Benzo with novel activity - potent, fast-acting antidepressant

[clubcard]

https://imgur.com/fIPr67e


Based on the work of Jackson B. Hester (we were






https://imgur.com/uqmgKwS


When Upjohn were taken over, Jack (Jackson B Hester) had got adinazolam in stage 2 but the medical profession discounted benzos - a very good, very fast acting antidepressant was lost. It's action was very different. Potency was much lower and it was it's effect of sleep (increasing neuroplasticity and increasing REM sleep). The goal was to bridge the gap between initial presentation to a doctor and traditional antidepressants beginning to work. It is during this phase that the suicide, parasuicide and other serious risks occured. He had been unable to place a nitro at the 8 position so extended the 1-methyl to a 2-diethylamino moiety. It turns out that the earlier 1-methyl was good enough IF a sufficiently EWG group could be placed at the 8 position.

In forced-swim tests, just 4 hour pretreatment has startling effects. A small cohort study in a small group of people with refractive unipolar depression reported restful sleep, reduced anxiety and was well tolerated. The duration of action is only about 4 hours but when taken at bedtime, it greatly increased REM sleep but did not suppress other sleep phases. This was the worst blow. Having known 2 people who committed suicide, I was aware of the crucial 12-16 day period after presentation.

The duration meant no hangover, reduced sleep onset and re-awakening as well as numerous reports that the emotional content of dreams were much less negative. Having suffered depression, repeated awakening meant that each time I re-entered REM, the emotional content got worse re-entering REM. Synthesis proved problematic with low-yields from -Br -> NO2 step.

I do believe that it had the potential for abuse so a minimum dose for a minimum period of time was the only way to mitigate these issues. In the end, adding Jack's diethyl ethyl amine did indeed improve activity but the synthetic issues made the simpler structure was effective.

The 3 oldest members of the cohort compared it to methaqualone so we carefully looked into AMPA affinity.

Once again, a compound of almost certain value to treating refractive depression but, just like pyeyzolam, it's obvious similarity to more traditional benzos would make medical professionals concerned about dependence issues but 3-5mg before bed did not appear to produce tolerance or dependence.

I hope in future, I hope someone might consider this agent as a starting point for new treatments for the acute phase of depression. Once again, it is likely not the best of it's class but the excitement within the tram within the first week of treatment meant that its eventual cancellation did harm team spirit.

I hope superior medicinal chemists will find these findings of benefit in developing a truly useful treatment for patients in future.

 

[Hodor]

No offense to Hester, but I think the idea of the triazolos being antidepressants has been mostly marketing hype. Remember, *Xanax* was once touted to have antidepressant activity, but at this point, I think it's safe to say that the "antidepressant" effects are simply the result of short-term anxiolysis via positive allosteric Modulation of the GABA receptors (i.e. the same as any other benzo, just more selective for the anxiolytic subunits).

Don't get me wrong: for all its faults, alprazolam is still a godsend for people with panic attacks, and maybe the 5-pyridino benzos would have merited more research for their potentially superior anxiolysis-to-sedation ratio, and yes, I'd much rather take something like Pyeazolam than drink ethanol, but I'm veeery skeptical about claims of benzos producing clinically significant "antidepressant" effects through non-GABAergic means.

 

[Limpet_Chicken]

Hodor-there are several atypical benzodiazepines, 2,3-benzodiazepines rather than the 1,4-benzodiazepine skeleton seen in the GABAa receptor PAM variety most usually (although some 1,4-benzos are of atypical activity such as cholestocystokinin-A receptor antagonist in the case of devazepide, and an mGLuR type II/III antagonist in the case of RO-4491533, and in the case of tifluadom and lofuradom, again 1,4-benzos, these are not GABAergics but instead kappa opioid agonists.

And there are another couple of oddballs, this time atypical 2,3-benzodiazepines, such as the DARI GYKI-52895 and GYKI-52,46 a mixed AMPAr non-competitive antagonist (IC:50 10-20 micromolar for AMPA receptor and about 50uM for NMDArs, with some kainate receptor antagonism, but in the half millimolar or so region, so clinically speaking, insignificant)

So not all benzos are GABAergic at all. And there are some that are both anxiolytic and in excessive quantities, convulsant, that act on the 'peripheral benzodiazepine receptor', now known as the TSPO, or 18-kilodalton mitochondrial translocator protein
, first described as a PNS-located binding site for diazepam. Aside from your generic GABAa sedative-hypnotic positive allosteric modulators, the benzos that doctors dish out, there are a non-insignificant other few groups of pharmacophores present in the benzodiazepine scaffold, depending where the double bonds are and substitution patterns etc. and of quite widely varying effect profiles.

 

[Cotcha Yankinov]

I'd imagine even subunit selectivity at GABA-A could possibly result in a benzo with some antidepressant potential, non-GABA effects notwithstanding

 

[Hodor]

So not all benzos are GABAergic at all.

My bad, I should have been more specific.

Obviously there are non-GABAergic benzos out there - I've been wanting to try tofisopam (probably the most well-known 2,3-benzodiazepine) for years, and even the blockbuster antipsychotic olanzapine (zyprexa) is technically a benzodiazepine (as well as a thienodiazepine).

I'm just skeptical about whether a benzodiazepine as "conventional" in layout as the one postet by OP (electronegative substituent in the 7 position, nitrogens at 1 and 4, aromatic ring at 5, and a triazole ring) is going to produce most of its activity via non-GABAergic means.

 

[clubcard]

Well, I am basing my statements on animal an human studies. Adinazolam has a totally different binding profile to alprazolam. The dose was 30-50mg/day and it's LogP is very similar to alprazolam. As with pyeyzolam, it is the selectivity that produces quite different responses. As I mentioned, the euphoria from alcohol is not due to a steady-state increase in Cl- ions through the α5β1 subunit but a dynamic increase in Cl- ions. Likewise, the action of pynazolam is not due to a steady state increase in Cl- ions through the central α3β1 & α5β1 subunits. The short-term cognitive effects mitigate depression and improve sleep but it is the longer acting indirect increase in neuroplasticity that makes it work for a whole day.

As you have seen, the pyridinylbenzodiazepines are a great scaffold for confiring subtype selectivity. As you know, aromatic nitros are EWGs via 2 different effects which is why it is selective to 2 different subtypes. That is the only limitation of the system. It is hard to produce selectivity to more than one subtype. The -Cl is α2 selective which is why the -Br was chosen. I've read totally invented affinity values. It looks like the results of 2 tests for the α2/α3 affinity have been used to furnish data for all 4 diazepam sensitive sites.

I am not going to be going anywhere with this scaffold so as I have said, it seems to me that sharing what is known (that I can tell) with people who are professionals in the world of drug design. I know of at least 2 people in the field that are on here and several more quite amazing people who are self-taught. I'm sure they are all a lot cleverer than I am so I hope that this unpatented stuff can be picked up and used. It may well be the case that adding an o-'F to the pyridine will not alter activity much and would allow patenting.

It's interesting to put all of the halogens, pseudohalogens, alkanes, alkenes, alkynes, sulfone, sulfonyl, nitro and, well, everything that is shorter than an ethyl and EWing onto the 8 to see the affinity. The nitro gives away the (previously unknown) reason of why it acts as it does and the alkynes and others show that H donators, lone-pairs and so on prove the 8 to be the key moiety. Anyone doing pst-grad would find it a fascinating choice. I cannot post the whole synth but why we started from the -Br is obvious so it comes down to swapping out the -Br. I think I can say that oxygen containing solvents are the key. Specifically ones with more than 1 oxygen. If you think about it, you can see why. Hard-won knowledge for others to take and help find medicines to save life.

 

[markosheehan]

I really appreciate these posts clubcard.

do you have all subunit binding info for clobazam?
Do you know any other 1,5 Benzos with less affinity for a1 than clobazam? is clobazam a full or partial agonist?

 

[clubcard]

The 1,5 benzos bind at the β2 junction. The benzooxazinamine (e.g. etifoxine) bind at the β3 junction. If you put all 3 into Chemoffice, only the angle of the ('2 substituted) benzene (or 2-pyridine in our case) ring differs. On paper they might look quite different but be it software or just a plastic molecular model kit (which has the benefit of actually BEING 3D and is cheap), it is that angle that alters subtype affinity.

Pynazolam mediates effects via α3β1 & α5β1 (but not α1β1 so it isn't like any of the nitrobenzodiazepines or Z-drugs) so it is more predictable. It would only be a bridge between presentation and conventional antidepressant onset; the period the patient is most likely to self-harm. It does not feel like pyrazolam or pyeyzolam. The most important insight we gained was that it is the difference in -Cl ion flow through the subtypes that engenders the subjective effects. Given that the class we went with turned out to have such great selectivity dependent on just 1 site was luck as much as anything. So we did what all researchers secretly want to do - fully explore a pharmacore via the now outdated rational design model.

Of course, it's almost never as simple as we would wish it to be but α5β2 & α5β3 ligands might produce novel conscious states. That α5β1 mediates seemingly ALL the positive effects of alcohol and indeed fully substitutes for it would make it an obvious choice for an alcohol replacement. But who knows what states α5β2 and/or α5β3 ligands might produce? I am prepared to bet that the 8-ethynyl analogue of alprazolam will be very similar to pyeyzolam and of course, the immediate precursor is a chemical of commerce. Given the LogP I would expect it to be slightly more potent. I for one would enjoy something like those premium energy drinks with 2-5mg/l of the alcohol mimic. It will never happen. Kind of annoying considering alcohol kills 2.5 million people per annum. Of course, the $7 billion alcohol industry would go all out to stop it. I was made aware that cheap, blended whiskey is actually distilled to 60% v/w for bulk transport and then diluted. Access to overproof alcohol is always a risk. Likewise, only people with the equivalent of a license to distill alcohol should have access to the undiluted alcohol mimic. Without the pyridinyl moiety, benzos and 4-ring benzos especially aren't very soluble but it's still in the order of 0.5-1mg/ml so spiking people would need to be stopped before it started...

 

[Limpet_Chicken]

As far as spiking someone goes-assholes are going to be assholes, whether it means getting someone hammered on some novel substance, just inducing them to consume too much C2H5OH, or outright resorting to a stab in a dark alley in order to get their rape fix. If someone is THAT much of a fuckup, to begin with, its already there, you don't DO that kind of thing unless you got some nasty piece of shit lurking under the surface to begin with.

As for a more Z-drug like compound, is that REALLY the best idea for public human consumption....
Lets just say I've one or two weird accounts of the likes of zolpidem that really need kept shut up haha. And greater similarity to nitrobenzodiazepines is a good thing IMO. the nitro group seems to be ideal for that crucial EWG, in the likes of nitrazepam, loprazolam etc. And co-incidence that I've never rated any of the other, non-nitrobenzodiazepines at all, for anything like recreational use? And as for the un-blended versions, with alcohol it just makes it worse to consume.

 

[browri]

and even the blockbuster antipsychotic olanzapine (zyprexa) is technically a benzodiazepine (as well as a thienodiazepine).

olanzapine worked great for me for anxiety despite its apparent lack of affinity for the GABA allosteric sites. It's a shame that they didn't really delve into the thieno- class more. Looks like telenzepine was the only other major one that they developed but only for its anti-cholinergic properties. Ideally you would want a thieno- with less anticholinergic activity than olanzapine to avoid diabetegenic effects, but then of course you lose olanzapine's advantage of low EPS relative to other options.

 

[clubcard]

olanzapine worked great for me for anxiety despite its apparent lack of affinity for the GABA allosteric sites. It's a shame that they didn't really delve into the thieno- class more. Looks like telenzepine was the only other major one that they developed but only for its anti-cholinergic properties. Ideally you would want a thieno- with less anticholinergic activity than olanzapine to avoid diabetegenic effects, but then of course you lose olanzapine's advantage of low EPS relative to other options.

I cannot argue if the stuff works for YOU. I will admit losing a friends to refractive schizophrenia. For a decade or more I have said that it is 2 different metabolic irregularities that cause the same set of symptoms. About 90% of sufferers have too many dopamine receptors in one part of the fore-brain, the other have too few NMDA sites in said fore-brain. Samples of cerebrospinal fluid show and/or too much DOPAC (dopamine metabolite) or too little NMD. We are working with the 'dopamine hypothesis;. I mean, 50 years and still drug design is based on a hypothesis. Trials with PCP proved that patients in remission due to medication developed the full set of positive and negative symptoms when given PCP. The refractive patients who end up taking clozapine show an overwhelming propensity to have too little NMD.

It's 2 diseases with the same symptoms. I've bet my wife and I've bet my kids that in my lifetime we will finally agree that it is 2 separate issues and need 2 different treatment regimes. Now I am getting old. I am MUCH closer to the coffin than the cradle but I would die happy if I knew 2 facts were established:

1)That schizophrenia is 2 diseases sharing 1 set of symptoms.
2)The Riemann hypothesis is a fact.

Two kind of odd things but this country has a chronic shortage of eccentrics. When one can garner fame without merit, it is disappointing. Jeffrey Bernard was the oracle Keith Waterhouse channeled and without those people; the people who will bet how many bricks in a cell, how many paintings by an artist or indeed how many flies on a corpse. To make the most of what ephemera abounds. We have nothing left but the clinical, commercial and corporate. Three witches that need burning for the warmth and the light and to give good cheer to the everyday folk.

 

[Limpet_Chicken]

Are we not these days hopefully beyond the burning of witches?

That schizophrenia, is a disease (assuming it is one) with a complex etiology, but the crux of things does sound a lot like there is an ionotropic glutamate receptor hypofunction, particularly NMDA, possibly AMPAr. And a dopaminergic hyperfunction. With the theory that the NMDA receptor acts as a sort of biological molecular 'co-incidence detector' logic gate, that would on the face of it make a lot of sense, with people coming to faulty conclusions through fallacious reasoning, whilst something akin to amphetamine psychosis makes the things acquire threatening character for the sick man.

If one's coincidence detector is triggering in the wrong way, it seems logical that that would cause magical thinking, the ascribing of faulty cause and effect with delusional beliefs. The effects of stimulant psychosis alone, one can override by willpower, sometimes at least, by means of deciding to stay there, KNOWING that 'I have taken a drug, this is an ill effect as a result of that drug's overuse or bad character, and therefore I ought to stay calm, and focus upon what makes sense. Using logic and willpower to keep calm and soldier through it.

But if that were to be accompanied by inability to validly ascribe cause and effect, I see that being a perfect storm for delusional symptomatology and people undergoing more or less exactly what happens in schizophrenia. IMO it would be a very good idea to concentrate not just on the DA hyperfunction, but on restoring NMDAr activity.

 

[clubcard]

Well you know LC, that for decades we have sought a bio-marker for schizophrenia. I found just 1 paper in which these 2 markers were spotted. It was a largish cohort of 312 if memory serves. In people with excess NMD, they were refractive to almost everything but clozapine.... and of course you know the history of clozapine. Another wonder drug that killed some people and was licensed only for refractive patients and only in conjunction with blood tests. My friend cannot tolerate clozapine which is why he is poorly medicated. 20+ years in an RSU are not a good thing. I hope has the chance to enjoy some life.

 

[Limpet_Chicken]

I wonder how schizos would react if given AMPAkines, or other AMPAr-potentiating glutamatergic modulators like say, aniracetam or pramiracetam. Phenylpiracetam could be an interesting potential adjunct, due to the stimulatory effects that aren't AFAIK, mediated via DA release/reuptake inhibition, that could help perhaps counter negative symptoms.

Don't know how well known this is, but thinking along the lines of how NMDA antagonist dissociatives are used to model schizophrenia to a degree, I found even piracetam to effectively function as an antidote to dissociatives. To the extent where I once forgot, when I was on probation quite some years ago for something, that I'd hit the MXE, and my voice would have been impossible to hide, as I find NMDA antagonist drugs make it difficult to articulate, and cause not quite a slurring, but a halting vocal praxis, I know exactly what I would want to say and am clearheaded at the beginning levels of dosing dissociatives this happens at but the vocal apparatus doesn't want to play ball.

So, I prepared an intramuscular shot of a couple of grams of piracetam, and spiked it into a convenient large muscle site on a leg. And would you believe it, having noticed in the past that piracetam etc. seemed to counter the NMDA antagonist dissociative drugs to some extent, that reversed the effects within maybe 10 minutes to 15 minutes whilst en route to the probation appointment.

And something strong like pramiracetam? I could really see that, knowing what I've read about the biology of schizophrenia, as being potentially significant in those with a prominent NMDAr hypofunction. I bet it could do a fair bit for positive symptoms. And the 'racetams and low-impact type AMPAkines are a lot less unpleasant than the likes of D2 antagonists. I can't even take fucking domperidone for example, which isn't meant to cross the BBB much at all, without its causing severe akathisia, which is just horrible, awful, a living hell of an experience. And my docs had to end up, when all else either failed or the often used typicals for severe nausea and vomiting and other GI tract issues, putting me on ondansetron and cyclizine as main GI meds, plus antacid as needed. And it works something pretty amazingly for that. But the APs they wanted to try, had been tried before once or twice when I'd had food poisoning, and they make me really ill. I'm not schizophrenic but shit, its no wonder so many of them refuse their antidopaminergic meds, those things are pretty poisonous all around, as a general character goes for them.

I'd only wish such horrible drugs on the very worst of my enemies-police filth, those guilty of animal cruelty, those who
are child abusers and rapists of women. Otherwise nobody deserves to suffer something as nasty as neuroleptics.

 

[clubcard]

The 1960s trial of PCP on hospitalized patients was deeply unethical. The very closest drug to mimic the positive and negative symptoms of schizophrenia remains dizocilpine. I have read several coroners inquests into deaths caused by the stuff but as I've mentioned somewhere else on the site, the angle and position of the basic nitrogens lone-pair is 107.5? and as you can see, it has that precise angle and position and is a secondary amine (the most basic). Ephenidine is more or less a non-rigid analogue although as I mentioned, the N-isopropyl was vastly better (DRI) and the sulphate is soluble.

I've read some trip reports on dizocilpine and they all have the cardinal symptoms.

Positive:

auditory hallucinations:
thought withdrawal, insertion and interruption.
thought broadcasting.
somatic hallucinations.
delusional perception.
feelings or actions experienced as made or influenced by external agents.

Negative:

Apathy.
Absent, blunted or incongruous emotional responses.
Poverty of speech.
Social withdrawal.
Impaired attention.
Anhedonia.
Reduction or total absence of libido. anorgasmia.
Lethargy


Your thoughts on piracetam are so apposite. Indeed an NMDA agonist was trialled in Russia (unethical again) with an Eli Lilly drug - LY2140023 (pomaglumetad) AKA (−)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (3 chiral centres... well 4 but I think 2 cannot be trans). Now it was dropped because although it worked perfectly for about 10% of the patients, it had much less utility to the majority. I think that lends a bit of weight to my '2 diseases presenting the same symtoms' and cloazpine is a dual dopamine antagonist/NMDA silent agonist (or possibly a slight inverse agonist). If the trials had benefited from initial screening of cerebrospinal fluid and targeting just the group with an excess, I'm sure it would have worked. As the research was wound down, the final paper stated "a meaningful subset of patients who showed significantly improved outcomes". I feel rather resentful that the team lead didn't get the support to develop a drug that would only have been of value to 10% of people blighted by such a cruel disease. How ignorant not to at least make the full trial data available to all (support alltrials.net).

Jeremy was about 24 or 25 when I saw him deteriorate before my eyes. He started stalking my cousins flat-mate and told people I was the devil. I had told my parents to be careful and my mother blithely ignored my warnings. In the end he hired a car (on his credit card), drove it to the continent, drove around the continent burning through his credit limit and when he went to fill the car up with petrol at a service station, the attendant seized his card. Then Jeremy seized him and almost beat the guy to death. He didn't even stay in a cell for a whole night. He was arrested at 10AM, doctor arrived at 2:30PM, he was transfered to Victoria Ward - Farnham Road Hospital. He was first detained by Section 5.2 (immediate danger to self and/or others), Section 3 (up to 6 months, a review at 6 months, and then every six months). That was in 1992 or 1993 and apart from a single, brief period at home, he was recalled and is now lost in the system. Who, where and how to communicate with someone undergoing medical care is difficult. For a start, they don't hand out addresses or any other contact details. Then, if the contents are legal it will be passed on to the consultant who may choose not to let the patient read or take a call or receive an E-mail. So that is 25 years.

Now pynazolam certainly would not ameliorate psychotic symptoms but it MAY treat the anhedonia and some of the side-effects of neuroleptics namely akathisia and tardive dyskinesia as well as having a positive effect on mood and sleep. When people are that ill, tolerance and dependence is of little concern in the scheme of things. I read 'Phone at Nine Just to Say You're Alive' by Linda Hart the day it was released. This was 3 or 4 years after my friend disappeared into the system and it was and still is very upsetting to me but it is a reminder of why we try to make better drugs. She was prescribed quite vast amounts of diazepam. It starts on the day she was released from a secure unit and over the course of the day I believe she took 5 or 6 blue (10mg) diazepam tablets. It just isn't an issue. Without benzos she could not have coped. Who cares if she ends up having to take 100mg/day if it means she's living a life.

 

[Limpet_Chicken]

For something like say, a glycine-site partial agonist perhaps, as are in trials, in some cases fast-tracked, that might be interesting to offer schizophrenia patients trials of. If its proven to be safe, etc. then why not? even if not everyone, or only a modest fraction derive benefit from the drug, then all the same, if SOME do, IMO its still worth developing, even if its one in ten.

And the likes of the 'racetams. They have proved themselves, with the possible exception of nefiracetam (testicular toxicity in canids) to be very, very benign drugs. Those I'd love to see trialled, or at least trials offered to, schizophrenic people.

And drugs to treat the awful akathisia (the word itself, meaning 'to not sit still' in greek, just doesn't even begin to convey how horrible it is. I've had it happen such as when treated (VERY briefly I might add) with mirtazepine (told y'all I didn't take well to alpha2 adrenergic autoreceptor antagonists), that even taking a quarter pill was bad enough that I literally wanted to die, if only it would stop it. And when having food poisoning some fuck shot me with IIRC trifluorperazine, jesus god it was bad enough having severe food poisoning, but that on top? I'd only wish that on pigs, and animal/child abusers.

Anything that can help such people as are cursed with akathisia, or help prevent or treat tardive dyskinesias, that in and of itself, even without a cure or improving the schizophrenia itself, it would help vastly with people remaining on their medications, such side effects are horrific. Even domperidone does it to me. Its like RLS, only all over, and caused by stinging ants covered in acid and set on fire crawling about under your skin, and biting and stinging your very brain. One of the worst things in the world. Something the body should never have evolved the capacity to experience. Words, mere words, cannot come within a million miles of depicting the actuality of the living, breathing, skinless and salted screaming hell made flesh that akathisia is.

 

[clubcard]

Yes - the quality of neuroleptic design is poor. Every new class has one or both sets of major side-effects. As for the racetams. Well it seems to me like the big late 70s-early 80s trend to add 3,4-dichloro to benzenes on all manner of scaffolds. It seems it alters the electron-density of the ring in some manner that is common to the CNS. A lactam moiety seems to be similarly promiscuous.

If you look on a binding database for any given neuroleptic (apart from clozapine) and then look at the affinity of LY2140023 you will see the clear overlap, hence cloazpine being used in refractive cases. If it's only 10% of sufferers, a vastly better quality of life is lost to them because who will market a drug that doesn't have a huge profit margin and is only of benefit to a minority?

 

[Limpet_Chicken]

Clozapine also has to be used with great care, due to potential risk of agranulocytosis.

 

[sekio]

Not only that, it has FIVE black box warnings!

Clozapine carries five black box warnings, including warnings for agranulocytosis, central nervous system depression, leukopenia, neutropenia, seizure disorder, bone marrow suppression, dementia, hypotension, myocarditis, orthostatic hypotension (with or without syncope) and seizures.

I wonder who was bribed to put this on the WHO Essential Medicines list... certainly doesn't seem "one of the most effective and safe medicines".

 

[Limpet_Chicken]

Probably because there are still a subset of schizophrenic patients who don't respond to other antipsychotics, but who nevertheless need one. If its the ONLY option we have, then sometimes, drugs with a bunch of nasty side effects still end up being used, because we have nothing else to offer the patient.

Its frequent enough in cancer treatment. A lot of chemo meds are nasty as hell (just look at the use of one of the military CW agent nitrogen mustards, one of those, HN1 or HN3 IIRC, is sometimes used as a chemo agent, and there needs to be bugger all said about how noxious military CW agents are in general, they wouldn't be used for such purposes as killing soldiers on the battlefield, or incapacitating them/use for area denial etc. if they were nice, friendly compounds)

If a patient needs treatment, be it for cancer, schizophrenia, orphan diseases, or last-line last hope antibiotics then if its all we have, and our only option, then side effects or no, we have no choice but to either use the nasty-ass treatment or simply not treat the patient.

Just look at say, pentavalent antimony compounds for treating leishmaniasis, nasty as hell but still used when resistance to other drugs is present. And then the likes of arsenic-based drugs for treating african trypanosomiasis, that has progressed to the second, neurological stage. Drugs of that sort are downright toxic at best, but the alternative is certain fatality, in second-stage sleeping sickness. You either get treated, or you die. Simple as that, so pretty much any treatment is better than no treatment. Even if it is poison.

(and for that matter, arsenic trioxide is listed (hospital specialist use only) in the BNF here in the UK, its used in cancer treatment)

Obviously, the use of a direct, orthosteric NMDA agonist is going to lead to no good, in schizophrenics or otherwise. The likes of ibotenic acid, an NMDA agonist is used via microinjection intracerebrally in lab animal studies to lesion specific parts of the brain. Obviously not the sort of thing one wants to administer systemically to a living human being.

But the likes of glycine co-agonist site agonists don't seem to possess the same neurotoxic effects. And given the glutamatergic hypofunction induced by dissociatives is completely reversed by say, pramiracetam or aniracetam, even piracetam, there might be hope for such meds as at least an adjunct to antidopaminergics. I've experienced the complete reversal of a hefty dose of..I forget which one now but either MXE, or 4-MeO-PCP, tripping my arse off, and remembering oh shit, got to go to probation and can't go like this. IM injection of the 'racetam drug reversed the effects within minutes.

Such symptoms definitely seem to be related to NMDAr hypofunction. Just look at how similar the symptoms of anti-NMDAr encephalitis are to schizophrenia (this condition is caused by the body producing autoantibodies against NMDA receptors, and results in delusions, delirium, paranoia, hallucinations, dissociation etc.

And given the distinct lack of toxicity of the 'racetams, IMO its at least worth exploring the potential. And of low-impact AMPAkines (and, to prevent patient noncompliance, supervised dosing of high-impact AMPAkines [the supervision intended to prevent patients upping the dose of their own accord and excitotoxicity, seizures etc. resulting], again, IMO should at least be subjected to clinical trials.