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https://en.wikipedia.org/wiki/Amitriptyline https://en.wikipedia.org/wiki/Nortriptyline Both are quite similar, and that is no surprise, given that Notrtiptyline is Amitriptyline's major metabolite. When comparing both, we can ascertain the following: Amitriptyline has somewhat more SERT blocking going on, so might be slightly more "serotonergic" than Nortriptyline, although I am not quite sure if clinically relevant. Both are equally strong NRIs and 5HT2 antagonists. Amitriptyline is a stronger ALPHA1 blocker compared to Nortriptyline, so might cause more postural hypotension. Amitrptyline is a stronger antihistamine than Nortriptyline, so might cause more sedation and appetite. Amitriptyline is a stronger anticholinergic than Nortriptyline, so will probably cause more side effects. (Although stronger sedative and anticholinergic properties might be welcome, depending on the condition) What I am interested in: Who's been on both and how did they compare? (not only theoretically, but practically) binding affinities: picture source: https://abload.de/img/nortgpk1f.png

It would seem so, at least according to many studies... Gillman regularly mentions that his patients did substantially better on TCAs than on SSRIs (Sertraline might be an exception). Especially Amitriptyline, Clomipramine and Imipramine seem to be superior in effectivity. Is it wise to completely shun those very effective older antidepressants?

I've been reading the following articles: https://psychotropical.info/clomipramine-potent-snri-anti-depressant/ https://psychotropical.info/tca-intro/ https://psychotropical.info/snri-intro/ Seems to be a pretty potent drug: SNRI, antagonist of the alpha1-adrenergic receptor, the histamine H1 receptor, the serotonin 5-HT2A, 5-HT2C receptors, the dopamine D1, D2, and D3 receptors, and the muscarinic acetylcholine receptors. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system; so that speaks for itself. The reviews on drugs.com and other sites also are quite positive. The following ranking is interesting: http://slatestarcodex.com/2015/04/30/prescriptions-paradoxes-and-perversities/ These numbers are based on aggregated patient ratings. Top 4 drugs: # Nardil 1.25 # Parnate 1.23 # Chlomipramine 1.22 # Emsam/selegeline 1.07 => Clomipramine roughly on pair with MAOI, followed by Nefazodone (R.I.P) and Imipramine. Imipramine is also a potent SNRI, but lacks the strong 5HT-antagonism compared to Clomipramine. I suppose that's the pharmacological difference which makes Clomipramine superior... ? Clomipramine exhibits some antagonism of dopamine D1, D2 and D3 receptors... can one expect some clinical & therapeutic benefits from this? Clomipramine acts as a functional (potent!) inhibitor of acid sphingomyelinase (FIASMA): http://en.wikipedia.org/wiki/FIASMA Some interesting graphs regarding antidepressant FIASMAs: http://d-nb.info/1011278227/34 Who here has been on Clomipramine and what were your experiences with it?

There is a certain irony here: "Ugh, tricyclics! Low selectivity for the serotonin transporter over the noradrenaline transporter, and what's with all the antagonism at histamine, alpha and 5HT2A receptors? Dirty stuff! Thankfully this is the 90's, and we have Selective Serotonin Reuptake Inhibitors!" "...eh, maybe you do need a bit of a noradrenaline boost on top. Thankfully this is 2000, and we have SNRI's!" "...and maybe it would be nice to have some histamine/5HT2-antagonism-mediated anti-anxiety action, too. It's 2010, try some Seroquel or Mirtazapine on top of your antidepressant!" "...and we do want some alpha1-adrenergic receptor antagonism to normalize the HPA axis! And some FIASMA / BDNF would be nice. R&D, get started! It's 2018!" "...or just have a tricyclic." I would not be surprised if they try to market anticholinergics as new groundbreaking anxiolytics in a few years from now...