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Classics in Chemical Neuroscience: Amitriptyline

This was really helpful for neuropathic pain for me. It also works for psychogenic cough.
 
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That is the interesting thing about amitryptaline, it's other uses were discovered purely through serendipity rather than 'indication creep' which is common in medicines developed after the early 1980s.

It's like the first class of antidepressants, the MAOIs. They were trialled as treatments for tuburculosis and it was noted that many of the cohort of patients who were suffering clinical depression found significant relief.


They were the first and are very effective but the multiple toxicities and diet restrictions make them difficult to use clinically in a safe manner.

But 64 years after it's introduction, new antidepressants are compared with amitryptaline but often in a VERY dubious manner. For example, studies on paroxetine stated that it had 'similar effacacy to amitryptaline' BUT they were prescribing the control group tiny doses of amitryptaline and the test group the highest prescribabde dose of paroxetine... because medicinal chemistry isn't particularly ethical.

It's extremely difficult to model clinical depression in animals and it may well be the case that while the major action of amitryptaline is on extracellular serotonin and extracellular norepinephrine levels, it's likely that those other activities are also important to the action of the drug.

I was told that only one in around 10,000 candidate antidepressants is ever licenced for use in man. So while some even made it to stage 2 human trials which roughly means they are likely not toxic, an enormous number aren't developed further simply because they don't work.

All manner of different targets have been suggested but it seems that amitryptaline is still considered the 'gold standard'. The only issue is that it IS toxic in overdose. Well, if you are concerned that a patient may intentially overdose on a tricyclic, only issue a 7 day supply. Yes, they could hoard the medication but I would suggest that anyone who is prepared to plan for weeks to end their own life (as opposed to someone having a dreadful moment and necking all the pills) will find another way.

So by no means perfect, but still considered the most effective antidepressant. By that, I mean it works for around 43% of patients. Yes, even the best works for less than half the people prescribed it.

But the SSRIs were designed to tackle the toxicity issue and I contend that they did so at the expense of effacacy. Certainly none has ever claimed to be better.
 
I'm gonna do some amitriptyline now. My usual dose is 150mg in the evening.
 
Well, be aware that it does carry a risk. It doesn't even work for the majority of people - but then no single antidepressant does.

You will note that several homologues were also covered and a small Danish study suggested that chloripramine MIGHT have a slight edge on amitryptaline.

I would certainly say to anyone prescribed 150mg/day or more of amitryptaline might want to consider things like a history of heart problems within the family and if so, ask if an ECG is appropriate. I mean, we really SHOULD be giving more ECs to people prescribed medications that have the capacity to be cardiotoxic. It's not invasive or nasty although I always kept finding the sticky-pads on my clothing for days. Not dangerous, but my sister did point out that I looked like an idiot with several of them stuck on the back of my teeshirt.

It's your health, don't be scared to ask.
 
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I would be VERY careful. 150mg is the maximum daily dose prescribed in the UK and that's supposed to be divided TID. If you are prescribed anything else or indeed consume anything else, who knows what the risks are?

In fact the BNF specifically states that doses over about 100mg/day should be prescribed with caution.

Don't forget, no antidepressant is meant to work immediately. It can take 2-4 weeks to reach full activity.

At the very least make someone else aware of what you are consuming. I've known people who intentially overdosed on amitryptaline and died. One did not intend self harm, they just thought it would provide an ASC.

If the worst happens, if it's known that amityptaline has been consumed, their is a (pretty successful) protocol for treatment.

Lastly - don't forget that appropriate councelling is proven to be FAR more effective than any medication. But not CBT (or as I term it 'one size fits none') but rather person-centered techniques which I am the first to say can take a long time. But they do have the virtue of being the safest.
 
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Note prescribing of tricyclics, to whit:

Avoid in patients at risk of arrhythmias.
Consider ECG at higher dose or when co-administered with other drugs that may increase the risk e.g. fluoxetine.
Increased cholinergic burden, especially when co-prescribed with other anticholinergic drug.

I should add that it is my belief that the anticholinergic action of TCAs is a key part of their activity.


Now there aren't many decent papers on the topic but I hope you get the idea.
 
4DQSAR said:
That is the interesting thing about amitryptaline, it's other uses were discovered purely through serendipity rather than 'indication creep' which is common in medicines developed after the early 1980s.

It's like the first class of antidepressants, the MAOIs. They were trialled as treatments for tuburculosis and it was noted that many of the cohort of patients who were suffering clinical depression found significant relief.


They were the first and are very effective but the multiple toxicities and diet restrictions make them difficult to use clinically in a safe manner.

But 64 years after it's introduction, new antidepressants are compared with amitryptaline but often in a VERY dubious manner. For example, studies on paroxetine stated that it had 'similar effacacy to amitryptaline' BUT they were prescribing the control group tiny doses of amitryptaline and the test group the highest prescribabde dose of paroxetine... because medicinal chemistry isn't particularly ethical.

It's extremely difficult to model clinical depression in animals and it may well be the case that while the major action of amitryptaline is on extracellular serotonin and extracellular norepinephrine levels, it's likely that those other activities are also important to the action of the drug.

I was told that only one in around 10,000 candidate antidepressants is ever licenced for use in man. So while some even made it to stage 2 human trials which roughly means they are likely not toxic, an enormous number aren't developed further simply because they don't work.

All manner of different targets have been suggested but it seems that amitryptaline is still considered the 'gold standard'. The only issue is that it IS toxic in overdose. Well, if you are concerned that a patient may intentially overdose on a tricyclic, only issue a 7 day supply. Yes, they could hoard the medication but I would suggest that anyone who is prepared to plan for weeks to end their own life (as opposed to someone having a dreadful moment and necking all the pills) will find another way.

So by no means perfect, but still considered the most effective antidepressant. By that, I mean it works for around 43% of patients. Yes, even the best works for less than half the people prescribed it.

But the SSRIs were designed to tackle the toxicity issue and I contend that they did so at the expense of effacacy. Certainly none has ever claimed to be better.
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The sedating effects even at 25 mg for me was intense. I don’t know how people could be awake on higher doses.
 
SeekingOblivion said:
The sedating effects even at 25 mg for me was intense. I don’t know how people could be awake on higher doses.
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That's why it's often prescribed to be taken at bedtime. Most people develop tolerance to the sedative side-effects but it's one of the issues that the SSRIs were intended to solve. But I contend that one of the most common symptoms of clinical depression is anxiety and for such people amitryptaline can treat that symptom very quickly.

Nortryptaline is supposed to be less sedating and I suspect it was introduced to deal with the sedation some people suffer and it is a metabolite of amitryptaline, but I'm not sure how the tricyclics compare. I don't think anyone has been able to prove one is superior, or, rather, not is reliably superior.
 
4DQSAR said:
That's why it's often prescribed to be taken at bedtime. Most people develop tolerance to the sedative side-effects but it's one of the issues that the SSRIs were intended to solve. But I contend that one of the most common symptoms of clinical depression is anxiety and for such people amitryptaline can treat that symptom very quickly.

Nortryptaline is supposed to be less sedating and I suspect it was introduced to deal with the sedation some people suffer and it is a metabolite of amitryptaline, but I'm not sure how the tricyclics compare. I don't think anyone has been able to prove one is superior, or, rather, not is reliably superior.
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Interesting, thanks. I have found SSRIs terrible and have long wondered if tricyclics or even MAOIs could help. I wish tianeptine was allowed in my state.
 
Clinicians rarely tell patients that it's more likely than not that any given antidepressant WON'T work. Even amitryptaline is only effective for about 43% of patients. That's still higher than any other antidepressnt I am aware of.

My theory is that when prescribed an antidepressant, a person may still suffer low mood but will wonder if they would feel even worse without the medication so they don't go back to their doctor after 28 days to say the medication isn't working. I know I suffered when, looking back, I was being a prescribed an antidepressant that is now regarded as being little better than a placebo. When I got REALLY ill, my sister took me back to the doctor and told him to give me amitryptaline. Now that DID work for me, but one person is not of statistical value.

I posted that link given to doctors in the UK and I feel that while maybe certain SSRIs may be considered first, if an SSRI fails, a second SSRI is less likely to work than a different class. In fact I think that was the protocol back then, so I suspect the doctor was already going to choose a tricyclic.

Even MAOIs have there place. If both SSRIs and tricyclics fail, as long a a patient is prepared to accept the risk and stick to the dietry restrictions, they should be given a try. Clinical depression can lead to very bad outcomes. So even as a DLR, MAOIs should be considered.

But I was prescribed amitryptaline for neuropahic pain and realized I just felt much better (and the pain levels went down) which is when I went back and really read every paper I could find on antidepressants and realized what an absolute shitshow the entire class IS.

A handful of medications that really do seem to be of value along with a host of 'me too' drugs (i.e. if one pharmacutical company releases an SSRI, every other pharmacutical company rushes to have a product - for the MONEY) and the entire human trials were rigged to make those 'me too' drugs look like they work.
 
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I would be extremely careful in asscribing a specific action in the brain as the cause of clinical depression. I'm old enough to have seen dozens of mechanisms proposed. It may well be the case that like schizophrnaia, it's actually more than one illness that presents with the same set of symptoms.

Often we don't know if a given action is the cause OR is the result of something further upstream.

Certainly if animal models agree one one thing, it's that depression in man cannot be modelled in animals very well. Hence so many candidates that showed robust antidepressent action in animal models proved to be of little or no value in man.
 
In the butaclamol chapter in chronicles of drug synthesis the following is written:

It is evident from a cursory inspection of the structures of imipramine and chlorprothixene, both inspired by the phenothiazines, that the stage was set for the synthesis of amitriptyline. In fact, no less than 15 independent groups in Europe and North America were involved in the study on amitriptyline and related dibenzo[a,d]cycloheptenes. The competition to synthesize amitriptyline was so fierce that five applicants were involved in a patent interference declared in the United States Patenbt office.
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I can believe it. No doubt someone had noted that amtohistamines such as promethazine had quite a robust antidepressant action BUT was not optimized for that indication.

I wonder if the competition was for the FIRST synthesis so that one partly holds the patent rights OR was it the fact that their success meant a 'lively' industry in finding cheaper synthetic routes culminated with echical standards even lower than is common to medicinal chemists?
 
4DQSAR said:
I can believe it. No doubt someone had noted that amtohistamines such as promethazine had quite a robust antidepressant action BUT was not optimized for that indication.

I wonder if the competition was for the FIRST synthesis so that one partly holds the patent rights OR was it the fact that their success meant a 'lively' industry in finding cheaper synthetic routes culminated with echical standards even lower than is common to medicinal chemists?
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Promethazine is another one that is too ignored imo both in psychiatry and physical medicine. It’s considered old, clunky and anticholeragenic. Except for pregnancy associated nausea and vomiting. But it has instantly given me relief from anxiety. Can’t function on it directly because it is too sedating, but it has an immediate anxiolytic effect that is beyond just sedation, and I wake up with a much better mood from it.
 
SeekingOblivion said:
Promethazine is another one that is too ignored imo both in psychiatry and physical medicine. It’s considered old, clunky and anticholeragenic. Except for pregnancy associated nausea and vomiting. But it has instantly given me relief from anxiety. Can’t function on it directly because it is too sedating, but it has an immediate anxiolytic effect that is beyond just sedation, and I wake up with a much better mood from it.
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It's still available in many nations. I have a box of it in front of me.

Always have a box handy - lasts me many months but handy. I just buy it at the local Boots.
 
4DQSAR said:
It's still available in many nations. I have a box of it in front of me.

Always have a box handy - lasts me many months but handy. I just buy it at the local Boots.
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Oh it’s available in the US by prescription, but rarely used out of hospital settings
 
Well, I can only speak of the UK. I'm uncertain what the legal position of the stuff IS in the US. Is it prescription only or is it simply so old that nobody sells it any more. I mention that because a couple of quite legal antihistamines such as cyclizine are still in theory available from a pharmacy, none of them stock it. It's not a prescriptiom medicine, it's just died out because nobody was buying.
 
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