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personalized treatment after gene test - Is the vision dead?

genetics personalized medicine

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#1 Olon

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Posted 31 December 2013 - 12:50 PM


I just found this:

RATIONALE:

Advances in understanding the underlying mechanisms of conditions such as fragile X syndrome (FXS) and autism spectrum disorders have revealed heterogeneous populations. Recent trials of novel FXS therapies have highlighted several challenges including subpopulations with possibly differential therapeutic responses, the lack of specific outcome measures capturing the full range of improvements of patients with FXS, and a lack of biomarkers that can track whether a specific mechanism is responsive to a new drug and whether the response correlates with clinical improvement.
OBJECTIVES:

We review the phenotypic heterogeneity of FXS and the implications for clinical research in FXS and other neurodevelopmental disorders.
RESULTS:

Residual levels of fragile X mental retardation protein (FMRP) expression explain in part the heterogeneity in the FXS phenotype; studies indicate a correlation with both cognitive and behavioral deficits. However, this does not fully explain the extent of phenotypic variance observed or the variability of drug response. Post hoc analyses of studies involving the selective mGluR5 antagonist mavoglurant and the GABAB agonist arbaclofen have uncovered significant therapeutic responses following patient stratification according to FMR1 promoter methylation patterns or baseline severity of social withdrawal, respectively. Future studies designed to quantify disease modification will need to develop new strategies to track changes effectively over time and in multiple symptom domains.
CONCLUSION:

Appropriate selection of patients and outcome measures is central to optimizing future clinical investigations of these complex disorders.


http://www.ncbi.nlm....pubmed/24173622


According to often-heard propaganda the monogenetic cause resulting in a (more or less) genetic monogenity should mean that a drug that acts in close proximity to the defect should give a (more or less) homogeneous treatment result (which it obviously doesn't). I wonder how far this applies to psychiatric diseases.

#2 socialpiranha

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Posted 02 January 2014 - 07:31 AM

Is there any reason to think FXS is not a polygenetic phenomenon? I suspect most psychiatric illnesses are and i doubt we will discover otherwise....especially by treatment results.

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#3 Olon

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Posted 02 January 2014 - 09:10 AM

As far as I know the Fmr1 mutation that defines FXS has a very high penetrance. So there were probably very few in the study who carry a second high/medium risk mutation for autistic diseases. My conclusion is that the low risk common SNPs were sufficient to modulate the treatment response in a clinically relevant way. But I don't think that could have been assumed from the beginning.

Edited by Olon, 02 January 2014 - 09:14 AM.


#4 socialpiranha

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Posted 02 January 2014 - 10:31 AM

well i mean that shouldn't discourage anyone from developing therapies based on genetic tests, Fmr1 might be more of a marker rather than functional. Do you have FXS or something more like aspergers?

#5 Olon

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Posted 02 January 2014 - 11:40 AM

I have schizophrenia, but currently very interested in autism, because luteolin (a diatary supplement used against autism) has recently been shown to inhibit the Ras/Raf/MEK/ERK cascade, whereas the antipsychotic effect of clozapine (the commonly most effective drug against schizophrenia) is dependent on ERK activation in animal models. So I am watching out for a possible common target that could be responsible for the effects of ERK inhbition / activation.

#6 socialpiranha

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Posted 02 January 2014 - 09:50 PM

luteolin is also a phosphodiesterase inhibitor as is clozapine, Schizophrenia and autism are very similar i understand your thinking but I think the reason clozapine is superior to haloperidol for example is it's agonist activity at the 5ht1a receptor. It has 10x affinity over haloperidol, which is the main pharmacological difference between them. 5ht1ar in the dorsal raphe and prefrontal cortex are strongly implicated in schizophrenia... and autism i believe. It may just be clozapines direct effects on the receptors themselves rather than indirectly through a more primary cascade effect. I don't really understand neuroscience enough to know though. Maybe the differential effect on erk, arrestins and grk's are downstream effects of 5ht1a agonism i dunno.

#7 Olon

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Posted 03 January 2014 - 09:15 AM

I think the most important receptors for ERK activation by clozapine are the delta-opioid and the GABA-B-receptor, but there is also ERK activation by 5-ht1a receptors. ERK inhibition has been shown to abandon the antipsychotic effect of clozapine in a rodent model, and MAPK mutations are risk factors for autism. L-type calcium channels are essential for ERK activation by GABA-B-receptors, and the corresponding CACNA1C mutations are gain of function mutations in autism and loss of function mutations in schizophrenia and bipolar disorder.

Edited by Olon, 03 January 2014 - 09:22 AM.


#8 socialpiranha

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Posted 03 January 2014 - 04:24 PM

I would think the affinity for the opioid and gaba receptors would be too low to have much affect compared to other receptors? I wonder if it is only loss of function in bipolar and schizophrenia due to conflicting and differential mutations which turn the gain into a loss? For example (increased ability to visualize possibilities) vs (increased ability to visualize plus increased ability to empathize)

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#9 Olon

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Posted 03 January 2014 - 05:26 PM

EGF receptor transactivation by clozapine/desmethylclozapine is well-established. But apart from delta-opioid receptors also M-type acetylcholine receptors do that, which of them is more important, who knows? Concerning the relevant targets of ERK I am still in a very speculative state. Maybe increase of astrocyte-coupling, maybe inactivation of Kv4.2 potassium channels, but my search goes on. From the outside healthy people see social deficits in both autistic and schizophrenic persons and are tempted to believe in common neurophysiological causes, but I believe these two disorders represent opposite ends of a scale in almost every respect.





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