When we talk about “stress,” or allostatic load, in terms of the perception of an event, we must realize that these “events” must first be translated into neurochemical signals before they trigger the HPA axis.
Therefore, the sensitivity and outcome of translating these events (whether they are ongoing events, memories of past events, or stressful anticipation of unrealized events), is highly dependent upon signaling from other neurotransmitters. In fact, the signaling neurotransmitters that manage mood and affect often overlap with measures of HPA axis activation, and cannot be easily distinguished in some subjects. 
While the detailed influence of neurotransmitters, such as GABA, glutamate, serotonin, norepinephrine, dopamine and a host of neurosteroids, on the HPA axis is beyond the scope of this blog post, we will outline some of the fundamental activities clinicians should keep in mind when evaluating patients for HPA axis dysfunction.
The Prevalence of Anxiety & Depression
Anxiety disorders are the most common mental illness in the United States, affecting 40 million adults age 18 and older (18% of the population). Major depressive disorder (MDD) is the leading cause of disability in the United States for those age 15 to 44. MDD affects approximately 14.8 million American adults age 18 and older each year, or about 6.7 % of the population. 
These disorders are often associated with abnormal amounts, ratios or activities of various neurotransmitters. For this reason, more than 1 in 10 Americans are prescribed a medication intended to modulate or mimic neurotransmitter function with a variety of outcomes and side effects.
The manifestations of HPA axis dysfunction caused by mood and stress, such as a feeling of a loss of control, burnout-withdrawal, and worry, overlap with those of both anxiety and depression. For this reason, it is often difficult to separate the diagnostic and treatment approaches in such individuals. It is common for researchers to use depression scales (e.g., Hamilton Depression Scale) along with perceived stress scales in subjects undergoing HPA axis function testing.  It is also well-known that the brain regions most responsible for interpreting perceived stress (hippocampus, pre-frontal cortex, amygdala and hypothalamic PVN), are highly influenced by neurotransmitter-signaling, though these interactions are multi-layered and not well-understood. 
Depression & HPA Activation
Higher cortisol levels are most pronounced in subjects with more severe depression symptoms, especially if the patient is hospitalized due to depressive symptoms.
A recent summary/meta-analysis of the past 40 years of research has affirmed that elevated activity of the HPA axis during depression is one of the most reliable findings in biological psychiatry.  Higher cortisol levels are most pronounced in subjects with more severe depression symptoms, especially if the patient is hospitalized due to depressive symptoms.
Melancholic and psychotic depression are linked with notable higher average cortisol than those with regular depression. Atypical depression, characterized by hypersomnia, fatigue and hyperphagia, does not appear to cause elevated cortisol levels, and in some studies, correlates with lower cortisol output. ACTH output, when measured, also mirrors most of these findings, as it is elevated in more severely depressed subjects.
HPA hyperactivity in depressed subjects appears to be caused, at least in part, by impairment within the negative feedback inhibition process. Essentially, the feedback inhibition is less sensitive to elevated cortisol secretion, which prevents appropriate down-regulation of the HPA axis.  Research has primarily focused on the function and polymorphism of the glucocorticoid receptor (GR) and its co-chaperones within the hippocampus, amygdala, hypothalamus and other areas of the brain that send signals to the HPA axis.  Changes to GR function result in a form of “glucocorticoid resistance” within these neurons, leading to a hyperactive HPA axis (with measurably higher ACTH and cortisol) and a blunted feedback inhibition (less inhibition noted in dexamethasone suppression tests).  Furthermore, GR regulation is now considered to be a major mechanism for several classes of antidepressants. 
Along with GR-related feedback inhibition common to depressive disorders, increased inflammatory signaling is also considered to drive the depression/HPA axis activation.  While these actions seem contradictory, as cortisol is known to be an anti-inflammatory steroid, it is possible that the same GR-resistance that occurs within the brain may also prevent the down-regulation of inflammatory mediators like IL-1β and IL-6 in certain immune cells.
Also, not all patients with elevated inflammatory cytokines will have depression, though most will have some level of HPA axis activation (or down-regulation after chronic activation).  Nonetheless, blunted feedback inhibition and inflammatory signaling are considered to be major pathways that bridge depression with HPA axis dysfunctions. 
For more on stress and depression, refer to Dr. Guilliams’ book The Role of Stress and the HPA Axis in Chronic Disease Management.
Watch Dr. Guilliams' Webinar
- Blog: Is it Adrenal Fatigue? Reassessing the Nomenclature of HPA Axis Dysfunction.
- Blog: How to Use the Cortisol Awakening Response (CAR) in Addressing Adrenal Function
- Blog: Diurnal Fluctuations in Norepinephrine & Epinephrine as Part of the Health Stress Response
Thomas G. Guilliams, PhD, earned his doctorate from the Medical College of Wisconsin where he studied molecular immunology in the Microbiology Department. Since 1996, he has spent his time studying the mechanisms and actions of natural-based therapies, and is an expert in the therapeutic uses of nutritional supplements. Dr. Guilliams teaches at the University of Wisconsin School of Pharmacy, where he holds an appointment as a Clinical Instructor, and at the University of Minnesota School of Pharmacy, and he is a faculty member of the Fellowship in Anti-aging Regenerative and Functional Medicine (A4M).
 Baumeister D, Lightman SL, Pariante CM. The Interface of Stress and the HPA Axis in Behavioural Phenotypes of Mental Illness. Curr Top Behav Neurosci. 2014;18:13-24.
 Data from Anxiety and Depression Association of America website: www.adaa.org/about-adaa/press-room/facts-statistics accessed 5-12-2015.
 Hinkelmann K, Botzenhardt J, Muhtz C, et al. Sex differences of salivary cortisol secretion in patients with major depression. Stress. 2012 Jan;15(1):105-9.
 Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008 Sep;31(9):464-8.
 Stetler C, Miller GE. Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom Med.2011 Feb-Mar;73(2):114-26.
 Anacker C, Zunszain PA, Carvalho LA, Pariante CM. The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology. 2011 Apr;36(3):415-25
 Szczepankiewicz A, Leszczyńska-Rodziewicz A, et al. FKBP5 polymorphism is associated with major depression but not with bipolar disorder. J Affect Disord. 2014 Aug;164:33-7
 Sher L. Combined dexamethasone suppression-corticotropin-releasing hormone stimulation test in studies of depression, alcoholism, and suicidal behavior. ScientificWorldJournal. 2006 Oct 31;6:1398-404.
 Maric NP, Adzic M. Pharmacological modulation of HPA axis in depression - new avenues for potential therapeutic benefits. Psychiatr Danub. 2013 Sep;25(3):299-305.
 Makhija K, Karunakaran S. The role of inflammatory cytokines on the aetiopathogenesis of depression. Aust N Z J Psychiatry. 2013 Sep;47(9):828-39.
 Silverman MN, Sternberg EM. Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction. Ann N Y Acad Sci. 2012 Jul;1261:55-63