Posted by Shawn. T. on July 10, 2002, at 17:16:30
There is a theory stating that increased levels of cortisol is a possible cause of depressive symptoms. "Cortisol ... decreased body weight, food intake, plasma norepinephrine (NE), and epinephrine (E) levels." (1st link below)Also, "These data indicate that chronic exposure to high glucocorticoid levels alters 5-HT1 receptor-mediated functions and provides additional evidence relevant to the contribution of glucocorticoid elevation to the symptoms of depression." So increased stress leads to altered serotonin receptor function, which leads to increased release of cortisol and probably other stress related substances into the bloodstream. I have consistently seen scientifically derived notions correspond to real life experiences. Recent advances in neuroscience have lead me to believe that a more ideal antidepressant may have the following properties: serotonin reuptake inhibition, 5HT-2 antagonism, and 5HT-3 antagonism. Or possibly a drug like Remeron, just with increased activation of 5-HT1a receptors and reduced antihistamine function. Organon does own some 5-HT1 agonist drugs by the way. This is confirmed by the many reports of people with treatment resistant depression responding to combinations of SSRI's and Remeron. The role of norepinephrine in depression is also explained by my reasoning. I would guess that SSRI monotherapy may reduce norepenephrine levels, which may explain why the stronger SSRI's like Paxil are much more sedating than the weaker, especially Prozac which is activating."
5-HT1a activation is one possible action in the brain thought to contribute to cortisol release. My belief is that many depressed patients have increased sensitivity in their 5-HT1a receptors, thus facilitating cortisol release. Stress related migraines are thought to be caused by 5-HT1a hypersensitivity.
With regards to serotonin (5-HT), I'll give you a quick rundown. I have found that 5-HT1a activation is an important antidepressant mechanism. 5-HT1b may also be important in depression. 5-HT1b agonists have anti-agressive properties and probable anxiolytic (anti-anxiety) properties. 5HT-1a reduces 5HT levels, and the reduced sensitivity of these receptors due to tonic activation may be the cause of the delay in the onset of antidepressant action. Pindolol, a partial 5HT-1a agonist, decreases the delay in onset of SSRI's, thus contributing to this theory. 5-HT1b, on the other hand, contributes to the release of 5-HT (serotonin).
Cortisol secretion has been said to be caused by activation of 5-HT2 receptors (likely 5-HT2a and 5-HT2c) and 5-HT1a. An alternate explanation is that cortisol release is increased by 5-HT2 activation and 5-HT1c receptor activation. I am currently more convinced by the first explanation.
I would argue that tonic 5-HT1a receptor activation to reduce sensitivity helps to increase 5-HT release from neurons, which increases the amount of 5-HT available in the brain. Increased 5-HT transmission without a 5-HT2 antagonist is the best explanation for most SSRI side effects. 5-HT3 antagonism is said to reduce nausea.
Another idea is an eventual lack in the sensitity of 5HT-1b autoreceptors due to tonic activation, which would counteract the reduction in sensitivity of 5-HT1a receptors. This is a possible explanation for poopout, but it's my own theory and not proven, so take it with a grain of salt.
With regards to Remeron, I would guess that its faster onset is a result of a faster reduction in 5HT-1a sensitivity due to increased amounts of available 5-HT owing to the lack of 5-HT's ability to attach to 5-HT2 and 5-HT3 receptors. Another possible explanation is its actions on noradrenergic function simply allow for greater 5-HT release.
Remeron is particularly effective for depression based on its effects as a 5-HT2 antagonist and indirect 5-HT1 agonist. I believe its ability to fight depressive symptoms is partly because of effects on cortisol. Based on this, I hypothosized that a test for abnormally low cholesterol may be an indicator of depression, based on the fact that cholesterol is a precursor to the precursors of cortisol (cholesterol breaks down into cortisol). I found some confirmation of this idea in the second link provided below. "[There are] reported increases in depression, suicide and violence in individuals with low or lowered cholesterol." That is certainly intriguing.http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=20628415
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=16420132
Please feel free to disagree! I would very much like to improve all of this.
poster:Shawn. T.
thread:111957
URL: http://www.dr-bob.org/babble/20020709/msgs/111957.html