specific terms, the fact that reboxetine was approved for neither depression nor ADHD by the FDA, but atomoxetine was approved for depression - perhaps alluding to more effectiveness in some capacity?
    That being said - atomoxetine seemed to have been rejected by it's own company, Pfizer itself - in terms of potential use as an anti-depressant.
    Yet there are many case studies where it is used effectively as an adjunct to ameliorate lethargy etc.
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    #6
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    Default mode network relating to all neurotransmitters, but there is a high level of expression of serotonin terminals in some parts of the cingulate for example.

    Here are some DMN papers
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4797836/
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891968/

    EC50 is kind of a measure of how much of the substance you need to produce a half maximal increase in excitability, so in the case of transporters, there would only be an EC50 value for a reuptake enhancer. But reuptake inhibitors do have IC50 (inhibitory concentration 50) values. EC50 values are more useful for helping determine the potency of agonists, which may activate a receptor more or less. I'm sure that not all reuptake inhibitors block transporters the same way (see cocaine as a DAT inverse agonist), but I doubt its that appreciable.

    There are pharmacokinetic factors that make determining transporter occupation difficult. You may be able to find PET studies that examine transporter occupancy at different dosages.

    The non-approval of reboxetine may have to due with PK factors or side effects, not necessarily related to its actions at NET. But I still get the feeling that a selective NRI will not be a very complete antidepressant. It may be a helpful adjunct (especially in people who would already benefit from stimulants with regards to ADHD), or may help relieve a specific symptom like lethargy, but I don't know if its really the whole package that some people need.
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    #7
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    I remember vaguely that atomoxetine/Straterra was intended to compete with or replace fluoxetine/Prozac. Checking structures, you can see that Prozac is just a flourinated Straterra.

    I think the verdict is that atomoxetine just isn't good enough an AD to compete with fluoxetine, and just iffy enough with ADHD that they marketed it that way instead. Something similar may have happened with reboxetine. My point being is it sounds not particularly good at anything (compared to the rest of the market), but I haven't exactly gone through clinical results. I always think of this one as a reminder that drug development is hazy and no one really knows what they're doing to your brain. Every pharm is an experiment.


    And that default mode network vs. executive control mode is great info,thanks. I can't help but think, though, about implications for "mind" and how there's a 2500 year-old practice for diminishing the former in favor of the latter by just sitting.

    I remember now! Sorry, I'm on a multiday awake binge that I didn't even plan. The SPECIAL thing about atomoxetine,in re: depressio/anxiety, is that it's an NMDA antagonist, ala ketamine (obviously a less potent one). My understanding is that preliminary trials showed success with some special class of PTSD and chronic fatigue. It came up elsewhere, what with ketamine IV appearing to be an interventionist ER cure for depression for a week or two.[
    Last edited by Scrofula; Yesterday at 10:04.
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