Love Actually and Looping Disorders

 

 

None of the psychotropic drugs – SSRIs, antipsychotics – we now have or their clinical effects good or bad have been discovered in/with cohort studies, animal models, brain scans or randomized controlled trials (RCTs). They have been discovered by looking at and listening to people.

At the recent Enduring Sexual Dysfunction Congress and for several decades we have had compelling descriptions of the effects of Finasteride and SSRIs that establish the capacity of these drugs to cause the effects described. We do not need RCTs, cohort studies, animal models or brain scans to legitimize these reports. Irwin Goldstein’s studies on penile smooth muscle and the reversibility of these effects and Will Powers’ genome findings support the legitimacy of personal and clinical observation in a way that animal models, RCTs and cohort studies never could.

These descriptions also open a door to characterizing the problem we are dealing with. It is difficult to move forward without a model for the nature of the disorders we are dealing with,

PSSD and PFS are not

1. disorders in the sense of single gene defects,
2. epigenetic disorders – enduring effects are not necessarily epigenetic,
3. infections,
4. primarily neuro-inflammatory disorders,
5. cancers,
6. drug damage in general,
7. drug induced mitochondrial damage specifically.

Along with many people, I have wondered ir epigenetics or mitochondrial disorders might explain the enduring effects of these problems – one of their mysterious features. As outlined below, it is possible to mention things like epigenetics or mitochondria, along with post finasteride effects on allopregnanolone in animal models but without some indication of the nature of the problem in which these might feature, such statements on their own will be relatively meaningless and at present epigenetic and mitochondrial effects, which produce relatively permanent effects are inconsistent with what is seen clinically.

Feedback Loop Disorder

Another option is a feedback loop disorder.  Will Powers mentioned this at several points in the recent Congress but most of us were so busy counting the gene deletions he also mentioned we missed this.

The notion of a feedback loop disorder (FLD) may sound strange so let me outline the broad brush evidence that PSSD/PFS are FLDs rather than something else.

Several points consistent with FLD were raised by those affected at the Congress.

1. The symptom windows sufferers have, and permanent recoveries some have, are inconsistent with genetic causality, epigenetic effects and cell or mitochondrial damage.
2. The crashes that close windows are often linked to treatments that on symptomatic grounds can look like the obvious treatments to give also supports this viewpoint.
3. Irwin Goldstein’s evidence of penile shrinkage showing apparently dramatic but reversible smooth muscle effects allied to evidence of comparable effects around the body generally linked to both SSRIs and Finasteride support an FLD.
4. A peripheral neuropathy without clear evidence of nerve damage – points to a reversible state. When these states recover there is no apparent damage left behind.
5. We now know these enduring effects happen in visual and other sensory systems and may appear on starting, on stopping or after stopping treatment.

Catatonia offers an example of an FLD that shows features like 1-5 above.

Catatonia

Descriptions of catatonia are recognizable in the Graeco-Roman medical literature from 2000 years ago in a way that almost no other modern disorder except epilepsy and diabetes is. (Manic-depressive illness was not described by the ancients).

Catatonia supplied 20% of the patients in some asylums in the first half of the last century.  It was the most lethal condition in the asylums as some patients developed delirious states and died from them.  People who entered hospital catatonic could remain there for years defecating and micturating in the bed they were lying in. Their failure to recover led to catatonia being subsumed into schizophrenia, a disorder characterized by non-recovery.  Everyone was so certain schizophrenia could not recover, there were skeptical responses to claims of cures and sometimes outright derision.

Despite lengthy hospital stays, catatonic recoveries could happen and people left hospital normal – not psychotic.  It took decades and lobbying and clear evidence of cures for catatonia to be recharacterized as a syndrome independent of schizophrenia.

We had animal models of catatonia but these contributed nothing other than demonstrating drugs could cause the problem.  Making gerbils catatonic (as in this image) became a screening test for antipsychotics but it still took us 30 years to spot that antipsychotics could also cause a lethal neuroleptic malignant syndrome (NMS), now recognized as a form of catatonia.

NMS has links to Malignant Hyperthermia caused by anesthetics and to SSRI induced Serotonin Syndrome.

We could have researched neurosteroids as an explanation for catatonia because cortisol levels fluctuate wildly in this state, along with temperature, blood pressure, heart rate etc. While research on neurosteroids in catatonia should still be done, it would be for what catatonia reveals about neurosteroids rather than what neurosteroids reveal about catatonia.

Catatonia happens in people with physical disorders, or mental disorders or it can be triggered by emotional shocks.  Like cardiac arrhythmias, it is a syndrome that needs management in its own right but also after its resolution the triggering factor may need managing.

Given its mental aspects and faced with patients who seem willful and whose behaviors involve an inability to prevent themselves copying an examiner’s movements or doing the opposite to an examiner’s requests, you might think brain scans would help us nail this down.

Common sense, however, would have said that when we can make seagulls and mice catatonic brain scans are unlikely to reveal much of use. The problem looks like it lies at some lower sensori-motor level. Catatonic patients either feel no pain or simply do not respond to it – you can pinprick their cornea without them even involuntarily flinching.

Does this put us in a serious scientific bind?  No. We accidentally found a cure in 1930 but no-one noticed. We noticed a definite cure in the 1940s. The condition then began to disappear – it is still there but we usually nip it in the bud accidentally without even knowing we have done so.

Faced with a catatonic or NMS patient now, I can restore them to normal in a matter of minutes. I can teach them what to do when they feel an episode coming on to prevent it developing any further. The key is a benzodiazepine in a high dose – it was barbiturates in 1930. When these treatments fail electroconvulsive therapy (ECT) works usually only needing one dose, where treating depression might need 6-12 administrations.

I liaise closely with a full-time epigeneticist on issues like acetaminophen (paracetamol) and birth defects and the link to autism spectrum disorder (ASD) and I’m well versed in the epigenetic effects of valproate and other anticonvulsants, fluoxetine and other SSRIs. The epigenetic effects of acetaminophen come second only to valproate in impacting on ASD genes. Acetaminophen also works on serotonin systems.

At one point, like many of us, I figured epigenetics might explain the enduring PSSD effects. I told my epigeneticist about PSSD and she said nope. She said give them ECT.

Even though I have run an ECT service, prior to Irwin Goldstein’s smooth muscle data I have not mentioned ECT to anyone with PSSD.  Not even after a patient told me he’d been cured by ECT. I was prepared to concede he might have been windowed perhaps but figured it was likely the anesthetic or muscle depolarizing Suxamethonium or Rocuronium given to paralyze muscles had made the difference.  I’ve followed him up over several years and his consistent story has been that ECT was not a complete remedy but made a substantial difference.

On the basis that anesthetics rather than shockwaves might be playing a part I drew up a project and attempted to get anesthetists to see could they induce windows in PSSD patients. They refused to engage.  However PSSD patients get anesthesia for other reasons and the longest window I have seen for PSSD has been 3 months in a person given sevoflurane an anesthetic that damages mitochondria for an operation in a man’s groin area.

Will Powers’ repeated mentions of resetting and rebooting the system map well onto these effects. An FLD points to a stressed rather than broken system. There may, however, be more than one way to reboot stressed systems.

In the case of catatonia, the careful science that brought an extraordinary drop in hospital stays and increase in lives saved came from watching what was happening in and to people right in front of us. It did not come from animal models, brain scans or cohort studies.

Tardive Dyskinesia may be the original enduring post drug dysfunction. For over 60 years,  we’ve checked genes, receptors, enzymes, brain scans etc.  Cohort studies suggest people who have lost their teeth are more prone to it.  In TD there may be also be damage triggered by toxic treatment dosages but at the moment TD stands as a symbol of the failure of careful high-powered science. Have we looked in the wrong place?  We have focused exclusively on brains and been seemingly unaware of the large amount of dopamine in peripheral sensory receptors.

Two Missions

Catatonia reveals another point to note. There are two separable missions. One is to understand a disorder. The other is to remedy it, which can often be done without understanding a disorder’s fine details.  A remedy for some of those affected may reveal more than one disorder. If we remain unaware of this possibility, we risk going around in circles.

I find it difficult to see the lay scientists (demoted to patient advocate status at the Congress – inappropriately?) being prepared to tolerate an extended and careful research program that pushes to one side the research on remedies that Will’s work has opened up. This is not a moment for a triumph of credentialism.

We need to wait and see how Will’s efforts to remedy the problems turn out.  I expect a complex picture – clear responses in some with others not responding – as might be expected from an understanding in principle but only partial understanding of the details of a condition. There may be more than one way to disorder feedback loops that end in comparable final outcomes.

Repeating what Will has done for PFS in people with PSSD may help shed light on this, not least because there are equal numbers of women who have PSSD.

There is also room to think that disordered gut or other microbiota and other factors may be ancillary stressors in some of those affected and that these require careful studies in even more clearly defined subgroups to put right but also to advance our understanding more generally.

The Congress was not just a first congress, it also provided breakthroughs that might not otherwise have happened. These included a recognition that Irwin Goldstein’s smooth muscle changes are happening around the body and not just in genital areas and Will Powers’ evidence that points to possible remedies.

Any consensus statement that comes out of the meeting will hopefully engage with these points.

Genomes

Finally, Will Powers work on genomes, linking deletions to steroid and sexual metabolic abnormalities – see Ending Enduring Sexual Dysfunctions – has left him swamped with requests for screening and another problem – its find to gene screen his own patients and hold their data but it’s not so fine to hold the data or others, least of all several hundred people – see Grasping the Gene Genie.

I hope to set up a liaison with one or more European university departments to help with this but there is scope for a power to the people moment here – an outline of which is laid out in the Gene Genie.

If you’ve read this far in this post, please hop over to the Gene Genie and perhaps hand it on to someone you know who might know something about developing an App of the kind outlined there or might be able to alert us to other moving parts that need taking into account..

Functional Neurological Disorder – FND

An email turned up this morning after posting this from someone whose PSSD was recognized by a specialist but in writing to her Family Doctor, this doctor labelled it FND.

Some neurologists use an FND label to mean something other than a psychosomatic disorder (hysteria) but it is difficult to get them to specify exactly what the differences are or might be and in practice most of the rest of medicine reads ‘hysteria’ or PTSD and refers the person to therapy to uncover buried trauma and/or prescribes an SSRI.

See My Doctor thinks I’m Faking It.

The consequences for sufferers from PSSD and PFS at present of an FND diagnosis are so grim that these conditions should not be designated as instances of FND any more than Catatonia, Tardive Dyskinesia or Type 2 Diabetes are.

An alternate option is for supporters of non-hysterical, non-psychosomatic FND to specify where FND differs not just from hysteria but also from Feedback Loop Disorders.