Illustration: Is There Life After Meds?, © 2014 created by Billiam James
Here is a Question put to the recent RxISK post on Sensory Neuropathy.
I’m a psychologist and I have made numerous attempts to discontinue antidepressants only to experience significant withdrawal symptoms. I’ve been on antidepressants for 25 years at this point and have made four unsuccessful attempts at tapering. I have come to learn that most doctors have absolutely no clue how to taper and have no understanding that withdrawal is a reality that can be severe and long lasting.
After making an attempt to taper off of Effexor last year, I once again began to experience withdrawal symptoms which were mostly sensory in nature. When I started to experience autonomic nervous system symptoms, I then took it upon myself to find a neurologist to do a skin biopsy to determine if I had small fiber sensory neuropathy. She also sought to rule out MS (which I didn’t suspect). Of course, my brain and spine MRIs were normal as was my EMG.
The skin biopsy was positive for small fiber neuropathy which was upsetting but did not come as a surprise. I have significant reduction in the small nerve fiber density. Symptoms, of course, were relieved by the reintroduction of the medication. As far as I know, at this point I don’t have PSSD.
My question is: Is it the process of withdrawal from the antidepressant that causes the small fiber neuropathy or is it from the effects of the drug itself on the body?
Some years ago, groups in Holland and Britain began to champion the idea of hyperbolic tapering of antidepressants – serotonin reuptake inhibiting ones in particular. The idea was to reduce the binding of SSRIs to serotonin reuptake inhibiting sites in a steady way, in part because the way binding takes place means that there can be dramatic changes in how SSRIs interact with the site and these changes may not be the same at all steps in the process.
This idea caught on. World Tapering Day is set for early November. One of the things that tapering and tapering strips can be credited with is helping doctors and others accept the reality of antidepressant withdrawal. This is easier for doctors to accept if they think something positive can be done to help.
It now sounds almost sacriligious to say there can be problems with tapering. But many people find it impossible to taper even taking years. Having been sold the idea that tapering solves everything, they blame themselves.
Others find themselves left with enduring problems – a set of difficulties now termed protracted withdrawal. Again they blame themselves – did I taper too fast?
Antidepressant, antipsychotic and benzodiazepine withdrawal were all described by 1961. At the time opioid, barbiturate, and stimulant abuse and withdrawal had emerged as serious problems and these drugs of abuse captured the terms addiction, dependence, and withdrawal.
The problems these drugs caused were viewed as far worse than anything prescription drugs like antidepressants, antipsychotics or benzodiazepines might cause.
Some of us can stop antipsychotics without too much problem. Some can stop some antipsychotics but not others. Some can stop but have significant and pretty immediate problems – referred to as supersensitivity problems that can include supersensitivity psychosis.
But some of us develop enduring problems on an antipsychotic. The original problem described around 1960 was neurological and ended up called tardive dyskinesia (TD). TD is usually viewed as a motor problem. It emerges while on the drug and can sometimes be ‘managed’ by increasing the dose or reinstating the drug if the problem appears on stopping treatment.
There is a physical dependence here, and an element of tolerance, but no addiction, or craving. After stopping treatment, TD can endure for years.
The term tardive originally meant that this problem did not appear immediately after starting treatment, but TD has shaded over into meaning a protracted or enduring dyskinesia after treatment is withdrawn. Six decades of research has brought us no closer to solving the mystery of TD.
We now recognise that there are tardive akathisia, tardive dysthymia and other tardive states that withdrawal from antipsychotics can cause.
I wrote three papers on antipsychotic withdrawal in 1998, 1999 and 1999. These were efforts to smuggle antidepressant withdrawal into the literature – even adopting the term discontinuation syndrome rather than withdrawal to smooth the path.
[The comments following Antidepressants and Premature Death on the topic of smuggling things into the literature are pertinent here. In this case, the smuggling was into a journal edited by Dave Nutt – who was not inclined to believe any psychotropic drugs, even benzodiazepines, caused problems].
These antipsychotic withdrawal articles were about the tardive dysthymia, akathisia and what today would be called protracted withdrawal. This is now much more widely recognized with several RxISK posts on the topic that have hundreds of comments. See Sally’s Story, Still Treading Water and The Invisible Doctor.
Eli Lilly were busy at the time telling doctors about antidepressant discontinuation syndromes. Their target was paroxetine, whose short half-life supposedly caused problems that the long half-life of fluoxetine (Prozac), with its built in tapering mechanism, didn’t cause. This was marketing not science.
SmithKline (SK) and later GlaxoSK fought back claiming paroxetine was not addictive or habit-forming or dependence causing and that it had no withdrawal syndrome linked to it. DSM and most doctors and professional bodies went along with this word-play. All GSK would concede is that there can be ‘Symptoms on Stopping’ – SoS.
Shelley Jofre tackled this word play in the Panorama paroxetine programs. As she put it, most of us don’t want to know if SSRIs are addictive like opioids. We want to know whether we can get off them or not. If we can’t stop when we want, most of us figure we are addicted or hooked.
Ask a doctor if TD is a withdrawal syndrome and they will say no. Push them on what it is and they may uncertainly say nerve damage.
Like TD, Post-SSRI Sexual Dysfunction (PSSD) can start on treatment but is most notable on stopping. Like TD, it can last for years after stopping. It too looks like damage – although neither are irreversible.
What kind of damage? PSSD looks like a sensory neuropathy, affecting small nerve fibres. Numbness is its central feature, or pain/irritability in the case of persistent genital arousal disorder (PGAD).
Drugs are among the most common causes of sensory neuropathy. Alcohol was the best known cause for most of the twentieth century but in recent decades cancer chemotherapies have emerged as a cause. We can tolerate saying chemotherapies can cause sensory neuropathy because cancer drugs are supposed to almost kill us.
Chemicals appear to be the commonest cause of sensory neuropathies. These include all sorts of environmental toxins, prescription drugs and the recent COVID vaccines – see React19.org.
Just as TD is now recognized as only one of the tardive syndromes linked to stopping antipsychotics, so also PSSD and PGAD are almost certainly only two of the enduring syndromes linked to stopping serotonin reuptake inhibitors. There are enduring akathisia and dysthymia states here also.
There are a set of conditions often termed dysautonomia, a name that concedes damage, although hopefully not irreversible. Dysautonomia is common while on or while withdrawing from antidepressants. These are likely mostly sensory problems.
We don’t think of things inside the body as sensory but the autonomic system is primarily sensory. Out internal organs sense just as much as our external senses do and the vigilance systems in our brains pay more heed to sensory inputs from within than to those from without.
There are cardiac problems as outlined last week – Antidepressants and Premature Death.
Many cases of apparent urinary or prostate infections are interstitial cystitis (IC) which antidepressants can cause – see Girl on a Hot Tin Roof.
TD is usually thought of as a motor disorder, but even it may be a sensory problem, with the disturbance lying in the small fibres in our joints mediating proprioception. Parkinson’s disease, often thought of as a motor problem, also comes with painful sensory symptoms and the dopamine agonists used to treat it cause protracted withdrawal syndromes with many sensory features (Dopamine agonist Withdrawal Syndrome).
There is another piece to the jigsaw. Antidepressants are known to have analgesic effects – that are not opioid or anti-inflammatory effects. They share this action with anticonvulsants like carbamazepine, gabapentin and pregabalin and benzodiazepines, all of which are used in sensory neuropathies to relieve pain.
This gives rise to what we called Greg’s Dilemma in an earlier post. (There are a series of relevant posts featuring Greg – such as Riding a Bike Backwards). These drugs can alleviate painful symptoms occasionally – but at the price of potentially causing a more extensive problem over time. This image, featured in Greg’s Dilemma, shows amitriptyline working as a local anesthetic for rats causing nerve damage.
The image below is the traditional medical view of sensory neuropathy. Companies want to offer you a drug for this – Lyrica most recently – see Kicking Lyrica and The Day the Lyrics Lied. This is a very limited view of the sensory neuropathies which can involve every bit of the body and not just the feet and drastically impair our quality of life down to making us question if we are still ourselves.
A medical colleague got in touch some years ago, after finding to his surprise it was hard to get off the SSRI he was on. He eventually did and felt better but not good. Better because he could now do things the antidepressant inhibited. But he was still not right.
Several years later, rather abruptly, the colour came back into his life – he was normal again. This points both to the capacity of systems to regenerate but also to how profoundly disturbances to sensory systems can affect us.
Many with protracted withdrawal, or PSSD, report emotional numbing and depersonalization and see these as even worse than PSSD. These conditions are exactly what might be expected of a sensory neuropathy, which cuts off inputs to our brains that feed our emotions and givs colour to our lives.
The big problem for anyone with a sensory neuropathy is these conditions are subjective – like pain they hinge on the doctor believing you. Many doctors are slow to believe us particularly if we are complaining after being put on a pill for ‘nerves’.
RxISK attempted to solve this problem for PSSD by tracking down a machine to do Quantitative Sensory Threshold Testing. This led to a battle with a Parisian company – Impeto Medical and Device Wrecks – who have a QST machine and a genital adapter but they were unwilling to co-operate with us.
The alternative and possibly a better bet is a skin biopsy. As the recent Sensory Neuropathy post shows, several readers have got in touch reporting small fibre neuropathy (SFN) demonstrated on skin biopsy. This is very convincing.
But one comment on this post made clear that a reader with convincing PSSD had a negative skin biopsy.
There is however a paper that addresses just this point, describing a patient with genital neuropathy who had a negative ankle biopsy but positive thigh biopsy. This looks good but at present only ankles have a reference range – we can get results at the thigh and elsewhere and figure they look low but we don’t know what the usual figures are across all ages and sexes.
As the Sensory Neuropathy post made clear though, some discretion is needed when interpreting the results of any of these tests. Neurologists are not used to dealing with SFN in younger otherwise healthy people and a reference range taking in people on lots of drugs with loads of conditions may not be quite right for everyone.
The thigh result suggests a genital skin biopsy might be best of all but no one is likely to want to try one and there definitely is no reference range.
No-one either is going to want to go inside the body for a biopsy in the case of dysautomnia. In the case of vision though there is Corneal Confocal Microscopy which is safe and can be very convincing – but as another comment on the sensory neuropathy post shows that not all people with eye/vision symptoms will show up as having an SFN on CCM.
Still, it would be good to have a way to test genital areas directly and it remains important to get Impeto Medical to play ball. Hopefully readers can help with this.
If you approach a neurologist about a skin biopsy or try to get them to engage with a possible sensory neuropathy, they will suggest doing EMG conductance studies instead. These test motor systems and never show a problem with sensory nerves. It is mostly worse than pointless having one – as they will end up telling you there is nothing wrong with you.
Like most doctors, neurologists prefer the supposed objectivity of motor systems to the subjectivity of sensory systems.
SFN can give clinical pictures consistent with both PSSD and protracted withdrawal from SSRIs, benzodiazepines, anticonvulsants and antipsychotics.
Those of us with protracted withdrawal, like the psychologist above, or PSSD, vision problems or dysautonomia should chase biopsies and SFN and report back to RxISK or somewhere that can compile evidence, which others can use when faced with neurologists reluctant to engage.
[Reports are better with names attached but reports to RxISK (of PSSD in particular) will remain anonymized. The offer to neurologists, however, may have to be that we can put them in touch with you, if you are willing, to confirm that you and others have a similar clinical picture to the patient they are now dealing with. The offer of contact rather than actual contact may be all that’s needed].
SFN is not caused by tapering too quickly, any more than TD is. Testing for SFN before tapering might save a lot of discomfort and heartache. It may be possible to relieve the distress caused by tapering in someone who has SFN by going back on the drug or raising the dose but going back on a drug that has caused nerve damage doesn’t sound like a great option – Greg’s Dilemma.
Those of us who can taper smoothly and are left with little or no residual symptoms are unlikely to have SFN, so not everyone with psychotropic drug dependence should think about a biopsy.
When SFN is present, we need to find ways to stimulate repair of these small fibres. The good news is that it looks like it can happen but may take months or years – as my colleague above found and several people with PSSD have found.
It is worth revisiting the posts on sleep disturbance during SSRI withdrawal. Disturbed sleep and insomnia (Sleep problems after stopping antidepressants, Insomnia The Royal Road to Pills and Nightmares, Forty Winks – and Brain Fog are all found with sensory neuropathies and probably add to the difficulty in making the diagnosis.
These seem Brain related rather than Sensory – and almost suggest keep taking your antidepressants and hypnotics. But they are more likely consequent on disturbed sensory input rather than brain damage.
It is worth paying heed to Bob Fiddaman’s account of managing protracted withdrawal, in the above posts, especially sleeplessness. He remained resolutely drug free and as active as possible. He was doing just the right things to get small nerve fibres to regrow, which they do, including avoiding making the problem worse by trying other drugs out.
Soon after the psychotropic era began, the anticholinergic group of drugs, an old and cheap group of drugs, were branded as the source of all problems. Just get rid of their anticholinergic effects and our new marvel drugs will work wondefully well and have no side-effects – like urinary retention, constipation, blurred vision or anything else.
In the case of the antidepressants anyway, these side effects are all serotonergic or catecholaminergic, not anticholinergic.
Anticholinergics in contrast are euphoriant and likely in a clinical trial of moderately severe depression would beat the SSRIs and be better tolerated.
Benztropine, the best known anticholinergic at one point, which used to be marketed by Merck as Cogentin was withdrawn from some markets some years ago. Not because of problems. It followed publication of a paper claiming that in low doses it promotes nerve fibre regrowth. Looks like Merck might have been thinking about tweaking it to get this effect, and claim they had a new pill for which they could charge a fortune.
See What to do about Sex for links to this article and input on pirenzepine, another anticholinergic drug that might help.
There were later many RxISK posts on Sodium and Transient Receptor Potential (TRP) channels exploring their roles in helping with withdrawal and PSSD.
We may have mistakenly in these posts slipped into viewing these herbs and other treatments as a way to ease withdrawal when they are better seen as possible treatments for enduring problems – once the provoking drug has been removed from the system. These posts are all worth revisting.
Another great comment on the Sensory Neuropathy post points to interactions between VEGF – vascular endothelial growth factor – and the serotonin system. There is a link in the comment reproduced here to a paper showing a role for VEGF in reversing diabetic neuropathy. What we do not know is why these rather old findings have not been picked up
These leads need readers to investigate them further. Having a goal such as finding mechanisms to stimulate small nerve fibre repair is invaluable for any search and holds out promise for a possible treatment.
The Side Effexor Withdrawal post over a year ago, and the three posts on venlafaxine and enduring withdrawal that followed it, introduced the idea of an antidote. A woman, Helen, who could not even begin to taper, found all of a sudden that introducing another antidepressant, dosulepin, freed her up to get off a crippling dose of Effexor rather easily.
The Invisible Doctor introduced the idea that some people who can stop all other drugs easily might have problems with quetiapine only – which can be eased by taking spironolactone. Since this report, I have been aware of others who have greater difficulties getting off quetiapine after being put on an ACE inhibitor for instance – which pulls in the opposite direction to spironolactone.
It is now clear the serotonin and Renin-Angiotensin systems (ACE) interact just as extensively as serotonin interacts with anything else – but we have been ignoring this for a long time.
Its worth noting, though, that spironolactone in its own right can cause akathisia. This is uncommon, more common in children, but definitely happens and is not something anyone mentions when talking akathisia.
These examples suggest that we should be looking for antidotes. Antidotes are not needed for uncomplicated psychotropic withdrawal, where tapering works well. They may help in clinical pictures involving neuropathies.
At this point though we do not know what happens if we then stop dosulepin or spironolactone. Do these antidotes facilitate withdrawal or remedy the neuropathy. Neuropathies can heal but not quickly.
This post opens with a question. The answer seems to be that many of these drugs can cause a sensory neuropathy. Withdrawal can reveal this but does not cause the problem.
Antidepressant dependence caused by people unable to stop for fear of feeling bad now amounts to a serious public health problem – with close to fifteen percent of most Western populations taking these drugs chronically. This is contributing to falls in life expectancy and a reduction of reproduction rates below the replacement level. It is also seriously impairing the quality of life of many of us.
Not everybody who takes SSRI or other psychotropic drugs gets a sensory neuropathy – although there are demonstrable sensory changes in everyone.
It seems likely that the higher the dose, the longer the duration of treatment, and perhaps concomittant use of psychotropic or other drugs, the greater the likelihood of a problem. Some drugs in each group may be worse than others or worse for some of us.
These are matters for which we do not have answers but answers could be assembled with a modest research effort.
Many of us can stop these drugs without much problem. Others can stop without too much apparent difficulty and tapering helps in these cases. Some however don’t feel good afterwards and opt to return to treatment. Some doctors looking at this might figure this person is psychologically addicted to their drugs but a contribution from milder neuropathic changes should be considered in these cases.
For some of us, but we do not know what proportion, many psychotropic drugs seem capable of causing marked problems and in many cases these may be linked to sensory neuropathies. Some have very focussed neuropathies – genitals or eyes. Others have much more extensive problems.
Oaklander Slides See the third comment below.
RxISK acknowledges that the experiences of those who have been harmed by medical treatments are the cornerstone on which it is built, and believes this should be the case for all of medicine.
See Black Robe, White Coat for more detail on this people acknowledgement