The Cortisol Awakening Response (CAR) is the predictable rise in cortisol within the first hour of awakening. There are two events that contribute to this dynamic rise in morning cortisol. The first is in response to adrenocorticotropic hormone output from the pituitary as a part of the normal circadian activities of the hypothalamic–pituitary–adrenal (HPA) axis with involvement from the sympathetic nervous system. The second occurs in response to exposure to daylight with the activation of the suprachiasmatic nucleus in the hypothalamus, which happens within 30-45 minutes after awakening and can increase cortisol by 50-60% from the waking value. These events take place in a timed and metered fashion, allowing for a rise and fall of cortisol over a one-hour period [1].

The CAR is under the influence of the circadian clock and helps to synchronize the daily circadian rhythms, while the remainder of daily cortisol production is more influenced by daily stressors [2]. The purpose of the CAR is to mobilize glucose for energy needs, augment cardiovascular function, engage the motor system, and initiate and enhance cognitive processes that allow us to restore consciousness and engage in activity that requires us to be alert and ready for action [3]. Depression, anxiety, and early life trauma can influence the stress response. The CAR is often used to predict the onset of depression or anxiety in certain populations and may be used to monitor the efficacy of treatment for these conditions.

What Does the CAR Tell Us?

Since waking seems to function as a mini stress test, we can use the CAR to determine how robust the HPA axis is in response to the stress of waking up and relate those results to an individual’s history. The CAR is most often measured with additional cortisol levels taken throughout the day up until bedtime. This comprehensive analysis of cortisol dynamics allows us to visualize the morning rise (MR) in cortisol and the diurnal cortisol slope (DCS) throughout the day. A robust MR and steep decline in the DCS are associated with a healthy HPA axis [4, 5].

Personality and Life Experience: Factors that Influence the CAR

In a one-hour time period, the CAR can encapsulate the baseline response to stress and the status of the HPA axis. It is difficult to know if the association between cortisol levels and mood disorders, such as anxiety and depression, reflects a causal relationship and if so, in which direction. Which is the cause, and which is the effect? The studies mentioned below have used the CAR to predict events of major depressive disorder or anxiety, but it is unclear if cortisol patterns within the CAR are contributing to anxiety and depression or are a result of existing anxiety or depression [3].

We often refer to a perceived level of stress when addressing HPA axis dysfunction. My perception of stress may be quite different than yours under the exact same circumstances and that perception is built on past experiences, memories, and personality traits. Perhaps who we are can often be reflected in the chemicals that mediate our emotional responses to the events of life. Patterns of cortisol output, within the CAR and throughout the day, can provide necessary insight regarding personal characteristics, personality traits, and life experiences that can have far-reaching effects on health and wellness over a lifetime.

Trait vs State

The mental-emotional factors that influence the CAR and daily cortisol output can be either trait- or state-specific. A trait is a relatively stable characteristic that causes people to behave in certain ways; more specifically described as a personality trait. According to the American Psychological Association Dictionary of Psychology, a personality trait is stable, consistent, and enduring, and is inferred from behaviors, attitudes, feelings, and habits [6]. An article in Psychology Today outlines the “Big Five” personality traits, which are broad dimensions used to describe a person’s general temperament [7]. The Big Five include:

• Openness to Experience – interest in new ideas and experiences vs cautious and rigid
• Conscientiousness – completing what is started vs carelessness, loss of interest
• Extraversion – high degree of sociability and positive emotion vs solitary and reserved
• Agreeableness – friendly and compassionate vs critical and overly rational
• Neuroticism – anxiety, depression, low-self-esteem, nervous vs resilient, confident

These personality traits can exist along a spectrum, and we are usually a combination of all of them to varying degrees with perhaps a few that dominate [6]. Personality traits can change over time through both life experience and maturity, and a focused intention to change if the trait, or lack thereof, tends to result in psychological, social, or relational issues.

On the other hand, a state is a temporary way of being (i.e., thinking, feeling, behaving, and relating) and is usually situational and transient. The importance of the trait vs state distinction helps to differentiate between what might be a normal response to situational stress (state) and a predisposition to have an exaggerated stress response regardless of the situation (trait). Trait-specific influences may be more reflected in the CAR as these values tend to be remarkably consistent over time regardless of the stress a person may be experiencing [8].  Variations in diurnal cortisol output, outside of the CAR, may be more reflective of the stress response in relation to physiological and situational stressors.

Resilience

Resilience can be defined as the ability to withstand stress and recover without extending consequences, and it tends to be associated with more positive personality traits and better physical health. In a recent study on Chinese undergraduate students in which the CAR and the diurnal rhythm of cortisol were measured over three days, Lai et al determined that higher resilience was associated with an enhanced CAR and a steeper DCS from waking to bedtime. They conclude that an accentuated CAR indicates effective coping with life stressors and a steeper DCS indicates effective cortisol regulation [5]. The rise and fall of cortisol in this manner characterizes the effective activation and deactivation of the HPA axis and provides a neuroendocrine representation of the positive association between resilience and good health [5].

Resilience in life can be fostered through early life influences such as supportive and attentive parenting, a loving and supportive environment, positive relationships with adults and peers, experience in overcoming manageable life challenges, and avoidance of repeated exposure to uncontrollable stress and trauma. Other factors that support resilient behavior in adulthood include adaptive stress responses, rapid stress recovery, high coping skills, ability to cognitively evaluate situations, emotional regulation, and self-confidence [9]. The ability to implement coping strategies and foster resilience is often associated with positive personality traits and can be learned if early life influences were lacking.

Depression and Anxiety

Certain psychological traits such as neuroticism, hopelessness, negative affect, subclinical depression, or a family history of depression have been associated with increased vulnerability to developing a depressive disorder [3]. An elevated CAR at baseline measurement, seemed to be predictive of a major depressive episode (MDE) within two and a half years. Dedovic suggests that the CAR could be used as a predictor of an upcoming MDE independent of future stressful life events. An extremely stressful event often precedes the onset of a major depressive episode with subsequent episodes of depression occurring over minor events due to stress sensitization and perhaps maladaptation of the HPA axis, resulting in desensitization of normal feedback loops that regulate cortisol output [3].

Anxiety often coexists with depression and can result in an elevated CAR and a DCS that is flat but elevated throughout the day, indicating a prolonged activation of the HPA axis. In a 2014 six-year prospective study analyzing the association between the CAR and anxiety disorders (AD), a higher CAR was a strong and significant predictor of a first onset anxiety disorder. The study included 232 older adolescents who shared personality traits, and cognitive, life event, and biological factors that predisposed the participants for an increased risk of developing anxiety. Over 1,900 students were screened for neuroticism, which is a known risk factor for mood and anxiety disorders. The students who were chosen to participate in the study scored in the top third for neuroticism as they were most likely to go on to develop an anxiety disorder.

Salivary cortisol samples were taken six times a day for three consecutive days at the beginning of the study. Samples were collected upon waking, 30-40 minutes after waking and at bedtime with three additional collections of saliva at unanticipated times during the day. Each participant was evaluated annually for significant mood or anxiety disorders using a Structured Clinical Interview for DSM-IV (non-patient edition). Of the 232 participants, 25 developed an anxiety disorder, the majority of which (11/25) fell into the category of social anxiety disorder (SAD), while the remaining participants fell into five different categories of AD. As stated by Adams et al, HPA-axis activity is particularly sensitive to perceived social stress and is the most powerful activator of the HPA axis in studies of experimentally-induced stress. Social anxiety often results in loneliness and isolation, which is also associated with a higher CAR. Of those who developed an AD, the CAR turned out to be a significant predictor of onset [10].

Genetics and Environment

Both genetics and environment can play a crucial role in the development of personality traits that are either supportive of resilience, which fosters a healthy response to stressful events, or neuroticism, which can predispose to anxiety and depression. Through a search of the current literature on genetics and heritability of resilience, Maul et al determined that certain genes combined with epigenetic factors can predispose to less resilience. Polymorphisms in the genes of the neuroendocrine stress response system can lead to increased stress sensitivity and a tendency to develop depression under stress exposure especially in those who have experienced early childhood trauma. Variations in the genes that code for the production, metabolism and breakdown of serotonin, dopamine, and norepinephrine have been associated with less resilience and the development of post-traumatic stress disorder (PTSD) and major depressive disorder.

Specific genetic variations also occur within the HPA axis that can either promote resilience or increase the chance of dysregulation. Certain polymorphisms in the genes that code for corticotrophin releasing hormone (CRH) are associated with a reduced risk of depression after being exposed to early life stress and provides a strong indication of the genetic impact on resilience [9]. Polymorphisms in the glucocorticoid receptor (GR) genes are associated with PTSD and depression. Additional genes that interact with the GR can decrease negative feedback regulation of the HPA axis and lead to GR resistance [9]. We often see a blunted and elevated DCS in people with a maladaptive stress response indicating a loss of feedback regulation of cortisol output.

Epigenetic factors, which would include environment, play a large role in the development of any health issue and the same is true here. Maul et al referred to early childhood trauma as an epigenetic factor that contributes to the expression of genetic traits that reduce resilience and increase sensitivity to stressful events. Trauma in early childhood has often been associated with a maladaptive stress response linked to a deeply ingrained fear response in the amygdala of the brain. From a developmental perspective, young children lack the cognitive ability and life experience to make sense of terrible circumstances, which ultimately leaves them with an enhanced stress response that extends into adulthood.

Adverse Childhood Experiences (ACEs) and a Maladaptive Stress Response

Research into ACEs shows a strong correlation between early childhood adversity and poor physical and mental health later in life. The National Scientific Council on the Developing Child coined the term “toxic stress” to describe the effects of excessive activation of the stress response on a developing child’s brain, immune system, metabolic regulatory systems, and the cardiovascular system. When a child experiences multiple ACEs over time without the supportive relationships to buffer the effects of these stressors, these experiences will trigger an excessive stress response [11].

Toxic stress results in the derangement of the neuro-endocrine-immune response, leading to excessive and prolonged activation of cortisol along with a persistent inflammatory state.  The child cannot deactivate the stress response after the stressor is removed. Children who experience early life toxic stress are at risk of long-term adverse health effects that may not manifest until adulthood. ACEs often include one or more of the following: emotional, physical and/or sexual abuse, neglect, mental illness of a caregiver, household violence, and substance abuse. The adverse effects that may result from ACEs include maladaptive coping skills, poor stress management, unhealthy lifestyles, mental illness, and physical disease [12].

A child experiencing toxic stress is at risk of permanent changes to brain architecture, epigenetic alteration, and modified gene function. As mentioned above, polymorphisms associated with genes that regulate neuroendocrine function and the stress response are more pronounced in people who experienced adversity in childhood. Under these extremely stressful situations, children are at risk for long-term health and developmental effects including increased risk for stress-related diseases [12]. The toxic stress response is believed to play a role in the development of depressive disorders, behavioral problems, PTSD and psychosis, and is likely more common than we realize.

Physical Effects of Stress and a Maladaptive Stress Response

Having an intact stress response can literally save your life; however, eliciting a stress response that far exceeds the stressor without the ability to effectively deactivate that stress response can affect both mental and physical health. Sustained and persistent stressful conditions can precipitate the excessive production of free radicals, increasing oxidative burden and promoting inflammation that further contributes to chronic disease. Oxidative stress contributes to neuronal degeneration that can result in cognitive dysfunction, memory loss, dementia, and other neurodegenerative diseases that result from the loss of synaptic connectivity and neuronal networks throughout the brain. Excessive stress can also interfere with the normal production of neurotransmitters, the chemical messengers throughout our brain and nervous system that contribute to mood and cognitive function [13].

The long-term physiological effects of chronic stress can also lead to hormonal shifts that suppress reproduction, growth, and thyroid function via suppression of gonadotropin-releasing hormones, growth hormone, and thyrotropin-releasing hormone. Excessive levels of cortisol may precipitate high glucose levels that can ultimately lead to insulin resistance, increased visceral adiposity, and decreased lean body mass. High levels of cortisol can also suppress osteoblastic activity leading to bone loss that may advance to osteoporosis. Stress can be a contributing factor to just about every disease. When we understand how we respond to stressors and why we respond as we do, we can find ways to better manage our stress to avoid the long-term outcomes and improve overall health and well-being.

A Simple Salivary Test and a Good History Can Go a Long Way

Evaluating HPA-axis function by measuring salivary cortisol provides a link between an objective and quantifiable marker, and the subjective experience of stress. Cortisol is an end-point hormone that can tell the story of our past as well as our present. Using the CAR provides us with specific insight as to how a person operates and can be predictive of anxiety and depression if it is overly accentuated, or representative of chronic fatigue and burnout if it is blunted. Laboratory data in combination with a good patient history can reveal a lot about our patients and help guide us as practitioners to address the core issues.

We cannot undo our patients’ past, but we can help them navigate the present and future with more resilience by teaching skills to cope with stress in a more productive way that allows for the reframing of experiences to moderate an overly accentuated stress response. For individuals at risk for depression or anxiety, an elevated CAR may be the first clue as to where they are headed. If we can use this information to intervene early, we may have the opportunity to change the trajectory of their health on many levels.

ZRT Tests to Consider

ZRT Laboratory provides a comprehensive list of testing that is valuable in assessing the causes and contributors to anxiety and depression. The CAR can be assessed through ZRT’s Cortisol Awakening Response Profile, which measures six salivary samples of cortisol with the first three samples taken within the first hour of waking. The additional three salivary samples are taken at designated times up until bedtime. To measure sex hormone levels in combination with the CAR, the salivary Hormone Trio measures estradiol, progesterone, and testosterone.

When addressing the potential contributors to depression or anxiety, the NeuroAdvanced Profile provides a comprehensive measurement of urinary neurotransmitters. This test is performed on dried urine samples for ease of collection and handling. ZRT also provides several dried urine tests that can be added on to the NeuroAdvanced Profile. These tests include: 1) Diurnal Cortisol & Melatonin, 2) Diurnal Cortisol, Norepinephrine & Epinephrine, 3) Diurnal Cortisol, Melatonin, Norepinephrine & Epinephrine and 4) Urine Toxic & Essential Elements. Urinary cortisol measurements in combination with timed measurements of neurotransmitters can provide useful data regarding the stress response and its relationship to melatonin, norepinephrine, and epinephrine. The presence of toxic elements can predispose an individual to chronic illness and the deficiency or excess of essential elements can influence the production of neurotransmitters and hormones.

Related Resources

• Stress & Adrenal Hormone Testing
• Neurotransmitter Testing

References

1. Guilliams TG. The Role of Stress and the HPA Axis in Chronic Disease Management. Stevens Point, WI: Point Institute; 2015.
2. Dedovic K, Ngiam J. The cortisol awakening response and major depression: examining the evidence. Neuropsychiatr Dis Treat. 2015;11:1181-1189.
3. Contreras CM, Gutierrez-Garcia AG. Cortisol awakening response: an ancient adaptive feature. J Psychiatry Psychiatric Dis. 2018:2(1):29-40.
4. Stawski RS, Almeida DM, Lachman ME, et al. Associations between cognitive function and naturally occurring daily cortisol during middle adulthood: timing is everything. J Gerontol B Psychol Sci Soc Sci. 2011;66(Suppl 1):i71–81.
5. Lai JCL, Leung MOY, Lee DYH, et al. Biomarking trait resilience with salivary cortisol in Chinese undergraduates. Front Psychol. 2020;11:536510.
6. American Psychological Association Dictionary of Psychology. https://dictionary.apa.org/. Accessed June 14, 2021.
7. Markman A. What everyone should understand about the big five personality traits. Psychology Today. Accessed June 18, 2021.
8. Wust S, Wolf J, Hellhammer DH, et al. The cortisol awakening response - normal values and confounds. Noise Health. 2000;2(7):79.
9. Maul S, Giegling I, Fabbri C, et al. Genetics of resilience: implications from genome-wide association studies and candidate genes of the stress response system in posttraumatic stress disorder and depression. Am J Med Genet B Neuropsychiatr Genet. 2020;183(2):77-94.
10. Adam EK, Vrshek-Shallhorn S, Kendall AD, et al. Prospective associations between the cortisol awakening response and first onsets of anxiety disorders over a six-year follow-up – 2013 Curt Richter Award Winner. 2014;44:47-59.
11. What are ACEs? And how do they relate to toxic stress? Center on the Developing Child at Harvard University. https://developingchild.harvard.edu/resources/aces-and-toxic-stress-frequently-asked-questions. Accessed June 23, 2021.
12. Franke HA. Toxic stress: effects, prevention and treatment. Children. 2014;1(3):390-402.
13. Kumar A, Rinwa P, Kaur G, et al. Stress: neurobiology, consequences and management. J Pharm Bioallied Sci. 2013;5(2):91-97.