Why did psychiatry move to SSRI/SNRIs over tricyclics?

[thegreenhand]

As I understand it tricyclics essentially have action that increases serotonin and norepinephrine by inhibiting their reuptake. Specific drugs can do other things but this seems to be the main mechanism. I’m wondering why tricyclics are rarely prescribed anymore but SSRIs are a dime a dozen. SNRIs less so but they aren’t necessarily rare. At standard doses tricyclics seem quite safe. At least on par with SSRIs. Thoughts?

 

[Skorpio]

suicide risk. A lot of tricyclics have anticholinergic effects that decrease inhibitory acetylcholine signals to the heart, increase synaptic norepinephrine which speeds up the heart, and block sodium channels which messes with the electrical rhythm of the heart. The combo of effects makes tricyclics very cardiotoxic in overdose.

This is bad as antidepressants (especially activating ones) can often reduce the low motivation in depression before the depression itself lifts. This makes patients more vulnerable to suicide attempts.

 

[thegreenhand]

So are you saying people use them to commit suicide? Or that they cause suicidal ideation? I don’t know if I’m following how an accelerated heart rate leads to suicidal thoughts

 

[S.J.B.]

From a 1997 review on SSRIs in Anaesthesia:

The primary indication for the SSRIs is major depression. Indeed, fluoxetine (Prozac) attracted enormous attention in 1990 when Newsweek referred to it as a breakthrough drug in the treatment of depression and is currently the most prescribed antidepressant world wide. The SSRIs are now considered to be first-line therapy for depression because of their superior side-effect profile and documented efficacy of ≈ 65% and thus are as effective as the tricyclic antidepressants. Another advantage of the SSRIs is their ease of administration and dosing because they are generally prescribed once a day. The SSRIs do not cause sedation, dry mouth, orthostatic hypotension and cardiac conduction defects, all of which are seen with the tricyclic antidepressants. In contrast to the tricyclic antidepressants and the monoamine oxidase inhibitors, the SSRIs are also safer when taken as an overdose.

 

[Skorpio]

So are you saying people use them to commit suicide? Or that they cause suicidal ideation? I don’t know if I’m following how an accelerated heart rate leads to suicidal thoughts

Suicidal ideation can be caused by tricyclics (as well as most other antidepressants), but tricyclics are extremely effective for the act. Its a bad combo for a single drug.

Also, less morbid is that tricyclics being quite promiscuous have a higher incidence of side effects. SSRIs were thought to be equally efficacious, but more tolerated. (I feel that this thought is changing with people adding antipsychotics to ssris to mimic the broad action of tricyclics).

 

[Bravoncius Roxford]

As I understand it tricyclics essentially have action that increases serotonin and norepinephrine by inhibiting their reuptake. Specific drugs can do other things but this seems to be the main mechanism. I’m wondering why tricyclics are rarely prescribed anymore but SSRIs are a dime a dozen. SNRIs less so but they aren’t necessarily rare. At standard doses tricyclics seem quite safe. At least on par with SSRIs. Thoughts?

First of all, what you say isn't true. Psychiatrists who attend in offices prescribe SSRIs and SNRIs as first-line therapy because the people who go there usually have mild depression - and it's really only SSRIs, since the only true SNRI is clomipramine, which is definitely not prescribed as a first-line therapy. The psychiatrists that treat severely depressed patients in institutions actually pretty much don't use SSRIs and SNRIs at all. They use pretty much only tricyclics and MAOIs - besides Lithium and ECT. The only "modern" antidepressants used for severe depression by psychiatrists in clinics are paroxetine, which is a very strong SRI, and bupropion in the mistaken believe that it is a DRI(it is weak with an IC50 of 6.5 Umol)

As for why doctors and psychiatrists who attend in offices(the drugs they use in offices are completely different from the ones they use in clinics to treat seriously depressed people) have switched from tricyclics to SS(N(RIs, has to do with safety and need. People that go to offices tend to have less severe depression, so they don't need tricyclics, and since the SSRIs are much safer, that is what they prescribe. Those same psychiatrists continue to use clomipramine, imipramine and phenelzine for people that are suicidal. They used to treat people with mild depression with the same drugs used to treat serious depression up to early mid 1980's because there were no alternatives. Now there are safer alternatives, and since their depression does not require extremely powerful antidepressants, the safer alternatives are the obvious choice. Hence "need and safety".

The tricyclics and MAOI's are much more effective for suicidal depression than the modern SS(N)RIs, but they are also a lot more toxic, with more serious side effects and pharmacological interactions. For instance, tricyclics are very cardiotoxic, and will cause cardiac arrest in overdose. That is because most tricyclics are potent Sodium channel blockers, so they paralise the heart in overdose. Likewise, the non-selective MAOIs can cause hypertensive emergency when combined with tyramine from food and sympathomimetic releasers, many of which are used in anesthesia or sold over-the-counter. They can also caused serotonin syndrome when combined with several opioid analgesics. In fact, they cause lethal serotonin syndrome in overdose, unlike the SSRIs, which produce only mild serotonin syndrome in overdose when taken on their own.

Their greater toxicity, as well as their greater potency which causes greater and more severe pharmacological interactions, and the availability of effective alternatives for mild depression, explains why their use has declined. BUT they are still the "standard" for treating people with suicidal depression. They remain as used today in psychiatric institutions as they were in the 1960's. Nothing has changed.

 

[thegreenhand]

First of all, what you say isn't true. Psychiatrists who attend in offices prescribe SSRIs and SNRIs as first-line therapy because the people who go there usually have mild depression - and it's really only SSRIs, since the only true SNRI is clomipramine, which is definitely not prescribed as a first-line therapy. The psychiatrists that treat severely depressed patients in institutions actually pretty much don't use SSRIs and SNRIs at all. They use pretty much only tricyclics and MAOIs - besides Lithium and ECT. The only "modern" antidepressants used for severe depression by psychiatrists in clinics are paroxetine, which is a very strong SRI, and bupropion in the mistaken believe that it is a DRI(it is weak with an IC50 of 6.5 Umol)

As for why doctors and psychiatrists who attend in offices(the drugs they use in offices are completely different from the ones they use in clinics to treat seriously depressed people) have switched from tricyclics to SS(N(RIs, has to do with safety and need. People that go to offices tend to have less severe depression, so they don't need tricyclics, and since the SSRIs are much safer, that is what they prescribe. Those same psychiatrists continue to use clomipramine, imipramine and phenelzine for people that are suicidal. They used to treat people with mild depression with the same drugs used to treat serious depression up to early mid 1980's because there were no alternatives. Now there are safer alternatives, and since their depression does not require extremely powerful antidepressants, the safer alternatives are the obvious choice. Hence "need and safety".

The tricyclics and MAOI's are much more effective for suicidal depression than the modern SS(N)RIs, but they are also a lot more toxic, with more serious side effects and pharmacological interactions. For instance, tricyclics are very cardiotoxic, and will cause cardiac arrest in overdose. That is because most tricyclics are potent Sodium channel blockers, so they paralise the heart in overdose. Likewise, the non-selective MAOIs can cause hypertensive emergency when combined with tyramine from food and sympathomimetic releasers, many of which are used in anesthesia or sold over-the-counter. They can also caused serotonin syndrome when combined with several opioid analgesics. In fact, they cause lethal serotonin syndrome in overdose, unlike the SSRIs, which produce only mild serotonin syndrome in overdose when taken on their own.

Their greater toxicity, as well as their greater potency which causes greater and more severe pharmacological interactions, and the availability of effective alternatives for mild depression, explains why their use has declined. BUT they are still the "standard" for treating people with suicidal depression. They remain as used today in psychiatric institutions as they were in the 1960's. Nothing has changed.

Thanks for the insight, I’ll admit I wasn’t looking at data for script rates more so just looking at people I know who are prescribed antidepressants. I knew the safety profile was worse than SSRIs but not to that extent.

Thank you for enlightening me!

 

[paracelsius]

why did psychiatrists move to SSRI from MAOIs? money quite simply put. MAOIs patents run out in the 1990s or so they stop being marketed by BigPharma and replaced by SSRIS which at the time have patent protection think of Lilly Prozac which made the company billions$$. so SSRIs were aggressively promoted by BigPharma with Big$$ even though there were no evidence they are any better. Now the SSRIs patents are running (all) out, you'll see newer AD on the market (maybe psychedelics or ketamine-like dissociatives..

 

[Rectify]

Fewer lethal overdosages primarily.

 

[dopamimetic]

Somewhat OT, but what's the deal about moclobemide? It is a powerful RIMA as it does heavily potentiate the hypertensive effects of amphetamine, as just 1-2mg of that prove but it did nothing at all for mood, just felt strangely cognitively limiting at 600mg/d. As MAOIs generally seem to have superior efficacy to reuptake inhibitors, the only plausible option appears to be that it doesn't really cross the BBB in some individuals as I know of a few similar reports from other individuals ...

Could you do something like taking an irreversible MAOI and a handful of MAO-A enzymes before every meal, as the irreversible MAOI will have formed stable complexes with the endogenous MAO and thus not or less deactivate the ingested MAO? Somewhat like the lactase pills for lactose intolerant people.

Also, anybody having experiences with S/NRI and tricyclics and can compare their efficacy? It's not objective but sometimes I trust more in individual reports than small scale studies ...

 

[polymath]

Could you do something like taking an irreversible MAOI and a handful of MAO-A enzymes before every meal, as the irreversible MAOI will have formed stable complexes with the endogenous MAO and thus not or less deactivate the ingested MAO? Somewhat like the lactase pills for lactose intolerant people.

Then there's also this:

EMSAM (deprenyl patch): how a promising antidepressant was underutilized - PMC

The EMSAM patch is a unique monoamine oxidase inhibitor (MAOI) being the only antidepressant utilizing a transdermal delivery system. This was welcomed by clinicians who hoped that EMSAM would be better tolerated than oral MAOIs and non-MAOI ...

www.ncbi.nlm.nih.gov

Recently (2008 ), EMSAM ([R]-[-]-N, 2-dimethyl-N-2-propynylphenethylamine), a MAOI, was developed and approved as an alternative antidepressant with a novel transdermal delivery system. The transdermal delivery system was believed to offer a number of unique advantages. This mode of administration (transdermal) has provided for a beneficial pharmacokinetic profile, avoiding first-pass metabolism with gradual absorption over 24 hours and reduced absorption peaks.9 EMSAM, at low doses, is a selective MAO-B inhibitor (MAOI-B); at the doses approved (6–12 mg/ 24 hours), it is actually both a MAO-A inhibitor (MAOI-A) and a MAOI-B. But since transdermal administration avoids direct gastrointestinal exposure and first-pass effects, there is no significant MAOI-A inhibition in the gut. A tyramine-free diet is unnecessary for the dose of 6 mg/24 hours but is required for higher doses (9 mg and 12 mg dose) due to limited safety data for higher doses as judged by the FDA.10 The side effect profile for EMSAM 6 mg was no different than placebo except for an increased incidence of patch-site reactions (mild contact dermatitis).10,11 In summary, EMSAM has been shown to be a highly effective antidepressant for MDD (for acute and maintenance treatment) in double-blind placebo-controlled studies with a reduced risk of many of the side effects noted for oral MAOIs, particularly the “cheese reaction”.11–14 There have been three pivotal short-term (6–8 weeks), double-blind, placebo-controlled studies – two of these being a fixed dose of 6 mg11,12 and one being a flexible dose study of 6–12 mg13 – and one long-term (52 weeks), double-blind, placebo-substitution fixed dose (6 mg) study.14 Interestingly, one of the short-term studies found drug–placebo differences starting as early as the end of week 1 of treatment, suggesting an early onset of action not usually seen with antidepressants.

 

[dopamimetic]

Oh yeah certainly I am interested in EMSAM, just my own experience with 5mg selegilin and the similar reports about EMSAM in another thread (think it was the 'gold standard' one) make me very wary. And of course it isn't available in the EU.

They should make a tranylcypromine patch!

 

[fm3]

I just read something that talked about how pharmaceutical companies came to the realization that "activating" antidepressants were leading to suicides and that was the starting point of SSRI development.

 

[dopamimetic]

I just read something that talked about how pharmaceutical companies came to the realization that "activating" antidepressants were leading to suicides and that was the starting point of SSRI development.

Hmmh I thought this was especially a problematic of S/NRIs, they carry a black box warning and for some people like me the majority of them is heavily stimulating in a way somewhat worse than amphetamine. And it's not necessarily NE, as citalopram was the worst, had some serious outbursts on it and the situation did not improve for I think 3 months. Paroxetine rendered me hypomanic and straight out unable to sleep to the point of heavy deprivation. Venlafaxine in doses which relevantely increase NE are uncomfortably speedy yet less emotionally bad.

Never was on a tricyclic besides the weak opipramol so I can't compare but they having additional effects like H1 antagonism or channel blockade etc looks like they were less prone to impulsivity? A doc told me He doesn't prescribe amitriptyline anymore cause of strong side effects like dry mouth (and the mentioned suicide risk but of course they won't point you to that).

I wonder about what the limiting factor about SERT inhibition is, why there's no way to reach even light empathogenesis with them when DAT inhibitors can make stimulants on par with releasers. Or is that only true with inverse agonists like MPH/coke - and do SERT inverse agonists exist?

 

[fm3]

The dry mouth on Amitriptyline makes sense when you look at the similarities it has in structure with Diphenhydramine.

Can you believe 9,000,000 Americans are still prescribed Amitriptyline as of 2017? Off-label uses must be one reason.

Yet you are lead to assume that TCA's are a relic of the past in the world of Antidepressants from surface-level study of the topic.

 

[dopamimetic]

The dry mouth on Amitriptyline makes sense when you look at the similarities it has in structure with Diphenhydramine.

Ok then that Doc exacrebated (or it's highly individually variable) as from 50mg diphenhydramine, I get just a little sedation, nothing more. A silly experiment involving 10x 50mg gave me very weird physical feelings and some anxiety, yet no relevant dry mouth or the least sign of seeing spiders*. Got pronounced dry mouth with some other chem though but forgot what it was. Guess an antipsychotic.

Now anticholinerges appear to have rapid antidepressant activity but continued use is bad for brain health - but how bad is it really, as even paroxetine has ACh affinity?
Guess I will give amitriptylin a spin, as venlafaxine is the only S/NRI I tolerate (except fluvoxamine/fluoxetine which I havent tried) and lost its efficacy over time and while tranylcypromine sounds best, the risk of accidentally eating something tyrosine rich feels too real.

* (these were part of the reason for the experiment. Well at least did I try it alone; in earlier time DXM and DPH were often listed together, maybe cause of the similar abbreviations, and the probably wrong myth that you should take one DPH alongside a recreational dose of DXM to avoid nausea. I blindly copied this and found out that even these 50mg can and do add dark, psychotic hints. Auditoral hallucinations in particular.

Together with that calculator - the FAQ clearly states that the required doses vary greatly based on individual metabolism (and that grapefruit probably potentiates**) - but the calculator is understood in a way of why not directly aim for a higher plateau - 1 out of 4 indeed sounds bory - and of course you don't want to ruin your experience, so better go safe & add 3x 50mg DPH to a 3rd plateau. I suspect this to blame for at least part of psychosis in new DXM users specially in past time, guess today less people consult FAQ & calculator but instead orientate on forum reports.)

** Again, you read in many first time reports that they downed multiple litres of juice.

 

[fm3]

I guess it does make some sense that doctors would be more comfortable prescribing it to patients for OCD and chronic neuropathic pain when those individuals are not in the risk population for suicide like those with depression are.

It's interesting that Amitriptyline seems to be effective at treating a wide variety of ailments (IBS, Migraine, OCD, ADHD, Parkinson's Disease, Bipolar, Major Depressive Disorder, Neuropathy/Fibromyalgia, Bedwetting, Anxiety, Tension Headaches) and is actually indicated for many of the above in other countries.

Between the 9 million RX'ed Amitriptyline and the 3 million RX'ed Nortriptyline in the USA 3.6% (12/328 million) of Americans?

 

[dopamimetic]

I guess it does make some sense that doctors would be more comfortable prescribing it to patients for OCD and chronic neuropathic pain when those individuals are not in the risk population for suicide like those with depression are.

Just that it makes absolute sense to be hesitant about prescribing me a tricyclic then but at the same time hand me out 1-2 weeks worth of morphine and lorazepam. With these together suicide would be pretty easy.

 

[Flower Fairy]

It's interesting that Amitriptyline seems to be effective at treating a wide variety of ailments (IBS, Migraine, OCD, ADHD, Parkinson's Disease, Bipolar, Major Depressive Disorder, Neuropathy/Fibromyalgia, Bedwetting, Anxiety, Tension Headaches) and is actually indicated for many of the above in other countries

I know right, how can it help so many things

I was on it for fibromyalgia but it caused nightmares and a really dry mouth and eyes, and constipation so I stopped it, now I'm back to aching all the time, stiffness and aches and pains, and I'm not allowed anything decent

Yesterday I even done a CWE on 6 x 30mg codeine/500mg paracetamol and that still didn't help

What's up with that, codeine not helping, I know its shit as a high and don't do anything for me but I thought it would if helped my aches and stiffness etc

 

[Skorpio]

Opioids generally aren't great at treating fibro pain. Often ion channel fuckers like amitriptyline or gabapentin are used.