![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 31. This is the beginning of the thread.
Posted by Dr. Fried on April 25, 2000, at 23:15:44
Can anyone tell me how they determine the activity of an investigational drug at specific receptors, (5HT1a,5HT2a, etc., etc,), before human trials? What experimental model do they use, (particular tissue etc.)?
Posted by PeterJ on April 26, 2000, at 2:51:40
In reply to Investigational drug assay and specific receptors., posted by Dr. Fried on April 25, 2000, at 23:15:44
> Can anyone tell me how they determine the activity of an investigational drug at specific receptors, (5HT1a,5HT2a, etc., etc,), before human trials? What experimental model do they use, (particular tissue etc.)?
"Bind and grind" studies, they are colloquially called. Many techniques are in use.
One common method is to use suspensions of membranes from cell lines
which have been transfected with cloned receptor DNA to cause them
to express specific receptor types.Common cell lines in use are:
CHO: Chinese Hamster Ovary
HEK: Human Embryonic Kidney
Sf9: Spodoptera Frugiperda (fall army worm) pupal ovaryYou can purchase various serotonin receptor preparations
using these cell lines, for example 5-HT1a receptors
in Sf9 cells.Here is the URL of a typical company (one of many) which sells such
cell lines:http://www.receptorbiology.com/
(I don't have any financial interest in that company.)
Peter
Posted by Dr. Fried on April 27, 2000, at 0:51:02
In reply to Re: Investigational drug assay and specific receptors., posted by PeterJ on April 26, 2000, at 2:51:40
Are these experimental receptors known to correlate well with the target receptors in the human brain? I am wondering if the models have any bugs in them. Can human brain tissue be grown in vitro under any conditions? Would there be any point in doing this, would it be a more valid experimental model?
Posted by PeterJ on April 27, 2000, at 3:24:24
In reply to Re: Investigational drug assay and specific receptors., posted by Dr. Fried on April 27, 2000, at 0:51:02
> Are these experimental receptors known to correlate well with the target receptors in the human brain? I am wondering if the models have any bugs in them. Can human brain tissue be grown in vitro under any conditions? Would there be any point in doing this, would it be a more valid experimental model?
The correlation with brain receptors is good but not perfect. Since
the receptors are created from cloned human DNA their amino acid sequence
should be the exact sequence of the desired receptor. However,
differences in the cell membrane can affect the structure of the
receptor in subtle ways.Drug companies do try to use systems which accurately reflect the brain,
since -- for their own self interest if nothing else -- they want to get
drugs that work. They often use one proceedure for initial screening
and then use more complex proceedures to refine their understanding
of a given drug.Binding studies are only one stage in the process. For example a
chemical which is found to bind to a specfic receptor may then be
tested in animal tissues or whole animals to see if a specific
repsonse associated with that receptor is produced.Human brain tissue can be grown; but the cultures I am aware of are
generally derived from some type of brain tumor (astrocytoma or
glioblastoma). Tumor cells are immortalized and grow in an unrestricted
manner. That's what makes them tumors but that also makes them easy
to grow in cell cultures.Using real human brain cells might have some advantages, but also
some problems. Non-tumor cells are difficult to culture. Also
brain cells will express a large number of receptors which would make
it much harder if you only want to study binding to one specific
receptor.Post mortem human brain tissue is often studied in basic research on
receptors. The receptors survive and will still bind drugs after death.It is even possible to study receptor binding in brains of living
people using PET scan techniques. This is too difficult to do in
drug screening, but has been done in studying the effects of drugs.
For example, there have been several PET studies showing differences
in binding of typical vs. atypical antipsychotics. These studies
have also been helpful in determining the optimum dosage of drugs,
for example a dose of risperidone which will block 5-HT2 receptors
without fully blocking DA receptors.Peter
Posted by Dr. Fried on April 28, 2000, at 0:46:08
In reply to Re: Investigational drug assay and specific receptors., posted by PeterJ on April 27, 2000, at 3:24:24
I am wondering why the newer classes of antidepressants aren't panning out quite as well as would be hoped, which is pretty evident from this message board. The idea that effecting specific receptors to correct a given disorder, does this hold water? Or would it work well in one instance and not another? Also the variabilty of response, what would account for this? Different concentrations of receptors or genetic variability in the specific receptors? If an antidepressant drug could be developed that targeted a specific receptor with very high accuracy and the minimum of interactions with untargeted receptors, would it be expected to work more effectively, or is it still somewhat of a shot in the dark?
I thought that there are bound to be chemicals that would facilitate brain tissue cell culture. I have heard of a naturally occuring compound that is reputed to stimulate nerve growth, maybe in ways unheard of not to far in the past. Something like this might be useful.
Posted by PeterJ on April 28, 2000, at 2:21:30
In reply to Re: Investigational drug assay and specific receptors., posted by Dr. Fried on April 28, 2000, at 0:46:08
There is definitely some genetic variation in the amino acid sequence
of many receptors within human populations. This "polymorphism" is one
possible reason for the variation in drug response. In addition, there
are tremendous individual differences in other aspects of brain structure
and function (caused by both genetic and enviromental factors) which may
affect drug response.Targetting receptors is a good idea in theory, and has in fact produced
some very useful drugs. The set of facts we know about receptors is
pretty large. On the other hand, the set of facts we _don't_ know is much
larger. So drug development tends to focus on a few established connections,
e.g. blocking serotonin uptake helps some depressed patients, a combination
of 5-HT and DA blockade helps some psychotic patients, and so on. But we
only have a vague idea why a certain receptor affects a specific disease, and
we still can't tailor drugs to fit the variations in receptors found in
different individuals.Peter
Posted by Cam W. on April 28, 2000, at 7:01:18
In reply to Re: Investigational drug assay and specific receptors., posted by PeterJ on April 28, 2000, at 2:21:30
Hey Fried & Peter - Many European psychiatrists say that the TCAs are still much better ADs than any of the new ones. The only problem with TCAs is that they bind to 5 main receptors (serotonin reuptake, norepinephrine reuptake, muscarinic/cholinergic-M1, alpha-adrenergic and histaminic-H1). This tends to produce a lot of the unbearable TCA side effects at therapeutic doses (esp. alpha-adrenergic - bloood pressure problems; M1-dry mouth, blurred vision; and H1-drowsiness and weight gain).Researchers found lower levels of a serotonin metabolite in the CSF of depressed people and that by increasing serotonin in the synaptic gap between cells depression resolved, thus the SSRIs. But, one can be depleted of serotonin and not be depressed (same goes for the depleletion of norepinephrine).
Then the NRIs started popping up (eg. bupropion, reboxetine) and the mixed SNRIs (eg venlafaxine and, to some extent, nefazodone). These too treated depression. Still, none of these antidepressants was as good as the TCAs in a majority of depression. Obviously, some other mechanisim of action for antidepressants was at work.
Some hypotheses are:
1) an upregulation of glucocorticoid receptors (GRs). This is seen with all antidepressants, except citalopram, which upregulates mineralocorticoid receptors (MRs). These two receptors are related and part of the HPA axis. MRs are almost always bound up with cortisol at a basal level and GRs bind more cortisol at higher stress levels. GR binding is not as efficient in people with depression.
2) a desensitization of ACTH receptors in the adrenal cortex, even though thae adrenal cortex keeps pumping out cortisol during depression (and an uncoupled HPA axis). This mechanism is probably addaptive.
3) a dysregulation of CRH release from the hypothalasmus and/or a problem with CRH-receptors in the pituitary. This could be caused by faulty signaling of the GRs. (cyclical process - so is this the chicken or the egg?).
4) Some minor problems with vasopressin (binding or release?) which works in conjunction with CRH to stimulate the pituitary to release ACTH and ß-endorphins. You need both of these processes for proper pituitary function and adrenal stimulation. This is probably why opiates resolve depression in the short term, before tolerance and addiction screw things up.
There are other things that are proposed to happen, but these are the main ones in the HPA axis. Depression is, yet it is not, a simple process.
BTW Peter - Some really cool posts, dude. The in vitro animal and human cell receptor binding studies do seem not to correlate precisely with in vivo actions (eg venlafaxine should not inhibit norepinephrine reuptake very well, as seem in vitro; but does when seen in vivo).
Sincerely - Cam W.
Posted by Scott L. Schofield on April 28, 2000, at 9:24:08
In reply to Re: Investigational drug assay and specific receptors., posted by Cam W. on April 28, 2000, at 7:01:18
I am feeling like crap now, but an idea occured to me about a week ago when my brain was working better.
Perhaps biological probes can be used to try to help determine the initial choices of treatment. The first thing that popped into my head was to use PET scans superimposed upon MRIs or using SPECT scans to determine baseline brain activity, and then challenge the system with various chemical probes such as receptor ligands, precursors, neuromodulators, hormones, etc. We could even use the therapeutic agents themselves. The resultant changes in brain activity can then be analyzed to determine what, where, when, and how much. I guess non-pharmacological probes could also be used, including electrical and magnetic stimulation. The choice of drug (or other treatment) could then be prescribed according to the interpretations of the test results.
Something like this might represent an in vivo evaluation of things like receptor function, availability of neurotransmitter, interactions between neurons and pathways, and many more microscopic details. However, it avoids the necessity to delineate relationships between these details by observing the macroscopic effects of these challenges on each individual brain.
- Scott
Posted by Scott L. Schofield on April 28, 2000, at 9:33:56
In reply to Re: Investigational drug assay and specific receptors., posted by Cam W. on April 28, 2000, at 7:01:18
Hi Cam.
I know you have recently performed a ton of research into HPA stuff. What sorts of things have persuaded these researchers to consider anomalies in these systems to be causes of depressive disorders rather than the consequences of them?
- Scott
Posted by Cam W. on April 28, 2000, at 21:36:15
In reply to Re: Investigational drug assay and specific receptors., posted by Scott L. Schofield on April 28, 2000, at 9:33:56
> Hi Cam.
>
> I know you have recently performed a ton of research into HPA stuff. What sorts of things have persuaded these researchers to consider anomalies in these systems to be causes of depressive disorders rather than the consequences of them?
>
>
> - ScottScott - To do justice to why I believe that a dysregulated HPA axis is the 'cause of the depressive symptoms' of depression I will need at least three studies that I have in my files at work. I think depression is 'caused' by physical or psychological trauma(s) which result in a dysregulation of the HPA axis, sustaining the depressive symptoms. I have already written myself a note to pick these up Monday. (I really need my files at home, but to duplicate them would unnecessarily kill a couple extra trees). I will muddle through with an overview of how I understand this concept and, if necessary give a more complete hypothesis in Monday's posting. Tell me if you would like a further explanation than the following (it does get a little more involved, but is way cool). The following is from notes that I made from a Charles Nemeroff article (didn't write down the reference) and supplemented by a subsequent readings that I think I remember.
The hypothalamus is the controller of hormone secretion in the brain (and body). Peptides secreted by the hypothalamus stimulate or inhibit the pituitary's release of various hormones [eg thyroid stimulating hormone (TSH); growth hormone (GH); adrenocorticotropic hormone (ACTH)]. These hormones control the release of other hormones from various glands throughout the body (outside of the nervous system) and also control their own release, via negative feedback by attaching to inhibitory receptors in the hypothalamus and pituitary (keeping TSH, GH, and ATCH levels from becoming excessive).
The release of TSH and GH (by a number of stimulators) is blunted in people with depession. Lowered levels of TSH (thyroid insufficiency) causes a depression that is non-responsive to antidepressants (as Noa has pointed out on a number of occasions).
The HPA axis (hypothalamus-pituitary-adrenal axis) controls the body's response to stress (the fight-or-flight reaction to physical or psychological stress). To prepare this response to stressful situations, the hypothalamus increases the production and secretion of corticotropin releasing hormone (CRH) which, via the portal blood vessels, and with the help of vasopressin, induces the pituitary to release ACTH and ß-endorphins.
ACTH is released into the body's circulatory system, which attaches to receptors on the adrenal gland (located on top of the kidneys) and causes the adrenal gland to dump cortisol into the bloodstream.
CRH instructs the body to slow the activity in certain bodily areas (eg raphe - leading to a decrease in sleep response; digestion - decreased appetite; and decreased sexual desire - leading to a 'limp willy') while corisol increases the activity of other areas of the body involved in self-preservation (eg increase in blood flow to muscles - leading to restlessness; and more alertness - heightened senses).
Chronic activation of the HPA axis reduces the ability of cortisol to shut off the release of CRH and ACTH (a breakdown of the negative feedback system) and leads to the syndrome we call depression. Unmedicated depressed individuals show chronically increased HPA axis activity (as seen by increased cortisol levels in the CSF, urine and blood).
Researchers have also shown that the pituitary and adrenal glands are enlarged in depressed people, probably due to increased production (and thus release) of ACTH and cortisol, respectively. These chronic hypersecretions are probably due to uncontrolled or aberrant CRH activity in the hypothalamus. It is thought that the dysregulated hypothalamus is the main cause of HPA axis hyperactivity and thus the development of depressive symptoms (eg lowered libido, anxiety, insomnia, etc.). Depressed people also show a blunted response by the adrenal glands to ACTH, but still the adrenals pump out excess cortisol. This blunted response could be the body trying to curb cortisol release.
One thing that all ADs have in common (be they SRIs, NRI, TCAs, MAOIs, NDRIs, ECT, etc.) is that they all decrease CRH levels. An eloquent article by Frank Hoebester (sp?) explains this in detail (I have cited this article earlier this year as a must read, but I can't remember in which thread - this was the article that I said was not bathroom reading). This is one of the articles that I have in my files at work.
Everyone has a different level of stress needed to induce depression. It is sort of like everyone has a bar set at a different level from everyone else. The level of this bar is determined by genetics and early life environmental factors (eg physical or emotional abuse as a child). After a certain level of stress is surpassed, the HPA axis uncouples and depression ensues. It is thought that similar levels of a bar are seen in people predisposed to schizophrenia or bipolar disorder. If a certain level of stress or 'trigger' (emotional, physical, drug-induced, etc.) is surpassed the disorder is manifested. I believe this is called the stress-diathesis model (diasthesis = environment, I think). Both Nemeroff from Emory (for depression) and Ming Tsuang from Harvard (for schizophrenia) champion this theory.
Also, as I mentioned in my last post, that decreasing serotonin (and to a lesser extent norepinephrine) in someone without depression will not cause depression; but adding these neurotransmitters (by SRI or NRI) does resolve depressive symptoms.
It is interesting to note that the downregulation of ß-adrenoceptors caused by most antidepressants (which incidentally takes 2 to 4 weeks - the time it takes for AD effect to kick in) causes a decrease in the expression of the CRH gene in the hypothalamus (thus decresed CRH production).
Also, CRH-receptor antagonists resolve depression and anxiety immediately (like downregulating ß-adrenoceptors, but with immediate action). The CRH-receptor antagonists currently being tested for relief of anxiety seem only to work for a short period of time and the increased CRH gene expression returns. There are also some side effect problems with these agents.
Also, another study that I have implicates glucocorticoid receptor (GR) function in depression. GRs are the receptors for cortisol that shut off the flow of CRH from the hypothalamus and ACTH from the pituitary. Basically, they are the negative feedback receptors that breakdown in the dysregulation of the HPA axis.
I hope that I have made this sort of clear, as this is why I think the HPA axis is linked to depression, but like you say, HPA axis dysregulation could be a consequence of depression. Although the evidence against this seems fairly strong (but not conclusive).
Thanks for putting me throught this mental work-out. I think that I now have a clearer picture in my mind of what I have been talking about. This is such an excellent forum to think out loud.
Your companion in curiosity - Cam W.
Posted by Chris A. on April 28, 2000, at 23:46:21
In reply to HPA Axis and Depression - Way Too Long, posted by Cam W. on April 28, 2000, at 21:36:15
Cam,
My brain is limping - chronic illness and ECT, so never ever thought I'd find myself trying to correct you! But here it is: TSH (thyroid stimulating hormone) increases as thyroid function decreases. Its function is to stimulate the thyroid to produce. Since having Hashimoto's thyroiditis some 14-15 years ago and being redendered permanently hypothyroid, nothing seems to be effective in treating my depression, now diagnosed mixed bipolar (you were right on that count). Even ECT is only minimally effective. I like to keep my TSH at 1-2 with T3 and T4, which is considered low, as I feel somewhat better that way. BTW, a low TSH is not for everyone, as thyroid supression with exogenous hormones can lead to osteoporosis. For me it's a matter of life and death, so I also take Evista (raloxefine-sp)and lots of Ca and D. I definitely didn't learn this stuff in nursing school (won't say how long ago that was). They didn't teach us how to help clients with chronic depression in counseling school, either. They were all supposed to get better and get on with their lives! Only my faith in God and viewing suicide as a public health problem have taught me to persevere. It helps to have a loving family and friends here who care. Thanks again for all of your input.Blessings,
Chris A.
Posted by Cam W. on April 29, 2000, at 0:16:40
In reply to Re: HPA Axis and Depression - TSH, posted by Chris A. on April 28, 2000, at 23:46:21
Chris - Thank you. That's the kind of imput I am looking for. I am only starting to look at the systems interconnected to the HPA axis. My notes from the Nemeroff study were incorrect in a few places. I know a little more now than when I originally wrote them over a year ago (I've also learned to write down the reference where I took the notes from as well - makes it a heck of a lot easier to find the original paper). Understanding of the TSH stuff still eludes me and I wrote down what I had. Thanks for the correction. - Cam W.
Posted by Noa on April 29, 2000, at 12:05:01
In reply to Re: HPA Axis and Depression - TSH - Chris A., posted by Cam W. on April 29, 2000, at 0:16:40
Cam, I recommend reading Living Well with Hypothyroidism: what your doctor doesn't tell you that you need to know,by Mary Shomon, and visiting the author's website at www.thyroid-info.com (I might have the punctuation wrong, sorry, but it is correct in previous posts--you can search).
Another book, that I have only glanced at and skimmed, and have yet to read, is The Thyroid Solution. Don't know the author's name.
I am also new to this, but it is so crucial for me to understand it because like Chris, it is a big reason my depression has been so treatment resistant.
Chris, BTW, I just yesterday saw an endocrinologist for the first time, and it was so helpful. He OK'd my TSH being super super low because I feel so much better this way. He isn't that concerned about osteoporosis for me, relative to the quality of life benefit that comes with the low tsh. My internist, on the other hand, is probably going to have a cow when she sees my latest lab results!\
My pdoc agrees with the endocrinologist, and it is so clear that my mood is better and I am so much more functional this way.
Posted by Noa on April 29, 2000, at 12:07:33
In reply to HPA Axis and Depression - Way Too Long, posted by Cam W. on April 28, 2000, at 21:36:15
>Lowered levels of TSH (thyroid insufficiency) causes a depression
Correction: When TSH is HIGH, it means hypothyroid.
Posted by Cam W. on April 29, 2000, at 14:16:15
In reply to Re: HPA Axis and Depression - Way Too Long, posted by Noa on April 29, 2000, at 12:07:33
> >Lowered levels of TSH (thyroid insufficiency) causes a depression
>
>
> Correction: When TSH is HIGH, it means hypothyroid.Noa - Thanks, I knew I was going to get into trouble adding TSH into my explanations. I cannot remember much of what I learned on thyroid function in school (besides, it probably has changed). I was taking the information from an article by Nemeroff that I paraphrased a year or two ago. I had also noticed some other transcribing errors that I had made at the time, but fixed them before posting. I knew one of these errors would slip through. Thanks again - Cam W.
Posted by Chris A. on April 29, 2000, at 16:49:58
In reply to Re: HPA Axis and Depression - TSH - Chris A., posted by Noa on April 29, 2000, at 12:05:01
Noa,
Thanks for the references. I'm glad to hear your endocrinologist gave his blessing. We have one in our whole area and I haven't seen him for about five years. He's wonderful and I'd like to have him for my primary care doc if he'd take me and my HMO would approve. My pDoc prescribes my T3 and 4, which works out well. It is so much more complicated than meets the eye. Right now I must admit to being too depressed to care a whole lot about the details. When given lab results, though, I always ask for the specific numbers and write them down. The history behind that is a long story.
Hang in there.
Thanks,Chris A.
Posted by Noa on April 30, 2000, at 16:32:51
In reply to Re: HPA Axis and Depression - TSH - Noa, posted by Chris A. on April 29, 2000, at 16:49:58
Chris, I also always get all the numbers, and have started asking for a copy of the lab report. I think my internist is slightly annoyed when I do that although she is agreeable, just not warmly so. But the actual numbers are important, because there is a lot of controversy about what the numbers mean, and most docs are not that knowledgable about treating mild hypothyroid disease, or in understanding that the psychiatric manifestations of thyroid problems show up even when the numbers are supposedly within normal limits.
Sorry you are so depressed. What do you think might help?
Posted by Noa on April 30, 2000, at 17:10:34
In reply to Re: Depression and Thyroid, posted by Cam W. on April 29, 2000, at 14:16:15
Cam, I got the other book from the library. Here is the citation:
The Thyroid Solution : A Mind-Body Program for Beating Depression and Regaining Your Emotional and Physical Health
by Ridha Arem. Hardcover (June 1999)So far so good, and I'll say more as I get further into it.
BTW, it appears it has good reviews from Amazon customers.
Posted by Chris A. on April 30, 2000, at 23:42:52
In reply to Re: HPA Axis and Depression - TSH - Noa, posted by Noa on April 30, 2000, at 16:32:51
Dear Noa,
Thanks for caring. Wish I knew what would help. The tip you shared on splitting the Cytomel dosage makes sense - that's one I'm not even going to bug my poor overworked pDoc about. I started adding back selegiline (Eldepryl) a couple of days ago. It has been somewhat helpful in the past. Today I realized that my dose of Omega 3s has been too low because my math was off! To get the dose that was successful in the Harvard study requires 34 capsules per day of the brand I currently have - gulp. In the meantime we'll probably continue with maintenance unilateral ECT. It is not great, but is better than nothing. If I stopped it I'd go back on Lamictal. ADs with any punch cause me to switch, a major problem. At my last visit my consultant thought I should try ziprasidone as soon as it comes on the market, but so far it hasn't in the US. My next appointment with him is Oct 1st, so hopefully I can hang in there until then. My hubby thinks carefully watching my Choline (B6) intake is crucial. It all gets very tiresome. Exercise usually helps a little, but that has been a problem since spraining my ankle about three weeks ago. Thanks for asking. It helps me to think through what I am trying to do to get better.
It is so good to hear you feeling better.Best,
Chris A.
Posted by Racer on August 3, 2004, at 14:35:38
In reply to HPA Axis and Depression - Way Too Long, posted by Cam W. on April 28, 2000, at 21:36:15
While doing a search for info to answer some of my biochem/med questions, I found this link right here at home!
Aside from the most obvious -- it's on point regarding the questions that have come up lately about cortisol, thanks to those bruxism-inducing ads for things like Cortislim -- it's also nice to remind old timers -- and introduce newcomers -- to the wisdom of Cam W.
Posted by h2_tomlin on May 15, 2008, at 20:56:07
In reply to HPA Axis and Depression - Way Too Long, posted by Cam W. on April 28, 2000, at 21:36:15
Hello Cam,
I just read what you posted a few years back about the HPA axis being dysregulated (uncoupled) and causing depression by continual hyperstimulation of CRH and cortisol. This makes such sense, thank you. Are there any good books about this and how to re-couple the HPA Axis?
I have bipolar disorder and a touch of PTSD, I think. I call bipolar "variable hypersensitivity of the HPA axis"...
Many thanks!
Tomlin
> > Hi Cam.
> >
> > I know you have recently performed a ton of research into HPA stuff. What sorts of things have persuaded these researchers to consider anomalies in these systems to be causes of depressive disorders rather than the consequences of them?
> >
> >
> > - Scott
>
> Scott - To do justice to why I believe that a dysregulated HPA axis is the 'cause of the depressive symptoms' of depression I will need at least three studies that I have in my files at work. I think depression is 'caused' by physical or psychological trauma(s) which result in a dysregulation of the HPA axis, sustaining the depressive symptoms. I have already written myself a note to pick these up Monday. (I really need my files at home, but to duplicate them would unnecessarily kill a couple extra trees). I will muddle through with an overview of how I understand this concept and, if necessary give a more complete hypothesis in Monday's posting. Tell me if you would like a further explanation than the following (it does get a little more involved, but is way cool). The following is from notes that I made from a Charles Nemeroff article (didn't write down the reference) and supplemented by a subsequent readings that I think I remember.
>
> The hypothalamus is the controller of hormone secretion in the brain (and body). Peptides secreted by the hypothalamus stimulate or inhibit the pituitary's release of various hormones [eg thyroid stimulating hormone (TSH); growth hormone (GH); adrenocorticotropic hormone (ACTH)]. These hormones control the release of other hormones from various glands throughout the body (outside of the nervous system) and also control their own release, via negative feedback by attaching to inhibitory receptors in the hypothalamus and pituitary (keeping TSH, GH, and ATCH levels from becoming excessive).
>
> The release of TSH and GH (by a number of stimulators) is blunted in people with depession. Lowered levels of TSH (thyroid insufficiency) causes a depression that is non-responsive to antidepressants (as Noa has pointed out on a number of occasions).
>
> The HPA axis (hypothalamus-pituitary-adrenal axis) controls the body's response to stress (the fight-or-flight reaction to physical or psychological stress). To prepare this response to stressful situations, the hypothalamus increases the production and secretion of corticotropin releasing hormone (CRH) which, via the portal blood vessels, and with the help of vasopressin, induces the pituitary to release ACTH and ß-endorphins.
>
> ACTH is released into the body's circulatory system, which attaches to receptors on the adrenal gland (located on top of the kidneys) and causes the adrenal gland to dump cortisol into the bloodstream.
>
> CRH instructs the body to slow the activity in certain bodily areas (eg raphe - leading to a decrease in sleep response; digestion - decreased appetite; and decreased sexual desire - leading to a 'limp willy') while corisol increases the activity of other areas of the body involved in self-preservation (eg increase in blood flow to muscles - leading to restlessness; and more alertness - heightened senses).
>
> Chronic activation of the HPA axis reduces the ability of cortisol to shut off the release of CRH and ACTH (a breakdown of the negative feedback system) and leads to the syndrome we call depression. Unmedicated depressed individuals show chronically increased HPA axis activity (as seen by increased cortisol levels in the CSF, urine and blood).
>
> Researchers have also shown that the pituitary and adrenal glands are enlarged in depressed people, probably due to increased production (and thus release) of ACTH and cortisol, respectively. These chronic hypersecretions are probably due to uncontrolled or aberrant CRH activity in the hypothalamus. It is thought that the dysregulated hypothalamus is the main cause of HPA axis hyperactivity and thus the development of depressive symptoms (eg lowered libido, anxiety, insomnia, etc.). Depressed people also show a blunted response by the adrenal glands to ACTH, but still the adrenals pump out excess cortisol. This blunted response could be the body trying to curb cortisol release.
>
> One thing that all ADs have in common (be they SRIs, NRI, TCAs, MAOIs, NDRIs, ECT, etc.) is that they all decrease CRH levels. An eloquent article by Frank Hoebester (sp?) explains this in detail (I have cited this article earlier this year as a must read, but I can't remember in which thread - this was the article that I said was not bathroom reading). This is one of the articles that I have in my files at work.
>
> Everyone has a different level of stress needed to induce depression. It is sort of like everyone has a bar set at a different level from everyone else. The level of this bar is determined by genetics and early life environmental factors (eg physical or emotional abuse as a child). After a certain level of stress is surpassed, the HPA axis uncouples and depression ensues. It is thought that similar levels of a bar are seen in people predisposed to schizophrenia or bipolar disorder. If a certain level of stress or 'trigger' (emotional, physical, drug-induced, etc.) is surpassed the disorder is manifested. I believe this is called the stress-diathesis model (diasthesis = environment, I think). Both Nemeroff from Emory (for depression) and Ming Tsuang from Harvard (for schizophrenia) champion this theory.
>
> Also, as I mentioned in my last post, that decreasing serotonin (and to a lesser extent norepinephrine) in someone without depression will not cause depression; but adding these neurotransmitters (by SRI or NRI) does resolve depressive symptoms.
>
> It is interesting to note that the downregulation of ß-adrenoceptors caused by most antidepressants (which incidentally takes 2 to 4 weeks - the time it takes for AD effect to kick in) causes a decrease in the expression of the CRH gene in the hypothalamus (thus decresed CRH production).
>
> Also, CRH-receptor antagonists resolve depression and anxiety immediately (like downregulating ß-adrenoceptors, but with immediate action). The CRH-receptor antagonists currently being tested for relief of anxiety seem only to work for a short period of time and the increased CRH gene expression returns. There are also some side effect problems with these agents.
>
> Also, another study that I have implicates glucocorticoid receptor (GR) function in depression. GRs are the receptors for cortisol that shut off the flow of CRH from the hypothalamus and ACTH from the pituitary. Basically, they are the negative feedback receptors that breakdown in the dysregulation of the HPA axis.
>
> I hope that I have made this sort of clear, as this is why I think the HPA axis is linked to depression, but like you say, HPA axis dysregulation could be a consequence of depression. Although the evidence against this seems fairly strong (but not conclusive).
>
> Thanks for putting me throught this mental work-out. I think that I now have a clearer picture in my mind of what I have been talking about. This is such an excellent forum to think out loud.
>
> Your companion in curiosity - Cam W.
Posted by SLS on May 22, 2008, at 5:10:04
In reply to Re: HPA Axis and Depression - Way Too Long » Cam W., posted by h2_tomlin on May 15, 2008, at 20:56:07
Hi.
I still think the "uncoupling" or dysregulation of the HPA axis is a symptom rather than a cause of Major Depressive Disorder and Bipolar Disorder.
- Scott
Posted by FredPotter on May 22, 2008, at 21:19:45
In reply to Re: HPA Axis and Depression - Way Too Long, posted by SLS on May 22, 2008, at 5:10:04
Often these things are functional relationships. That is A affects B and B affects A, but not necessarily directly
Posted by SLS on May 22, 2008, at 21:36:27
In reply to Re: HPA Axis and Depression - Way Too Long, posted by FredPotter on May 22, 2008, at 21:19:45
> Often these things are functional relationships. That is A affects B and B affects A, but not necessarily directly
I agree with you. That's a real good way of looking at it.
My guess is that, once triggered, a HPA dysregulation contributes to the perpetuation of the depressive state.
- Scott
Posted by h2_tomlin on May 27, 2008, at 20:29:28
In reply to Re: HPA Axis and Depression - Way Too Long, posted by SLS on May 22, 2008, at 21:36:27
> > Often these things are functional relationships. That is A affects B and B affects A, but not necessarily directly
>
> I agree with you. That's a real good way of looking at it.
>
> My guess is that, once triggered, a HPA dysregulation contributes to the perpetuation of the depressive state.
>
>
> - ScottGood points and, having experienced it on and off (I am bipolar) for a while I think, I would also observe that congenital susceptibility to HPA dysregulation is a precondition for the perpetuation of the depressive state. Stress initiates a depressive state and, if the stress continues and encounters an HPA axis that is susceptible to deregulation, it pushes the individual into full-blown depression (by upsetting the balance of neurotransmitters through over stimulation) perpetuated by the haywire HPA axis, just like a traffic cop on an hallucinogen might cause (instead or prevent) accidents. If the prolonged stress occurs on an individual who has a "stronger" HPA axis, s/he will likely ride out the stress storm on an even keel and come up ready for the next engagement.
So might a goal of depression research be the complete understanding of the operation of the "normal" HPA axis both at rest and under stress and its emulation and re-regulation in individuals who have varying degrees and aspects of dysregulation?
Tomlin
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