Chronic Stress

Chronic Stress

If you have ever received bad news and felt a cold feeling in the pit of your stomach, that feeling might have been adrenaline being released into your bloodstream. That is one of the most notable signs that your body has triggered the stress response, or the fight-or-flight response.

This response is supposed to be a life-saving measure. Your body releases extra sugar into your bloodstream, shunts resources from the digestive tract to the brain, stops repairing bone and cartilage and gets amino acids flowing in the blood to be ready to repair damage, heightens your ability to remember dangerous situations, and triggers your brain’s alarm system and moods.

In our daily lives, the stress response is more likely to be triggered by deadlines at work or some other non-life-threatening event. Deadlines are not life-threatening, but try explaining that to your adrenal glands. Your body will sacrifice a little health tomorrow in order to ensure that you make it to the end of the day today.

When the body’s alarm system is triggered over and over, the stress response becomes less helpful and more harmful. The body’s primary stress hormone is cortisol, which is one of the glucocorticoid hormones, and its job is to make you instantly ready to meet stress with a full mobilization of the body’s resources.

The stress response involves the Hypothalamic-Pituitary-Adrenal axis. This system is triggered by the amygdala, which is the alarm system of the brain. The amygdala recognizes danger and signals the hypothalamus to begin the hormonal cascade that will make you ready for the fight.

The Hypothalamus, the first part of the HPA axis, secretes corticotropic releasing hormone (CRH). Corticotropic releasing hormone stimulates the Pituitary (which is the second part of the HPA axis) to release adrenocorticotropic hormone (ACTH), which causes the Adrenal glands (the third part of the HPA axis) to release glucocorticoid hormones, including cortisol.

In the brain, cortisol affects the memory. It works in conjunction with epinephrine (adrenaline) in the hippocampus of the brain to form sharp memories of things that are perceived as dangerous. Long term hippocampal exposure to cortisol damages cells in the hippocampus, which causes reduced memory recall and impaired learning. Damage to hippocampal cells can actually cause the hippocampus to shrink! This can make a person more prone to PTSD as well as affecting memory and learning. “Indeed, impaired glucocorticoid receptor function has been suggested to be causal for HPA (Hypothalamic-Pituitary-Adrenal) axis hyperactivity in depression, as glucocorticoids usually regulate the HPA axis through negative feedback inhibition and thereby reduce the production of glucocorticoids themselves. This effect is thought to be mediated in part by the [Glucocorticoid Receptors]. Therefore, hyperactivity of the HPA axis has been explained by an impaired feedback inhibition of glucocorticoids, possibly due to an impaired or dysfunctional glucocorticoid receptor (so-called “glucocorticoid resistance”) (Anacker, Zunszain, Carvalho, & Pariante, 2011).

Sometimes people get so used to being stressed that it seems normal to them.  How would you know whether you are chronically stressed? One way is to check your blood cortisol level. Draw a lab sample at 8AM and a second sample at 4PM. Cortisol should vary in its blood level through the day. The 8AM draw should be the high level of the day, and the 4PM should be the low level. If the levels are similar, then further investigation of the matter is warranted.

Another option is to measure stress with an EEG. Different brain areas will show increased and decreased electrical activity in response to chronic stress.  Other imaging techniques such as PET scans and fMRI can also be helpful in confirming chronic stress, but those tests have more serious risks and contraindications than EEG or lab work. By assessing the client for biomarkers that do not rely on self-report, a clinician can compare biomarker results with the client’s verbal report of stress. If the client reports less stress than the biomarkers indicate, this might mean that the client is experiencing the placebo effect or has sufficient hope that the future will improve.

What can help calm the HPA axis?

Ginseng is a plant that has been part of traditional Chinese medicine for thousands of years, and its use has spread globally. Since the 1960s, it has been studied by Western allopathic medical practitioners, and quite a bit of what it does is now known.

The medicinally active components of ginseng are called “ginsenosides.” There are more than 90 ginsenosides, with some that are more abundant and active in the human body than others.

Two ginsenosides, Rg1 and Re, interact with glucocorticoid receptors. The action they take on the receptor is a “partial agonist.” Agonists help a mechanism to work to its greatest potential, partial agonists help a mechanism of action work, but at a weaker level. These ginsenosides have a strong attraction to the glucocorticoid receptor, so they bind very well, but only weakly stimulate the receptor. If a person had too much glucocorticoid in the receptor space and their HPA axis was causing an excessive release of stress hormones, the application of these ginsenosides would crowd the stress hormones out of the receptor sites and weakly stimulate (Mukherjee, Knisely, & Jacobson, 2004).

Note:  This part is too technical, there is a translation from jargon to English below!

Stimulating that receptor causes the HPA axis to stop secreting ACTH, which interferes with adrenal production of glucocorticoids and cortisol. The antidepressant Imipramine uses this mechanism of action to treat psychotic depression (Mukherjee, Knisely, & Jacobson, 2004). There is some evidence that the HPA axis is stimulated by glucocorticoid receptors in parts of the brain that are newly implicated in the presentation of psychosis and depression, such as the amygdala. The amygdala is the warning bell of the brain (Vincent et al., 2013).

In order for these ginsenosides to have that mechanism of action, the ginsenosides have to be absorbed and transported into the blood. Han and Fang (2006) explain that, “Elimination in the stomach, large intestine and liver contributed to the low oral bioavailability of Rg1 but low membrane permeability might be a more important factor in determining the extent of absorption.” However, an emerging method of ginseng fermentation demonstrates a way to increase the absorption and bioavailability of ginsenosides. Fermented red ginseng has an increased amount of polyphenols (antioxidants), ginsenosides, and ginsenoside metabolites. Non-fermented red ginseng is absorbed at a rate of about 0.1-3.7% (Ryu et al., 2013). “The sum of Rb1 and Rg1 (this is the ginsenoside that is a partial agonist in glucocorticoid receptors) in the NFRG (10.25±0.51 mg/g) was significantly higher (p<0.05) than that of the FRG (2.33±0.07 mg/g). However, the level of ginsenoside metabolites (Rg2, Rg3, Rg5, Rk1, CK, Rh1, Rh2, and F2) was significantly higher (p<0.05) in the FRG (33.90±0.97 mg/g) compared to that of NFRG (14.75±0.46 mg/g).”

Let’s go over that last paragraph again and translate it from statistics into English. The ginsenosides have to make it into the bloodstream in order to work on glucocorticoid receptors. The stomach, large intestine, and liver remove ginsenosides from the GI tract and the blood, which decreases their bioavailability. However, it is probably the inability of ginsenosides to move from inside the intestine into the bloodstream that blocks most of the ginsenosides, leaving only 0.1-3.7% of the ginsenosides biologically active in the blood. A fermentation process can improve the total amount of ginsenosides available, and is absorbed by the small intestine as much as fifteen times more than non-fermented ginseng.

The fermentation process breaks down the large molecules of ginsenosides to smaller molecules, which more easily pass through the GI tract and are absorbed better into the blood.

In this discussion, we considered stress and how it negatively affects the brain and body. We considered one possible mechanism of action for stress, and two possible pharmacologic approaches to address stress. We went over two biomarkers that can help a clinician accurately diagnose chronic stress, and two diagnostic tests that have elevated risks to the client. In later articles, I will cover some lifestyle changes a person can use to successfully cope with stress with or without pharmacological support.

If you think chronic stress is negatively affecting your life, call Mid-Valley Counseling at (503) 364-6093. As of 10/2/2015, I am accepting new clients.  Salem, OR is located between Portland, OR and Eugene/Corvallis, OR.


Anacker, C., Zunszain, P. A., Carvalho, L. A., & Pariante, C. M. (2011). The glucocorticoid receptor: Pivot of depression and of antidepressant treatment? Psychoneuroendocrinology, 36(3), 415-425. doi:10.1016/j.psyneuen.2010.03.007

Electro-Physiological Data Fusion for Stress Detection (PDF Download Available). (n.d.). Retrieved from

In Fischbach, F. T., & In Dunning, M. B. (2015). A manual of laboratory and diagnostic tests (11th ed.). Philadelphia, PA: Lipincott Williams & Wilkins.

Han, M., & Fang, X. (2006). Difference in oral absorption of ginsenoside Rg1 between in vitro and in vivo models. Acta Pharmacologica Sinica, 27, 499-505. doi:10.1111/j.1745-7254.2006.00303.x

Leung, K. W., & Wong, A. S. (2010). Pharmacology of ginsenosides: a literature review. Chinese Medicine, 5(20). doi:10.1186/1749-8546-5-20

Mayo Clinic. (2013, July 11). Chronic stress puts your health at risk – Mayo Clinic. Retrieved September 7, 2015, from

Mukherjee, K., Knisely, A., & Jacobson, L. (2004). Partial Glucocorticoid Agonist-Like Effects of Imipramine on Hypothalamic-Pituitary-Adrenocortical Activity, Thymus Weight, and Hippocampal Glucocorticoid Receptors in Male C57BL/6 Mice. Endocrinology. doi:10.1210/en.2004-0147

Ryu, J. S., Lee, H. J., Bae, S. H., Kim, S. Y., Park, Y., Suh, H. J., . . . Jay, Y. H. (2013). The bioavailability of red ginseng extract fermented by Phellinus linteus. Journal of Ginseng Research, 37(1), 108-113. doi:10.5142/jgr.2013.37.108

Vincent, M. Y., Hussain, R. J., Zampi, M. E., Sheeran, K., Solomon, M. B., Herman, J. P., . . . Khan, A. (2013). Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors. Brain Research. doi:10.1016/j.brainres.2013.05.031

Natural sleep enhancement with tart cherry juice

Tart Cherry Juice for Sleep

Sometimes my clients complain of insomnia. Some expect that I will prescribe one of the medications they have seen advertised on TV or a heavy-duty sedative/hypnotic like Ambien.  Instead, I often ask clients to try adding tart cherry juice to their diet and see if that improves their symptoms.  I like to try interventions that have a side effect profile that people can live with easily.  It’s even better if my clients can go to their local supermarket and buy something off the shelf that will help them with their situation. I think it helps clients develop the sense that they are in charge of their recovery.

As much as I wish all natural remedies were effective, it seems to be the case that only a limited number of them work when tested in well-regulated clinical trials. Some work in very limited environments such as in a petri dish with some viable cells, but animal experiments and human trials are really the only way to know how something is going to work in the real world

A study regarding the effectiveness of tart cherry juice on insomnia was published in 2010 and can be accessed on the National Institute of Health website.

The study was conducted by the University of Rochester Medical Center in New York. Clients who reported symptoms of sleeplessness were invited to participate in a double-blind, placebo-controlled trial. (Double-blind means that neither the clients nor the University knew who was receiving the placebo during the study.)

The University tested a tart cherry and apple juice blend (that I would not recommend, see comments later in this article). The placebo was a Kool-aid blend that was made to look and taste like the cherry/apple juice. The testers were asked to drink 8 oz in the morning and another 8 oz about 1-2 hours before bedtime. The reason for the 1-2 hour timing before bedtime was only to avoid having the client wake up to use the bathroom.

The study found that the tart cherry juice “produced significant reductions in insomnia severity (minutes awake after sleep onset)”.

A more detailed study with similar results was conducted in Europe in 2012. In that study, participants wore sleep monitors and also provided urine samples daily.

The urine samples showed that the cherry juice drinkers had increased melatonin in their systems. Melatonin is a hormone that can is well-known for being effective in producing sleep. Food chemists have verified that a significant amount of melatonin is present in Montmorency tart cherries.

There are several common forms of tart cherry juice. Make sure you check the label to see whether yours is a cherry juice blend that contains some tart cherry juice (not as effective), a “100% juice” blend that is part tart cherry and part other fruits (not as effective), all tart cherry juice (that’s the one we’re looking for in the grocery store), and tart cherry juice concentrate (should be somewhere around $30 for a 32oz bottle on Amazon).

Tart cherry juice has a few ingredients that help with sleep. One is melatonin. Melatonin has been widely researched and is effective at helping people get their regular sleep rhythm on track, meaning that they go to sleep at the same time and wake at the same time every day. Melatonin can also make your dreams vivid! Some good news about melatonin is that it’s hard to take so much melatonin that it would hurt you. Montmorency cherries contain approximately 6 times more melatonin than other kinds of tart cherries (Burkhardt, Tan, Manchester, Hardeland, & Reiter, 2001) so look for Montmorency cherry juice over any other kind in order to maximize your exposure to melatonin.

Tart cherry juice is rich in anthocyanins, which have a number of anti-inflammatory properties. Anthocyanins are a more potent anti-inflammatory than aspirin! If part of the reason you have trouble sleeping is due to aches and pains in the joints or muscles, tart cherry juice can relieve that discomfort. Interestingly, pectin interferes with the way that tart cherry juice relieves pain and inflammation, so it’s probably a good idea to avoid apples (pectin comes from apples) and jelly (jelly is commonly made with pectin) when you plan on using tart cherry juice to promote comfortable rest (Lila, 2004).

If the anti-inflammatory properties of tart cherry juice are more important to you than the melatonin content, then it’s less important to find Montmorency cherry juice. Montmorency cherries have about a third of the antioxidant and anti-inflammatory properties of the other tart cherries (Siddiq et al., 2011).

Melatonin is a potent antioxidant and anti-inflammatory as well. For people with any kind of GI disturbance, melatonin prevents ulcers in the intestines through an antioxidant action (reduction of hydrochloric acid, stimulation of the immune system, the healing of intestinal “skin”, and increasing blood circulation). Because of its unique properties, melatonin could be considered for prevention or treatment of colorectal cancer, ulcerative colitis, gastric ulcers, irritable bowel syndrome, and childhood colic (Bubenik, 2002).

In addition to the tart cherry juice available in your local supermarket, there are other ways to consume tart cherries. Tart cherries are available flash-frozen, dehydrated, as juice, and as juice concentrate. ”In summary, all processed tart cherry products possessed antioxidant and anti-inflammatory activity, but processing differentially affected phytochemical content and in vitro bioactivity. On a per serving basis, juice concentrate was superior to other tart cherry products” (Ou, Bosak, Brickner, Iezzoni, & Seymour, 2012).

In other words, buy tart cherry juice concentrate from Amazon, but in a pinch you can buy tart cherry juice at your local grocery store,.

If you are having trouble with insomnia, and you live in the Portland, OR area, call Mid Valley Counseling at 503-364-6093.


Bubenik, G. A. (2002). REVIEW: Gastrointestinal Melatonin: Localization, Function, and Clinical Relevance. Digestive Diseases and Sciences, 47(10), 2336-2348. doi:10.1023/A:1020107915919
Burkhardt, S., Tan, D. X., Manchester, L. C., Hardeland, R., & Reiter, R. J. (2001). Detection and Quantification of the Antioxidant Melatonin in Montmorency and Balaton Tart Cherries ( Prunus cerasus ). Journal of Agricultural and Food Chemistry, 49(10), 4898-902. doi:10.1021/jf010321+
Lila, M. A. (2004). Anthocyanins and Human Health: An In Vitro Investigative Approach. Journal of Biomedicine and Biotechnology, 2004(5), 306-13. doi:10.1155/S111072430440401
Ou, B., Bosak, K. N., Brickner, P. R., Iezzoni, D. G., & Seymour, E. M. (2012). Processed tart cherry products–comparative phytochemical content, in vitro antioxidant capacity and in vitro anti-inflammatory activity. Journal of Food Science, 77(5), 105-12. doi:10.1111/j.1750-3841.2012.02681.x
Siddiq, M., Iezzoni, A., Khan, A., Breen, P., Sebolt, A. M., Dolan, K. D., & Ravi, R. (2011). Characterization of New Tart Cherry (Prunus cerasus L.): Selections Based on Fruit Quality, Total Anthocyanins, and Antioxidant Capacity.International Journal of Food Properties, 14(2), 471-480. doi:10.1080/10942910903277697

Depression, Diagnosis, Treatment, Medication, and Biomarkers

How many times has it been said that “There’s no lab test for depression.” That was the case for thousands of years. Even since the beginning of the modern mental health treatment era with Freud and Kraepelin in the late 1800s, the causes of mental illness were guessed at by observations of behavior.

There are many reasons a person might be depressed, and there are many tools available to treat depression. How can a person know how to move forward with medication or talk therapy treatment? When is talk therapy most effective? What kind of medications are available to treat depression? Why would you choose one treatment over another? What is a biomarker, and why might it be useful in treatment?

One generally accepted treatment method is to use the STAR*D treatment steps. Start with Citalopram and see how that goes for 14 weeks. Why Citalopram? That medication is a selective serotonin reuptake inhibitor. That means that Citalopram helps keep serotonin in the part of a person’s brain where it can be most effective. Insurance companies tend to reimburse providers for this kind of treatment without complaint, and they’ll pay for those medications.

If you have a serotonin problem then this can be a nice solution. Women get better results from Citalopram than men. This is because women have more problems with serotonin than men do. The female reproductive system and hormone system affect serotonin more than men’s systems.

A biomarker is an objective medical status that can be accurately measured and reproduced. Here is a link to a study that uses an electroencephalograph (EEG) to locate a biomarker for depression and response to Prozac (fluoxetine), a similar SSRI medication. An EEG looks something like a swimming cap with a bunch of spark plugs stuck in it that are connected to a computer. First, the research team screens the patient for depression using the standard questionnaire, the Hamilton Rating Scale for Depression (HRSD). Here is a copy of that questionnaire. Insurance companies want PMHNPs and psychiatrists to use this form to decide whether a patient has depression and will accept it as documentation supporting that diagnosis. Then, researchers measured electrical brain activity in several areas of the brain and recorded their results.


I would like to call your attention to the difference between those two methods. The HRSD takes the patient’s verbal response to questions, and the EEG reads electrical brain activity.

Within that study, researchers found that using the EEG they could measure a patient’s response to Prozac at the end of the first week of treatment and predict how they would do at 8 weeks of treatment. They repeated the EEG at one week and calculated the difference between their first result on day 1 and their second result a week later. Using this calculation (called the Antidepressant Treatment Response Index), researchers could predict the patient’s response to treatment seven weeks in the future. By contrast, the HRSD did not offer a prediction of success. The EEG does not record the placebo effect, the change in the patient’s biomarker reflects the performance of the medication only. The HRSD assessment includes the placebo effect.

Wouldn’t it be nice to know whether you are experiencing the benefit of the medication vs the placebo effect? As a provider, this is vital information. I would not want to continue a medication that has the side effects that many antidepressants have (nausea and sexual dysfunction) when talk therapy would probably be a better option. A strong placebo effect indicates that a patient probably has hope. Hope is a wonderful thing to find in a patient seeking treatment for depression! Their depression might be event-driven, temporary, due to something that is not connected to serotonin, or otherwise resolvable.

Using the EEG in addition to the HRSD shortens the time from 14 weeks to 1 week. Isn’t that an incredible outcome? 13 weeks of medication costs money, and imagine spending 14 weeks waiting to see whether you are going to feel less depressed only to find out that it’s not ultimately going to work for you. Even if the medication seems to be working, there is still a significant chance that you feel better because of the placebo effect. Finding out that Citalopram or Fluoxetine probably isn’t going to work for you might not sound like good news, but it is. That tells us that your answer lies elsewhere. Instead of trying to find a version of serotonin that will be helpful, maybe we should look to dopamine or norepinephrine for a more likely solution.

The fact that a person can distinguish between these outcomes changes everything.

While this study is interesting and I believe very helpful, it was the follow-up to this one that converted me to a biomarker-hunter. We can look at that one next.

What’s new in mental health care?

I’m glad you asked! The good news is that there are an increasing number of tests that can help a clinician chase down what is causing some mental health problems.

Genetic testing can help find out how your body processes medication. Why does that matter? Some medications have to be metabolized before they can be used by the body for their intended purposes. For example, codeine is metabolized in the liver by cytochrome P450 CYP2D6. CYP2D6 is an enzyme that is about 2% of the liver’s CYP system, but it processes about 25% of clinically used drugs (Wang et al, 2006). 2D6 is polymorphic, which means that it comes in a number of different forms as dictated by the DNA that codes for its construction. Some people have a low speed, some a medium speed, and some have a high speed version of 2D6. If you have a low speed 2D6, codeine may not be transformed into morphine at a rate that would provide you with pain relief. A medium speed 2D6 would metabolize codeine as the manufacturer expects. A high-speed 2D6 might convert codeine into morphine too quickly, and oversedate before it wears off much too early. Maybe codeine is not a good fit for a person with a high-speed 2D6!

That information alone is very useful, but it is even more useful in the context of a patient’s personal situation. There are substances that affect how 2D6 processes medication. For example, Prozac (fluoxetine) slows down 2D6. The importance of this is that changes in one medication can affect how another one works. “After I started taking Prozac my depression got better, but now my knees hurt just like before I started taking codeine. What happened?” Now we can find out.

There is a small group of people who have the right enzyme to make the best use of Zyprexa (olanzapine). They can use a low dose and get relief of their symptoms without running the risk of winding up with metabolic syndrome. The weight gain alone can cause people to stop taking that medication, but the diabetes that comes with metabolic syndrome can take years off a person’s life. As a prescriber, I want to avoid causing a person to go through that series of events. Genetic testing can help me avoid causing that particular problem.

Genetic testing is a great tool to have available. Ten years ago, it was simply not available. Psychiatrists had to work with trial and error to find medications that would work for patients. It’s a good thing that era has finally come to an end.

Wang, B., Yang, L., Zhang, X., Huang, S., Bartlam, M., & Zhou, S. (2009). New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme. Drug Metabolism Reviews, 41(4), 573-643. doi:10.1080/03602530903118729