The Corpus Callosum

Selection of Antidepressants: Asendin — amoxapine

Posted by Joseph j7uy5 on June 3, 2007
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i-d732a33d5e0cbeea16ffd70fb39791c5-150px-Amoxapine.svg.png
face="Helvetica, Arial, sans-serif">This is
an interesting drug.  Rarely prescribed, but interesting.
 It is older than what we typically give today.  It
is an antidepressant with a twist.



face="Helvetica, Arial, sans-serif">In
order to understand why it is interesting, you need to know a little
bit about the pharmacology of the drug.


rel="tag" href="http://en.wikipedia.org/wiki/Amoxapine">Amoxapine
is a tricyclic antidepressant, in my book, or at least in my
head; but I have seen it referred to as a tetracyclic.  It
depends on whether you think all the rings have to have an adjoining
side to count.

face="Helvetica, Arial, sans-serif">i-52245ebde567466bfc466b1481f005a5-Loxapine.png

The
top diagram shows the antidepressant, amoxapine.
 The second one shows a closely related drug, href="http://en.wikipedia.org/wiki/Loxapine" rel="tag">loxapine.
 Except loxapine is not an antidepressant.
 It is an antipsychotic. That one methyl
group on top makes all the difference…


The
main known mechanism of action for amoxapine is the inhibition of the
reuptake of norepinephrine.
 It has a much smaller effect of inhibiting the reuptake of href="http://en.wikipedia.org/wiki/Serotonin" rel="tag">serotonin.
In that way it is similar to desipramine or nortriptyline, or
maprotiline, for that matter.  But there is a twist.

Most drugs are altered in various ways before they are finally
eliminated from the body.  Loxapine typically will have that
methyl group lopped off, turning it into amoxapine.  So you
can’t give someone the antipsychotic loxapine, without the person also
getting some of the antidepressant, amoxapine.  But wait,
there’s more…

Amoxapine is metabolized to two active metabolites, 7-hydroxyamoxapine
and 8-hydroxyamoxapine ( href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=92200">ref.).
 Both are active metabolites, and both inhibit reuptake of
norepinephrine.  The twist is that 7-hydroxyamoxapine also
blocks D2 receptors.  That means that loxapine has an active
metabolite that is an antidepressant, and the antidepressant has an
active metabolite that is an antipsychotic!  Holy moley!
 But that’s not all!  

If you thought is was a good deal to get two drugs for the price of
one, wait ’til you hear this.  Amoxapine also blocks 5-HT2
receptors.  (As does loxapine.)  So, not only is it
an antipsychotic, but it is an href="http://en.wikipedia.org/wiki/Atypical_antipsychotic">atypical
antipsychotic.  Probably the href="http://www.nature.com/npp/journal/v30/n12/abs/1300796a.html">cheapest
one there is, by an order of magnitude.  

Now, to get to the point of this post: when would a clinician pick
amoxapine as an antidepressant to prescribe to someone?  

If a patient has depression with psychotic features, it would be an OK
choice.  In general, we don’t want to expose people to
antipsychotics unless there is a good reason to.  Depression
with psychotic features typically does not respond well to an
antidepressant without an antipsychotic.  

Also, because amoxapine is so distinctly different from other
antidepressants, it is really in a class of its own.  Thus, it
could be considered as a treatment for patients who have had adequate
trials of several other antidepressants, without good results.
 

As a tricyclic antidepressant, it has the disadvantages I’ve already
noted in the post about amitriptyline.  

(This post is not really intended to stand alone, you might want to
read the more abstract posts I wrote on the topic of selection of
antidepressants.  They can be found by clicking on the
Category link in the sidebar for antidepressants.)
 

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Comments

  1. #1 Mostafa Hussein
    June 3, 2007

    It looks very interesting, I wonder if it could be used with bipolar depression?

    As an Antipsychotic does it cause extra-pyramidal side effects ? What about efficacy, depression with psychotic features is usually severe and the risk of suicide is high.

  2. #2 Joseph j7uy5
    June 3, 2007

    Sure you can use it with bipolar depression, after you have decided whether you are going to use an antidepressant at all. EPS can occur, but are somewhat ameliorated by the 5-HT2 antagonism and by the anticholinergic effects. In actual practice it usually is not a big concern, more of a theoretical thing.

    Toxicity in overdose is probably high; that is a concern of course.

    As for efficacy, I am not aware that there are good head-to-head comparisons. (But I did not do a lit search specifically on that.) As an older drug, it seems unlikely that anyone will do the kind of studies we would want to see.

  3. #3 Greg P
    June 4, 2007

    The science is all well and good, but how is it out on the street? And maybe the psychiatrist likes the results, what about the patient?

    In many cases a lot of the pharmacology of these drugs (and many others) gets worked out only after they are found to be useful for something, so the logic tends to be retrospective. When you read all this pharmacology up front you might think that the drug was oh so carefully designed to have this very precise chemical profile and receptor interactions. No way.

  4. #4 Joseph j7uy5
    June 4, 2007

    It never occurred to me that someone might think that drugs were designed with these properties in mind, a priori. I think you are right, though, that people do get that impression. When amoxapine was developed, very little was known about the structure of various receptors, the different subtypes, up-regulation, down-regulation, and so forth. It was all empirical.

    Of course , these days, various companies do try to make use of that level of knowledge to design drugs. But even if that line of research produces something useful, there is no guarantee that it will actually be better than the old stuff.

  5. #5 Greg P
    June 5, 2007

    Even when they do use some knowledge of receptors to design drugs, it’s still an empiric result.

    We have several of the newer anticonvulsants carefully crafted with some receptor interaction in mind, found to be effective, then when they have studied how they actually work, the answer comes out something like, “we don’t know how this drug works, but we know it’s not by the mechanism used for the drug’s design.”

  6. #6 daedalus2u
    June 5, 2007

    My experience with amoxapine is that it did work pretty well as a supplement to sertraline to counter some of the side effects and provide a little more antidepressant activity. It worked pretty well. As I remember I was taking 100 mg sertraline twice a day (it made a big difference vs 200 mg once a day), and then 37.5 mg amoxapine once a day. When I went on that combination it was the best I had ever felt in my entire life. It was then that I realized just how bad my depression had been.

    The way my doc and I figured it out, was to look at the various receptors being inappropriately activated by the sertraline (ie, adrenergic side effects) and find something that would inhibit those receptors and start it at a low dose and see what happened. I am pretty sensitive to how well my brain is working, and what side effects I was getting, so it was a useful way to go.

    I then added some nefezadone, there was some improvement, but not that much.

    Since I have raised my NO level, I have stopped the nefezadone (which isn’t available anyway), and the amoxapine and am now down to 100 mg sertraline once a day. I have never felt better. I now understand that much of my depression was due to my low NO physiology (which I have now fixed). That is ultimately what leads to the vascular rarefaction that is associated with vascular depression (and all the other things associated with hypoperfusion in the brain).

  7. #7 doug
    May 17, 2012

    Question To Author OF This Article Or Anyone Else:

    I have racing thoughts very badly. OCD thinking. Can amoxapine help slow down and help me to manage these thoughts???