Schizophrenia and heredity / genetics - current state of knowledge & implications?

[dopamimetic]

Schizophrenia and heredity / genetics - current state of knowledge & implications?

My mother has (probably, diagnosis of mental disorders is never without doubt) what is called chronic, paranoid schizophrenia. It's a mix of 'negative' and 'positive' symptoms but I'd say the negative ones - social withdrawal, anxiety and defensive aggression, etc. are stronger. No hallucinations, no voices, but strong paranoia that can escalate to thinking about others installing electric devices in her walls, having killed her cat (who died because of over-feeding and diabetes) and she has some ADHD like restlessness. Sleeps little, has always to do something and goes out to walk for hours and hours every day (this I don't worry about, just to mention).

I'm trying to unravel things a bit currently. I don't know about the current state of science really, but I think we have evidence for that the psychosis / schizophrenia risk is genetically encoded and can be inherited.

Partially I experience the same things like she does (especially the restlessness, but unfortunately also paranoia and anxiety when I'm not medicated). We both are very sensitive and overly emotional. The difference is that I try to reflect everything and develop coping strategies - something that still doesn't work without chemical aid - while she lost touch with herself probably long ago, it's all the fault of others. But this is more a thing of personality and not neurology.

Now what I'm thinking and worrying about is - will this progress with age? I know of the theorizing about all the proposed mechanisms for schizophrenia, dopaminergic (proven to be wrong for me, and I'd say for my mum too), glutamatergic and recently oxidative stress with glutathione / N-acetylcysteine supplementing possibly delaying or halting the worsening. This could make sense when thinking of the link to apoptosis of GABAergic interneurons in the ketamine / PCP model - but all these experiments were done on 'healthy' rodents, not taking genetics into account.

There's an interesting paper about the duality of NMDA antagonists - neuroprotection vs. neurotoxicity, it's only about the developing brain, but the concept might fit to adults too. That ketamine can be neurotoxic on it's own, but other things like stress can be even more toxic and then it is actually protecting. This is something I have had in mind for some time now, we can't tell about brain changes / neurotoxicity without considering the environment, personality and all that. Genetics of course. My theorizing is that depression, chronic anxiety, stress etc. can be equally 'toxic' as drugs. These factors can sum up of course, but so can non-drug ones. Our biology is taking care of itself every second, and we have to do our best to support it with that ... am I correct on this?

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Now I don't remember what I've intended to ask in the end yeah, when having these genetics and reading about the 'ketamine model of schizophrenia', using ketamine therapeutically sounds like a really bad choice. Just that it doesn't appear to be so simple. These NMDA antagonists actually stabilize and normalize me when used correctly. Far too reliable and reproducible to be coincidence at all. In retrospective, every single day when I've used MXE was a good day, and the sober days were mixed with a tendency to the worse the longer I've abstained.

Yes, I've gone psychotic twice from reckless dosing (1st time venlafaxine + DXM + codeine + alcohol - no surprise. 2nd time DXM + 3-MeO-PCP - again, no surprise). These episodes didn't last long, I've been a bit agitated and manic and responded to benzos. And twice from strong dopamine antagonists (here I suspect it's either about the lowered seizure threshold and something like temporal lobe anomalies, and/or the lack of dopamine leading to glutamate/NMDA over-activity). So I know that it's a thin line, but I fail to see a worsening even after years on and off dissociatives now. I'm literally going crazy when I'm off any meds for too long. Bad problems with emotional flooding and rigidity at the same time, insufficient impulse control and so on.

Probably nobody will be able to give me answers, because we don't know it yet ... but what do you think?

(I know, I should go out and live more.. but it's holidays and I'm having too much time to think...)

 

[Burnt Offerings]

I think the current conclusion is that genetics vis-à-vis schizophrenia are an indicator but not wholly deterministic, because they've done twin studies with schizophrenic patients and have found that if one identical twin has paranoid schizophrenia, the other has about a 50 percent chance of also developing it. Which is a lot higher than the 1 percent chance for the general population but nowhere near 100 percent. So IIRC there's typically an interplay of genetic and environmental factors at work.

 

[dopamimetic]

We have some really interesting conflicting data if you ask me.

Schizophrenia has recently been linked to a superoxide related and NADPH oxidase mediated loss of parvalbumin and GABAergic interneurons, this is seen in what's called the PCP model but appears to have been confirmed in humans more or less. This is also the suggested mechanism by which dissociatives can induce psychotomimetic states, but the point here is that this effect seems to be more acute than chronic (in a study they administered 0.3mg/kg and 0.6mg/kg of ketamine to haloperidol-treated schizophrenics, and it caused a dose-dependent brief worsening of positive symptoms but only as long as the ketamine was active). N-acetylcysteine when dosed early and high enough could prevent the apoptosis by scavenging the free radicals over glutathione.

So NMDA antagonism is psychotomimetic. Yeah, we've known that before. But somehow I feel these conclusions are a bit diffuse, you can't extrapolate from an acute worsening in a pre-existing chronic disorder that the substance will induce that disorder in a healthy person, or?

What does it mean when the NMDA antagonists aren't psychotomimetic to me at all (below a certain dosage threshold, that is) but rather normalizing, calming, opening ... the opposite of what they 'should' do. Like if I had the opposite genetics, kinda of anti-schizophrenia. High dosages of NAC have a definite effect for me, but it's not all-over positive. It makes me sad and a bit anxious, which is a really strange reaction, haven't found anything in this direction. Everyone who gets effects from NAC has positive ones.

Could this mean in the end that I do have a GABA / glutamate imbalance, and too many or overactive GABAergic neurons? GABA can sometimes induce depression and is anti-manic... when I'm being depressed and inhibited, I'm longing for mania... Raises my interest in sarcosine again.

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More general question - if the death of GABA neurons causes schizophrenia, shouldn't we then use things like tiagabine, picamilon (like L-dopa in Parkinson's) or valproate (promotes CTNF whose levels also seem to fall during progression), pregabalin etc. more often instead or alongside neuroleptics? They do, through the dopamine antagonism, lead to more glutamatergic activity what might even contribute to a worsening and countering this could bring relief.

N-acetylcysteine as a potentially useful medication to prevent conversion to schizophrenia in at-risk individuals. (use sci-hub.io)

 

[Cotcha Yankinov]

I think there is this assumption going around in the public sphere that all schizophrenia is the same, I think there might be different causes biologically, with both environmental and genetic factors at play. There is a difference between substance induced psychosis and true schizophrenia at least in mechanism. Though are you saying some schizophrenia had been linked to loss of GABA interneurons? It seems to me that the sensory gating issues often seen in schizophrenia could be from a faulty thalamus or something. Maybe this is shared with other disorders but there is more to the schizophrenia.

There is an association between serotonin mutations and schizophrenia http://www.ncbi.nlm.nih.gov/m/pubmed/8655141/

There is pretty small chance of full on schizophrenia rearing it's ugly head after 40 years old. I think it might be 15% or something. Mania and sleep deprivation combined with a little substance induced psychosis can certainly feel like a little schizophrenia though.

 

[clubcard]

people with this illness show high levels of the dopamine metabolite and/or low levels of NMDA metabolite in cerebrospinal fluid. Refractive patients respond to clozapine because it affects both NDMA & Dopamine levels. 86% have too much dopamine,10% too little NMDA, 4% BOTH.

 

[Ozle]

Oversensitivity and overemotionality aren't really typical of schizophrenia (quite the opposite, usually), they're more typical of bipolar or BPD (both of which also commonly include anxiety and paranoia).

 

[dopamimetic]

Yeah, it's kinda confusing all-over - also think I'm really not schizophrenic, but have borderline personality together with being overly sensitive and part of Asperger autism (which also appear to be opposition diagnosis). But I'd agree with you, would match with that - oversimplificated in my eyes, but nevertheless interesting - 'dissociative' / ketamine & PCP model of schizophrenia. In that these drugs can induce a schizo-like state, and when dosed low enough they indeed help me a ton. So it could really be overemotionally <---> schizophrenia being the both extreme poles of NMDA dysfunction and the dissociatives make a shift to the right if this is understandable.

clubcard, I thought that NMDA doesn't occur naturally - these receptors are activated by glutamate and things like quinolinic acid, but are named of the xenobiotic selective agonist NMDA..? So there can't be a NMDA metabolite?

Also do high levels of a transmitter metabolite really say that there has to be a high level of the transmitter occurring? What if we had e.g. over-active MAO and thus less actual transmitters because all gets so quickly metabolized out?

 

[Cotcha Yankinov]

For a while I thought I was schizophrenic because I was hearing so many voices and whispers, but they always cleared up if I got sleep (with a combo of strong sedatives) so I have come to the conclusion I am most likely bipolar with a tendency towards mania that when combined with chronic sleep deprivation can start to look a bit like schizophrenia.

Aspergers is another syndrome I relate to, I feel as though Aspergers and bipolar can "explain" a lot of myself.