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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 8 of 8. This is the beginning of the thread.
Posted by Phillipa on January 19, 2010, at 19:07:07
Seems a new study has found that an excess of Serotonin receptor sites may be reason SSRI's dont work for many and thus TRD. Please experts explain the technical stuff and the possible meds to take to revers as claimed in article. Phillipa
From Medscape Medical News
Surplus of Serotonin Receptors May Explain Failure of Antidepressants in Some Patients
Janis C. Kelly
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Review data January 18, 2010 Individuals with treatment-resistant depression tend to have the G/G genotype associated with higher levels of 5-HT1A autoreceptors, and turning off some of those autoreceptors might turn on response to selective serotonin reuptake inhibitors (SSRIs), according to researchers at Columbia University Medical Center in New York City.Previous genetic and imaging research has suggested a link between high 1A receptor levels in the raphe neurons and antidepressant treatment failure. However, the current study, conducted in mice, is the first to show directly that increasing 1A receptor levels in raphe neurons reduces antidepressant response and, conversely, that reducing 1A receptor levels in raphe neurons can restore drug effectiveness.
The research team, led by René Hen, PhD, professor of pharmacology in the Departments of Psychiatry and Neuroscience at Columbia University and a researcher the New York State Psychiatric Institute, discovered that too many serotonin receptors of the 1A type on the raphe neurons sets up a negative feedback loop that reduces serotonin production.
"The more antidepressants try to increase serotonin production, the less serotonin the neurons actually produce, and behavior in mice does not change," Dr. Hen told Medscape Psychiatry.
The study was published online January 14 in Neuron.
Causal Relation
Dr. Hen and colleagues measured the effect of antidepressant medications using a common behavioral test that measures the boldness of mice retrieving food from bright, open areas. Mice on antidepressants usually become more daring, but the drugs had no such effect on mice with surplus serotonin receptors.
"Our study is the first to establish a causal relation between 5-HT1A autoreceptor levels and stress response, depression, and response to antidepressants in an animal model," said Dr. Hen.
"Autoreceptors are located on serotonin neurons, where they control serotonin levels, while heteroreceptors are located in other brain areas, where they mediate the effects of serotonin. Our research suggests that even subtle changes in a specific serotonin receptor (the 5-HT1A autoreceptor) are sufficient to make an individual vulnerable to depression and unresponsive to SSRIs," he added.
Using new genetic engineering techniques, Dr. Hen created a knock-out mouse that can be programmed to produce high or low levels of serotonin receptors of the 1A type only in the raphe neuron. The levels present in the mice mimicked those found in humans with treatment-resistant depression.
"By simply tweaking the number of receptors down, we were able to transform a nonresponder into a responder. The biggest surprise was that a small decrease in 5-HT1A autoreceptor levels was sufficient to change serotonin levels and to convert a nonresponder into a responder (to SSRIs)," said Dr. Hen.
The researchers suspect that a similar strategy of reducing the number of 1A autoreceptors or blocking their activity might help treatment-resistant patients. .
"Adrenergic drugs may be useful, or drugs that target the intracellular signaling cascades activated by 5-HT1A autoreceptors," he said.
The next step is to confirm that surplus serotonin autoreceptors play the same role in humans as in mice.
"To generalize our findings to humans, we need first to investigate whether individuals with high 5-HT1A autoreceptor levels are less responsive to SSRIs in clinical trials," Dr. Hen said.
"The next question is what mechanisms are triggered by these changes in serotonin levels in other parts of the brain to produce an antidepressant response."
Plausible Hypothesis
Commenting on the findings, Paul R. Albert, PhD, professor, senior scientist, and CIHR/Novartis Michael Smith Chair in Neurosciences at the Ottawa Hospital Research Institute, in Ontario, said the data are convincing. Dr. Albert, who was not involved in the study, was one of the first investigators to report an association between 5-HT1A receptors, gene repression, and depression in humans.
These data show that selective knock-down of 5-HT1A autoreceptors in adult mice by only 30% is sufficient to produce an "antidepressant-like" phenotype for at least some established behavioral assays. Interestingly, there was no effect on anxiety-like phenotypes.
"These studies provide important evidence for the model that 5-HT1A autoreceptors exert negative feedback inhibition on 5-HT neuronal firing, and that decreasing 5-HT1A receptors by only 30% is sufficient to enhance 5-HT neuron firing and 5-HT release in response to the SSRI fluoxetine; this correlated with a reduced latency in the behavioral actions of fluoxetine," Dr. Albert told Medscape Psychiatry.
He noted that the matching time courses of increased 5-HT release and behavioral actions of fluoxetine in mice low in 5-HT1A strongly suggests that the autoreceptor restrains SSRI responsiveness, and that blocking or reducing its expression enhances the response.
However, Dr. Albert also noted that 5-HT neurons can be regulated by other systems, such as dopamine and noradrenaline, and that compounds targeting these systems could act synergistically with reduced 5-HT1A autoreceptors to mediate antidepressant response.
Dr. Albert said that these new data match very well with the expected changes from the C(1019) resilience, compared with the G(1019) risk 5-HT1A promoter alleles, that are associated with major depression and were reported by his group in 2008 (Neuropharmacology. 2008;55:977-985).
"The G allele is expected to increase 5-HT1A autoreceptor expression, and the G/G genotype is associated with higher levels of 5-HT1A autoreceptors in depressed subjects. We, and others, have also associated the G/G genotype with reduced response to SSRI treatment, or vice versa, although this association needs further replication," Dr. Albert said.
This study was supported in part by NIMH, NARSAD, and AstraZeneca. Dr. Hen reports receiving compensation as a consultant for Braincells, Inc and from AstraZeneca in relation to the generation of novel antidepressants.
Neuron. Published online January 14, 2010.
Posted by Phillipa on January 19, 2010, at 21:11:42
In reply to Surplus of SSRI receptors may lead to TRD, posted by Phillipa on January 19, 2010, at 19:07:07
They are advocating stimulants? If so what controls anxiety or is there none in TRD? Phillipa
Posted by bleauberry on January 20, 2010, at 18:50:06
In reply to Surplus of SSRI receptors may lead to TRD, posted by Phillipa on January 19, 2010, at 19:07:07
Interesting find! It kind of confirms personal ideas I've had for a while.
You know how some people here, including myself, say they experience a short time of feeling really well shortly after stopping an SSRI? In my theory, it is during that time that the 5ht1 autoreceptors sense a declining serotonin presence and send signals to step up serotonin production and firing. That feels good. But then, as the feedback loops catch up, they again slow down to predetermined genetic commands. They only sped up temporarily during the serotonin drop to maintain balance.
Some of us experience feeling good the first few days on an AD, and then either get nothing or feel worse after that. In my hypothesis, it takes 3 to 4 days for the feedback loops (the autoreceptors they talked about) to sense that things have changed, and they then send commands to slow down serotonin production. So it doesn't matter that the AD is increasing serotonin, because less of it is being made...the body's genetic command to keep balance...it doesn't know that we feel bad, it is just following its genetic code.
The assumption with ADs is that they need several weeks to work. The receptors will initially shut down during the massive increase of serotonin. But, as they become adjusted to that, they will resume production and firing. In nonresponders, that probably doesn't happen...they stay shut down the whole time.
There are few drugs that have impact on the 5ht1 receptors. The ones I am aware of are:
Pindolol
Buspar
Abilify
SavellaMaybe that's why the first three have been found to be helpful in augmenting or speeding AD response.
Savella is too new for most people to know about, but several studies at pubmed have looked at its rapid action on 5ht1a as the thing that makes it unique amongst ADs. My own personal experience, I would have to agree.
As the article pointed out, norepinephrine meds can in a roundabout way accomplish the same thing. Maybe that's why I found Savella to be more potent than ECT or any previous meds...it had both NE and 5ht1 stuff going on at the same time?
Anyway, nice find Phillipa! I am in the camp that believes 5ht1 and feedback loops are big players. Merely increasing neurotransmitters in the assumption that everything else will continue working as normal is a big and flawed assumption as I see it.
Posted by Phillipa on January 20, 2010, at 23:06:47
In reply to Re: Surplus of SSRI receptors may lead to TRD, posted by bleauberry on January 20, 2010, at 18:50:06
Thanks blu kind of explains Scotts three day blips of feeling better and me always feeling better off ad's. I wrote in other thread to you that met the drug reps for technically lexapro today but their company just released the savella also. Seems the man that bought the company used to sell supplements and candy Son was depressed he went to Europe somehow came back started lexapro, also aricept and now savella. Nice folks. And will be sending a long babblemail need your help in near future. I think your explanation makes sense. Love Phillipa
Posted by Meltingpot on January 21, 2010, at 16:10:32
In reply to Re: Surplus of SSRI receptors may lead to TRD » bleauberry, posted by Phillipa on January 20, 2010, at 23:06:47
This is interesting but it wouldn't explain why people initially respond to antidepressants and then later on become TRD. It also doesn't explain why some people respond very quickly to ADs (I used to) within a matter of days.
I suppose this doesn't explain why all people are have TRD.
Denise
Posted by bleauberry on January 21, 2010, at 18:07:41
In reply to Re: Surplus of SSRI receptors may lead to TRD, posted by Meltingpot on January 21, 2010, at 16:10:32
> This is interesting but it wouldn't explain why people initially respond to antidepressants and then later on become TRD.
Well, you are correct. The brain is too complicated. It will be decades or longer before we have more advanced wisdom of what is going on here.
Common theories are that whatever neurotransmitter is being enhanced...usually serotonin...the others are slowly drowned out over time...and that somewhere in that adaptation various genes, enzymes, and/or receptors lose their ability to do what they were initially programmed to do. Almost as if they have been deprogrammed.
It also doesn't explain why some people respond very quickly to ADs (I used to) within a matter of days.
Well actually yes it does explain this. The feedback loop doesn't catch on instantly. It takes several days to recognize something has changed and then to switch gears. During that short window, the increased neuros at the synapse can indeed provide a quick blip of feeling much better. As soon as the feedback loop catches on to what is happening, the party is over.
>
> I suppose this doesn't explain why all people are have TRD.
>
>
> Denise
Posted by linkadge on January 22, 2010, at 17:54:15
In reply to Re: Surplus of SSRI receptors may lead to TRD, posted by bleauberry on January 21, 2010, at 18:07:41
I personally don't think it really explains things all that well.
For starters all sorts of studies have tried to link the expression of presynaptic 5-ht1a receptors to depression, anxiety, suicide etc.
Essentially, they have found nothing however. In some animal models, hypoactive 5-ht1a autoreceptors is linked to increased anxiety since this increases serotonergic neurotransmission in the dorsal raphai. Studies have found overexpressed and underexpressed presynaptic 5-ht1a receptor expression in human depression, suicide and anxiety.
The other thing too is that long term SSRI administration was supposed to desensitize presynaptic 5-ht1a autoreceptors. This was suggested with animal models using fluoxetine at least. So this would (in theory) counteract the overexpression of 5-ht1a autoreceptors seen in depression.
The other thing too is that running (long term) has documented antidepressant effects and it is associated with an increase in presynaptic 5-ht1a autoreceptor expression. Mind you it decreases 5-ht1b autoreceptors. So it decreases serotoninergic functioning in certain areas of the brain and increases it in others (as 5-ht1a and 5-ht1b autorceptors influence other areas of the brain).
Lithium works as a 5-ht1b autoreceptor antagonist yet it has no effect on 5-ht1a autoreceptors. Clomipramine also desensitizes 5-ht1b autoreceptors but not 5-ht1a. rTMS induces a subsensitivity of both 5-ht1a and 5-ht1b autoreceptors.
Linkadge
Posted by Sigismund on January 22, 2010, at 18:07:46
In reply to Re: Surplus of SSRI receptors may lead to TRD, posted by bleauberry on January 21, 2010, at 18:07:41
>Savella is too new for most people to know about, but several studies at pubmed have looked at its rapid action on 5ht1a as the thing that makes it unique amongst ADs. My own personal experience, I would have to agree.
Is that where the nice calm feeling from milnacipran comes from?
Do SSRIs generally have that nice calm feeling?
Silly question?
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