Mood

Stress

Our very lives depend on how well we manage stress.

A study by Ahmad Hariri PhD et al of the NIMH appearing in the July 19, 2002 Science divided 28 subjects into two groups, those who had a short form (allele) of the serotonin transporter gene SLC6A4, and those with the long allele. Cells with the long variant express nearly double the serotonin reuptake as those with the short allele. The subjects were placed in an fMRI machine and completed a simple exercise involving processing the images of three different faces. The brain scans revealed that those with the short allele displayed a significantly greater response in the right amygdala while engaged in the task. The amygdala is a tiny, almond-shaped part of the brain which governs fear. When the subjects were given a thinking task not involving emotions, no variants were seen.

In the authors’ words: "Our results directly implicate a genetically determined link between serotonin transporter function and the response of brain regions critical for emotion processing."

This may very well be the first study linking genes to emotions in humans, and it certainly was by no means the last.

A year later, SLC6A featured in the publication in the July 18, 2003 Science of a University of Wisconsin/King's College (London) study that analyzed 14 stressful events (including employment, finances, housing, health, and relationships) in the lives of 847 New Zealanders from ages 21 to 26. The study found that 33 percent of those with one or two copies of the short allele and with four or more life stresses developed depression as opposed to 17 percent with two copies of the long variant. Stressed individuals with the short allele experienced more suicidality (11 vs four percent) than those two copies of the long allele.

What We Know About Stress and Depression

Stress is to mood what that iceberg was to the Titanic, with therapies increasingly geared toward neutralizing its vast destructive powers. According to the Surgeon General in his landmark Report on Mental Health:

"The compelling impact of past parental neglect, physical and sexual abuse, and other forms of maltreatment on both adult emotional well-being and brain function is now firmly established for depression."

A study of rhesus monkeys separated from their mothers found higher levels of the stress hormone cortisol, as well as ACTH (adrenocorticotropic hormone), and lower cerebrospinal fluid levels of noradrenaline. Twenty percent of the infants from the same study also reacted negatively to brief separations from their mothers.

At the 2003 American Psychiatric Association's annual meeting, Michael Meaney PhD of McGill University described his studies of rats who were reared by mothers who were either high or low "lickers and groomers." Those reared by low lickers and groomers showed an excess of various stress hormones, including high ACHT response, CRF messenger RNA, and hippocampal cortisol. Maternal care, Dr Meaney said, is just one of many early life experiences such as poverty that can influence neural and endocrine responses to stress in a way that sets up one for depression, anxiety, heart disease, and a host of other ills later in life.

At the same symposium, Christine Hein PhD of Emory University cited a 1997 survey by McCauley et al that found that women who reported experiences of childhood abuse had higher depression and anxiety scores, greater drug and alcohol dependence, and a higher rate of suicide attempts. Various studies have found higher concentrations of stress hormones in the cerebrospinal fluid of depressed and anxious humans, and a 2002 study by Frodl et al found a smaller hippocampus, associated with short-term memory, in depressed patents. Throw in one overworked amygdala and we begin to get a picture of just some of the things that can go wrong under the hood long before depression sets in

Much of our current understanding of how stress and trauma may trigger a mood disorder is the result of the work of Charles Nemeroff MD, PhD, Chair of the Department of Psychiatry and Behavioral Sciences at Emory University. At a symposium entitled, "The Neurobiology of Mood Disorders" at the 2002 American Psychiatric Association annual meeting, Dr Nemeroff recounted his now-famous study that was published in the August 2, 2000 Journal of the American Medical Association. In that study, 49 healthy women were recruited into four groups: those with no history of childhood abuse or psychiatric disorder, those with current major depression who had been physically or sexually abused as children, those without current major depression who had been physically or sexually abused as children, and those with current major depression with no history of childhood abuse. The women were given math tests and made to speak in public. Blood samples and heart readings showed that the women with a history of childhood abuse exhibited increased pituitary and autonomic responses to stress compared with the controls. This was especially true for the women with current depression and anxiety.

"Is the biology of depression the biology of early trauma?" Dr Nemeroff asked his audience.

In an experiment designed to startle lab rats by blowing an air puff in their faces, Dr Nemeroff and his colleagues found those who had been separated from their mothers as pups showed a greater stress response, with tissue samples revealing higher concentrations of the hormone CRF (corticotropin-releasing factor).

In response to stress, the hypothalamus in the brain secretes CRF, which results in the pituitary gland releasing another hormone, ACTH (the abused and depressed women in Dr Nemeroff’s study exhibited a six-fold greater ACTH increase over the controls), which activates the adrenal glands that turn loose the stress hormone cortisol. This neuroendocrine feedback loop is referred to as the HPA (hypothalamic-pituitary-adrenal) axis

Women abused in childhood, Dr Nemeroff explained, end up with a sensitized brain system, where CRF receptors are to be found in abundance. Depressed patients have high concentrations of CRF in their cerebrospinal fluid.

Situational occurrences such as marriage breakup or bereavement also loom large. A study of major depression in twins found that recent stressful events were the most powerful risk factor for an episode of major depression. According to the study, those with the lowest genetic risk of depression had only a 0.5 percent probability of depression that month, but this shot up to 6.2 percent with exposure to severe stress. Those with the highest genetic risk faced a 1.1 percent probability that skyrocketed to 14.6 percent when stress was present.

The HPA axis is working overtime during these stressful situations, and new studies are beginning to suggest two areas of the brain responsible for kicking this axis into action:

The hippocampus and the amygdala are two key regulatory centers located in the cerebral areas of the brain, governing memory storage and emotions, respectively. Both are major nuclei of the limbic system, which underlies emotions. According to the Surgeon General's Report:

"Sensory information enters the lateral amygdala, from which processed information is passed to the central nucleus, the major output nucleus of the amygdala. The central nucleus projects, in turn, to multiple brain systems involved in the physiologic and behavioral responses to fear. Projections to different regions of the hypothalamus activate the sympathetic nervous system and induce the release of stress hormones."

Stress can lead to neuronal loss and atrophy in the hippocampus, which is reduced in depressed patients. In one elaborate lab study involving the creation of a "visible burrow system" approximating life in the wild, the dominant rats made more new brain cells than their more stressed-out subordinate burrow-mates. A recent Yale University study has found that antidepressants (an MAOI, Prozac, or reboxetine) can restore this loss and grow new neurons.

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.

Fight or Flight

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 ..."

Dr Sapolsky asks us to imagine a rat trained to press a lever to avoid a mild shock. The anticipation of mastery might activate pleasurable dopamine release to the frontal cortex. If the lever is disconnected, however, so that pressing it no longer prevents shocks, the rat will frantically press the lever repeatedly, attempting to gain control. This, says Dr Sapolsky, is the essence of anxiety, characterized mainly by adrenaline and norepinephrine secretion and to a lesser extent by cortisol production. As the shocks continue and the rat finds its attempts at coping useless, a transition occurs where cortisol dominates and key neurotransmitters are depleted. In the words of Dr Sapolsky: "It has learned to be helpless, passive and involuted. If anxiety is a crackling, menacing brushfire, depression is a suffocating heavy blanket thrown on top of it."

Two Centers for Disease Control studies recently examined stress on large populations. The studies looked at the effects of armed conflict on groups of Albanians and Serbians, and represent the first of their kind by virtue of being conducted in the midst of war or very soon after, in the region where the conflict occurred. In both studies, survivors were given psychiatric evaluations.

In the first study, two-thirds of the Albanians surveyed reported being deprived of food and water, being in a combat situation, and being close to death. More than half had been forced to flee their homes, and nearly 40 percent had experienced at least eight specific traumatic events, from the murder of a family member to rape.

Not surprisingly, the researchers found a high rate of psychiatric disorder amongst the survivors. What surprised them was how high this figure was - 43 percent, twice their expectations. Adopting less conservative criteria raised the incidence to 83.5 percent.

A study of the Serbian population remaining in Kosovo also surprised researchers, as the findings virtually matched those of the Albanians. Apparently, war in all its terrible horror pays no regard to which group suffers the most. It's simply enough that stress hormones flood into the system like refugees streaming across the border. The stress hormones, of course, are too dumb to know that the war in Kosovo is the cause of their migration into the blood stream. Any war will do, as will any situation approximating war. In this regard, we all represent a population at risk.

Those hormones, it seems, have plenty of places to go - the heart, the pancreas, the bones, and so on. Depression has been linked to illnesses from heart disease to diabetes to stroke to bone loss to cancer. What may be occurring on a cellular level, in response to stress, is glutamate reuptake in the synapse is compromised, resulting in increased calcium influx through the NMDA receptors and ion channels into the neuron and the activation of certain calcium-dependent enzymes that can result in cell atrophy and death.

The mediators between stress and a breakdown in the immune system are cytokines, which are peptides that orchestrate the immune response. In addition to their primary role, a cytokine response to sickness or stress also brings on mood and hormonal changes. In cancer patients, the administration of the cytokines interferon and interlukin bring on flu-like and depressive symptoms.

Fortunately, our brain circuits are not permanently welded into place. Our thought patterns can be changed, and cognitive therapy is especially useful in restructuring how we perceive and react to stressful situations. With a bit of practice, "It's the end of the world!" can be altered to, "Let's find a solution." For those with trauma, coming to terms with past abuse or neglect may be the key to real healing.

A 2003 secondary analysis of a 2000 study (led by Dr Nemeroff) found that while there was little difference between antidepressant and talking therapy among the patients with no early childhood trauma, those who had lost their parents at an early age, been physically or sexually abused, and/or neglected fared significantly better on talking therapy than on an antidepressant.

All the patients in the 681-patient study experienced chronic depression. Of these, about one-third lost their parents before age 15, 45 percent experienced childhood physical abuse, 16 percent childhood sexual abuse, and 10 percent endured neglect, representing more than half those in the study. In classic understatement, the authors note, "these findings alone highlight the remarkably high prevalence rate of early life trauma in patients with chronic forms of major depression."

Taking an antidepressant improved Hamilton depression scores by about 10 points for those without childhood trauma compared to eight points for those with childhood trauma. Remission rates between the two groups on antidepressants were about 40 percent and 32 percent, respectively. Talking therapy improved Hamilton scores to nearly double (12 points) among the trauma group while dropping slightly for the non-trauma group (eight points). The remission rate for the trauma group in talking therapy shot up to about 48 percent compared to about 28 percent for the non-trauma group. Adding an antidepressant only improved depression scores another two points to about 14 in the trauma group and resulted in slightly higher remission at about 52 percent.

The authors of the study note that the findings "have significant implications for research on the pathophysiology of chronic forms of major depression and for [its] treatment," but caution that further studies are needed.

Nevertheless, our current antidepressants may normalize the stress response, Dr Nemeroff pointed out at the APA symposium, which has been borne out in studies with Paxil on lab rats. 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.

Other possibilities include:

* Beta blockers occupy some adrenaline receptors, preventing adrenaline from transmitting information. Used for reducing high blood pressure, beta blockers have also been found to blunt the formation of emotionally disturbing memories.
* Substance P is released by stress and pain and binds to NK-1 receptors, especially in the amygdala. One clinical trial suggested a substance P antagonist may be effective in treating depression and anxiety but another did not support this finding.
* BDNF is vital to the creation of new neurons. Injecting BDNF into the brains of rats may counteract the destructive effects of cortisol on neurogenesis (new brain cell growth) in the hippocampus.
* Finally, this mind-boggler: Dr Sapolsky’s lab is working on introducing on introducing new gene material into the amygdala and hippocampus that would switch on protective proteins in response to stress (see article).

Our lifestyle choices play an essential role in nipping stress in the bud. A diet of mood-buster foods is simply tempting fate, as is irregular sleep, lack of exercise, and putting off things till the last minute. Ultimately, you may have to lower your expectations - from what you demand of yourself to how clean you want your house to be.

In the meantime, though, it pays to manage your stress as if your life depended upon the outcome - which, as we are finding more and more every day, it does.

Slaughterhouse One

At the 2003 APA annual meeting, Ned Kalin MD of the University of Wisconsin cited a passage from Kurt Vonnegut’s 1973 novel, Breakfast of Champions, to illustrate the workings of the HPA axis, which pumps stress hormones into the system:

"My mind sent a message to my hypothalamus, told it to release the hormone CRF into the short vessels connecting my hypothalamus and my pituitary gland.

"The CRF inspired my pituitary gland to dump the hormone ACTH into my bloodstream. My body had been making and storing ACTH for such an occasion. And nearer and nearer the Zeppelin came.

"And some of the ACTH in my bloodstream reached the outer shell of my adrenal gland, which had been making and storing glucocorticoids for such emergencies.

"My adrenal gland added the glucocorticoids to my bloodstream. They went all over my body, changing glycogen into glucose. Glucose was a muscle food. It would help me fight like a wildcat or run like a deer."

Updated Dec 15, 2003

For a Deeper Scientific Undertanding on Stress, Please See

Psychiatry"s Big Bang

How Two Landmark Studies Are Changing How We Think

Knowledge is Necessity

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