Here is some interesting research! :)

BTW, anyone know why the Net******** (Nether.lands) would be filtered on our forum?

I don't think our friends in the Nether.lands would appreciate having the name of their country banned on our forums! LOL :D

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Abortion drug could rapidly treat depression
12:45 10 July 2006
Helen Phillips, Vienna

A hormone treatment used to induce abortion could provide a rapid-acting treatment for depression.

The drug, called RU486, was one of two new rapid treatment strategies, revealed on Sunday at the Federation of European Neuroscience Societies' annual meeting in Vienna, Austria.

Most antidepressants are thought to work by raising levels of the signalling chemical serotonin, which acts in the brain. But these drugs can take several weeks to take effect. The new treatments could be effective within days or even hours.

The hormone treatment is based on earlier findings that stress plays a major part in triggering and prolonging depression. Stress hormones appear to damage a part of the brain called the hippocampus. The region is susceptible because it is particularly rich in hormone receptors, allowing it to regulate ongoing hormone release.

"Rescue effect"

In experiments on rats, Paul Lucassen from the University of Amsterdam in the Nether.lands :) discovered that stress hormones seemed to be interfering with the birth of new neurons in the region. “The whole turnover of cells is affected,” he reported.

As an alternative to existing antidepressants, Lucassen and his team were keen to find ways to halt the stress response directly. Using a high dose of RU486, which blocks the stress hormone receptors, they were able to maintain normal neuron counts in rats. “It points to a rescue effect on survival of these cells,” says Lucassen.

The drug is already used for severe psychotic depression, and is licensed for use to treat several conditions, including Cushing's disease, and to induce abortion because it also acts on progesterone receptors. Pro-life activists have long campaigned for its withdrawal, and its use for routine depression treatment would undoubtedly be controversial.

Gene link

At the same meeting, Nicholas Barden at the Centre Hospitalier de l'Université Laval in Quebec, Canada, revealed a second treatment based on his group’s discovery of a gene that makes people susceptible to depression.

He initially identified the faulty version of the gene P2XR7 in a family from a region of Quebec in which the depression rate is particularly high. More recently he and other research groups have confirmed the same gene defect in several European families – some with major depression and others with bipolar disorder, or manic depression.

These conditions are still generally thought of as two distinct diseases and treated very differently, says Barden. But these findings suggest they may be closely related and could be treated in the same way.

The gene is expressed in cells of the immune system. In the nervous system, it appears in cells called glia, some of which have an immune function. Low levels of the protein produced by the gene seem to be related to depression and, in common with Lucassen’s findings, the effects are exacerbated by stress hormones.

The development of drugs that raise levels of the gene product are well underway, he told the meeting: “There’s a good hope in the near future of more effective and specialised antidepressants,” he said. “Prozac takes three weeks, but when we target the gene directly [in mice] we see rapid effects within hours.”

From: http://www.newscientist.com/channel/health/mental-health/dn9516-abortion-drug-could-rapidly-treat-depression.html
...

Please note that this news article is about the treatment of depression, a frequent co-existing condition with ADD. It is not about abortion and the subject will not be debated in this thread.

Thank you,
from your anxious, motherly moderator.

I did a google on anti-stress drugs and stress hormones-very interesting stuff out there! I found some supplements that might be a good option.

I am very interested in this because I have recurrent depression, anxiety disorder and PTSD-all affected by stress. I am documenting my depressive episodes-even mild ones and they always-always-occur after or during some type of stressor! I find myself telling doctors and other this-and now my mind is really captured by this. I do want to pursue the stress-hormone and drug/supplement treatment option for these disorders! This gives me hope for possible treating my disorders much more effectively and preventing panic attacks, flashbacks, and depressive episodes!

I had a hysterectomy-so would seriously consider a trial of RU486! No doctor would hesitate in my case-avoiding the banned topic but showing why it would not be a problem for an older woman to consider this treatment option. A supplement called pregnenolone kept popping up in my googles-I am going to check it out and possibly try it out and see what happens. It is not too expensive-in fact, it cost less than I thought it would!

A good subject seek! Thanks-I am tired of battling depression!

Yeah, I'm with you RADD, stress and/or anxiety has always seemed to be the underlying cause for my depression.

It would be good to have something that acted very quickly-when depression hits, it is so tremendously difficult. The time it takes for some of the meds to work means quite a few basically lost days out of my life. Today, if someone offered me a fast-acting drug, I would not hesitate to take it. Right now, I have to wait to call my doc tomorrow, get and appointment - which should be very soon-she is a good doc. Then we have to try another anti-depressant, and the majority take 2-4 weeks to work. I am tired of losing so much of my life to recurrent depression.

Side note-It could be the Wellbutrin-exacerbating my anxiety disorder. However, after 14 years on medications and the way each med is effective for a time and then the effect fades-makes me wonder if I have refractive depression-or drug resistant depression. There are options thank goodness. It is hard when you think you have found a treatment and after time-the darkness and pain creep back into your life.

RADD

Side note-It could be the Wellbutrin-exacerbating my anxiety disorder. However, after 14 years on medications and the way each med is effective for a time and then the effect fades-makes me wonder if I have refractive depression-or drug resistant depression. There are options thank goodness. It is hard when you think you have found a treatment and after time-the darkness and pain creep back into your life.

RADD Strattera is making me overly emotional about stuff. I was watching "Leave it to Beaver" a while back and started getting all teary eyed because it was so touching! LOL :D

Since then I've noticed it happening even more. Like when I am watching a touching movie!

I think Strattera is turning me into a girl!!!!!! LMAO :D

Speaking of "turning me into a girl"! With the luck I have, the RU486 hormone treatment for depression would probably cause me to start growing breasts or something weird like that! LMAO :D That's all I need, cry at the drop of a hat and start growing breasts too! LOL :D

You can rest assured that I will be checking the list of possible side-effects before I take any hormones for depression! :D

The visual image seek! I am a girl and never cried over the Beav! Tell your doc! Or could it be depression? I hate to even bring that word up. It is no fun getting emotional when you don't want to.

RADD

It's hard to say whether it's depression or not! Strattera can be very sedating as you know, so excessive sleeping isn't out of the ordinary.

But for me to get teary eyed watching leave it to beaver certainly is out of the ordinary! LOL :D

There is a thread here on our forums called anyone get obsessed or mood swings? (http://www.addforums.com/forums/showthread.php?t=33414) where multiple people (including me) are complaining about being overly emotional on Strattera.

Mood swings is listed as a side-effect of Strattera BTW. :)

Gee, Glad I had a hysterectomy and am not on Strattera! I got to take down the mood swing in my backyard!

That is an interesting side effect-it is kind of touching, all you guys on Strattera getting in touch with your feminine side! Here is a tissue....... Seriously though, I hope things get better! Thanks for being a good sport, I need a little therapeutic humor tonight! It is helping me stay a little more light hearted.

RADD

Speaking of "turning me into a girl"! With the luck I have, the RU486 hormone treatment for depression would probably cause me to start growing breasts or something weird like that! LMAO :D That's all I need, cry at the drop of a hat and start growing breasts too! LOL :D
RU486 is not a hormone. I don't remember what it is but it was orginally developed to treat ulcers or intestinal seizures or something like that. (Used to work at University of Michigan Medical Lib: I looked it up when it got FDA approval as an abortive)

You'd think they'd have noticed the antidepressant effect then. I know I'd get down if I was having intestinal seizures.

RU486 is not a hormone. I don't remember what it is but it was orginally developed to treat ulcers or intestinal seizures or something like that. I believe RU486 is a synthetic steroid hormone.
RU486 (Mifepristone)

The drug is composed of a 19-nortestosterone steroid compound, which has anti-progestagenic and anti-glucocorticoid effects, meaning it counters the effects of progesterone (http://en.wikipedia.org/wiki/Progesterone) and glucocorticoid (http://en.wikipedia.org/wiki/Glucocorticoid) on the body.

This synthetic compound is related to the naturally occurring anabolic steroid (http://en.wikipedia.org/wiki/Anabolic_steroid), nandrolone (http://en.wikipedia.org/wiki/Nandrolone).

Mifepristone acts as a competitive inhibitor at progesterone (http://en.wikipedia.org/wiki/Progesterone) receptors, by decreasing progesterone and increasing estrogen.

From: http://en.wikipedia.org/wiki/RU-486
Anabolic Steroid

Anabolic androgenic steroids (AAS) are a class of natural and synthetic steroid (http://en.wikipedia.org/wiki/Steroid) hormones (http://en.wikipedia.org/wiki/Hormone) that promote cell growth and division, resulting in growth of several types of tissues, especially muscle and bone. Different anabolic androgenic steroids have varying combinations of androgenic (http://en.wikipedia.org/wiki/Androgen) and anabolic (http://en.wikipedia.org/wiki/Anabolism) properties, and are often referred to in medical texts as AAS (anabolic/androgenic steroids). Anabolism (http://en.wikipedia.org/wiki/Anabolism) is the metabolic process that builds larger molecules from smaller ones.

From: http://en.wikipedia.org/wiki/Anabolic_steroid (http://en.wikipedia.org/wiki/Anabolic_steroid)

Here are two more articles regarding stress and depression that I found informative.


The Invisible Epidemic: Post-Traumatic Stress Disorder, Memory and the Brain

<!-- author -->J. Douglas Bremner, M.D.

<!-- author info -->Dr. Bremner is a faculty member of the Departments of Diagnostic Radiology and Psychiatry, Yale University School of Medicine, Yale Psychiatric Institute, and National Center for PTSD-VA Connecticut Healthcare System.

The research reviewed in this article was supported by an NIH-sponsored General Clinical Research Center (GCRC) Clinical Associate Physician (CAP) Award and a VA Research Career Development Award to Dr. Bremner, and the National Center for PTSD Grant.

<!-- content -->Post-traumatic Stress Disorder (PTSD) is something of an invisible epidemic. The events underlying it are often mysterious and always unpleasant. It is certainly far more widespread than most people realize. For example, a prime cause of PTSD is childhood sexual abuse. About 16% of American women (about 40 million) are sexually abused (including rape, attempted rape, or other form of molestation) before they reach their 18th birthday.<SUP>1 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref1)</SUP>

Childhood abuse may be the most common cause of PTSD in American women, 10% of whom suffer from PTSD (compared to 5% for men) at some time in their lives,<SUP>2 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref2)</SUP> but many other types of psychological trauma can cause the disorder -- car accidents, military combat, rape and assault. Symptoms of PTSD include intrusive memories, nightmares, flashbacks, increased vigilance, social impairment and problems with memory and concentration.

It's Not Just Psychological

While such symptoms are commonly understood to be psychological problems, some or all of them may well be related to the physical effects of extreme stress on the brain.<SUP>3 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref3),4 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref4)</SUP>

Recent studies have shown that victims of childhood abuse and combat veterans actually experience physical changes to the hippocampus, a part of the brain involved in learning and memory, as well as in the handling of stress.<SUP>5 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref5)</SUP> The hippocampus also works closely with the medial prefrontal cortex, an area of the brain that regulates our emotional response to fear and stress. PTSD sufferers often have impairments in one or both of these brain regions. Studies of children have found that these impairments can lead to problems with learning and academic achievement.

Other typical symptoms of PTSD in children, including fragmentation of memory, intrusive memories, flashbacks, dissociation (or the unconscious separation of some mental processes from the others, e.g., a mismatch between facial expression and thought or mood), and pathological ("sick") emotions, may also be related to impairment of the hippocampus.<SUP>6 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref6)</SUP> Damage to the hippocampus, which processes memory, may explain why victims of childhood abuse often seem to have incomplete or delayed recall of their abusive experiences.<SUP>7 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref7)</SUP>

A Disease of Memory

Memory problems play a large part in PTSD. PTSD patients report deficits in declarative memory (remembering facts or lists -- see below), fragmentation of memory and dissociative amnesia (gaps in memory lasting from minutes to days that are not caused by ordinary forgetting).

Psychiatric Symptoms Associated with Childhood Abuse

PTSD

Nightmares
Flashbacks
Memory and concentration problems
Hyperarousal
Hypervigilance
Intrusive memories
Avoidance
Abnormal startle reponses
Feeling worse when reminded of trauma
Dissociative

Out-of-body experiences
Derealization
Amnesia
Fragmented sense of self and identity
Anxiety

Panic attacks
Claustrophobia
Substance Abuse

Alcoholism
Drug addiction
Many abuse victims report that they remember seemingly random or minor details of the abuse event, while forgetting central events. For instance, one woman who had been locked in a closet had an isolated memory of the smell of old clothes and the sound of a clock ticking. Later, she connected these details with feelings of intense fear; only then was she able to recall the whole picture of what had happened to her. PTSD also causes problems with non-declarative memory (subconscious or motor memory, such as remembering how to ride a bicycle). This can show up as abnormal conditioned responses and the reliving of traumatic experiences when something happens to remind the sufferer of past abuse. These types of memory disturbance may also be related to physical changes in the hippocampus and medial prefrontal cortex.

How Psychological Trauma Affects the Hippocampus and Memory

Childhood abuse and other sources of extreme stress can have lasting effects on the parts of the brain that are involved in memory and emotion. The hippocampus, in particular, seems to be very sensitive to stress.<SUP>8 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref8),9 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref9),10 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref10),11 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref11),12 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref12),13 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref13),14 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref14),15 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref15),16 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref16)</SUP> Damage to the hippocampus from stress can not only cause problems in dealing with memories and other effects of past stressful experiences, it can also impair new learning.<SUP>17 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref17),18 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref18)</SUP> Exciting recent research has shown that the hippocampus has the capacity to regenerate nerve cells ("neurons") as part of its normal functioning, and that stress impairs that functioning by stopping or slowing down neuron regeneration.<SUP>19 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref19),20 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref20)</SUP>

We recently conducted a study to try to see if PTSD symptoms matched up with a measurable loss of neurons in the hippocampus. We first tested Vietnam combat veterans with declaratory memory problems caused by PTSD.<SUP>21 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref21)</SUP> Using brain imaging, these combat veterans were found to have an 8% reduction in right hippocampal volume (i.e., the size of the hippocampus), measured with magnetic resonance imaging (MRI), while no differences were found in other areas of the brain (Figure 1).

http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/figure1.gif


<CENTER>Figure 1 </CENTER>
Our study showed that diminished right hippocampal volume in the PTSD patients was associated with short-term memory loss.<SUP>22 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref22)</SUP> Similar results were found when we looked at PTSD sufferers who were victims of childhood physical or sexual abuse.<SUP>23 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref23),24 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref24)</SUP>

More recent studies have since confirmed hippocampal volume reduction in PTSD<SUP>25 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref25),26 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref26)</SUP> These studies also show that hippocampal volume reduction is specific to PTSD and is not associated with disorders such as anxiety or panic disorders.<SUP>27 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref27)</SUP>

Further study on the question of memory and the hippocampus may some day shed light on the controversy surrounding delayed recall, or so-called "recovered memories" of childhood abuse. The hippocampus plays an important role in connecting and organizing different aspects of a memory and is thought to be responsible for locating the memory of an event in its proper time, place and context.

We suspect that damage to the hippocampus following exposure to the stress brought on by childhood abuse leads to distortion and fragmentation of memories. For instance, in the case of the PTSD sufferer who was locked in a closet as a child, she had a memory of the smell of old clothes but other parts of her memory of the experience, such as a visual memory of being in the closet or a memory of the feeling of fear, are difficult to retrieve or completely lost. In cases like this, psychotherapy or an event that triggers similar emotions may help the patient restore associations and bring all aspects of the memory together.

This new understanding of the way childhood trauma affects memory and the brain has important implications for public health policy. One example would be the case of inner-city children who have witnessed violent crimes in their neighborhoods and families. If this kind of stress can cause damage to brain areas involved in learning and memory, it would put these children at a serious academic disadvantage in ways and for reasons that programs such as Head Start may be unable to address. Studies confirm this: in war-torn Beirut, traumatized adolescents with PTSD, as compared to non-traumatized adolescents who were without PTSD, lagged behind in academic achievement.<SUP>28 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref28)</SUP>

PTSD and Other Brain Areas

Besides the hippocampus, abnormalities of other brain areas, including medial prefrontal cortex, are also associated with PTSD.

The medial prefrontal cortex regulates emotional and fear responses.<SUP>29 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref29)</SUP> The medial prefrontal cortex is closely linked to the hippocampus. In several studies we have found dysfunction of both the medial prefrontal cortex and the hippocampus at times when patients were suffering from PTSD symptoms.<SUP>31 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref31)</SUP>

We believe that dysfunction in these medial prefrontal regions may underlie pathological emotional responses in patients with PTSD.<SUP>30 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref30)</SUP> For example, we sometimes see a failure of extinction of fear responses -- a rape victim who was raped in a dark alley will have fear reactions to dark places for years after the original event, even though there is no threat associated with a particular dark place. In a study using combat-related slides and sounds to provoke PTSD symptoms, combat veterans with PTSD had decreased blood flow in the area of the medial prefrontal cortex. Significantly, this did not occur in combat veterans without PTSD<SUP>32 (http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/#ref32)</SUP> We saw similar results when we compared women with PTSD and a history of childhood sexual abuse to women with a history of abuse but no PTSD.

Conclusion

Traumatic stress, such as that caused by childhood sexual abuse, can have far-reaching effects on the brain and its functions. Recent studies indicate that extreme stress can cause measurable physical changes in the hippocampus and medial prefrontal cortex, two areas of the brain involved in memory and emotional response. These changes can, in turn, lead not only to classic PTSD symptoms, such as loss and distortion of memory of events surrounding the abuse, but also to ongoing problems with learning and remembering new information. These findings may help explain the controversial phenomenon of "recovered" or delayed memories. They also suggest that how we educate, rehabilitate and treat PTSD sufferers may need to be reconsidered.

From: http://www.thedoctorwillseeyounow.com/articles/behavior/ptsd_4/
And then there is this information about depression.


The Neurobiology of Depression

<!-- author -->Juan F. Lopez, M.D.

<!-- author info -->Dr. Lopez is a faculty member of the Department of Psychiatry and Mental Health Research Institute, University of Michigan, Ann Arbor.

<!-- content -->Being clinically depressed is very different from just feeling down or blue.

Depressive episodes (there are several kinds) can last months, sometimes years, and can interfere with your social and work functioning. Unfortunately, depressive episodes also tend to recur and, if left untreated, will become more frequent and/or more severe as the disease progresses.<SUP>41 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref41)</SUP>

According to the official professional reference guide, Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), to be considered depressed, you have at least five of the following symptoms and they represent a change in your life:

Depressed mood most of the day, nearly every day
Markedly diminished interest or pleasure in all, or almost all, activities
Significant weight loss when not dieting or weight gain, or decrease or increase in appetite nearly every day
Insomnia or sleeping too much (hypersomnia) nearly every day
Psychomotor agitation or retardation nearly every day
Fatigue or loss of energy nearly every day
Feelings of worthlessness or excessive or inappropriate guilt
Diminished ability to think or concentrate, or indecisiveness
Recurrent thoughts of death, recurrent suicidal ideation, or a suicide attempt or a specific plan for committing suicide
All Too Common

Depression is very common. Seventeen per cent of people will experience depression sometime during their life. To add insult to injury, if you are acutely or chronically ill, you are even more likely to suffer from it, with rates ranging from 30% to 50%, depending on your specific medical condition.

Though the picture sounds grim, (and will seem especially so if you are depressed, for thinking nothing will get better is often a symptom of depression) we are starting to learn more about the biochemical and other factors that may be involved. Hopefully, with this knowledge, will, eventually, come effective treatment strategies.

Do We Know What Causes Depression?

The actual basis of depression is unknown but it is widely accepted that it is influenced by genetic, environmental and neurobiological factors. Depression does run in families<SUP>26 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref26)</SUP> but whether this is genetic or simply reflects the kind of parenting a depressed person is able to offer their child is difficult to determine. In addition there are many environmental factors, such as loss of a loved one, unemployment, an unexpected medical illness, that appear to increase the likelihood of depression.

Many brain chemicals ("neurochemicals") and hormones have been linked to the development of depression (e.g., norepinephrine, dopamine, thyroid hormones). However, research studies have implicated disturbances in the serotonin (5-HT) system and the Limbic Hypothalamic-Pituitary-Adrenal (LHPA) axis as two of the neurobiological alterations most consistently associated with mood-altering illness.<SUP>18 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref18),36 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref36),24 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref24),39 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref39)</SUP> Recent work, in fact, has strongly suggested that the interaction between these two biochemical systems may play a significant role.

Adrenal glucocorticoid (the "stress" hormone), which helps regulate your metabolism and is produced by the adrenal gland, a tiny gland that sits on top of the kidneys, interacts with serotonin 5-HT receptors in the brain during conditions of chronic stress or severe allostatic load (http://www.thedoctorwillseeyounow.com/articles/behavior/stress_3/index.shtml#alldef)." This is not surprising, as we have known from studies on animals that the two systems are linked in a variety of ways.<SUP>33 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref33),7 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref7),30 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref30)</SUP>


One of these linked regions, the limbic HPA axis (LHPA), regulates arousal, sleep, appetite and the capacity to experience and enjoy pleasure, as well as the control of mood. As the list of symptoms at the beginning of this article indicates, the functioning of each of these areas can be disturbed in a depressive episode.

LHPA Axis: The Link Between Stress and Depression

Imagine that you're crossing the street and a car suddenly swerves toward you. Instinctively, you jump out of harm's way. Your rapid and automatic response is triggered by, among other things, the LHPA axis. Its response to stress is critical for adaptation and survival. The perception of stress provokes, ultimately, the release of the glucocorticoid "stress" hormones (cortisol in humans, corticosterone in rats) from the adrenal gland and this is regulated by the LHPA axis.<SUP>11 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref11)</SUP> A very delicate and effective feedback mechanism is set in motion through nerve connections that link the hippocampus, an important area of the brain that's also affected by these biochemicals, to the LHPA. This feedback allows receptors in the hippocampus to control both your hormonal and higher thinking response to stress.<SUP>34 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref34)</SUP> In other words, thanks to the hippocampal receptors, you are better able to decide how you should handle the stress -- should you let it go or stand your ground? Should you leave your stressful job and confront your boss, or continue working without saying anything?

Pioneer work by one of our TheDoctorWillSeeYouNow.com contributors, Dr. Bruce McEwen from the Rockefeller University, demonstrated two types of receptors in the hippocampus. We believe these two receptors -- "MR" (also known as Mineralocorticoid Receptors) and "GR" (also known as Glucocorticoid Receptors) -- work together to control metabolism, blood cortisol levels and the LHPA axis.<SUP>15 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref15)</SUP> Investigators have found, for example, that the MR and GR receptors are able to decrease your stress hormone levels and help defend your body against the effects of stress.<SUP>14 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref14)</SUP>

Hyperactivity of the LHPA axis is a well-documented event in depression. Not only is too much of the stress hormone, cortisol, produced<SUP>6 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref6),22 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref22),27 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref27),17,23</SUP> but we have also found, in a group of suicide victims with a history of depression, lowered levels of MR and GR other in the hippocampus<SUP>29 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref29)</SUP> and the prefrontal cortex, an area of the brain which is associated with higher thinking and executive function. We don't know whether these changes represent a genetic or developmental vulnerability "marker" for suicide or for depression. Nevertheless, these findings are consistent with a history of exposure to chronic stress.<SUP>20 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref20),21 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref21)</SUP>

There is little doubt among scientists that glucocorticoids, the final products of the LHPA axis, have profound effects on mood and behavior.<SUP>32</SUP> For example, those afflicted with Cushing's syndrome, a disease where excess cortisol (the "stress" hormone) is produced, have a high incidence of depression. Most interestingly, their depression disappears when cortisol levels return to normal with treatment.<SUP>23 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref23),38 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref38)</SUP>

The precise mechanism by which glucocorticoids exert this influence on mood is not well understood. We do know that in depression the LHPA axis is very often hyperactive. We suspect that the mechanism likely involves interactions with brain neurotransmitters, since we know that the brain's central control of your mood is intimately associated with the actions of serotonin, norepinephrine and dopamine, the neurotransmitters affected by the most common antidepressant medications.

Serotonin Receptors and Depression

The serotonin 5-HT system has been widely investigated as a key element in the development of depression<SUP>36</SUP> and of suicide,<SUP>32 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref32)</SUP> and the means by which many antidepressants provide relief.<SUP>1 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref1)</SUP> Although the 5-HT system has many components, there are two serotonin molecules closely associated with the neurobiology of mood: the serotonin 1a receptor (5-HT1a) and the serotonin 2a receptor (5-HT2a).

Most newer (as well as older) antidepressants inhibit the re-uptake of serotonin from the communicating space between nerves (synapse), hence their name: selective serotonin reuptake inhibitors (SSRIs).<SUP>28 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref28),40 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref40)</SUP> Animal studies have demonstrated that chronic antidepressant administration affects the function and number of these two receptors. Other studies have shown that antidepressants "upregulate" or "sensitize" 5-HT1a receptors in the hippocampus, while at the same time "down-regulating" or "desensitizing" 5-HT2a receptors elsewhere in the brain.<SUP>3 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref3)</SUP> We have found that suicide victims, with a history of depression, have fewer 5-HT1a receptors in the hippocampus.<SUP>29</SUP>

These research findings have led several scientists to theorize that a disturbed balance of these receptors may be contributing to the development of depression<SUP>2</SUP> and that restoring this balance is necessary for antidepressant action.<SUP>4 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref4)</SUP>

Stress and Serotonin

Stress and depression have been linked in a variety of ways. Both physical and psychological stressors, such as physical illness or financial problems, have been shown to have a cause and effect relation to the onset of depressive episodes.<SUP>41</SUP>

We are not saying that stress "causes" depression in people. Rather, stress is very likely interacting with an inborn genetic predisposition, such that, in some vulnerable individuals, a stressor can precipitate a mood disorder (i.e., vulnerability + stress = depression). Studies in twins have shown a clear interaction between genetic predisposition and a recent stressful life event in the precipitation of a depressive episode.<SUP>26</SUP> There are even cases in which the genetic predisposition is so high that an episode of depression can occur in the absence of any apparent precipitating factors.

The study of chronic unpredictable stress in animals has given us important clues about depression. In our research, we expose rats to different, mild to moderate stressors every day, therefore making the stress "unpredictable" from day to day. Rats that undergo this treatment show LHPA overactivity and increases in peripheral glucocorticoids, very similar to those found in depression.<SUP>9 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref9)</SUP> Other changes in brain chemicals occur which we have also found in suicide victims with a history of depression.<SUP>32</SUP> This suggests that a chronic or severe stress (e.g., loss of a spouse, serious illness or injury, history of abuse) may cause similar neurochemical changes in vulnerable people, therefore triggering episodes of depression.

How Different Antidepressant Medications Work...and Don't Work

The LHPA overactivity observed with chronic unpredictable stress can be prevented by the daily chronic administration of either imipramine or desipramine, two tricyclic antidepressants.<SUP>29</SUP> Both desipramine and imipramine (key ingredients in Norpramine<SUP>®</SUP> and Tofranil<SUP>®</SUP>) also reverse the stress induced downregulation of 5-HT1a in hippocampus, and the 5-HT2a upregulation in brain cortex. On the other hand, zimelidine (Zelmid<SUP>®</SUP>, an antidepressant formerly used in Europe) and fluoxetine (Prozac<SUP>®</SUP>), two specific serotonin reuptake inhibitors are unable to prevent the stress-induced elevation in corticosterone levels and correct LHPA overactivity. Although it is not clear if this also occurs in humans, these research findings may explain why some patients with severe depression exhibit "treatment resistance."

There is, in fact, some clinical evidence that the various depressive disorders might have differing physiological explanations. These differences may explain why some patients benefit from one antidepressant and not another. Continued persistence, for example, of high levels of stress hormones (hypercortisolemia) after antidepressant administration in depressed patients has been associated with relapse and poorer treatment outcome.<SUP>19 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref19),42 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref42)</SUP> Some clinical studies have found that tricyclic antidepressants are more effective than SSRIs in the treatment of melancholia.<SUP>12 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref12),13 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref13),43 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref43)</SUP> Melancholia is a severe form of depression characterized by complete loss of the capacity for pleasure, psychomotor slowing or "retardation" and worse symptoms in the morning. Patients with melancholia also tend to have high cortisol levels.<SUP>24,35 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref35)</SUP>
Venlafaxine (Effexor<SUP>®</SUP>), an antidepressant with both norepinephrine and 5-HT reuptake activity, was reported in one study to be more effective than fluoxetine in treating melancholic depression<SUP>10 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref10)</SUP> and in patients with both depression and anxiety.<SUP>44 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref44)</SUP> In spite of this, we cannot predict accurately which specific antidepressant will be the "right one" for a particular individual, and it often requires a process of trial and error.

What's Ahead

Glucocorticoid modulation of 5-HT receptors has important implications for the understanding and treatment of mood disorders and, perhaps, suicide. It may be one of the mechanisms by which stressful events can precipitate depressive episodes in some (genetically) vulnerable individuals and/or precipitate suicidal behavior.

An important therapeutic implication of this model is the prediction that agents which can reduce the stress response and/or decrease LHPA activation will be useful in the pharmacological treatment of anxiety, depression and, perhaps, suicidal behavior. In fact, patients with major depression, who are resistant to antidepressant treatment, have been reported to improve after receiving steroid suppression agents, like ketoconazole.<SUP>37 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref37),45 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref45)</SUP>

These suppressor agents, unfortunately, have many side effects and are often difficult to tolerate. A new drug class, CRH receptor antagonists, which decrease the release of the stress hormones, currently under development, may provide a therapeutic option.<SUP>16 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref16),8 (http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/#ref8)</SUP> The CRH antagonist could, theoretically, be used in conjunction with antidepressants to improve the effectiveness of antidepressants, particularly for those patients who have treatment resistance.

Research, now on going, will, hopefully, soon provide new pharmacological treatments for all those who suffer from depression and other disorders of mood. We have made much progress and we will make more.

From: http://www.thedoctorwillseeyounow.com/articles/behavior/depressn_5/

Seek, These articles are wonderful. I did a google and found a plethora of info on this subject. It all fits with what I intuitively have thought about my own experience with depression and my reactions and effectiveness of meds and my own response to stressors! It is relieving to understand more about these disorders.

I am eager to see what drugs develop from the CRH research! This gives me hope for even better treatment and quality of life. At least I understand the ups and downs of my depression/PTSD better now. If you hear of any studies in the St. Louis area let me know-I would be glad to volunteer.

RADD

Oops, my bad. Sorry. It was like 5 or 6 years since I read this. Still not an estrogen drug, though.