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Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 12 of 12. This is the beginning of the thread.
Posted by SLS on September 14, 2014, at 12:20:51
Brain-derived neurotrophic factor (BDNF) is a protein in the brain that protects neurons (neuroprotection) from stress-induced damage and tissue atrophy. It also promotes the growth of existing neurons and produces the formation and reinforcement of neuronal connections (dendritic spines). These things are necessary conditions for ketamine to produce an antidepressant effect. Recently, this association has been demonstrated for the medial prefrontal cortex, an area of the brain implicated in depression.
There are two different versions (alleles) of the gene that codes for BDNF (V or M). They differ in their efficiencies to manufacture and transport BDNF in the cell. Each person inherits two alleles for this gene; one from each parent. Thus, there are three possible combinations of the two alleles for the BDNF gene. People who have VV respond best to ketamine. People who have VM respond less well. People who have MM won't respond at all.
V = valine
M = methionine
- Scott
Posted by linkadge on September 14, 2014, at 13:04:13
In reply to BDNF gene predicts the response to ketamine, posted by SLS on September 14, 2014, at 12:20:51
Hi SLS,
When you say:
"People who have MM won't respond at all."
Is this established or just a hypothesis of the study?
Thanks,
Linkadge
Posted by Lamdage22 on September 14, 2014, at 14:39:08
In reply to Re: BDNF gene predicts the response to ketamine, posted by linkadge on September 14, 2014, at 13:04:13
Is this also the case for Glyx-13, NRX1074? (Nmda modulators?)
Posted by SLS on September 14, 2014, at 16:32:56
In reply to Re: BDNF gene predicts the response to ketamine, posted by linkadge on September 14, 2014, at 13:04:13
Hi Linkadge.
> Hi SLS,
>
> When you say:
>
> "People who have MM won't respond at all."
>
> Is this established or just a hypothesis of the study?
>
> Thanks,
>
> LinkadgeIt is a consistent observation in both human and animal studies that VV is more likely to respond to ketamine than either VM or MM. MM is relatively rare.
-------------------------------------
http://bipolarnews.org/?p=2318
"Depressed patients with the better functioning Val66Val allele of BDNF respond best to ketamine, those with the intermediate functioning Val66Met allele respond less well, and those with the poorest functioning Met66Met allele virtually do not respond at all."
----------------------------
* The details of my explanation regarding the genetics involved with BDNF were in error. There are three different alleles for the BDNF gene, not two. An individual will have a combination of any two alleles; one from each parent. If either of these alleles contains the M (Met) domain, BDNF activity will be reduced.
BDNF gene alleles:
VV = Val66Val
VM = Val66Met
MM = Met66MetVal = valine
Met = methionineMy guess is that someone who is homozygous for the MM allelle will be very resistant to ketamine treatment. If cognitive impairment is an index of BDNF genotype (Met load), I probably will not respond to ketamine.
- Scott
Posted by Phillipa on September 14, 2014, at 17:50:58
In reply to Re: BDNF gene predicts the response to ketamine » linkadge, posted by SLS on September 14, 2014, at 16:32:56
Scott you won't? What is next or what on now? P
Posted by SLS on September 14, 2014, at 20:30:52
In reply to Re: BDNF gene predicts the response to ketamine » SLS, posted by Phillipa on September 14, 2014, at 17:50:58
> Scott you won't? What is next or what on now? P
I had been thinking of making ketamine my next choice of treatment. However, I don't plan on having tests performed for BDNF genotype or blood levels. It is cheaper and faster to just go ahead and try intranasal ketamine. The Met BDNF genotype has been reported by researchers to be associated with both cognitive deficits and resistance to ketamine treatment. One might suggest that the cognitive impairments I have are indicators of a Met genotype, and are therefore prognosticators of non-response to ketamine.
Who knows for sure?
I don't.
I guess I'll have to try ketamine in order to find out.
- Scott
Posted by Phillipa on September 14, 2014, at 21:05:44
In reply to Re: BDNF gene predicts the response to ketamine » Phillipa, posted by SLS on September 14, 2014, at 20:30:52
You are correct. Phillipa
Posted by Lamdage22 on September 14, 2014, at 23:12:40
In reply to Re: BDNF gene predicts the response to ketamine » SLS, posted by Phillipa on September 14, 2014, at 21:05:44
Cool Scott,
i wish i could. But it is probably contra-indicated with my shizo type disorder.
Posted by linkadge on September 15, 2014, at 17:56:18
In reply to Re: BDNF gene predicts the response to ketamine » linkadge, posted by SLS on September 14, 2014, at 16:32:56
Hi SLS,
I know that the antidepressant effect of certain AD's requires the enhancement of BDNF production or binding or the like.
I know that BDNF binds to the trk-b receptor. Certain agents (i.e. amitriptyline) are direct trk-b agonists. In other words, they mimic the effects of BDNF in the absence of BDNF.
I wonder if trk-b agonists might benefit individuals with the low functioning version of the BDNF gene.
Linakdge
Posted by SLS on September 15, 2014, at 19:43:15
In reply to Re: TRK-b agonists for BDNF knockouts, posted by linkadge on September 15, 2014, at 17:56:18
> Hi SLS,
>
> I know that the antidepressant effect of certain AD's requires the enhancement of BDNF production or binding or the like.
>
> I know that BDNF binds to the trk-b receptor. Certain agents (i.e. amitriptyline) are direct trk-b agonists. In other words, they mimic the effects of BDNF in the absence of BDNF.
>
> I wonder if trk-b agonists might benefit individuals with the low functioning version of the BDNF gene.
>
> Linakdge
Great thinking!I was unaware of the Trk receptors.
I excerpted several passages from the following article:
- Scott-----------------------------------------------------
http://www.jci.org/articles/view/41356
Brain-derived neurotrophic factor (BDNF) activates the receptor tropomyosin-related kinase B (TrkB) with high potency and specificity, promoting neuronal survival, differentiation, and synaptic function. Correlations between altered BDNF expression and/or function and mechanism(s) underlying numerous neurodegenerative conditions, including Alzheimer disease and traumatic brain injury, suggest that TrkB agonists might have therapeutic potential.
The findings that TrkB is important for long-term survival, differentiation, and function of newborn neurons in the adult hippocampus (1618), and that neurogenesis plays a fundamental role in depression, suggest that discovery of TrkB ligands might open new treatment avenues for this disorder.
A number of properties limit the therapeutic application of BDNF. Its plasma half-life in rats is less than 1 minute, and it has poor blood brain barrier penetration (21) and poor brain intraparenchymal penetration (22). In addition, BDNF interaction with p75NTR might contribute to its ability to promote pain (23) and other undesired effects. Thus, a long-sought goal has been the development of non-peptide, small molecule ligands capable of activating TrkB signaling with high potency and specificity.
LM22A compounds interact with and act through TrkB.
In preliminary assays, 5 compounds emulating the loop II region of BDNF were considered to have activity significantly above baseline as defined as a percentage of BDNF maximal efficacy. Four compounds with the highest activity (LM22A-1 to -4) were selected for further characterization. Each of these 4 compounds exhibits a distinct chemotype; LM22A-1 is a tripeptide (Pro-His-Trp), and compounds LM22A-2, LM22A-3, and LM22A-4 contain no peptide bonds (Figure 1B).
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Posted by linkadge on September 15, 2014, at 19:57:40
In reply to Re: TRK-b agonists for BDNF knockouts, posted by SLS on September 15, 2014, at 19:43:15
Its interesting that amitriptyline is both a trk-b and trk-a agonist with high potency.
TRK-a agonists mimic the effects of nerve growth factor (NGF) and TRK-b agonists mimic the effects of BDNF.
Linkadge
Posted by linkadge on September 15, 2014, at 20:03:59
In reply to Re: TRK-b agonists for BDNF knockouts, posted by linkadge on September 15, 2014, at 19:57:40
BDFN is an interesting target. Enhancement of BDNF signalling interacts with P11 to enhance the surface expression of 5-ht1b receptors. It also can increase reward sensitivity via enhancing dopamine d3 expression. I think there is interaction too with gsk3. I think gsk3 inhibitors can enhance BDNF. I remember reading that ketamine's enhancement of BDNF was abolished if the effect of gsk3 was abolished.
I just have a surface knowledge though.
Linkadge
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Dr. Bob is Robert Hsiung, MD,
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