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Are TCAs more effective than SSRIs? In your experience....


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Since the introduction of the SSRIs, it has been repeatedly observed that severely depressed inpatients, usually those with melancholia, show a more robust response to TCAs than to SSRIs. The first studies to demonstrate this were by the Danish University Antidepressant Group, which published 2 widely cited studies showing the superiority of the TCA clomipramine to 2 SSRIs, citalopram and paroxetine, in hospitalized patients who had depression.19,20 Subsequent studies replicated the finding that TCAs are superior to SSRIs in specific populations.... 21-23 - source: https://www.psychiatrictimes.com/articles/not-obsolete-continuing-roles-tcas-and-maois

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?

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Almost 20 years ago I was in a black depression, and at that time was still dx'ed with MDD, recurrent (since been changed to bipolar II). Wellbutrin was working okay, but it wasn't enough, so my pdoc added on Vivactil/protriptyline. Per the Wikipedia article below, it's considered the most activating of the tricyclics. I didn't like it because of the drying side effects of constipation and dry mouth, but my pdoc observed that it was working, and my daily mood chart showed the same thing, so I hung in there. It's been so long ago now I don't remember any details of dose, titration, or exact start and stop dates. I moved out of state, maybe a year or two later?, and I don't recall if I went off it with that pdoc, or the next one in my new state. 

My recollection from looking into it all those years ago is that the biggest difference between TCAs and SSRIs is that SSRIs have a much reduced side effect profile, That has been my experience as well, although I was only on the one TCA; I had previously tried a few SSRIs, but they made me zombie-like. I'm pretty good about side effects and I will keep using a med for the recommended 4 or 6 weeks or whatever and give it a chance, but I definitely remember the Vivactil side effects.

Wikipedia Vivactil/protriptyline

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i've talked about clomipramine in another one of your threads, i think, but clomipramine is the most effective AD i've tried. it nukes my anxiety, racing thoughts and intrusive thoughts and gives me a bit of a higher baseline for my mood to boot. i was on an AD + AAP combo before and was pleasantly surprised to find that clomipramine covers all my symptoms on its own.

i have noticed side effects (dry mouth and a slight tremor in my hands), but honestly, they're not worse than the dizziness and sedation i had on venlafaxine, or the agitation i got on sertraline, or the fogginess escitalopram gave me. also, for me personally, taking a TCA has had less side effects than the other second-line option i tried, which was SSRI + atypical antipsychotic. so, do TCAs have more side effects? compared to taking an SSRI by itself, yes, but in a choice between a TCA or an SSRI + augmenting medication, maybe not.

i also know that my dad took a TCA (amitriptyline) for MDD for most of his adult life, and did not respond well to SSRIs when doctors tried to get him off the TCA.

i don't think doctors should shun their usage, but i think i agree with them being a second-line option. being mentally ill often ends up being a choice between symptoms or side effects, and if there are effective meds with lighter side effect profiles (like SSRIs), then they should be the first option. that said, i don't think a patient should be made to fail most or all SSRIs before it's presented as an option. from reading here, i've gathered that SSRIs as a class just plain do not work for some people.

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Here are my experiences with the TCAs I've taken.

  • amitripyline: Taken as an adjunct for sleep/insomnia at 25 mg as needed, wasn't effective for sleep or mood (25 mg is below the dose for depression). Not too excited about giving it a try for depression what with the weight gain, sedation, and cardiotoxic propensities.
  • clomipramine: Taken as the only antidepressant (had other meds on board like antipsychotic, mood stabilizer(s), etc.). Started with 50 mg at bedtime, gradually increased to a max of 225 mg/day. Was by far one of the worst psychiatric meds I've ever taken. It caused the absolute worst side effects: it worsened my depression and anxiety significantly, caused marked anticholinergic side effects, such as dry eyes, blurry vision (loss of close-up accommodation/focusing), dry mouth/throat that was unable to be sated by any amount of any fluids, weight gain (20 lb within 3 months), extreme constipation (exacerbated internal and external hemorrhoids, caused very painful, bloody movements—seriously, sometimes it looked like a scene from a horror movie...), and the worst sexual dysfunction I've ever experienced from a psych med (literally made it impossible for me to get off but once every 1-2 weeks). I would never take this med again, nor would I ever recommend it to anybody, even as a last resort. Its highly epileptogenic and cardiotoxic properties make it that less of an attractive medicine to me.
  • desipramine: Taken as an adjunct, mostly along with sertraline, from a dose range of 25-200 mg/day. By far, one of the best TCAs I've ever taken. Being a secondary amine TCA (the active metabolite of imipramine), it is a selective NRI (the most selective and potent of the TCAs) is mostly devoid of anticholinergic, antihistaminergic, and antiadrenergic side effects. At the same time, it is also devoid of any 5-HT2A/2C antagonism. I did try it briefly on its own at a dose of 200 mg/day and I didn't really find it to be that effective on its own. Works extremely well with sertraline IME, also fluoxetine. I had to stop taking it as it "turned against" me once I started Caplyta recently. It's supposed to be pretty stimulating and beneficial for ADHD. I will say that it's not sedating, at least, and I did take it in the AM instead of bedtime, because if I took it at bedtime I found it a little harder to sleep, but it wasn't markedly stimulating. I guess it may have had some benefit for my ADHD, but nothing remarkable.
  • doxepin: Taken as an adjunct for sleep/insomnia from 10-75 mg as needed. It's okay for sleep—not great for sleep induction, pretty good for sleep maintenance, pretty bad about causing next-day sedation/hypersomnolence (even causes me to sleep 10-15+ hours at night sometimes, or to go back to bed for 5-7 hours more after waking up, sleeping all day). At the doses I've tried, it did nothing considerable for mood or anxiety. In the US, there is a brand-name only version of it called "Silenor" that comes in micro-doses of 3 mg and 6 mg that are supposed to be selective for the H1 histamine receptor and supposed to be better for sleep than the higher-dosed doxepin (lowest it comes in is 10 mg, and they're all capsules).
  • imipramine: Taken briefly as the only antidepressant at a dose of 25 mg. It was kind of a nightmare... It caused extreme hyperhidrosis, markedly exacerbated my tremor (I was so jittery I had barely any fine motor control and had difficulty doing many basic everyday tasks), caused extremely vivid, horrifying nightmares, and caused me to gain 10 lb within the 2 weeks that I took it. (That was how long I lasted... I stopped it after the first 2 weeks.) Would maybe try it again, but I would have to be desperate.
  • nortriptyline: Taken off and on here and there as an adjunct to various antidepressants at the dose of 50 mg. Have taken as an adjunct to various SSRIs, SNRIs, and the MAOI Emsam. Being a secondary amine TCA (the active metabolite of amitriptyline), it is a (relatively) selective NRI is relatively devoid of anticholinergic, antihistaminergic, and antiadrenergic side effects (though nortriptyline still retains some of these effects to a degree compared to the other secondary amine TCAs). This was combined with Emsam (MAOI) because NRIs attenuate the pressor response from tyramine (AKA the "cheese effect"), sort of acting as a "prophylactic" against hypertensive crisis in case I accidentally ingested something with high tyramine content. I never did experience any noticeable benefit from nortriptyline though. Once, when I was washing out between an MAOI and going to I think an SNRI (or maybe the other way around), I kept taking the nortriptyline (against my pdoc's instructions) and even increased the dose to the maximum of 150 mg/day (on my own, without any blood tests...), and for those 2 weeks that I took it like that, I started to feel a little benefit from it, but nothing too strong or remarkable. It's pretty mild IME. It's supposed to be one of the stimulating ones, but this one was so benign that I felt pretty much nothing from it—no side effects or benefits to speak of. Nothing for or against depression, anxiety, ADHD, etc.
  • protriptyline: Taken off and on here and there as an adjunct to various antidepressants at the dose of 30 mg divided in 3 doses per day (10 mg 3x/day). Have taken alongside various SSRIs, SNRIs, and the MAOI Emsam. Being a secondary amine TCA (the N-methylated derivative of amitriptyline), it is a selective NRI (the second most selective and potent second to desipramine) and is devoid of antiadrenergic side effects, though retains potent anticholinergic properties (which @Catnapper complained of, and I also experienced problems from, but were not nearly as bad as with clomipramine...) and moderate antihistaminergic properties (somewhat close to nortriptyline's). Protriptyline is very unique amongst the TCAs in that it is, (1) stimulating (likely the most stimulating of the TCAs), borderline psychostimulant-like stimulating, and (2) taken during the day in divided doses, anywhere from 2-4 times depending on the dose, the last dose usually not to be taken after 5 PM to avoid insomnia. It comes in only 5 mg and 10 mg tablets, unlike the other TCAs which come in a variety of doses of tablets/capsules, maybe with the exception of imipramine, the hydrochloride form comes in 10 mg, 25 mg, and 50 mg, and the pamoate form coming in 75 mg, 100 mg, 125 mg, and 150 mg capsules (that are extremely expensive unless you have insurance). Protriptyline is used off-label for ADHD and narcolepsy due to its stimulating properties. I can definitely say that IME, even 30 mg/day (max is 40-60 mg/day depending on the prescriber's training and what other meds you're taking already as well as your CYP2D6 metabolizer status) is sufficiently and noticeably stimulating. I think that of all TCAs, this is my favorite, with desipramine as a close second.
  • trimipramine: Taken as an adjunct for sleep in a range of 25-75 mg. I didn't get to take it for very long because it went on backorder until further notice and my pharmacy could no longer get it for me. It worked well for sleep, but for a short time, worked against my depression. Then things leveled out a bit. This is likely because it acts mostly like an antipsychotic rather than a monoamine reuptake inhibitor (it has virtually no reuptake inhibition of any monoamines, but has 5-HT2A antagonism, D2 antagonism, as well as antiadrenergic, anticholinergic, and very potent antihistaminergic properties (almost as potent as doxepin)). A unique property about trimipramine is that its D2 antagonism is supposedly preferentially presynaptic (D2S), which means that it disinhibits dopamine release from the presynaptic dopamine-producing neurons, and may be responsible for its sleep-architecture-enhancing effects, like enhancing REM sleep (as opposed to suppressing REM sleep like almost all other antidepressants). I would very much like to try this one again, and just might swap out the doxepin for this one at my next visit, but I would be risking not being able to get it from my pharmacy (may have to do some pharmacy shopping to see if I can find one that can actually get it).

For kicks, may as well include the tetracyclic antidepressants.

  • amoxapine: Taken as my only antidepressant briefly. Never really got to a therapeutic dose, took in a range of 25-100 mg/day, where typical depression dose ranges from 150-300 mg/day to a max of 400 mg for outpatients (600 mg for inpatients). It's a very selective NRI with "built-in" atypical antipsychotic properties (5-HT2A antagonism and D2 antagonism with greater affinity for 5-HT2A). It is actually the active metabolite of the first-generation antipsychotic, loxapine, which is also sometimes referred to as an atypical antipsychotic, as it, in low doses (i.e., ≤20 mg/day), exhibits a more "atypical" binding profile (5-HT2 > D2), whereas higher doses (>20 mg) exhibit a more "typical" binding profile (D2 > 5-HT2). I didn't really experience much from this, but I didn't take it long or at any significant dose. I'd kinda like to give it a try some time if I ever have to. It would definitely be one to revisit some time if I needed to change my regimen. Could possible take the place of antidepressant and antipsychotic simultaneously. (Kinda like what Caplyta is starting to do for my regimen currently as it has an SSRI "built in" to it.)
  • mirtazapine: Technically classified as a tetracyclic, but not related to the other TeCAs (amoxapine or maprotiline). Taken as an adjunct to venlafaxine (or was it duloxetine?) (at 45 mg) and desvenlafaxine (at 30 mg) in an attempt to try the "California Rocket Fuel" combination, but I couldn't tolerate the effects of mirtazapine, especially at the higher, 45 mg, dose. It was by far the most sedating med I've ever taken, which made me feel absolutely miserable (made my depression visibly worse to other people while I took the 45 mg dose), gained a ton of weight both times I tried it, and just generally felt like crap. I couldn't make it through the side effects no matter how long I stuck with it and had to stop taking it...

TCAs/TeCAs I've not tried (that are in the US):

  • maprotiline

I guess really I've tried every single TCA available in the US... lol.

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I've never personally taken a TCA, but have always understood from a clinical perspective that they have always been known for having the potential to be more effective than traditional SSRI's. That being said, they're also well known for having a wider side effect profile along with greater likelihood of the possibility of side effects as compared to SSRI's. Furthermore, they're also very potent — much more so than SSRI's — in the event of overdose, which might make some prescribers nervous and reluctant to prescribe.

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On 6/10/2020 at 5:26 PM, psychwardjesus said:

I've never personally taken a TCA, but have always understood from a clinical perspective that they have always been known for having the potential to be more effective than traditional SSRI's. That being said, they're also well known for having a wider side effect profile along with greater likelihood of the possibility of side effects as compared to SSRI's. Furthermore, they're also very potent — much more so than SSRI's — in the event of overdose, which might make some prescribers nervous and reluctant to prescribe.

They aren't necessarily more potent in all cases... They're just very, very, very "DIRTY" drugs... In other words, lots and lots of off-site targets (like H1, α1, mACh receptors, plus sodium channels, which can actually be beneficial for pain but bad for cardiotoxicity especially in overdose) in addition to the desired target (like monoamine transporters SERT and NET).

There are tertiary amine TCAs and secondary amine TCAs.

The tertiary amines are all more serotonergic than noradrenergic, produce a secondary amine TCA as an active metabolite, and are generally more sedating than stimulating (until perhaps the levels of their active metabolites become significantly high enough).

The secondary amines are all more noradrenergic than serotonergic (some even are virtually "selective NRIs") and are generally more stimulating than sedating.

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10 hours ago, mikl_pls said:

There are tertiary amine TCAs and secondary amine TCAs.

The tertiary amines are all more serotonergic than noradrenergic, produce a secondary amine TCA as an active metabolite, and are generally more sedating than stimulating (until perhaps the levels of their active metabolites become significantly high enough).

Amitriptyline as a tertiary amine is, when counting in its metabolite Nortriptyline, more noradrenergic than serotonergic... all in all.

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On 6/18/2020 at 7:15 AM, Skeletor said:

Amitriptyline as a tertiary amine is, when counting in its metabolite Nortriptyline, more noradrenergic than serotonergic... all in all.

It depends on the dose of amitriptyline... Low doses of amitriptyline are primarily serotonergic. Higher doses become more noradrenergic from the nortriptyline.

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