Tolle Causam

Janelle Louis, ND

Because the very core of our foundational principles teaches us to identify and address the underlying causes of our patients’ health concerns, as naturopathic doctors we have the unique ability to help many people effectively address their depressed moods without or with minimal use of psychotropic medication, even in cases where conventional therapies have failed. Yet if we treat mental health concerns for any extended period of time, we are destined to come across at least 1 patient with whom we have not achieved the results seen with previous patients, despite addressing all of the usual culprits, based on objective testing and presenting symptoms.

These cases should force us to go back to the basics – back to our Therapeutic Order. And, if we’re true to the foundational principles of our profession, we’ll likely end up right back at square one: looking for additional obstacles to our patients’ healing. In my quest to answer this question – what is preventing my patient from getting well? – I’ve come to the realization that the impact of adverse childhood experiences (ACEs) on health is either too little known or too widely ignored, as even after years and years of research, this important health risk is frequently overlooked. Because of their effect on the hypothalamic-pituitary-adrenal (HPA) axis, ACEs in fact serve as significant causative and/or contributory factors in the pathogenesis of many psychiatric concerns including depression. Moreover, because ACEs can affect virtually every bodily system, it is our duty to educate ourselves about this important concept, assess our patients for these risk factors, and address any dysregulation that is present.

The Basics of ACEs

The most common definitions of ACEs typically include any psychosocial stressor that leads to chronic activation of the stress response during early life, which technically stretches from the prenatal period to 17 years of age. The most researched ACEs include parental divorce or separation; witnessing violent treatment of the mother or other caregiver; household member incarceration or addiction; household member depression or other mental illness; physical, emotional, or sexual abuse; and physical or emotional neglect. Nevertheless, ongoing research and my own clinical experience demonstrate that any factor that leads to excessive activation of the stress response during childhood, such as experiencing the loss of a parent or sibling, growing up in foster care, being chronically bullied, or experiencing chronic childhood illness, can have similar effects on the HPA axis and on chronic disease risk.^1-4

When a person experiences chronic stress during childhood, the stress response is activated. As a review, normal activation of the stress response involves the hypothalamus secreting corticotropin-releasing hormone (CRH). In response, the pituitary gland releases adrenocorticotropic hormone (ACTH), and ACTH binds to receptors on the adrenal cortex, stimulating the release of cortisol and other glucocorticoids. This is a very simplified rendition of the normal process of HPA axis activation.

HPA Hyperactivation or Hypoactivation?

In many individuals who have experienced ACEs, however, the HPA axis does not function as it should. Excessive activation of the stress response during crucial developmental periods results in a sort of rewiring of the brain.³ HPA axis dysregulation ensues, which can take the form of either hyperreactivity or hyporeactivity. Changes in glucocorticoid signaling and in glucocorticoid receptor expression result in alterations to the normal functioning of the stress response.⁵

Although we have observed ACE-induced HPA axis dysregulation as either hyperactivation or hypoactivation of the stress response, HPA axis hyperactivity – which we observe objectively as elevated salivary or plasma cortisol levels and clinically as stress maladaptation and increased proclivity toward psychiatric concerns such as anxiety and depression – tends to be the most common finding.

Individuals who develop HPA axis hyporeactivity, as evidenced by reduced morning cortisol and flattened diurnal slope,^6,7 tend to be those who have experienced significant trauma and carry diagnoses of posttraumatic stress disorder (PTSD). These individuals tend to also have elevated CRH levels. Research suggests that elevated CRH and low diurnal cortisol levels (HPA axis hyporeactivity) – as seen in many PTSD patients – may be due to an adaptive downregulation of pituitary CRH receptors as a result of CRH hypersecretion.³ In other words, as a compensatory response to the high CRH levels, the body attempts to modulate the stress response by decreasing CRH receptors at the pituitary, which results in less ACTH secretion and lower cortisol levels.

In contrast to patients with PTSD, depressed individuals who have experienced ACEs tend to have elevated cortisol awakening responses (CAR). This elevated CAR appears to persist even with a remittance of major depressive disorder,⁸ suggesting that the elevated CAR is likely a biological predisposition towards or vulnerability for depression that probably results from ACE-induced HPA axis dysregulation rather than from the depression itself. In other words, ACEs lead to HPA axis dysregulation, which serves as a significant physiological risk factor for depression and other mental health concerns.

HPA Axis Dysregulation & Immune Dysfunction

Hyperactivity of the stress response in early childhood has significant effects on the immune system as well. When we are exposed to an acute stressor, HPA axis activation leads to an upregulation of the innate immune system⁹ and an increase in inflammation.¹⁰ Under normal circumstances, the stressor resolves and cortisol binds to glucocorticoid receptors on immune cells in order to downregulate the initial inflammatory response. Higher levels of circulating cortisol and rapid increases in the rate at which cortisol levels rise in the body both trigger negative feedback loops that result in cortisol stimulating glucocorticoid receptors at the levels of the hypothalamus and the pituitary gland. This negative feedback promotes decreases in circulating CRH and ACTH, which in turn results in a decrease in circulating cortisol. Thus, cortisol plays a crucial role in downregulating the immune response and the termination of the stress response.

In many individuals who have experienced adversity during childhood, something slightly different occurs. When the stressor persists for days, months, or years, more and more cortisol is secreted, leading to alternative immune system responses. This can include a downregulation of aspects of both the innate and adaptive immune systems,⁹ as well as a disinhibition of the inflammatory reflex, mediated by the vagus nerve.¹¹ This disinhibition of the inflammatory reflex has been shown to result in higher baseline inflammation levels in individuals who have experienced ACEs, for up to 20 years after initial exposure to the stressor.¹⁰ Even when researchers controlled for stress levels in adulthood, these elevated inflammatory markers in ACE survivors persisted compared to controls, suggesting that adversity during childhood results in HPA axis changes that foster longstanding alterations in immune system function, regardless of how much stress individuals endure in adulthood.

It’s important to note that depression is considered by some researchers to be an inflammatory disorder based on the fact that anti-inflammatory pharmaceutical and nutraceutical therapies have resulted in varying degrees of symptom improvement,¹² while others reject this idea, citing conflicting results. The inconsistency between research findings may actually be due to variations in study participants’ experiences of childhood trauma. For example, a small study looked at a group of patients diagnosed with major depressive disorder and separated them into 2 groups – those who had experienced at least 1 ACE and those who did not experience trauma during childhood.¹³ Researchers found elevated inflammatory markers in the group that had experienced ACEs relative to the group that had not, suggesting that the apparent inconsistencies in previous studies may be due to there being a subset of depression that is characterized by increased inflammation and is most prevalent in individuals who were affected by adversity during childhood.

Addressing Depression in ACE Survivors

Assessing and addressing depression in patients who have experienced ACEs should involve searching for physiological concerns that may be causing or contributing to depressed mood, including suboptimal thyroid function, reproductive hormone dysregulation, vitamin or other nutrient deficiency, poor lifestyle choices such as dietary imbalances and a lack of exercise, occult infection and/or gastrointestinal dysbiosis, genetic predispositions, poor glycemic control, and all of the other factors that frequently contribute to or masquerade as mood disorders.

We should also assess for adversity during childhood and address HPA axis dysregulation when present. Methods that I use in my practice for addressing HPA axis dysregulation in ACE survivors include the following:

• Adequate sleep. Because the circadian rhythm is responsible for the diurnal secretion of cortisol,¹⁴ factors that negatively impact circadian rhythm, such as disrupted or otherwise inadequate sleep, also affect the HPA axis. I recommend that my patients with depression and a history of ACEs aim for 7-9 hours of sleep per night and, as much as is possible, to avoid napping during the day. For my patients with comorbid insomnia, I make botanical recommendations as appropriate, including hypnotics like Passiflora incarnata (passion flower) and Valeriana officinalis (valerian), and anxiolytic herbs like Eschscholzia californica (California poppy), help them achieve their sleep goals.
• Dietary recommendations. I’ve found an elimination & challenge diet to be extremely helpful in addressing HPA axis dysfunction with my patients who have experienced ACEs. My patients have reported both improved mood and a decrease in symptoms associated with their various other chronic conditions, including improved energy, metabolic improvements, and improvements in joint pain and swelling in those with autoimmune conditions. As a part of my protocol, I have my patients follow an anti-inflammatory, nutrient-dense, well-balanced, and completely plant-based diet for 4 weeks before reintroducing foods in a calculated manner in order to identify any problematic foods.
• Physical activity. Physical exercise is extremely important among ACE survivors with depression, as it has been shown to improve mood and stress resilience¹⁵ and decrease inflammatory biomarkers like C-reactive protein (CRP).¹⁶
• Anti-inflammatory therapy. I also utilize anti-inflammatory herbal therapies with my patients whose objective test results indicate elevations in acute-phase reactants such as CRP. I have achieved favorable results using herbs like Salix alba (white willow), Boswellia spp (frankincense), Curcuma longa (turmeric), and Pelargonium sidoides (umckaloabo).
• Adaptogenic herbal therapy. The research strongly supports the efficacy of adaptogenic herbs in modulating cortisol levels and improving psychiatric concerns such as depression.^17-20 I use adaptogenic herbs to help modulate my patients’ HPA axes, and have seen phenomenal results using Withania somnifera (ashwagandha), Rhodiola rosea (rhodiola), Bacopa monnieri (brahmi), Glycyrrhiza glabra (licorice), and Cordyceps sinensis (cordyceps), depending on my patients’ comorbid conditions.
• Probiotic supplementation. Supplementation with targeted strains of probiotic bacteria, such as Lactobacillus rhamnosus, Lactobacillus helveticus, Lactobacillus casei, Bifidobacterium bifidum, and Bifidobacterium longum, has also been shown to have favorable effects on the HPA axis, decrease inflammation levels, and improve mood,^21-24 all of which are highly relevant in cases of depression that are complicated by a traumatic past. I typically start my patients on a dose ranging from 30 to 100 billion CFU, depending on the degree of dysbiosis present and the degree of HPA axis dysregulation in a given patient.
• Therapy referrals and therapy-based activities. Finally, because depression is extremely difficult to address when caused by deep-rooted, unresolved trauma, I refer my patients for cognitive behavioral therapy (CBT) and/or acceptance and commitment therapy (ACT), or I give them therapy-based activities to do by themselves at home, to help them process their past experiences in a healthy manner.

Looking Beyond Depression

In conclusion, not only do ACEs increase our patients’ risk for depression and other psychiatric concerns; they also significantly increase their risks for chronic diseases and their complications, including autoimmune disease,¹⁰ reproductive concerns,^25-26 type 2 diabetes,²⁷ cardiovascular disease,²⁸ pulmonary concerns,²⁹ and many other conditions.^30-32 Unprocessed trauma and grief frequently serve as a barrier to healing and should be addressed; however, even after the trauma is attended to, ACE-induced HPA axis dysregulation can persist and so should also be addressed. As naturopathic doctors, it is our duty to familiarize ourselves with the effects of ACEs so that we can best serve the patients who entrust us with their care.

References:

1. MacMillan HL, Georgiades K, Duku EK, et al. Cortisol response to stress in female youths exposed to childhood maltreatment: results of the youth mood project. Biol Psychiatry. 2009;66(1):62-68.
2. Ouellet-Morin I, Odgers CL, Danese A, et al. Blunted cortisol responses to stress signal social and behavioral problems among maltreated/bullied 12-year-old children. Biol Psychiatry. 2011;70(11):1016-1023.
3. Faravelli C, Lo Sauro C, Godini L, et al. Childhood stressful events, HPA axis and anxiety disorders. World J Psychiatry. 2012;2(1):13-25.
4. Kuhlman KR. Characterizing the Role of Different Childhood Trauma Subtypes in the Neuroendocrine Functioning of Youth: Implications for Adolescent Depression. 2014. Deep Blue. Available at: https://deepblue.lib.umich.edu/handle/2027.42/107089. Accessed December 17, 2018.
5. Danese A, Pariante CM, Caspi A, et al. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci U S A. 2007;104(4):1319-1324.
6. Kumsta R, Schlotz W, Golm D, et al. HPA axis dysregulation in adult adoptees twenty years after severe institutional deprivation in childhood. Psychoneuroendocrinology. 2017;86:196-202.
7. Heim C, Newport DJ, Bonsall R, et al. Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. Am J Psychiatry. 2001;158(4):575-581.
8. Varghese FP, Brown ES. The Hypothalamic-Pituitary-Adrenal Axis in Major Depressive Disorder: A Brief Primer for Primary Care Physicians. Prim Care Companion J Clin Psychiatry. 2001;3(4):151-155.
9. Segerstrom SC, Miller GE. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull. 2004;130(4):601-630.
10. Dube SR, Fairweather D, Pearson WS, et al. Cumulative childhood stress and autoimmune diseases in adults. Psychosom Med. 2009;71(2):243-250.
11. Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex–linking immunity and metabolism. Nat Rev Endocrinol. 2012;8(12):743-754.
12. Rosenblat JD, Cha DS, Mansur RB, Mcintyre RS. Inflamed moods: a review of the interactions between inflammation and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2014;53:23-34.
13. de Punder K, Entringer S, Heim C, et al. Inflammatory Measures in Depressed Patients With and Without a History of Adverse Childhood Experiences. Front Psychiatry. 2018;9:610.
14. Nicolaides NC, Charmandari E, Chrousos GP, Kino T. Circadian endocrine rhythms: the hypothalamic-pituitary-adrenal axis and its actions. Ann N Y Acad Sci. 2014;1318:71-80.
15. Chen C, Nakagawa S, An Y, et al. The exercise-glucocorticoid paradox: How exercise is beneficial to cognition, mood, and the brain while increasing glucocorticoid levels. Front Neuroendocrinol. 2017;44:83-102.
16. Ford ES. Does exercise reduce inflammation? Physical activity and C-reactive protein among U.S. adults. Epidemiology. 2002;13(5):561-568.
17. Pratte MA, Nanavati KB, Young V, Morley CP. An alternative treatment for anxiety: a systematic review of human trial results reported for the Ayurvedic herb ashwagandha (Withania somnifera). J Altern Complement Med. 2014;20(12):901-908.
18. Olsson EM, von Schéele B, Panossian AG. A randomised, double-blind, placebo controlled, parallel group study of the standardised extract shr-5 of the roots of Rhodiola rosea in the treatment of subjects with stress-related fatigue. Planta Med. 2009;75(2):105-112.
19. Anghelescu IG, Edwards D, Seifritz E, Kasper S. Stress management and the role of Rhodiola rosea: a review. Int J Psychiatry Clin Pract. 2018 Jan 11:1-11. doi: 10.1080/13651501.2017.1417442. [Epub ahead of print]
20. Muszyńska B, Łojewski M, Rojowski J, et al. Natural products of relevance in the prevention and supportive treatment of depression. Psychiatr Pol. 2015;49(3):435-453.
21. de Weerth C. Do bacteria shape our development? Crosstalk between intestinal microbiota and HPA axis. Neurosci Biobehav Rev. 2017;83:458-471.
22. Scott LV, Clarke G, Dinan TG. The brain-gut axis: a target for treating stress-related disorders. Mod Trends Pharmacopsychiatry. 2013;28:90-99.
23. Akkasheh G, Kashani-Poor Z, Tajabadi-Ebrahimi M, et al. Clinical and metabolic response to probiotic administration in patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial. Nutrition. 2016;32(3):315-320.
24. Messaoudi M, Violle N, Bisson JF, et al. Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes. 2011;2(4):256-261.
25. Jacobs MB, Boynton-Jarrett RD, Harville EW. Adverse childhood event experiences, fertility difficulties and menstrual cycle characteristics. J Psychosom Obstet Gynaecol. 2015;36(2):46-57.
26. Smith MV, Gotman N, Yonkers KA. Early Childhood Adversity and Pregnancy Outcomes. Matern Child Health J. 2016;20(4):790-798.
27. Huffhines L, Noser A, Patton SR. The Link Between Adverse Childhood Experiences and Diabetes. Curr Diab Rep. 2016;16(6):54.
28. Su S, Jimenez MP, Roberts CT, Loucks EB. The role of adverse childhood experiences in cardiovascular disease risk: a review with emphasis on plausible mechanisms. Curr Cardiol Rep. 2015;17(10):88.
29. Gilbert LK, Breiding MJ, Merrick MT, et al. Childhood adversity and adult chronic disease: an update from ten states and the District of Columbia, 2010. Am J Prev Med. 2015;48(3):345-349.
30. Hillis SD, Anda RF, Felitti VJ, Marchbanks PA. Adverse childhood experiences and sexual risk behaviors in women: a retrospective cohort study. Fam Plann Perspect. 2001;33(5):206-211.
31. Kajeepeta S, Gelaye B, Jackson CL, Williams MA. Adverse childhood experiences are associated with adult sleep disorders: a systematic review. Sleep Med. 2015;16(3):320-330.
32. Bright MA, Alford SM, Hinojosa MS, et al. Adverse childhood experiences and dental health in children and adolescents. Community Dent Oral Epidemiol. 2015;43(3):193-199.

Janelle Louis, ND, is a licensed naturopathic doctor and the author of the best-selling book, Optimize Your Body, Heal Your Mind. Dr Louis specializes in helping women who have experienced adversity during childhood overcome their risks for psychiatric and autoimmune conditions so they can break the cycle and live their healthiest and best lives. She does so through online health programs at the Mental Health Advocate Spot™ [https://www.mhaspot.com] and through her private practice, Focus Integrative Healthcare™ [https://www.focusih.com], in Overland Park, KS. You can find her on Facebook [https://www.facebook.com/drjanellelouis/] and on YouTube [https://www.youtube.com/channel/UC0mraI062MqQ4b4oybGnV2A].