In Greg’s Dilemma 1 and Dilemma 2, Greg outlined more than one dilemma linked to getting hooked to antidepressants and benzodiazepines. The responses to these posts were all over the shop – from pull yourself together, to entrust your life to God, to support for descriptions of positions others find themselves in. The responses also split in terms of what the response should be – should it be to outline steps that might be practical and helpful or was the issue as much about why we are voiceless and what can be done about that.
The clinical and neuroscience establishment view of antidepressants (Dr Junig) is caught in the image above – taken from an advertisement for one of the SSRIs just before launch. This will be a drug that goes exactly and only to where it is needed and does the job that is needed. This drug is a Magic Bullet.
This is the kind of image used to hypnotize Dr Junig and a lot of other doctors and even more the insurers and others in the business of covering our healthcare costs. Any other problems you have with these drugs are linked to the rest of your neurons which are clearly messed up or we wouldn’t have been giving you these wonder drugs in the first instance.
The idea of a Magic Bullet came from the use of Methylene Blue to stain cells in the 1870s. This was a time when the idea that the key unit of the human body and of disease was the cell was a new idea and when bacteria were still not fully accepted as a cause for infections. Paul Ehrlich, using new dyes just created by chemical companies, was able to stain the germ that causes sleeping sickness (trypanosomiasis) with Trypan Red, and stain malaria parasites with Methylene Blue.
Methylene Blue also stained nerve cells, and helped prove they had long axons that acted as a means of communication between cells.
On the basis that it visibly acted on these cells, as early as the 1890s, Methylene Blue was tried out in malaria and in psychosis. The effects on malaria were not compelling although the parasite cleared from blood. The effects on psychosis were clear enough – it tranquilized – but not sufficiently striking it seemed to warrant continued use.
These are extraordinary hints however because Methylene Blue is essentially a phenothiazine – the structure from which Rhone-Poulenc’s chlorpromazine and the early major tranquilizers (antipsychotics) came. The striking benefits of chlorpromazine led other pharmaceutical companies to look for similar structures.
Geigy turned to Summer Blue and from this created the tricyclic antidepressants, most of which are serotonin reuptake inhibitors. From these drugs the SSRIs subsequently came.
But far from being highly specific drugs that go to one place only, Methylene Blue and Summer Blue coat nerve and other cells pretty completely as the image of cells stained with Methylene Blue below shows. These drugs may hit certain receptors but they certainly hit a lot of other things as well – likely including Sodium, Potassium, Calcium and TRP channels – see the Complex Withdrawal and PSSD section.
It was realized pretty quickly that the tricyclic group of drugs had some pain relieving properties. While we usually think of carbamazepine (Tegretol) as an anticonvulsant, it is in fact a member of the tricyclic class, and one of its most striking effects is the relief it produces in the severe facial pain of trigeminal neuralgia where soon after it was first used it became the drug of choice.
There are millions of people around the world who have been put in tricyclics or SSRIs for pain relief with amitriptyline, the second oldest tricyclic, now being among the most commonly used drugs. At first the hunch was that these drugs improved mood which made any pain more tolerable but it is now very clear that drugs like amitriptyline can have a direct analgesic effect. Who knows their effect on mood may be secondary to their pain (dysphoria) relieving effects.
In the Complex Withdrawal and PSSD section, one of the ideas put forward is that many of the problems people have come from antidepressant actions on peripheral nerves. This idea comes from a simple observation that anyone reading this can replicate for themselves. Within thirty minutes of having an SSRI most people can feel some genital numbness. This is not unlike the numbness that comes from rubbing a small amount of the local anesthetic lidocaine onto genital skin. This effect underpinned lidocaine’s use to manage premature ejaculation – a market that the SSRIs now occupy.
Lidocaine genital numbness seems to comes from its effects on Sodium channels. This thought led to the hypothesis that perhaps what is happening in Post-SSRI Sexual Dysfunction (PSSD) and in complex withdrawal is linked to disturbances of Sodium channels.
The local analgesic (lidocaine like) effects of amitriptyline are now so clear that it has in recent years been used as a local anesthetic in its own right.
In 2004, Jean-Pierre Estebe and Robert Myers published a paper looking at the safety of amitriptyline given as a local anesthetic. Their main findings are in the image below. Applied locally to nerves amitriptyline caused a dose dependent destruction of nerve fibers and their myelin sheaths in rats.
The nerves in these images are stained with Methylene Blue. The immediate effects of the lowest dose are seen on the upper left. The later effects of the higher dose are on the lower right. Nerve cells have been destroyed after exposure to doses that are in the clinical range. The black dots are fatty deposits where nerves once were.
Here is the full paper on Amitriptyline Neurotoxicity.
The meaning of blue
There is a temptation not to raise something like this, but in these days of crowd-sourced research someone is going to find articles like this and trying to explain them away after the fact will not be convincing.
The article doesn’t absolutely nail down beyond a shadow of doubt that some of the problems of dependence and protracted withdrawal and of PSSD come from irreversible nerve damage. But it certainly opens up this possibility.
There is good evidence that some people with PSSD can for instance have temporary relief from their problem suggesting that the disturbance of function is temporary rather than permanent.
There is enough here to warrant giving serious attention to people when they report ongoing difficulties. Helpful suggestions to Greg or anyone else need to take this into account.
Its probably worth bringing the article along to some prescribers – not to confront or antagonize them but to see if some can be recruited to finding answers. The answers might come from the one per cent of us who feel left outside the tent at the moment, but they are more likely to come if we can recruit some of the ninety-nine per cent still inside to engage with the issues.