[Sometimes psychotic]

So today they unveiled two new research papers that used more or less complete genome sequencing of the coding regions of genes(as opposed to SNPs) to identify rare variants in schizophrenia. Basically what they found were more mutations in genes that had already been identified as risk factors...in short there is huge genetic variation in what is identified as a single disease---they basically said they had no way to make a meaningful group of individuals that could be studied or tested independently.

I can't link the originals because they are behind a paywall but here is a summary.

New genetic mutations shed light on schizophrenia

I actually find this encouraging as it makes it unlikely that we will be able to be identified in the future thus eliminating attempts at eugenics before birth. It does make the development of new drugs more difficult as it seems that each of us has a unique condition although it has been previously suggested that this is a pathway disease so net commonalities may still exist(as suggested by the general success of D2 antagonists)

[nbritton]

Originally Posted by Sometimes psychotic

in short there is huge genetic variation in what is identified as a single disease---they basically said they had no way to make a meaningful group of individuals that could be studied or tested independently.

That's because it's not a single disease. They need to drill down on the different clinical presentations of the illness to get useable data. The DSM 5 completely eliminated subtypes, which I think is a backwards step.

Instead of focusing on global symptom groups, they need to focus on medication groups. For instance, all those that respond exceptionally well to Latuda should be grouped together and then studied at the genetic and symptomology level. Rinse and repeat for each major medication until trends emerge.

[Sometimes psychotic]

Originally Posted by nbritton

That's because it's not a single disease. They need to drill down on the different clinical presentations of the illness to get useable data. The DSM 5 completely eliminated subtypes, which I think is a backwards step.

Instead of focusing on global symptom groups, they need to focus on medication groups. For instance, all those that respond exceptionally well to Latuda should be grouped together and then studied at the genetic and symptomology level. Rinse and repeat for each major medication until trends emerge.

I agree...the problem is this stuff isn't being done by the pdocs they don't seem to have great academic medicine departments. The genome studies never seem to correlate med response...all you need is a survey for the sequenced patients meds that worked well side effects etc...legally you'd probably need a psychologist to design it to get past an IRB but it's so easy...

The closest I've seen to this is 23 and me...they basically were investigating several types of drugs and APs were one...the problem was a very low sample of people with sz...it would work so much better if people with actual patient access did these studies along with the genetic experts...

I have a great interest in evolution. The concept that seemed so simple when discovered , it was a wonder how naturalists had not come across it sooner. The basic principle of evolution by natural selection is that a very simple process could account for so much complexity. Looking at a living animal , it was impossible to fathom how an event could account for such a giant leap. Of course our mental biases saw this as a single event rather than minute steps taken over milions of years. It could well be possible that there is a simple genetic mutation or enviromental phenomenon that could have a knock on effect , on say the , process of embryology , through childhood and onto adulthood. When we come to look at schizophrenia we usually do at its presentation , at which stage the disease has developed beyond its basic pathology , incrementally adding more and more complexity in terms of its definition.

For example there is a hypothesis I read that neuron migration from deep brain, out to the cerebrum in embryology and early childhood could account for the differing and varying symptoms you see in psychotic presentation. Just because the symptoms differ that does not mean there is not a basic underlining pathology at fault. Again how the brain stem , cerebral cortex, hind brain , mid brain fore brain develop , is essential like an opening flower with neuron migration pushing outwards to form the cortex. Such is the complexity and uniqueness of this migration it could well be responsible for all kinds of varying symptoms as characterised by the migration towards and formation of the cortex.

Just an idea.

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[Sometimes psychotic]

Originally Posted by paulycoll

I have a great interest in evolution. The concept that seemed so simple when discovered , it was a wonder how naturalists had not come across it sooner. The basic principle of evolution by natural selection is that a very simple process could account for so much complexity. Looking at a living animal , it was impossible to fathom how an event could account for such a giant leap. Of course our mental biases saw this as a single event rather than minute steps taken over milions of years. It could well be possible that there is a simple genetic mutation or enviromental phenomenon that could have a knock on effect , on say the , process of embryology , through childhood and onto adulthood. When we come to look at schizophrenia we usually do at its presentation , at which stage the disease has developed beyond its basic pathology , incrementally adding more and more complexity in terms of its definition.

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Yeah there are definitely some theories that go back to development and some which use epigenics which is transient changes in expression so it could be anything. But I guess what I was saying here is that you and I probably have different mutations that have the same net outcome...this is like the third or fourth study like this where all of the suspected mutations are in fact rare...like I know somebody specifically studied the d2 receptor and found variations in some sz patients and there are also copy number variants and snps for gwas studies. I personally have two copies of a rare mutation in the metabotropic glutamate receptor grm3 which regulates levels of glutamate at the synapse thus altering nmda activity...it has a 0.0% frequency in the population(for two copies...10% for one but clearly that's not in equilibrium or you would expect like 2.5% for the double).

I had to look up knock on effect....it's not a common US expression...at first I thought you meant that we had a gain of function like psychic abilities or something.

Originally Posted by paulycoll

I have a great interest in evolution. The concept that seemed so simple when discovered , it was a wonder how naturalists had not come across it sooner. The basic principle of evolution by natural selection is that a very simple process could account for so much complexity. Looking at a living animal , it was impossible to fathom how an event could account for such a giant leap. Of course our mental biases saw this as a single event rather than minute steps taken over milions of years. It could well be possible that there is a simple genetic mutation or enviromental phenomenon that could have a knock on effect , on say the , process of embryology , through childhood and onto adulthood. When we come to look at schizophrenia we usually do at its presentation , at which stage the disease has developed beyond its basic pathology , incrementally adding more and more complexity in terms of its definition.

For example there is a hypothesis I read that neuron migration from deep brain, out to the cerebrum in embryology and early childhood could account for the differing and varying symptoms you see in psychotic presentation. Just because the symptoms differ that does not mean there is not a basic underlining pathology at fault. Again how the brain stem , cerebral cortex, hind brain , mid brain fore brain develop , is essential like an opening flower with neuron migration pushing outwards to form the cortex. Such is the complexity and uniqueness of this migration it could well be responsible for all kinds of varying symptoms as characterised by the migration towards and formation of the cortex.

Just an idea.

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Originally Posted by Sometimes psychotic

Yeah there are definitely some theories that go back to development and some which use epigenics which is transient changes in expression so it could be anything. But I guess what I was saying here is that you and I probably have different mutations that have the same net outcome...this is like the third or fourth study like this where all of the suspected mutations are in fact rare...like I know somebody specifically studied the d2 receptor and found variations in some sz patients and there are also copy number variants and snps for gwas studies. I personally have two copies of a rare mutation in the metabotropic glutamate receptor grm3 which regulates levels of glutamate at the synapse thus altering nmda activity...it has a 0.0% frequency in the population(for two copies...10% for one but clearly that's not in equilibrium or you would expect like 2.5% for the double).

I had to look up knock on effect....it's not a common US expression...at first I thought you meant that we had a gain of function like psychic abilities or something.

I was editing my post as you were writing yours. Look at the last paragraph as an example. By knock on effect I mean that a problem with migration could account for all types of complex problems with thought ,perception etc. But the migration itself could be governed by a simple process. Do you get me?

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[Sometimes psychotic]

Originally Posted by paulycoll

I was editing my post as you were writing yours. Look at the last paragraph as an example. By knock on effect I mean that a problem with migration could account for all types of complex problems with thought ,perception etc. But the migration itself could be governed by a simple process. Do you get me?

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Oops sorry about that, yep totally get you, had to look it up it's really interesting and for insidious onset sz that's chronic I totally think it's pretty plausible. I guess I tend more for something that can be rapidly changed because I had total functioning one day and then pure hallucination without the chance to even sleep the next day. I know the briefer psychotic disorders are classified differently in the dsm v and the icd-10 but they never seem to be studied because they resolve...the only place they come in is FEP studies and I've never seen any genetic studies or or structure studies on people with only psychosis. I suppose I'm wrong in assuming they have the same mechanism but they pretty much get treated like a baby form of sz because the pdocs have no idea if you meet the criteria unless you have had 6 months of symptoms when they meet you.

Anyway in my grm3 there is just an over abundance of a non-functional splice variant and splicing is easy to change. So I genuinely feel that's what's wrong with me and I wonder if stress can change the splicing of that gene...

I guess my general feeling is that psychosis isn't a single entity I mean there are tons of medical conditions and drug induced psychosis it seems like the drugs they do understand all have different mechanisms.

[faerie_moon_x]

I think it's awesome they are discovering that each person is a little different. I think that speaks volumes to why maybe meds work for some and not for others. I'm also glad is lessens the chance of it being "identifiable" in unborn babies. I think that's important.

Pauly, I think the underlying issues may be similar and also different at once. There are multiple causes of type 2 diabetes and type 1 and type 2 are caused by totally different things but in the end they lead to the same result. This is a really basic example as this is a well understood diagnosis. However, at the same time everyone reacts to diets differently. There is a vast spectrum of how people respond to food and even meds. I think it just goes to show that humans are much more complex than we would like to believe. One small shift in chemical or development from person to person is going to have a huge effect overall. It's almost like a butterfly effect, but with biology instead of time theory.

Originally Posted by faerie_moon_x

I think it's awesome they are discovering that each person is a little different. I think that speaks volumes to why maybe meds work for some and not for others. I'm also glad is lessens the chance of it being "identifiable" in unborn babies. I think that's important.

Pauly, I think the underlying issues may be similar and also different at once. There are multiple causes of type 2 diabetes and type 1 and type 2 are caused by totally different things but in the end they lead to the same result. This is a really basic example as this is a well understood diagnosis. However, at the same time everyone reacts to diets differently. There is a vast spectrum of how people respond to food and even meds. I think it just goes to show that humans are much more complex than we would like to believe. One small shift in chemical or development from person to person is going to have a huge effect overall. It's almost like a butterfly effect, but with biology instead of time theory.

Yeah I understand. But that does not rule out the same pharmacological intervention to prevent type
1 or type 2 diabetes. Mental disorders may be drastically cut in the future by intervening in early child development in the womb and while the child is developing as a baby. Take for example choline , it seems may have inherited value to a baby in the womb.

Once any of these conditions become expressed and active , we maybe curtailed in our pharmacological response because the micro anatomy is already defined.

But I do believe that there will be medical interventions that will drastically cut mental illness rates in the future.

Originally Posted by Sometimes psychotic

I actually find this encouraging as it makes it unlikely that we will be able to be identified in the future thus eliminating attempts at eugenics before birth.

I think this is a good thing too. And I totally agree that sz is a heterogenous condition made up of lots of different mechanisms & symptoms.

*Willow*

[faerie_moon_x]

Originally Posted by paulycoll

Yeah I understand. But that does not rule out the same pharmacological intervention to prevent type
1 or type 2 diabetes. Mental disorders may be drastically cut in the future by intervening in early child development in the womb and while the child is developing as a baby. Take for example choline , it seems may have inherited value to a baby in the womb.

Once any of these conditions become expressed and active , we maybe curtailed in our pharmacological response because the micro anatomy is already defined.

But I do believe that there will be medical interventions that will drastically cut mental illness rates in the future.

True, but type 1 and type 2 are not treated the same. With type 1 you have one treatment: insulin therapy. With type 2 you have treatments for insulin resistance, GLP1 therapy, therapy that helps the liver decrease glucose production, therapy to help the pancreas produce more insulin (without taking insulin,) and now even a new therapy that increases the output of glucose in the urine (which is one I'm kind of unsure about.) Then, after all of that fails, then doctors consider insulin. It's a completely different process and algorythm, and a complicated one, because with type 2 everyone's combination of issues is different and sometimes it's not so clear what's going on until the pancreas just wears out, and even then it's common to see people with type 2 on insulin and still continue other therapies as well.

So, it is more basic than mental illness, I agree, but it's just kind of like a simple example of how two illnesses with the same outcome are actually pretty different.