Salivary Test Identifies Depression, Anxiety, Traumatic Stress, and Sleep Disorders

By Timothy Schwaiger, NMD.

The use of salivary cortisol in evaluating a patient’s condition can be a valuable tool for physicians. Although there is a vast quantity of research in this area, the laboratory results can be confusing when trying to choose a therapy best suited for the patient. In this article, I will discuss evidence that abnormal cortisol patterns can be a reflection of basic underlying dysfunction in physical, emotional and psychological well-being, and that treatment of the hypothalamic–pituitary–adrenal (HPA) axis dysregulation requires a very individualized approach. I will start with a brief explanation of the HPA axis and the relationship to cortisol.

Adrenal function is an important subject of debate and has significant clinical relevance, especially when exploring the ramifications and intricacies of the hormone cortisol. The conventional interpretation of cortisol is often restricted to the diagnosis of hypocortisolism or hypocortisolism. The most common examples of these disorders are Addison’s disease and Cushing’s syndrome. Naturopathic medicine, in some cases, has embodied the approach of simplifying the non-conventional approach to the definition of "adrenal fatigue"; which is quite often inadequate. Therefore, I would like to expand the view to include a more detailed approach of evaluating patients with adrenal or hypothalamic–pituitary–adrenal (HPA) axis dysregulation. Adrenal function is complicated and involves numerous levels of functioning in the body.

The hypothalamus is a small organ located below the thalamus and controls reactions to stress and regulates various body processes such as mood. This system is deeply related to the very make-up of our physical and emotional well-being. One approach to treat individuals with dysregulation of this system is to provide them with "adrenal" supplements or glandular products containing the adrenal gland. While this can be very beneficial at times; a more elaborate understanding of the HPA axis, especially the diurnal secretion patterns of cortisol, can better assist us in evaluating and treating patients. Before we explore this idea, I will review the basic pathways and mechanism of cortisol secretion.

Cortisol Regulation

Cortisol is the primary regulator in the activity of the hypothalamic–pituitary–adrenal (HPA) axis by its negative feedback effects on adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH). CRH is transported to the anterior lobe of the pituitary via the portal system, where it stimulates corticotropes to secrete ACTH. ACTH is released on a pulsatile basis with peaks approximately every 30 minutes and a half-life of up to 15 minutes. Cortisol is then released following ACTH bursts about 30 minutes later. The negative feedback effects of cortisol are exerted at the level of both the hypothalamus and the pituitary glands. The cortisol response to ACTH bursts is quite steady; however the bursts may fluctuate. Therefore, it is the number of secretory periods of CRH and ACTH that determines the total daily cortisol secretion. Dehydroepiandrosterone (DHEA) is also made by the adrenal glands and is thought to be an antagonist to the action of cortisol. Some studies have shown dehydroepiandrosterone-sulfate (DHEA-s) to be decreased during times of stress.

Daytime (Diurnal) Changes

ACTH secretion follows a circadian rhythm with peak cortisol blood levels attained upon awakening with a gradual decline throughout the day. There does seem to be a day-to-day variation in the pattern; however, the typical pattern of an early morning peak with a gradual decline is a "typical pattern". The increased cortisol secretion observed during the early morning hours, and the increased secretion in response to stress, result primarily from increased central nervous system (CNS) or autonomic activity, possibly also affected by vasopressin as well as cortisol. Vasopressin, or anti diuretic hormone (ADH), is secreted by the posterior pituitary and mainly responsible for water re absorption in the kidneys. However, vasopressin also acts as a neuropeptide-neurotransmitter and increased secretion of this substance have been linked to depression and anxiety.

Numerous factors can have an effect on diurnal cortisol patterns. Aging, quality of sleep, and time of awakening will affect this pattern. For example, in normal individuals, earlier than usual awakening is associated with increased morning peak levels of cortisol while late awakeners’ exhibit decreased levels. This variation is important when performing and interpreting salivary cortisol tests. In addition, conditions such as depression, anxiety, Chronic Fatigue Syndrome (CFS), Fibromyalgia, cancer and metabolic syndrome all show dysregulation of the HPA axis as exhibited by either blunted or inconsistent (atypical) diurnal cortisol patterns.

Changes with Aging

As we grow older, there are some obvious changes that occur in the neuroendocrine system. In respect to the glucocorticoids, levels of DHEA are decreased with age. On the other hand, the daytime (diurnal) rhythm of cortisol may be blunted and a general shift to increased evening levels of cortisol have been noted in the normal healthy elderly population. In the same manner, the ratio of cortisol to DHEA is increased with age.7 This occurs with other hormones as well. For example, it is not uncommon for the ratio of estrogen to testosterone to increase in elderly men. In relation to cortisol, studies suggest that frailty, depression, and dementia can affect the "typical" diurnal pattern in elderly persons. One study found that elderly persons with memory deficit and/or depression demonstrate a flat or blunted diurnal pattern of cortisol. Supplementation with DHEA for these individuals has produced mixed results.

Stress - The Effects of "Fight or Flight"

I was intrigued by the writings of Anna Dahlgren from Stockholm University when she explained the reaction of the fight or flight response. She states that the immediate reaction to a stressor is a catabolic (breaking down processes) activity during which time the sympathetic system is activated as a reaction to the increased sympathetic response to a threat. These metabolic processes occur during these periods in order to increase energy production. Anabolic (or building up processes) occur during relaxation and sleep. Consequently, if someone spends abnormally long periods in the catabolic phase without adequate anabolic activity, therein lays the dysfunction. If these catabolic periods are temporary and intermediate, the body adapts, and then homeostasis is established. If periods are of longer duration homeostasis is threatened.

The locus ceruleus (LC), a nucleus located in the brainstem, is a very special mediating area for regulating the stress response in the body. During periods of stress, the LC will release norepinephrine, which in turn activates the HPA axis, and therefore is responsible for increasing cognitive function and motivation. Epinephrine is released by the adrenal glands in response to stress. This neurotransmitter has stimulatory affects such as an increase in heart rate and is well known for its key role in the "fight or flight" response. The amino acid l-glycine and neurotransmitter gamma-aminobutyric acid (GABA) have an inhibitory affect on the system.

Salivary Cortisol Patterns and Illness

Salivary cortisol assessment can aid in the evaluation of conditions such as depression, anxiety, Chronic Fatigue Syndrome (CFS), Fibromyalgia and sleep disorders. It is important; however, to realize that it is just that, a tool, and not an end all for diagnosis. The next section will summarize some abnormal patterns seen with this testing. Some of the research demonstrates inconsistency in the findings, so this article does not serve as a meta-analysis of all the data.

Sleep Disorders

The amount and quality of sleep can have a huge effect on the HPA axis. Anytime patients present with difficulty initiating and maintaining sleep (DIMS), excessive daytime somnolence (EDS) or problems related to insufficient sleep they must be evaluated for a number of sleep disorders. Disorders of EDS include narcolepsy, idiopathic hypersomnolence and even sleep apnea can present with overt daytime sleepiness. In addition, disorders such as restless legs or periodic limb movements during sleep may be associated with DIMS or EDS.
Individuals with complaints of difficulty initiating and maintaining sleep exhibit dysfunctional diurnal bursts in diurnal salivary cortisol levels. A study performed on middle-aged individuals who have poor sleep quality have been shown to have increased levels of salivary cortisol upon awakening; whereas sleep deprived individuals show increased evening cortisol levels.

Insomnia is a subjective complaint and not a medical diagnosis. In other words, there is always an underlying cause to insomnia, whether medical or psychological. The physician must distinguish between difficulty falling asleep and staying sleep. For example, patients with CFS often report a subjective feeling of un refreshed sleep upon awakening. However, most research shows cortisol hypo secretion in these patients. Patients with insomnia secondary to generalized anxiety are more likely to have a dysfunction of hyper secretion of cortisol. Individuals with sleep deprivation or inadequate amounts often show elevated evening cortisol.

Depression/Anxiety

Some studies show an association of early morning cortisol hyper secretion with major depression., Others suggest a "blunted" or low cortisol pattern in the early morning hours. Another study demonstrated non-depressed individuals have increased spikes in morning cortisol levels associated with social contact in the morning hours; however depressed people have a "blunted" response to early morning social contact. The following graph represents this blunted response in a group of mild to moderately depressed females. This study demonstrates the need to treat the depression and not just encourage increased social networking or increased contact with other people.

Reprinted by Permission of the Journal of Abnormal Psychology, American Psychological Association

A common symptom of depression is early morning awakening. Many of my patients prior to successful treatment of depression report a "cortisol-like" surge upon awakening. In addition, if the salivary cortisol is measured on early awakening it may increase this peak surge level. This surge will most likely correct following treatment. It may take the patient some time to adjust to this normalization to a more normal baseline. Individuals showing major depression with associated anxiety or post traumatic stress syndrome (PTSD) may demonstrate a pattern of evening cortisol hyper secretion.

Consideration in Treatment of HPA-axis (Cortisol) Dysfunction

Relaxation (Lifestyle) Techniques

In a study published in Applied Psychophysiology & Biofeedback it was reported that the use of progressive relaxation resulted in lower salivary cortisol levels and an increase in salivary immunoglobulin A (sIgA). Reduced levels of sIgA have been linked to increased upper respiratory infections in endurance runners. These relaxation techniques have also been shown to reduce conditions of high blood pressure, depression and anxiety. In a study done in Spain on preoperative patients, a comparison was done between the use of diazepam and listening to music on the day of surgery. It was concluded that the use of music was as effective as diazepam in reducing preoperative anxiety. Prior to this study the same results were found in preoperative patients in Australia.

Studies have been conducted on the effects of the HPA axis and immune system using Mindfulness Based Stress Reduction (MBSR). A one year follow up involving patients trained in MBSR with breast and prostate cancer showed reduction in pro-inflammatory cytokines, reduced cortisol levels and reduction in self-reported stress levels.

Nutraceutical Interventions

Supplementation for cortisol dysfunction should be centered on trying to correct or adjust the underlying problem. Supplementation with hydrocortisone or DHEA may have a place; however, the use of these products may not be getting to the root of the patient’s condition.
The use of amino acids such as l-glycine, dl-phenylalanine, and l-tryptophan has been a foundation in my therapy in treating depression and anxiety, as well as insomnia associated with mental disorders.

L-glycine is a strong neurotransmitter inhibitor, acting on the locus ceruleus, giving the patient a sense of well-being and calmness, without sedative affects. High doses of 3-4 grams three times per day may be needed to get such an effect. I almost always use L-glycine in cases of anxiety or substance abuse related anxiety and/or withdrawal.

L-tryptophan, in combination with melatonin can be very effective for insomnia associated with depression and/or anxiety. A starting does of 1-3 grams of l-tryptophan with 3 mg of sustained-release melatonin seems to be a standard dose for my patients. L-tryptophan, of course, is a precursor to serotonin and also melatonin. An increased intake of l-tryptophan results in increased brain levels of serotonin. Serotonin is found primarily in blood platelets and in the gastrointestinal tract. Other practitioners find similar results with 5-Hydroxytryptophan (5-HTP).

I use dl-phenylalanine quite often as a compliment to l-tryptophan and melatonin when dealing with major depression and associated difficulty initiating or maintaining sleep. For patients suffering from chronic pain and depression, dl-phenylalanine works very well. D-phenylalanine acts as an enkephalinase inhibitor, and prevents the breakdown of the brain's natural endorphins. I use 3-9 grams in three divided doses depending on the situation.

B-Complex is an important adjunct therapy when given with neurotransmitters. The vitamins are involved in numerous physiological processes.

Phosphatidylserine (PS) has been shown to reduce levels of cortisol. It appears that this activity is somewhat dose dependent. The researchers concluded that PS appears to lower cortisol after exercise and increase feelings of well-being while blunting muscle soreness. Similar to the results of older studies on PS, findings suggest that the mechanism involves a PS-induced inhibition of ACTH release by the pituitary gland. The fact that ACTH didn’t rise in those taking PS but did in the placebo group substantiates that idea.

Case 1: Hypertension

A 44 year-old man who was diagnosed with hypertension 10 years previous to his visit with me. During periods of stress he states that he has numbness in left chest and left arm; which would last up to three hours. He has been to a cardiologist and all tests have been negative for heart disease. He says that stress has always been a problem (past 20 years). He had been taking 60 mg of nifedipine for the past ten years and he desires a natural approach. Salivary cortisol revealed the following results:

Cortisol8 amNoon 4 pmMidnight
Patient
6
16
4
6
Normal
13-23
5-10
3-8
1-3

He was placed on 10 mg of DHEA each morning, 3 grams of L-Glycine three times per day and 100 mg of phosphatidylserine three times per day. Within three months I was able to discontinue his blood pressure medication. Following six months of the natural protocol he was able to eliminate all supplements without consequential blood pressure elevation. In addition to the supplements he entered counseling and started relaxation practice.

Case 2: Anxiety and PTSD

A 48-year-old man came to my office with depression associated with Post Traumatic Stress Disorder (PTSD) with generalized anxiety for one year duration. He had a negative history of any organic sleep disorder; however, his total sleep time was only around 5 to 6 hours. His normal bedtime was 11:00 pm and his wake time 4:00 am. He awakened in the morning with subjective complaints of un refreshed sleep and excessive daytime sleepiness and fatigue. He had difficulty with periods of anxiety and worry all the time, especially in the evening.

His initial salivary cortisol revealed quite elevated levels at 11:00 pm. The remaining three periods basically revealed hypo secretion (see pre and post treatment figures below, which were provided by Diagnos-Techs, Inc. 6620 S. 192nd Place, Bldg. J. Kent, WA 98032). This fits the characteristic elevated cortisol seen with sleep deprivation and PSTD. The typical morning elevation in depression is not seen, which may represent more of a "blunted" effect.

The following figure is two months post therapy. At this time his depression and anxiety were under control; however, he was experiencing fatigue during the day. He was still only sleeping 5-6 hours per night. I made the recommendation at this time he increase his total sleep time to 7 hours; and the use of full-spectrum light therapy in the morning to reinforce the circadian rhythm and daily exercise. My hope is to bring the diurnal pattern to a more normal range following several months of therapy. At this point, I have not repeated the cortisol test; however he reports more energy with increased sleep time and regular exercise.

Summary

Salivary cortisol can be a valuable tool in the evaluation and treatment of many conditions. In addition, it can be a very helpful tool to evaluate progress and success of therapy. The HPA-axis and diurnal patterns of cortisol is much more complex than outlined in this brief article. When using the test, it is particularly important that each patient be as consistent as possible in the collection of the samples. I encourage all physicians to establish a working relationship with the laboratory of choice in obtaining the most accurate measurement possible. In theory, the patient’s success will be reflected favorably in the test results.




Timothy Schwaiger

Author Timothy Schwaiger is a licensed naturopathic physician in the state of Arizona.

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