![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 45. This is the beginning of the thread.
Posted by Elroy on June 19, 2005, at 9:49:11
PART ONE:
Chronic stress can make you clinically depressed. Stress- either physical or emotional stress- produces a cascade of different hormonal changes in the body.
These hormones act in a feedback called the HPA (hypothalamic-pituitary-adrenal) axis. Stress prompts the release of CRF (cortisol releasing factor) from the hypothalamus. CRF alerts the pituitary gland to secrete ACTH (adrenocorticotrophin hormone). Then ACTH tells the adrenals to produce more cortisol.
Like adrenalin, cortisol is an essential stress hormone without which we would not survive. However, too much of it can be damaging, especially to the heart, brain, muscles and organs.
Fortunately, cortisol inhibits further secretions of CRF and ACTH, thus completing the feedback loop and shutting down any excessive
secretions of CRF. These mechanisms are essential to stop the HPA axis from damaging the body.When something goes wrong, and the HPA axis secretes cortisol at dangerous levels, a whole plethora of familiar stress-induced diseases and mental complaints can arise.
The HPA axis drives the famous fight-flight response. Under threat, adrenalin rises, heart rate and blood pressure increases, and blood flows to the muscles for running and fighting.
However, when acute stress becomes chronic and long-term, then cortisol becomes the dominant hormone in positioning bodily functions to handle the stress.
Many of the normal bodily processes shut down for the perceived continuing emergency: cell reproduction slows, organ function slows, the immune system becomes suppressed, sleep is more difficult, but appetite actually increases (this is why cortisol is linked to weight gain).
Other effects include lowered sex drive, damage to brain areas including the hippocampus (where emotional memories are stored), distortion of neurochemical receptor sites (because cortisol reduces expression of the gene that produces the 5-HT1A serotonin receptor), destruction of neurons, and damage to the heart.
The destructive consequences of prolonged exposure to cortisol have led some health researchers to speak of "cortisol poisoning". It is easy to see why roughly 50% of severely depressed patients who have been tested have elevated cortisol levels.
In addition, chronic severe stress in newborns can damage the HPA axis itself, and cause increased sensitivity to stress in later life. This is partially why children who have a traumatic childhood are more prone to anxiety and depression later on.
The HPA axis evolved to help people cope with physical stress. Unfortunately, the HPA axis is also stimulated by emotional stress. The more primitive areas of the brain have great difficulty distinguishing between an imagined threat, and a real one. That means that over time, worry can be as dangerous a stressor to your body as real physical danger.
When The HPA Axis Shifts Into Overdrive
Prolonged stress may help create abnormalities in the HPA axis that can lead to depression. These abnormalities include raised levels of CRF and cortisol, abnormalities of the cortisol receptors, causing the HPA feedback loop to be constantly overactive, even when excess cortisol should shut down secretions.
How does cortisol cause depression?
Unremitting stress causes a continual release of cortisol that can transform anxiety into depression by depleting levels of dopamine. This denies dopamine to the pleasure circuitry of the prefrontal cortex, as well as other pleasure pathways, literally preventing the sufferer from feeling good.
The increased cortisol acts like an steroid bombardment on neurotransmitters involved in depression, influencing both the formation and breakdown of serotonin and noradrenaline (which are the targets of modern antidepressant drugs such as selective serotonin reuptake inhibitors). At the same time cortisol may disrupt the receptor sites for these neurochemicals. These are the likely mechanisms of cortisol's contribution to depression.
SSRIs (selective serotonin reuptake inhibitors) have been shown to reverse the damage done to the HPA axis, and to reduce damage to the hippocampus done by excessive cortisol. This is another example of the interrelationship of stress, the HPA axis, and depression.
Psychologists have long understood that severe chronic stress can cause depression. Genetic predispositions to stress related depression are probably common. Unfortunately, depression, even when caused by other means, is a major psychological stressor that can also active the HPA axis and release cortisol, which may further contribute to depression.
In short: stress, anxiety, and depression can exist in a feedback loop that contribute to the further degeneration of these conditions. By the same logic, many treatments that interrupt the HPA axis and lower cortsiol have the potential for alleviating both stress/anxiety and depression.
If you are concerned about your cortisol levels, then you should find a good endocrinologist, in order to receive specialized and complex
endocrine tests.http://www.anxiety-depression-alternatives.com/articles/cortisol,%20stress%20and%20depression.htm
In other words, long-term stress, chronic low-level anxiety or a severe trauma incident can ALL lead to a situation where the HPA Axis begins to wear down and soon becomes dysfunctional. At somepoint the cortisol becomes the dominant adrenal hormone being released and a condition of elevated cortisol exists. As specified above, elevated cortisol not only exaggerates the condition by actually "manufacturing" anxiety and/or depression (by its negative impact on neurological systems), but can create a number of physical symptoms also (and there's no set pattern as individuals react differently to different levels of elevated cortisol).
The first step that needs to be done is to verify cortisol levels through the employment of three 24-hour UFC tests (that's Urinary Free Cortisol). If those levels (any one of the three) come back as lelevated above the lab's normal reference range, then the first step is to determine if this is depression and / or anxiety induced Pseduo Cushing's, or if there's a possibility that one might be dealing with a physical caused form of Cushing's (usually a pituitary tumor, an adrenal tumor or an ACTH-secreting cancer). That is best done through the use of three "Late Night Salivary Cortisol tests". They are as simply as spitting required amount of saliva into a test tube between 11 PM andMidnite and then mailing the sealed tubes back to the lab. levated levels in saliva cortisol amounts (for that time of day) will be likely indicators of Cushing's Disease or Cushing's Syndrome and require further advanced testing.
More to come...
Elroy
Posted by ed_uk on June 19, 2005, at 11:08:51
In reply to HPA Axis and Anti-Cortisol Therapy, posted by Elroy on June 19, 2005, at 9:49:11
Hi Elroy,
Thank you for your report :-) It was very good.
~Ed
Posted by KaraS on June 19, 2005, at 17:58:53
In reply to HPA Axis and Anti-Cortisol Therapy, posted by Elroy on June 19, 2005, at 9:49:11
> PART ONE:
>
> Chronic stress can make you clinically depressed. Stress- either physical or emotional stress- produces a cascade of different hormonal changes in the body.
>
> These hormones act in a feedback called the HPA (hypothalamic-pituitary-adrenal) axis. Stress prompts the release of CRF (cortisol releasing factor) from the hypothalamus. CRF alerts the pituitary gland to secrete ACTH (adrenocorticotrophin hormone). Then ACTH tells the adrenals to produce more cortisol.
>
> Like adrenalin, cortisol is an essential stress hormone without which we would not survive. However, too much of it can be damaging, especially to the heart, brain, muscles and organs.
>
> Fortunately, cortisol inhibits further secretions of CRF and ACTH, thus completing the feedback loop and shutting down any excessive
> secretions of CRF. These mechanisms are essential to stop the HPA axis from damaging the body.
>
> When something goes wrong, and the HPA axis secretes cortisol at dangerous levels, a whole plethora of familiar stress-induced diseases and mental complaints can arise.
>
> The HPA axis drives the famous fight-flight response. Under threat, adrenalin rises, heart rate and blood pressure increases, and blood flows to the muscles for running and fighting.
>
> However, when acute stress becomes chronic and long-term, then cortisol becomes the dominant hormone in positioning bodily functions to handle the stress.
>
> Many of the normal bodily processes shut down for the perceived continuing emergency: cell reproduction slows, organ function slows, the immune system becomes suppressed, sleep is more difficult, but appetite actually increases (this is why cortisol is linked to weight gain).
>
> Other effects include lowered sex drive, damage to brain areas including the hippocampus (where emotional memories are stored), distortion of neurochemical receptor sites (because cortisol reduces expression of the gene that produces the 5-HT1A serotonin receptor), destruction of neurons, and damage to the heart.
>
> The destructive consequences of prolonged exposure to cortisol have led some health researchers to speak of "cortisol poisoning". It is easy to see why roughly 50% of severely depressed patients who have been tested have elevated cortisol levels.
>
> In addition, chronic severe stress in newborns can damage the HPA axis itself, and cause increased sensitivity to stress in later life. This is partially why children who have a traumatic childhood are more prone to anxiety and depression later on.
>
> The HPA axis evolved to help people cope with physical stress. Unfortunately, the HPA axis is also stimulated by emotional stress. The more primitive areas of the brain have great difficulty distinguishing between an imagined threat, and a real one. That means that over time, worry can be as dangerous a stressor to your body as real physical danger.
>
> When The HPA Axis Shifts Into Overdrive
>
> Prolonged stress may help create abnormalities in the HPA axis that can lead to depression. These abnormalities include raised levels of CRF and cortisol, abnormalities of the cortisol receptors, causing the HPA feedback loop to be constantly overactive, even when excess cortisol should shut down secretions.
>
> How does cortisol cause depression?
>
> Unremitting stress causes a continual release of cortisol that can transform anxiety into depression by depleting levels of dopamine. This denies dopamine to the pleasure circuitry of the prefrontal cortex, as well as other pleasure pathways, literally preventing the sufferer from feeling good.
>
> The increased cortisol acts like an steroid bombardment on neurotransmitters involved in depression, influencing both the formation and breakdown of serotonin and noradrenaline (which are the targets of modern antidepressant drugs such as selective serotonin reuptake inhibitors). At the same time cortisol may disrupt the receptor sites for these neurochemicals. These are the likely mechanisms of cortisol's contribution to depression.
>
> SSRIs (selective serotonin reuptake inhibitors) have been shown to reverse the damage done to the HPA axis, and to reduce damage to the hippocampus done by excessive cortisol. This is another example of the interrelationship of stress, the HPA axis, and depression.
>
> Psychologists have long understood that severe chronic stress can cause depression. Genetic predispositions to stress related depression are probably common. Unfortunately, depression, even when caused by other means, is a major psychological stressor that can also active the HPA axis and release cortisol, which may further contribute to depression.
>
> In short: stress, anxiety, and depression can exist in a feedback loop that contribute to the further degeneration of these conditions. By the same logic, many treatments that interrupt the HPA axis and lower cortsiol have the potential for alleviating both stress/anxiety and depression.
>
> If you are concerned about your cortisol levels, then you should find a good endocrinologist, in order to receive specialized and complex
> endocrine tests.
>
> http://www.anxiety-depression-alternatives.com/articles/cortisol,%20stress%20and%20depression.htm
>
> In other words, long-term stress, chronic low-level anxiety or a severe trauma incident can ALL lead to a situation where the HPA Axis begins to wear down and soon becomes dysfunctional. At somepoint the cortisol becomes the dominant adrenal hormone being released and a condition of elevated cortisol exists. As specified above, elevated cortisol not only exaggerates the condition by actually "manufacturing" anxiety and/or depression (by its negative impact on neurological systems), but can create a number of physical symptoms also (and there's no set pattern as individuals react differently to different levels of elevated cortisol).
>
> The first step that needs to be done is to verify cortisol levels through the employment of three 24-hour UFC tests (that's Urinary Free Cortisol). If those levels (any one of the three) come back as lelevated above the lab's normal reference range, then the first step is to determine if this is depression and / or anxiety induced Pseduo Cushing's, or if there's a possibility that one might be dealing with a physical caused form of Cushing's (usually a pituitary tumor, an adrenal tumor or an ACTH-secreting cancer). That is best done through the use of three "Late Night Salivary Cortisol tests". They are as simply as spitting required amount of saliva into a test tube between 11 PM andMidnite and then mailing the sealed tubes back to the lab. levated levels in saliva cortisol amounts (for that time of day) will be likely indicators of Cushing's Disease or Cushing's Syndrome and require further advanced testing.
>
> More to come...
>
> Elroy
>
Hi Elroy,I just read that article the other day. Just a quick question: why do we need to take the three 24-hour UFC tests (that's Urinary Free Cortisol)? Can't we just get the salivary tests to begin with?
K
Posted by Elroy on June 19, 2005, at 20:42:24
In reply to Re: HPA Axis and Anti-Cortisol Therapy, posted by KaraS on June 19, 2005, at 17:58:53
24-hour Urinary Free Cortisol test gives an absolute as to your specifi daily totals. Blood cortisol tests are not good because you could be at a very low secretion point - or very high one - at the specific time that the blood is drawn.
The salivary tests - not the late night ones - but the generic ones - are better than the blood test IF you do the four times a day (every six hours) test. Still doesn't have the accuracy of the total 24-hr UFC for showing daily levels.
Also some people are "cyclical" Cushings so they might not actually over-secrete every day. Hence doing three spread out over 2 - 3 weeks.
If none are elevated then there's no reason to do the Late Night Salivary Cortisol tests. It is just primarily designed for separating out "real" Cushing's versus the Pseudo Cushing's cases...
Elroy
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> Hi Elroy,
>
> I just read that article the other day. Just a quick question: why do we need to take the three 24-hour UFC tests (that's Urinary Free Cortisol)? Can't we just get the salivary tests to begin with?
>
> K
Posted by KaraS on June 19, 2005, at 21:22:37
In reply to Re: HPA Axis and Anti-Cortisol Therapy » KaraS, posted by Elroy on June 19, 2005, at 20:42:24
Posted by 4WD on June 20, 2005, at 0:34:05
In reply to HPA Axis and Anti-Cortisol Therapy, posted by Elroy on June 19, 2005, at 9:49:11
Elroy,
Well thought out and interesting post. Waiting for the next installment.
Where does the CRH test fit into this?
THank you
Marsha
Posted by Elroy on June 20, 2005, at 12:44:20
In reply to Re: HPA Axis and Anti-Cortisol Therapy » Elroy, posted by 4WD on June 20, 2005, at 0:34:05
CRH test is somewhat discounted anymore today. It was a test done once they knew you had elevated cortisol levels (for sure and quite elevated) and was done to see if it was "regular" Cushings or Pseudo Cushings and also to try and determine if it was adrenal or pituitary (if it was "regular" Cushings).
Problem was that it did not have the degree of reliability and accuracy needed. Too many "false negatives" and "false positives". Is still used by some, but generally replaced by other tests...
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x> Elroy,
>
> Well thought out and interesting post. Waiting for the next installment.
>
> Where does the CRH test fit into this?
>
> THank you
> Marsha
Posted by Elroy on June 21, 2005, at 18:06:56
In reply to Re: HPA Axis and Anti-Cortisol Therapy » 4WD, posted by Elroy on June 20, 2005, at 12:44:20
http://www.mcmanweb.com/article-44.htm
In an article in the Sept 2003 Scientific American, Robert Sapolsky PhD of Stanford writes on how the fight or flight response underpins both anxiety and depression.
The primate stress response, Dr Sapolsky begins, can be set in motion by the mere anticipation of an event, and when we erroneously believe a stressor is about to happen we "have entered the realm of neurosis, anxiety, and paranoia." The amygdala in the brain receives input on a conscious level from the cortex and unconsciously from specialized parts of the brain. In response to a perceived threat, the amygdala sets off a chain of events that results in the hormone CRF signaling the brain stem, which activates the sympathetic nervous system. In response, the adrenal glands produce adrenaline (epinephrine) and through a different pathway cortisol, both which prepare the body for fight or flight.
In addition, the amygdala sends information back to the frontal cortex and to sensory cortices, which accounts for emotionally-influenced decision-making and vivid sensations, respectively. In addition, the amygdala is involved in memory. Paradoxically, stress can strengthen the ability of the amygdala to form implicit or preconscious memories while inhibiting the hippocampus’ ability to form explicit or conscious memories. The individual may thus experience a fight or flight response to a voice in a crowd without knowing why, being unable to link the sound of that voice to the similar-sounding voice of a past assailant, resulting in "free-floating" anxiety.
Meanwhile, cortisol activates a brain region called the locus coeruleus, which sends norepinephrine to communicate back to the amygdala, thus initiating the stress response all over again and resulting in a destructive feedback cycle... The torpor of depression may appear to be the opposite of anxiety, but like anxiety can be related to stress. Moreover, depression is not a passive state. According to Dr Sapolsky, "the dread is active, twitching, energy-consuming, distracting, exhausting - but internalized. A classic conception of depression is that it represents aggression turned inward ..." In addition, several pharmaceutical companies have a CRF antagonist in development. Researchers are also working on drugs that target another hormone that regulates cortisol, glucocorticoid receptors (GRs). And the pregnancy-termination drug, RU486 (mifepristone) has demonstrated that it can zero in on the excess cortisol and ACTH that figure in psychotic depression....
Posted by Elroy on June 21, 2005, at 18:13:48
In reply to Re: HPA Axis and Anti-Cortisol Therapy - MORE INFO » Elroy, posted by Elroy on June 21, 2005, at 18:06:56
http://www.nih.gov/news/pr/sep2002/nichd-09.htm
Very Good explanation....
QUOTE:
The HPA axis is a feedback loop by which signals from the brain trigger the release of hormones needed to respond to stress. Because of its function, the HPA axis is also sometimes called the “stress circuit.”
Briefly, in response to a stress, the brain region known as the hypothalamus releases corticotropin-releasing hormone (CRH). In turn, CRH acts on the pituitary gland, just beneath the brain, triggering the release of another hormone, adrenocorticotropin (ACTH) into the bloodstream. Next, ACTH signals the adrenal glands, which sit atop the kidneys, to release a number of hormonal compounds.
These compounds include epinephrine (formerly known as adrenaline), Norepinephrine (formerly known as noradrenaline) and cortisol. All three hormones enable the body to respond to a threat. Epinephrine increases blood pressure and heart rate, diverts blood to the muscles, and speeds reaction time. Cortisol, also known as glucocorticoid, releases sugar (in the form of glucose) from the body reserves so that this essential fuel can be used to power the muscles and the brain.
Normally, cortisol also exerts a feedback effect to shut down the stress response after the threat has passed, acting upon the hypothalamus and causing it to stop producing CRH.
This stress circuit affects systems throughout the body. The hormones of the HPA axis exert their effect on the autonomic nervous system, which controls such vital functions as heart rate, blood pressure, and digestion.
The HPA axis also communicates with several regions of the brain, including the limbic system, which controls motivation and mood, with the amygdala, which generates fear in response to danger, and with the hippocampus, which plays an important part in memory formation as well as in mood and motivation. In addition, the HPA axis is also connected with brain regions that control body temperature, suppress appetite, and control pain.
Similarly, the HPA axis also interacts with various other glandular systems, among them those producing reproductive hormones, growth hormones, and thyroid hormones. Once activated, the stress response switches off the hormonal systems regulating growth, reproduction, metabolism, and immunity. Short term, the response is helpful, allowing us to divert biochemical resources to dealing with the threat... Stress suppresses the reproductive system at various levels, says Dr. Chrousos. First, CRH prevents the release of gonadotropin releasing hormone (GnRH), the “master” hormone that signals a cascade of hormones that direct reproduction and sexual behavior. Similarly, cortisol and related glucocorticoid hormones not only inhibit the release of GnRH, but also the release of luteinizing hormone, which prompts ovulation and sperm release. Glucocorticoids also inhibit the testes and ovaries directly, hindering production of the male and female sex hormones testosterone, estrogen, and progesterone....
One of the major disorders characteristic of an overactive HPA axis is melancholic depression. Chrousos’ research has shown that people with depression have a blunted ability to “counterregulate,” or adapt to the negative feedback of increases in cortisol. The body turns on the “fight or flight” response, but is prevented from turning it off again. This produces constant anxiety and overreaction to stimulation, followed by the paradoxical response called “learned helplessness,” in which victims apparently lose all motivation.
Hallmarks of this form of depression are anxiety, loss of appetite, loss of sex drive, rapid heart beat, high blood pressure, and high cholesterol and triglyceride levels. People with this condition tend to produce higher-than-normal levels of CRH. The high levels of CRH are probably due to a combination of environmental and hereditary causes, depending on the person affected.... Other conditions are also associated with high levels of CRH and cortisol. These include anorexia nervosa, malnutrition, obsessive-compulsive disorder, anxiety disorder, alcoholism, alcohol and narcotic withdrawal, poorly controlled diabetes, childhood sexual abuse, and hyperthyroidism.
The excessive amount of the stress hormone cortisol produced in patients with any of these conditions is responsible for many of the observed symptoms. Most of these patients share psychological symptoms including sleep disturbances, loss of libido, and loss of appetite as well as physical problems such as an increased risk for accumulating abdominal fat and hardening of the arteries and other forms of cardiovascular disease. These patients may also experience suppression of thyroid hormones, and of the immune system. Because they are at higher risk for these health problems, such patients are likely to have their life spans shortened by 15 to 20 years if they remain untreated...
END QUOTEElroy
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Posted by Elroy on June 21, 2005, at 18:19:37
In reply to Re: HPA Axis Anti-Cortisol Therapy - MORE INFO 2 » Elroy, posted by Elroy on June 21, 2005, at 18:13:48
Another VG explanation site...
http://dr-john.ca/depression_article13.php
A. The HPA Axis
This axis (hypothalamic-pituitary-adrenal axis) includes (a) the limbic system and pre-frontal cortex and (b) the neuro-endocrine system as described below. In response to a number of things including a current stressor, a chronic stressor, and stimuli or memories associated with a previous stressor, the HPA axis is activated.* The Limbic System Some major biological processes of motivation, emotion, and drive (including eating, drinking, sexual desbire, energy, emotional memory, and mood) are governed in part by an inter-related group of brain structures including the hypothalamus, the hippocampus, the amygdala, the pituitary gland, the thalamus, the locus coreleus, and parts of the pre-frontal cortex. Together, these structures are known as the limbic system. Disruption of any part of this system can lead directly to symptoms we associate with depression as well as having an impact on neuro-transmitters and the neuro-endocrine system.
* The Neuro-Endocrine System This system consists of a number of interconnected sub-systems including the limbic system which produce a large number of chemicals called hormones. Among them are CRF, ACTH, cortisol (from the hypothalamic-pituitary-adrenal system {the HPA axis}), TSH (from the hypothalamic-pituitary-thyroid system), melatonin, (from the pineal gland), and both estrogen and progesterone (from the female reproductive system). These chemicals are released into the blood stream and have very rapid effects on such things as blood glucose level, metabolic rate, nervous system tone, sex, sleep-wake cycle, regulation of the immune system, and certain aspects of emotion, and attention. Additionally, the HPA axis is linked to the neurotransmitters serotonin and nor-epinepherine. Thus, short-term activation of this system is associated with symptoms of anxiety or over-arousal while there is an association between prolonged activation or insufficient nervous system variability (sometimes referred to as vagal tone and measured as heart rate variability) and symptoms of depression and post-traumatic stress disorder as well as increases in the risk for high blood pressure, heart disease, and possibly auto-immune diseases. For example, 20% to 40% of outpatients with depression and 60% to 80% inpatients with depression have one or more signs of increased neuro-endocrine activation. Also, 50% to 70% of those with Cushing's Disease (a disorder of the adrenal gland) also have depression which often precedes other symptoms of the disease. Moreover, there is evidence suggesting that anti-depressant medication can normalize the HPA axis via effects on serotonin. Laboratory tests are available to assess the functioning of the neuro-endocrine system.B. Stressors
Stressors activate the HPA Axis so our bodies have the capacity to respond. Then, generally once the stressor is over, gradually the HPA Axis returns to normal. However, for a variety of reasons (for example, too many stressors, too severe in intensity, and too long in duration) sometimes the HPA Axis stays activated for a long time which ultimately leads to depletion of neuro-transmitters such as nor-epinephrine with the resulting symptoms of depression. There are many different types of stressors and I have identified a number of them below....Elroy
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Posted by Elroy on June 21, 2005, at 18:28:03
In reply to Re: HPA Axis Anti-Cortisol Therapy - MORE INFO 3 » Elroy, posted by Elroy on June 21, 2005, at 18:19:37
More good explanation info....
http://www.chronicfatiguesupport.com/library/showarticle.cfm/ID/1841
There is now firm evidence that major depression is accompanied by increased baseline activity of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by means of 24-h urinary cortisol (UC) excretion. Recently, there were some reports that fibromyalgia and post-traumatic stress disorder (PTSD), two disorders which show a significant amplitude of depressive symptoms, are associated with changes in the baseline activity of the HPA axis... In conclusion, this study found increased 24-h UC excretion in patients with PTSD comparable to that in patients with major depression, whereas in fibromyalgia no significant changes in 24- h UC were found....
NOTE: UC stands for Urinary Cortisol
Some more VG explanatory info at:
Posted by Elroy on June 21, 2005, at 18:46:08
In reply to Re: HPA Axis Anti-Cortisol Therapy - MORE INFO 4 » Elroy, posted by Elroy on June 21, 2005, at 18:28:03
A really great explanation page, with more specific data about cortisol amd hypercortisolism as relates to psychiatric disorders...
http://www.psychiatrictimes.com/p040592.html
Despite considerable advances in the treatment of mood disorders during previous decades, there remains an urgent need to identify compounds that will successfully treat mood episodes (including the associated neurocognitive impairments) and prevent their recurrence. This article reviews some of these recent developments, with an emphasis on the role of cortisol in relation to depression...
Glucocorticoids are the end product of the hypothalamic-pituitary-adrenal (HPA) axis and are central to the stress response. There is overwhelming evidence that during periods of acute stress, glucocorticoids promote survival by mobilizing energy reserves. In addition to these short-term adaptive changes, glucocorticoids are also involved in other longer-term, stress-related adaptive changes such as shaping and regulating a number of physiological processes, including immune responsiveness and activation of the sympathetic nervous system. Although glucocorticoid production is essential for survival, overproduction is associated with a significant disruption of cellular functioning, which, in turn, leads to widespread physiological dysfunction...
Cortisol, a glucocorticoid released from the adrenal cortex, is the end product of the HPA axis. The HPA axis comprises the tissues of the hypothalamus, pituitary and adrenal cortices; regulatory neuronal inputs; and a variety of releasing factors and hormones... A variety of stressors, both physical and psychological, cause the neurosecretory cells within the paraventricular nucleus of the hypothalamus to secrete corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) into the microportal circulatory system of the pituitary stalk. These secretions cause the release of adrenocorticotropic hormone (ACTH) from the anterior lobe of the pituitary. Cortisol is released from the adrenal cortex in response to ACTH. Cortisol has a panoply of central and peripheral effects that are mediated via at least two intracellular specialized glucocorticoid receptor subtypes: the high-affinity type I receptor (or MR) and the low-affinity type II receptor (or GR). ... activity of the HPA axis is highly regulated. Secretory cells within the paraventricular nucleus receive neuronal inputs from a number of brain regions including the amygdala, hippocampus and nuclei within the midbrain (Figure 2). The HPA axis also has an autoregulatory mechanism mediated by cortisol. Endogenous cortisol binds to glucocorticoid receptors in the HPA axis tissues and hippocampus and acts as a potent negative regulator of HPA activity. The relative contribution of the two receptor subtypes (GR and MR) in the regulation of HPA activity is as yet unclear. The MRs have a high affinity for endogenous glucocorticoids such as cortisol, as well as for the salt-regulating hormone aldosterone. However, the GRs have a relatively low affinity for cortisol, but bind avidly to synthetic steroids such as dexamethasone. These differences in affinity suggest that MRs play a primary role in regulating basal cortisol levels when hormone levels are low. When cortisol levels rise, as from stress or circadian fluctuations, the MRs become saturated, and GRs become the main transducers of glucocorticoid activity and therefore the primary mediators of HPA feedback. These regulatory mechanisms are important in determining basal levels and circadian fluctuations in cortisol levels. Changes in GR number or function may be important in altering the homeostatic function of the HPA axis observed in healthy individuals....
first observations of abnormalities of cortisol levels in patients with depression were made in the late 1950s by Board and colleagues (Michael and Gibbons, 1963), and these observations have been consistently replicated. Subsequent studies have shown that HPA hyperactivity--as manifested by hypersecretion of CRH; increased cortisol levels in plasma, urine and cerebrospinal fluid; exaggerated cortisol responses to ACTH; and enlarged pituitary and adrenal glands--occurs in individuals suffering from severe mood disorders... It is interesting, however, that neither citalopram (Celexa) (Seckl and Fink, 1992) nor fluoxetine (Prozac) (Rossby et al., 1995) alters GR mRNA or GR binding capacity, which suggests that the selective serotonin reuptake inhibitor class of antidepressants may lack the ability to modulate GR expression and/or function. This evidence suggests that if indeed GR regulation is involved in the therapeutic mechanism(s) of action of antidepressant drugs and mood stabilizers, it is not a unitary mechanism. Antidepressant drugs that have the ability to regulate GR expression and binding may, however, have greater therapeutic efficacy in patients who have hypercortisolemia...
Paradoxically, glucocorticoid receptor antagonists have also been advocated as agents with potential therapeutic properties for mood disorders. This is based on the ability of the GR antagonist to block any detrimental effect of hypercortisolemia and on the ability of an antagonist to upregulate its receptor. Administration of a GR antagonist results in an acute antiglucocorticoid effect, while presumably causing a compensatory upregulation of GR numbers, leading to enhanced negative feedback of the HPA axis. Initial clinical studies using the GR antagonist mifepristone (Mifeprex, RU-486) have been encouraging, but some clinical efficacy may have been masked by the prolonged administration of the drug (Murphy et al., 1993). Animal studies suggest that GR numbers are increased rapidly (within hours) after the administration of mifepristone, which may restore normal feedback, thus "resetting" the HPA axis (Lupien and McEwen, 1997). Such data suggest that a brief period of treatment with the GR antagonist may be adequate for restoring normal HPA axis function. This might reduce problems of noncompliance and side effects associated with longer-term administration.... Twenty patients, ages 18 to 65, with a diagnosis of BD (confirmed using the Structured Clinical Interview for DSM-IV [SCID]) and residual depressive symptoms were recruited. Patients' medication had been unchanged for six weeks prior to participation and remained so throughout the study period. Seventeen patients were taking at least one mood stabilizer, with 13 taking at least one antidepressant and 11 taking an antipsychotic agent. Following an initial baseline assessment of neurocognitive function and mood and basal neuroendocrine profiling, patients were randomly assigned to receive either 600 mg/day mifepristone or placebo for seven days. Administration was in a double-blind design. Mood ratings were taken after the week's treatment and then at weekly intervals. At day 21, the groups crossed over and received the alternative treatment (placebo or mifepristone) for seven days, again with ratings taken following the week's treatment and at weekly intervals. Neurocognitive function was assessed on three occasions over the study period: at baseline and 21 days after both treatments.... At 14 days following treatment with mifepristone, depression rating scores had significantly improved from baseline levels, without any significant change being observed at any time point following placebo. The Brief Psychiatric Rating Scale (BPRS) scores were also significantly lower in the mifepristone group at day 14 compared with baseline, with a similar lack of change in the placebo-treated group. With regard to neurocognitive performance, the mifepristone-treated group showed a significant reduction in the error rate of the spatial working memory task (Figure 4) compared with baseline. No such changes were observed in the placebo-treated patients. Furthermore, baseline cortisol output correlated positively with the percentage improvement in spatial working memory error rate following mifepristone administration. Verbal fluency and spatial recognition memory also improved in those patients treated with mifepristone...
Posted by Elroy on June 21, 2005, at 18:51:40
In reply to Re: HPA Axis Anti-Cortisol Therapy - MORE INFO 5, posted by Elroy on June 21, 2005, at 18:46:08
Misc Info:
Holsboer, F. (2003). "Corticotropin-releasing hormone modulators and depression." Curr Opin Investig Drugs 4(1): 46-50.
Basic and clinical studies demonstrate that the central corticotropin-releasing hormone (CRH) circuits are overactive among depressives, a phenomenon frequently reflected by enhanced cortisol and corticotropin levels in the peripheral blood of these patients. Behavioral pharmacology provided evidence that CRH overexpression accounts for many signs and symptoms characteristic of depression. CRH-type 1 receptors (CRHR), were identified as responsible for conveying the CRH signal into cellular circuitries, thereby inducing depression-related symptoms. In order to decrease CRH signaling, many pharmaceutical companies have developed small molecules that after oral ingestion, penetrate the blood-brain barrier and selectively bind at CRHR1 with high affinity. These compounds have been tested in animal models and patients with major depression. One of these compounds, R-121919 (Neurocrine Biosciences Inc), ameliorated depressive symptomatology without unwanted endocrine side effects or other adverse effects. While clinical trials of R-121919 have been discontinued after phase IIa studies, a number of other CRHR1 antagonists are being developed, and hopefully this advance will ultimately lead to a favorable alternative to currently available antidepressant drugs.
Parker, K. J., A. F. Schatzberg, et al. (2003). "Neuroendocrine aspects of hypercortisolism in major depression." Horm Behav 43(1): 60-6.
A consistent finding in biological psychiatry is that hypothalamic-pituitary-adrenal (HPA) axis physiology is altered in humans with major depression. These findings include hypersecretion of cortisol at baseline and on the dexamethasone suppression test. In this review, we present a process-oriented model for HPA axis regulation in major depression. Specifically, we suggest that acute depressions are characterized by hypersecretion of hypothalamic corticotropin-releasing factor, pituitary adrenocorticotropic hormone (ACTH), and adrenal cortisol. In chronic depressions, however, enhanced adrenal responsiveness to ACTH and glucocorticoid negative feedback work in complementary fashion so that cortisol levels remain elevated while ACTH levels are reduced. In considering the evidence for hypercortisolism in humans, studies of nonhuman primates are presented and their utility and limitations as comparative models of human depression are discussed.
Rothschild, A. J. (2003). "Challenges in the treatment of depression with psychotic features." Biol Psychiatry 53(8): 680-90.
Major depression with psychotic features (MDpsy), a disorder with considerable morbidity and mortality, is more common than is generally realized and is a most difficult form of depression to treat. Patients with MDpsy exhibit more frequent relapses and recurrences and have increased use of services, greater disability, and a poorer clinical course when compared with nonpsychotically depressed patients. Patients with MDpsy demonstrate distinct biological abnormalities in studies of the hypothalamic-pituitary-adrenal (HPA) axis, dopaminergic activity, enzyme studies, brain imaging, electroencephalogram sleep profiles, and measures of serotonergic function when compared with nonpsychotic depression. The social and occupational impairment in MDpsy has been hypothesized to be secondary to subtle cognitive deficits caused by the higher cortisol levels frequently observed in MDpsy patients. Several studies support a relationship between bipolar disorder and MDpsy, particularly in young-onset MDpsy. The most efficacious treatments for MDpsy include the combination of an antidepressant and an antipsychotic, amoxapine, or electroconvulsive therapy. Atypical antipsychotic medications may have particular relevance for the treatment of MDpsy because of the potential for reduced risk of extrapyramidal side effects and tardive dyskinesia, as well as antipsychotic and possibly antidepressant qualities. Based on the observations that MDpsy patients exhibit marked dysregulation of the HPA axis and elevated cortisol levels, several antiglucocorticoid strategies have been employed to treat MDpsy patients. Many questions regarding the acute and long-term treatment of MDpsy remain for future studies to address.
Elroy
Posted by Chairman_MAO on June 22, 2005, at 18:13:42
In reply to Re: HPA Axis and Anti-Cortisol Therapy, posted by KaraS on June 19, 2005, at 17:58:53
The best AD available for normalizing the HPA axis and reversing hippocampal atrophy due to excess cortisol is tianeptine.
Prevention of stress-induced
morphological and cognitive consequences
by
McEwen BS; Conrad CD; Kuroda Y;
Frankfurt M; Magarinos AM; McKittrick C
Laboratory of Neuroendocrinology,
Rockefeller University,
New York, NY 10021, USA.
Eur Neuropsychopharmacol, 1997 Oct, 7 Suppl 3:, S323-8.ABSTRACT
Atrophy and dysfunction of the human hippocampus is a feature of aging in some individuals, and this dysfunction predicts later dementia. There is reason to believe that adrenal glucocorticoids may contribute to these changes, since the elevations of glucocorticoids in Cushing's syndrome and during normal aging are associated with atrophy of the entire hippocampal formation in humans and are linked to deficits in short-term verbal memory. We have developed a model of stress-induced atrophy of the hippocampus of rats at the cellular level, and we have been investigating underlying mechanisms in search of agents that will block the atrophy. Repeated restraint stress in rats for 3 weeks causes changes in the hippocampal formation that include suppression of 5-HT1A receptor binding and atrophy of dendrites of CA3 pyramidal neurons, as well as impairment of initial learning of a radial arm maze task. Because serotonin is released by stressors and may play a role in the actions of stress on nerve cells, we investigated the actions of agents that facilitate or inhibit serotonin reuptake. Tianeptine is known to enhance serotonin uptake, and we compared it with fluoxetine, an inhibitor of 5-HT reuptake, as well as with desipramine. Tianeptine treatment (10 mg/kg/day) prevented the stress-induced atrophy of dendrites of CA3 pycamidal neurons, whereas neither fluoxetine (10 mg/kg/day) nor desipramine (10 mg/kg/day) had any effect. Tianeptine treatment also prevented the stress-induced impairment of radial maze learning. Because corticosterone- and stress-induced atrophy of CA3 dendrites is also blocked by phenytoin, an inhibitor of excitatory amino acid release and actions, these results suggest that serotonin released by stress or corticosterone may interact pre- or post-synaptically with glutamate released by stress or corticosterone, and that the final common path may involve interactive effects between serotonin and glutamate receptors on the dendrites of CA3 neurons innervated by mossy fibers from the dentate gyrus. We discuss the implications of these findings for treating cognitive impairments and the risk for dementia in the elderly.
Posted by Elroy on June 22, 2005, at 20:10:28
In reply to Re: HPA Axis and Anti-Cortisol Therapy » KaraS, posted by Chairman_MAO on June 22, 2005, at 18:13:42
This is a 1997 study that was performed just a year after Remeron came out and before testing had been done on Remeron. I don't doubt that tianeptine might be effective in that regard, but am also aware of sveral studies with Remeron (initial links are general studies with later links involving cortisol / HPA Axis):
http://www.pslgroup.com/dg/994E.htm
http://www.pslgroup.com/dg/88A7E.htm
http://www.pslgroup.com/dg/BC202.htm
http://www.pslgroup.com/dg/150D62.htm
http://www.pslgroup.com/dg/1D25B6.htm
http://my.webmd.com/content/article/35/1728_59748
http://www.docguide.com/news/content.nsf/news/EC40CE41EC274B65852569BC006474FA
http://www2.eclinicalpsychiatrynews.com/scripts/om.dll/serve?action=searchDB&searchDBfor=art&artType=full&id=aqc010291124
http://www.docguide.com/news/content.nsf/news/8525697700573E1885256C670056CC80
http://www.docguide.com/news/content.nsf/news/8525697700573E1885256DB7007131E7
http://www.docguide.com/news/content.nsf/news/8525697700573E1885256DBF00474CA2
http://www.docguide.com/news/content.nsf/news/8525697700573E188525700E00608A93Here's where it gets real interesting:
http://www.pslgroup.com/dg/2030E2.htm
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10451911&dopt=Abstract
http://www.docguide.com/news/content.nsf/news/8525697700573E1885256CFD004B4129
http://qualitycounts.com/fp/remeron.htmAt least one study, reported in 2001 showed that tianeptine actually (starting at week 4) INCREASED cortisol levels in test rats... It also referes to yet another study where the same thing (elevated cortisol levels were found)...
QUOTE: Stress-Induced Activation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis. Psychosocial stress induced a sustained activation of the HPA axis, as indicated by the nonadapting elevation of urinary cortisol excretion in the two stress groups (Table 2). No statistical differences between the Stress and Stress + Tianeptine group were found, except on week 4 yielding significantly HIGHER cortisol excretion (P < 0.02) in stressed animals treated with tianeptine. Despite the daily treatment of subordinate animals with tianeptine (Stress + Tianeptine), cortisol did not return to basal levels (Table 2). This finding is in line with one study in rats showing that stress-elicited elevations in plasma corticosterone were not reduced by tianeptine treatment (39). Other studies, however, demonstrated that tianeptine clearly reduces HPA response to stress (40). No effects on urinary cortisol excretion were observed in animals of the two control groups (Control; Control + Tianeptine). END QUOTE
I also noted the fact that it appears to "reduce HPA response to stress activity" (which is a far cry from "re-setting" the HPA Axis... if it did that the cortisol levels should return to normal and not remain elevated), but if one is experiencing effects of elevated cortisol above and beyond one's severe anxiety / depression then clearly more is needed...
Other sites have refered to tianeptine "countering the effects" of elevated cortisol. Again, quite different from actually reducing the cortisol and fully "re-setting" the HPA Axis (which should return cortisol secretions to normal).
Additionally, I believe that tianeptine is still not available in the US market (another disadvantage compared to Remeron).
And the bottom line is that neither of these show the benefits that have - so far - been noted in studies involving RU486 in a SHORT-TERM therapy mode. That protocol thereby avoided RU486's side effects (as when taken long term) but displayed some really significant results in re-setting the HPA Axis, resulting in lowered to normal cortisol levels and tremendous benefits with anxiety / depression situation.
FDA has supposedly "fast-tracked" RU486, so will be interesting to see just exactly what that ends up meaning....
That said, if Tianeptine was available on US market I personally would give a try if the Remeron doesn't do completely what I want it to! Have seen ancedotal instances of persons who have had very good AD effects from Tianeptine who had also tried Remeron and had just "so-so" effects.... unfortunately in none of those ancedotal stories did it mention the individual having elevated cortisol levels (they were taking it for anxiety and / or depression problems and made no mention of having certified high cortisol levels).
Elroy
X
X
X
> The best AD available for normalizing the HPA axis and reversing hippocampal atrophy due to excess cortisol is tianeptine.
>
> Prevention of stress-induced
> morphological and cognitive consequences
> by
> McEwen BS; Conrad CD; Kuroda Y;
> Frankfurt M; Magarinos AM; McKittrick C
> Laboratory of Neuroendocrinology,
> Rockefeller University,
> New York, NY 10021, USA.
> Eur Neuropsychopharmacol, 1997 Oct, 7 Suppl 3:, S323-8.
>
> ABSTRACT
>
> Atrophy and dysfunction of the human hippocampus is a feature of aging in some individuals, and this dysfunction predicts later dementia. There is reason to believe that adrenal glucocorticoids may contribute to these changes, since the elevations of glucocorticoids in Cushing's syndrome and during normal aging are associated with atrophy of the entire hippocampal formation in humans and are linked to deficits in short-term verbal memory. We have developed a model of stress-induced atrophy of the hippocampus of rats at the cellular level, and we have been investigating underlying mechanisms in search of agents that will block the atrophy. Repeated restraint stress in rats for 3 weeks causes changes in the hippocampal formation that include suppression of 5-HT1A receptor binding and atrophy of dendrites of CA3 pyramidal neurons, as well as impairment of initial learning of a radial arm maze task. Because serotonin is released by stressors and may play a role in the actions of stress on nerve cells, we investigated the actions of agents that facilitate or inhibit serotonin reuptake. Tianeptine is known to enhance serotonin uptake, and we compared it with fluoxetine, an inhibitor of 5-HT reuptake, as well as with desipramine. Tianeptine treatment (10 mg/kg/day) prevented the stress-induced atrophy of dendrites of CA3 pycamidal neurons, whereas neither fluoxetine (10 mg/kg/day) nor desipramine (10 mg/kg/day) had any effect. Tianeptine treatment also prevented the stress-induced impairment of radial maze learning. Because corticosterone- and stress-induced atrophy of CA3 dendrites is also blocked by phenytoin, an inhibitor of excitatory amino acid release and actions, these results suggest that serotonin released by stress or corticosterone may interact pre- or post-synaptically with glutamate released by stress or corticosterone, and that the final common path may involve interactive effects between serotonin and glutamate receptors on the dendrites of CA3 neurons innervated by mossy fibers from the dentate gyrus. We discuss the implications of these findings for treating cognitive impairments and the risk for dementia in the elderly.
Posted by Jakeman on June 22, 2005, at 22:26:41
In reply to Re: HPA Axis and Anti-Cortisol Therapy » Chairman_MAO, posted by Elroy on June 22, 2005, at 20:10:28
Remeron has its strong points. Unfortunately it made me want everything in the house. 25 pounds later I gave it up. I did a trial of tianeptine a few years ago and felt absolutely no effect. I think phosphatidylcholine is helpful as an anti-cortisol agent.
best regards ~ Jake
Posted by Jakeman on June 22, 2005, at 22:32:16
In reply to Re: HPA Axis and Anti-Cortisol Therapy » Elroy, posted by Jakeman on June 22, 2005, at 22:26:41
> Remeron has its strong points. Unfortunately it made me want everything in the house. 25 pounds later I gave it up. I did a trial of tianeptine a few years ago and felt absolutely no effect. I think phosphatidylcholine is helpful as an anti-cortisol agent.
>
> best regards ~ JakeI meant to say phosphatidyl*serine*
Posted by Elroy on June 23, 2005, at 1:32:46
In reply to Re: HPA Axis and Anti-Cortisol Therapy » Elroy, posted by Jakeman on June 22, 2005, at 22:26:41
Ahhh.. kind of opposite with me.. well PS - along with some other OTC products that I was taking, and taking very aggresively (things like Relora and Holy Basil and amino acis Glutamate w/ NAC, etc., etc.... and I was taking 800mg of PS daily know matter what other supps I was also taking for anti-cortisol) allowed me to get my cortisol levels down to 108, with a reference range of 20 - 100.. close... but when I stopped them for just two weeks prior to my next test, my cortisol was back up to 240-something... so clearlt by HPA Axis hadn't re-set (or my cortisol levels would started normalizing rather than going back up).
I had some significant sedation effects on first few days when dose was at 15mg but since I've gone to 30 mg I've had that swdation almost completely disappear. Appetite had no increase at 14mg and maybe a very, very slight increase at 30 mg... As to cortisol levels, won't know for about a month as
next testing time is around July 20th...Elroy
X
X
X
X
X
> Remeron has its strong points. Unfortunately it made me want everything in the house. 25 pounds later I gave it up. I did a trial of tianeptine a few years ago and felt absolutely no effect. I think phosphatidylcholine is helpful as an anti-cortisol agent.
>
> best regards ~ Jake
Posted by Jakeman on June 23, 2005, at 12:29:20
In reply to Re: HPA Axis and Anti-Cortisol Therapy » Jakeman, posted by Elroy on June 23, 2005, at 1:32:46
> Ahhh.. kind of opposite with me.. well PS - along with some other OTC products that I was taking, and taking very aggresively (things like Relora and Holy Basil and amino acis Glutamate w/ NAC, etc., etc.... and I was taking 800mg of PS daily know matter what other supps I was also taking for anti-cortisol) allowed me to get my cortisol levels down to 108, with a reference range of 20 - 100.. close... but when I stopped them for just two weeks prior to my next test, my cortisol was back up to 240-something... so clearlt by HPA Axis hadn't re-set (or my cortisol levels would started normalizing rather than going back up).
>
> I had some significant sedation effects on first few days when dose was at 15mg but since I've gone to 30 mg I've had that swdation almost completely disappear. Appetite had no increase at 14mg and maybe a very, very slight increase at 30 mg... As to cortisol levels, won't know for about a month as
> next testing time is around July 20th...
>
> Elroy
>Good luck with the Remeron, it works for many people. I'm glad you're posting results from your research and personal experience, it's very informative.
~Jake
Posted by KaraS on June 24, 2005, at 3:59:43
In reply to Re: HPA Axis and Anti-Cortisol Therapy » KaraS, posted by Chairman_MAO on June 22, 2005, at 18:13:42
> The best AD available for normalizing the HPA axis and reversing hippocampal atrophy due to excess cortisol is tianeptine.
>
> Prevention of stress-induced
> morphological and cognitive consequences
> by
> McEwen BS; Conrad CD; Kuroda Y;
> Frankfurt M; Magarinos AM; McKittrick C
> Laboratory of Neuroendocrinology,
> Rockefeller University,
> New York, NY 10021, USA.
> Eur Neuropsychopharmacol, 1997 Oct, 7 Suppl 3:, S323-8.
>
> ABSTRACT
>
> Atrophy and dysfunction of the human hippocampus is a feature of aging in some individuals, and this dysfunction predicts later dementia. There is reason to believe that adrenal glucocorticoids may contribute to these changes, since the elevations of glucocorticoids in Cushing's syndrome and during normal aging are associated with atrophy of the entire hippocampal formation in humans and are linked to deficits in short-term verbal memory. We have developed a model of stress-induced atrophy of the hippocampus of rats at the cellular level, and we have been investigating underlying mechanisms in search of agents that will block the atrophy. Repeated restraint stress in rats for 3 weeks causes changes in the hippocampal formation that include suppression of 5-HT1A receptor binding and atrophy of dendrites of CA3 pyramidal neurons, as well as impairment of initial learning of a radial arm maze task. Because serotonin is released by stressors and may play a role in the actions of stress on nerve cells, we investigated the actions of agents that facilitate or inhibit serotonin reuptake. Tianeptine is known to enhance serotonin uptake, and we compared it with fluoxetine, an inhibitor of 5-HT reuptake, as well as with desipramine. Tianeptine treatment (10 mg/kg/day) prevented the stress-induced atrophy of dendrites of CA3 pycamidal neurons, whereas neither fluoxetine (10 mg/kg/day) nor desipramine (10 mg/kg/day) had any effect. Tianeptine treatment also prevented the stress-induced impairment of radial maze learning. Because corticosterone- and stress-induced atrophy of CA3 dendrites is also blocked by phenytoin, an inhibitor of excitatory amino acid release and actions, these results suggest that serotonin released by stress or corticosterone may interact pre- or post-synaptically with glutamate released by stress or corticosterone, and that the final common path may involve interactive effects between serotonin and glutamate receptors on the dendrites of CA3 neurons innervated by mossy fibers from the dentate gyrus. We discuss the implications of these findings for treating cognitive impairments and the risk for dementia in the elderly.---------------------------------------------
Thanks for the info. I had read that tianeptine could reverse hippocampal atrophy but I didn't realize that it was any better at it than any other antidepressant.
Kara
Posted by Jakeman on June 25, 2005, at 16:14:23
In reply to Re: HPA Axis and Anti-Cortisol Therapy » KaraS, posted by Chairman_MAO on June 22, 2005, at 18:13:42
> The best AD available for normalizing the HPA axis and reversing hippocampal atrophy due to excess cortisol is tianeptine.
>It's my understanding that tianeptine is not available in the US. Does anyone know what's up with this.. is there a particular reason? I've read quite a bit of positive information in the scientific literature about this drug, but there seems to be a dearth of anecdotal reports. Is it used much in the UK?
thanks ~Jake
Posted by Elroy on June 25, 2005, at 17:48:11
In reply to Re: HPA Axis and Anti-Cortisol Therapy- tianeptine » Chairman_MAO, posted by Jakeman on June 25, 2005, at 16:14:23
No idea on this one.... maybe politics at play? How long has it been in use in Europe, etc? It seems that it has a really good track record....
Kind of like the situation with Pfizer and their drug Lyrica. It has been approved by FDA for over six months now and still hasn't been released to the US market....
Elroy
X
X
X> > The best AD available for normalizing the HPA axis and reversing hippocampal atrophy due to excess cortisol is tianeptine.
> >
>
> It's my understanding that tianeptine is not available in the US. Does anyone know what's up with this.. is there a particular reason? I've read quite a bit of positive information in the scientific literature about this drug, but there seems to be a dearth of anecdotal reports. Is it used much in the UK?
>
> thanks ~Jake
Posted by ed_uk on June 25, 2005, at 21:15:37
In reply to Re: HPA Axis and Anti-Cortisol Therapy- tianeptine » Chairman_MAO, posted by Jakeman on June 25, 2005, at 16:14:23
Hi,
>Is it used much in the UK?
No, it's not available in the UK. It is available in France and a few other European countries.
~Ed
Posted by cache-monkey on June 29, 2005, at 0:34:17
In reply to Re: HPA Axis and Anti-Cortisol Therapy » Chairman_MAO, posted by Elroy on June 22, 2005, at 20:10:28
Hi Elroy,
I've been reading your posts on cortisol with great interest. Thanks for posting all the useful information.
In some of the links you posted on Remeron as effective cortisol therapy, the authors attribute this to its 5-HT2 blockade. Remeron is known for its 5-HT2a antagonism, but less well known is that it also blocks the 5-HT2c receptors almost as hard [1]. This is a lot like Zyprexa at low doses, although with Z you also get the D-2 antagonsim. So, Zyprexa might present a reasonable altertnative in reducing cortisol levels for people who can't get over the anti-histaminic effects of Remeron.
I only have personal experience with Zyprexa. So far, it seems to have mitigated a fair chunk of my free-floating anxiety that was the residual from a prolonged period of stress.
Just a thought,
cache-monkey
Posted by SLS on June 29, 2005, at 6:28:35
In reply to Anti-Cortisol Therapy: Remeron ... or Zyprexa?? » Elroy, posted by cache-monkey on June 29, 2005, at 0:34:17
For those people living in the UK, there is an antiglucocorticoid named metyrapone that is used to treat Cushings Syndrome and other hypercortisolemic conditions. I believe metyrapone is also available in Canada. I hope someone can check on this.
Unfortunately, in the US, metyrapone is used only as a test for diagnostic purposes. It helps to differentiate the status of the adrenal glands versus the status of the HPA axis.
Ketoconazole is a cortisol synthesis inhibitor that might be of use for some people.
- Scott
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