The ZRT Laboratory Blog

Neurotransmitters, Mood & the Perception of Stress - Part 3

Fri, 01 Jun 2018 11:45:00 -0700

This is part three of Dr. Guilliams' Neurotransmitters & Mood series. Part one can be found here. Part two can be found here.

Monoamines and the HPA Axis

The hypothalamus is directly innervated by neuronal systems that produce neurotransmitters, such as serotonin (5-HT), dopamine and norepinephrine (NE), that are involved in mood regulation and play various other roles in cognitive health. During the acute stress crisis, the mesolimbic dopaminergic reward system is stimulated to help maintain morale. However, during chronic stress or depression, the reward system is down-regulated by stress mediators, resulting in anhedonia.

In early studies, the catecholamine theory (as well as the monoamine hypothesis of depression) of major depression concluded that depression resulted from a deficiency of NE throughout the CNS. This hypothesis was based on studies showing that pharmacological depletion of NE could induce major depression and the antidepressant effects reported by the augmentation of NE activity using MAO and NE uptake inhibitors. This hypothesis served as the foundation for modern biological psychiatry and supported the use of antidepressants for years, though it is being slowly replaced by more comprehensive theories that include HPA axis function through the mechanisms discussed above [1]. Although some forms of depression may be characterized by a deficiency of NE in the CNS, melancholic depression is associated with increased noradrenergic function in the CNS. Research has shown that the secretion of NE is elevated in patients with melancholic depression, rising throughout the night during sleep, and reaching its peak in the morning, when depression is often most intense [2]. Hyperarousal, increased anxiety and insomnia can all be driven by an excess of NE, which correlates with increased activity of the HPA axis.

Hyperarousal, increased anxiety and insomnia can all be driven by an excess of NE, which correlates with increased activity of the HPA axis.

The monoamine deficiency hypothesis also postulates that a deficiency in serotonin and/or dopamine decreases monoaminergic neurotransmission in the CNS, resulting in depression [3]. Monoamine deficiency may be caused by a number of mechanisms that compromise neurotransmission, including inhibition of the enzymes required for norepinephrine, dopamine, and serotonin synthesis, or low levels of the amino acid precursors (tyrosine and tryptophan) for these enzymes. Also, decreased sensitivity of autoreceptors that regulate serotonin function, including 5-HT1A and 5-HT1B, have been identified.

With respect to the perception of stress, serotonin levels may play a vital role as serotonin has been connected to regulating stress sensitivity [4]. Serotonin (5-hydroxytryptamine) has an inhibitory action in the brain and is directly involved in the regulation of emotion, behavior and aggression. In both animal and human studies, serotonin deficiency has been linked to exacerbating the stress cycle by contributing to increased aggression [5]. In addition to regulating mood and stress sensitivity, serotonin regulates the appetite, body temperature and pain sensation. Serotonin is converted into the sleep-regulating hormone melatonin in the pineal gland. Serotonin also supports mood and behavior, and decreases pain sensitivity by increasing β-endorphin levels [6].

Mutations in 5-HT system genes have been reported in patients suffering from anxiety disorders and severe impulsivity [7]. Reduced levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been found in cerebrospinal fluid measurements of patients with impulsive-aggressive behavior, suggesting serotonin deficiency. The enzyme tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme for brain serotonin synthesis. A polymorphism in THP2 gene, first identified in elderly patients with depression, has been reported to decrease 5-HT synthesis in both in vitroand in vivo models [8].

Current antidepressant therapy that inhibits the reuptake of serotonin and norepinephrine is based on the monoamine deficiency hypothesis. In recent decades, selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) have become the first-line drug treatment option for depression. SSRIs and SNRIs have replaced tricyclic antidepressants (TCA) and monoamine oxidase inhibitors (MAOI) due to fewer side effects. However, it has been estimated that only about 50-70% of patients respond to these medications, indicating a more complex mechanism for depression, as described above. A significant limitation of these medications is that, while they may inhibit the reuptake of neurotransmitters like serotonin, norepinephrine and to a lesser extent dopamine, they do not increase net levels of neurotransmitters within the nerve cells or throughout the CNS. This may limit the effectiveness of these medications in patients with extremely low levels of serotonin, norepinephrine or dopamine.

Supplementing 5-HTP

Serotonin is produced endogenously from the essential amino acid L-tryptophan. L-tryptophan is converted into 5-hydroxytryptophan (5-HTP), the direct intermediate for serotonin production. 5-HTP is produced commercially from the seeds of the African plant Griffonia simplicifolia and has been used clinically for over 30 years, due to its ability to increase serotonin levels in the brain [9]. Administration of 5-HTP has been associated with a significant increase in CSF fluid levels of 5-hydroxyindolacetic acid, the primary metabolite of serotonin [10].

Use of 5-HTP as a supplement is advantageous in that it bypasses the conversion of L-tryptophan into 5-HTP by the enzyme tryptophan hydroxylase. The activity of tryptophan hydroxylase can be inhibited by high stress levels, insulin resistance and vitamin B6 or magnesium deficiency [11]. The transport across the blood-brain barrier (BBB) requires L-tryptophan to be bound to a transport carrier. This step involves competition with other amino acids (tyrosine, phenylalanine, valine, leucine and isoleucine) for entry across BBB, which is consequential because most protein-containing foods consist of small amounts of L-tryptophan and larger proportions of these competitive amino acids. 5-HTP is advantageous because it does not require a transport carrier, does not compete with other amino acids for entry, and can cross the BBB. Studies on the use of 5-HTP for depression have been conducted since the 1970s. These included unipolar depression, and bipolar, neurotic and psychotic depression using a number of different study designs.

In a 2013 study conducted by Janqid et al., the effects of 5-HTP versus the antidepressant fluoxetine were studied in a randomized, double-blind study [12]. Sixty patients with a history of depression were recruited and given HAM-D assessments at baseline and after two, four and eight weeks. 5-HTP capsules was given as 150 mg in three divided dosages during the first 2 weeks and then the dose was doubled (300 mg) after the second week. The dose was further increased to 400 mg in three divided dosages after the fourth week. Fluoxatine doses were similarly stepped up from 20 mg to 30 and 40 mg respectively. Both treatment groups showed significant and nearly equal reduction in HAM-D scores beginning at week two and continuing until the end of the trial. Twenty-two patients (73.33%) in the 5-HTP group and 24 patients (80%) in the fluoxetine group responded to the therapy.

5-HTP has also been shown to be helpful in relieving panic attacks. In a study by Schruers et al., 24 panic disorder patients and 24 healthy subjects were given either 200 mg of 5-HTP or placebo while being subjected to a 35% carbon dioxide panic challenge. 5-HTP significantly improved reaction to the challenge in panic disorder patients, but not in the healthy volunteers. This included measures of subjective anxiety, panic symptoms scores and frequency of panic attacks. The study authors concluded that 5-HTP administration increased subject serotonin levels, which played a vital role in reducing panic. Previous studies had already shown that lower serotonin levels due to tryptophan depletion increased the vulnerability of panic disorder when using the carbon dioxide panic challenge [13].

For more on stress and depression, refer to Dr. Guilliams’ book The Role of Stress and the HPA Axis in Chronic Disease Management.

Related Resources

References

[1] Roy A, Campbell MK. A unifying framework for depression: bridging the major biological and psychosocial theories through stress. Clin Invest Med.2013 Aug 1;36(4):E170-90.

[2] Wong ML, Kling MA, Munson PA, et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. PNAS (USA). 2000; 97(1):325-330.

[3] Perovic B, Jovanovic M, Milikovic B, et al. Getting the balance right: Established and emerging therapies for major depressive disorders. NeuropsychiatrDis Treat 2010; 6:343-364.

[4] Durand D, Pampillo M, Caruso C, Lasaga M. Role of metabotropic glutamate receptors in the control of neuroendocrine function. Neuropharmacology.2008 Sep;55(4):577-83.

[5] Morrison TR, Melloni RH Jr. The role of serotonin, vasopressin, and serotonin/vasopressin interactions in aggressive behavior. Curr Top Behav Neurosci.2014;17:189-228.

[6] Pizzorno JE, Murray MT. (2013) Textbook of Natural Medicine. St. Louis, MO. Elsevier Inc.

[7] Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science1996; 274:1527-1531.

[8] Sachs BD, Rodriguiz RM, Siesser WB, et al. The effects of brain serotonin deficiency on behavioural disinhibition and anxiety-like behaviour following mild early life stress. Int J Neuropsychopharmacol 2013; 16(9):2081-2094.

[9] Turner EH, Loftis JM, Blackwell AD. Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan. Pharmacol Ther. 2006 Mar;109(3):325-38. 2011; 77(3): 368-70.

[10] Yound SN, Gauthoer AM. Effect of tryptophan administration on tryptophan, 5-hydroxyindolacetic acid and indoleacetic acid in human lumbar and cisternal cerebrospinal fluid. J Neurol Neurosurg Psychiatry 1981; 74(3):695-700.

[11] Birdsall TC. 5-hydroxytryptophan: a clinically-effective serotonin precursor. Alt Med Rev 1998; 3(4):271-280.

[12] Janqid P, Malik P, Sinqh P, Sharma P, Gulia AK. Comparative study of efficacy of l-5-hydrocytryptophan and fluoxetine in patients presenting with first depressive episode. Asian J Psychiatr 2013; 6(1): 29-34.

[13] Schruers K, van Diest R, Overbeek T, et al. Acute L-hydroxytryptophan administration inhibits carbon-dioxide induced panic disorder in panic disorder patients. Psychiatry Res 2002;113:237-243.

Neurotransmitters, Mood & the Perception of Stress - Part 2

Fri, 18 May 2018 09:03:00 -0700

This is part two of Dr. Guilliams' Neurotransmitters & Mood series. Part one can be found here. Part three can be found here.

Glutamate, GABA & Neurosteroid Activation

Glutamate (L-glutamic acid) and GABA (gamma-aminobutyric acid) are, respectively, the principal excitatory and inhibitory neurotransmitters in the CNS and play a significant role in HPA axis function and mood [1]. These two amino acid-based neurotransmitters account for over 50% of the synapses in the brain, while the monoamines (serotonin, norepinephrine and dopamine) account for only about 5% [2].

Glutamate is required for synaptic transmission and plasticity, and learning and memory. However, abnormal function of the glutamatergic system can lead to neurotoxicity, and has been implicated in the pathophysiology of several disorders, including amyotrophic lateral sclerosis (ALS), epilepsy, Huntington’s disease, Alzheimer’s disease, schizophrenia, depression and anxiety disorders [3].

Glutamate signaling from the prefrontal cortex and hippocampus, through activation of N-methyl-D-aspartate (NMDA) receptors on the parvocellular neurons of the paraventricular nucleus, increases HPA activation [4]. Subjects with depression (MDD) and bipolar disorder have notably higher glutamate levels, perhaps linking glutamate excitotoxicity with depression-related HPA axis activation. It is not known why glutamate levels (plasma and brain) are elevated in depressed subjects, but the potential to modulate glutamate signaling remains a promising area of research.

NMDA receptors are primarily responsible for the regulation of glutamate activity. Abnormalities in NMDA receptor expression and binding affinities have been identified in patients with mood disorders [5]. Alterations in glutamate binding through the glycine binding site on the NMDA receptor were identified in the frontal cortex of age-matched, post-mortem and interval-matched suicide victims [6]. NMDA antagonists have been found to have antidepressant activity, while chronic antidepressant administration, including monoaminergic-based and trycyclic antidepressants, regulate NMDA receptor function and expression [7]. Omega-3 fatty acids, considered to be helpful in some subjects with depression, have been shown to affect glutaminergic neurotransmission within the hippocampus [8].

Magnesium & Zinc Modulation

Lower plasma GABA levels have been reported in depressed and bipolar patients - levels which persist even after treatment with antidepressants.

Magnesium deficiency causes glutamate receptor (N-methyl-D-aspartate) calcium channels to open, resulting in an increase in glutaminergic activity and neuronal dysfunction. Both zinc and magnesium appear to modulate glutamate to nontoxic levels, preventing damage to the hippocampus and amygdala [9].

Studies in depressed subjects suggest a higher likelihood of low magnesium, and find some benefits associated with the use of supplemental magnesium, though more research is needed to make specific dose recommendations [10]. The role of magnesium is important enough in all metabolic processes that clinicians should consider measuring magnesium levels in depressed subjects and those with suspected HPA axis abnormalities. Clinicians should also be aware that most multivitamin-mineral products contain very little magnesium, or contain poorly absorbable forms of magnesium, such as MgO.

Serum zinc is also notably lower in depressed subjects [11]. Zinc supplementation (usually 25 mg zinc/day) has been used in several clinical trials with depressed subjects (often with antidepressant drugs) with some benefits, even when zinc levels are not measurably low [12].

GABA & GABAergic Activities

Balancing excitotoxic levels of glutamate is of vital importance in relieving depressive and anxiety disorders, as well as certain severe neurological conditions. GABA is the primary inhibitory neurotransmitter within the CNS, serving as an important counterpart to the excitatory activities of glutamate. More specifically, GABA has been identified as the dominant inhibitory neurotransmitter within the hypothalamic paraventricular nucleus (PVN) where it exerts significant inhibitory tone upon HPA axis function [13]. Lower plasma GABA levels have been reported in depressed and bipolar patients, levels which persist even after treatment with antidepressants [1]. Hypoactive GABAergic transmission within the PVN is therefore unable to properly down-regulate the HPA axis.

Increasing GABAergic activity can be accomplished by several non-pharmacological means (benzodiazepines are potent modulators of the GABA-A receptor, while gabapentin is a structural analog of GABA). A wide variety of natural ingredients, particularly flavonoid compounds are being explored for their GABAergic activities [14] [15]. Food sources of GABA are limited, but can be found in some fermented foods, such as kimchi, kefir, miso, sauerkraut, tempeh and some yogurts. Clinical studies using food-derived GABA with HPA axis-related outcomes have not been reported. PharmaGABA^®, a naturally-sourced form of GABA purified from a fermentation process using the bacterial Lactobacillus hilgardii, has been investigated in humans, specifically examining its anxiolytic and immune-supporting effects during stress exposure.

In a double-blind study using 13 healthy volunteers, electroencephalogram (EEG) readings were obtained after 100 mg of PharmaGABA^® were administered in distilled water [16]. These results were compared to distilled water alone (placebo) and distilled water containing 200 mg of L-theanine on separate days (7 day intervals). EEG waves were recorded at 0, 30 and 60 minutes after each administration. PharmaGABA^®produced a statistically significant increase in alpha waves, as well as a significant decrease in beta waves, when compared to the placebo. A significantly higher alpha to beta brain wave ratio was also found, even when compared to L-theanine administration.

In a separate study, Abdou et al. examined the effects of PharmaGABA^® using eight healthy volunteers with a history of acrophobia. Salivary IgA levels were measured as a biomarker for stress and immune response. Each participant was randomly assigned to either an experimental or placebo group. The participants crossed an extended pedestrian bridge while saliva samples were collected before crossing and at the middle and end of the bridge. The placebo group was found to have a decrease in IgA levels (decreased immune response) while the PharmaGABA^® group showed significantly higher levels. While additional studies of a larger size would help to demonstrate the immune and anxiolytic effects of GABA supplementation, these studies do point to the potential benefits of PharmaGABA^® in HPA-related stress, worry and anxiety following one hour of administration [17].

Neurosteroids

Some of the most potent modulators of the GABA-A receptor are steroid compounds known as neurosteroids [18]. Neurosteroids include a wide-range of pregnenolone-derived compounds, including DHEA, DHEA-S, pregnenolone-S, allopregnanolone (ALLO), and allotetrahydrodeoxycorticosterone (ALLO-THDOC). As the name implies, neurosteroids are compounds that have receptor-mediated neuromodulatory activities, although some clearly have other functions as well (e.g., DHEA acts as a precursor to androgens). There is some dispute about where the majority of these compounds are derived. They can be made in the brain, but several can enter the brain from the circulation (presumably made in the adrenal gland). Little is known about the regulation of their synthesis.

ALLO, the major neurosteroid in the brain, and ALLO-THDOC modulate feelings of depression and anxiety, as well as HPA axis stress. They affect several different pathways, including the GABA, glutamate, progesterone, and dopamine pathways [19] [20]. Stress-induced reduction in the levels of ALLO and ALLO-THDOC lowers the inhibitory GABAergic transmission, allowing the HPA axis to become overactive. This blunted neurosteroid signaling is considered to be a critical mechanism in the vicious cyclical pathology of recurrent depression. In several studies, both plasma and CSF ALLO concentrations have been found to be decreased in patients with MDD and anxiety [21] [22]. In patients with depression, an inverse relationship between ALLO concentrations and the severity of depressive illness has been reported [23]. In animal studies, pretreatment of rats with ALLO, ALLO-THDOC or progesterone has been shown to attenuate stress-induced increases in plasma ACTH and cortisol [24].

The use of supplemental DHEA and pregnenolone is common in clinical practice today. Many clinicians believe that the function of these hormones (usually consumed orally or sublingually) is primarily within the adrenal glands or in peripheral target tissue. However, in the case of pregnenolone specifically, oral doses appear to have demonstrable effects on neurological function (i.e. as a neurosteroid). In other words, oral pregnenolone appears to function as a precursor for CNS pregnenolone-S, and perhaps other neurosteroids like ALLO or ALLO-THDOC. For instance, ALLO serum levels have been reported to triple two hours after oral administration of 400 mg pregnenolone [25]. DHEA is also capable of passing into the CNS from the blood, and may also contribute neurosteroid effects [26].

For more on stress and depression, refer to Dr. Guilliams’ book The Role of Stress and the HPA Axis in Chronic Disease Management.

Related Resources

References

[1] Gao SF, Bao AM. Corticotropin-releasing hormone, glutamate, and γ-aminobutyric acid in depression. Neuroscientist. 2011 Feb;17(1):124-44.

[2] Leonard BE. Psychopathology of depression. Drugs Today (Barc). 2007 Oct;43(10):705-16.

[3] Sanacora G, Zarate CA, Krystal JH, Manjii HK. Targeting the glutamatergic system to develop novel, improved therapeutic for mood disorders. Nature2008; 7:426-437.

[4] Durand D, Pampillo M, Caruso C, Lasaga M. Role of metabotropic glutamate receptors in the control of neuroendocrine function. Neuropharmacology.2008 Sep;55(4):577-83.

[5] Ohgi Y, Futamura T, Hashimoto K. Glutamate Signaling in Synaptogenesis and NMDA Receptors as Potential Therapeutic Targets for Psychiatric Disorders. Curr Mol Med. 2015;15(3):206-21.

[6] Nowak G, Ordway GA, Paul IA. Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims. Brain Res 1995; 675: 157-164.

[7] Nowak G, Trulias R, Layer RT, et al. Adaptive changes in the N-methyl-D-aspartate receptor complex after chronic treatment with imipramine and 1-aminocyclopropanecarboxylic acid. J Pharmacol Exp Ther 1993; 265:1380-1386.

[8] Hennebelle M, Champeil-Potokar G, Lavialle M, Vancassel S, Denis I. Omega-3 polyunsaturated fatty acids and chronic stress-induced modulations of glutamatergic neurotransmission in the hippocampus. Nutr Rev. 2014 Feb;72(2):99-112.

[9] Prior PL, Galduroz JC. Glutaminergic hyperfunctioning during alcohol withdrawal syndrome: therapeutic perspective with zinc and magnesium. Med Hypothesis 2011; 77(3): 368-70.

[10] Derom ML, Sayón-Orea C, Martínez-Ortega JM, Martínez-González MA. Magnesium and depression: a systematic review. Nutr Neurosci. 2013 Sep;16(5):191-206.

[11] Siwek M, Dudek D, Schlegel-Zawadzka M, et al. Serum zinc level in depressed patients during zinc supplementation of imipramine treatment. J Affect Disord. 2010 Nov;126(3):447-52.

[12] Nowak G. Zinc, future mono/adjunctive therapy for depression: Mechanisms of antidepressant action. Pharmacol Rep. 2015 Jun;67(3):659-662.

[13] Cullinan WE, Ziegler DR, Herman JP. Functional role of local GABAergic influences on the HPA axis. Brain Struct Funct. 2008 Sep;213(1-2):63-72.

[14] Hanrahan JR, Chebib M, Johnston GA. Flavonoid modulation of GABA(A) receptors. Br J Pharmacol. 2011 May;163(2):234-45.

[15] Nilsson J, Sterner O. Modulation of GABA(A) receptors by natural products and the development of novel synthetic ligands for the benzodiazepine binding site. Curr Drug Targets. 2011 Oct;12(11):1674-88.

[16] Abdou AM, Higashiguchi S, Horie K, et al. Relaxation and immunity enhancement effects of γ-aminobutyric acid (GABA) administration in humans. BioFactors 2006;26: 201-208.

[17] Alramadhan E, Hanna MS, Hanna MS, Goldstein TA, Avila SM, Weeks BS. Dietary and botanical anxiolytics. Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2012;18(4):RA40-RA48.

[18] Crowley SK, Girdler SS. Neurosteroid, GABAergic and hypothalamic pituitary adrenal (HPA) axis regulation: what is the current state of knowledge in humans? Psychopharmacology (Berl). 2014 Sep;231(17):3619-34.

[19] Bali A, Jaggi AS. Multifunctional aspects of allopregnanolone in stress and related disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2014 Jan 3;48:64-78.

[20] Eser D, Schüle C, Baghai TC, Romeo E, Rupprecht R. Neuroactive steroids in depression and anxiety disorders: clinical studies. Neuroendocrinology.2006;84(4):244-54

[21] Esder D, Romeo E, Baghai TC, di Michele F, et al. Neuroactive steroids as modulators of depression and anxiety. Neuroscience 2006; 138:1041-1048.

[22] Strohle A, Romeo E, Hermann B, et al. Concentrations of 3alpha-reduced neuroactive steroids and their precursors in plasma of patients major depression and after clinical recovery. Biol Psychiatry 1999;45: 274-277.

[23] Nappi RE, Petraglia F, Luisi S, et al. Serum allopregnanolone in women with postpartum "blues". Obstet Gynecol 2001; 97:77-80.

[24] Owens MJ, Ritchie JC, Nemeroff CB. 5 alpha-pregane-3 alpha, 2-diol-20-one (THDOC) attenuates mild stress-induced increases in plasma corticosterone via a non-glucocorticoid mechanism: comparison with alprazolam. Brain Res 1992; 573:353-355.

[25] Sripada RK, Marx CE, King AP, et al. Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits. Biol Psychiatry. 2013 Jun 1;73(11):1045-53.

[26] Sripada RK1, Welsh RC, Marx CE, Liberzon I. The neurosteroids allopregnanolone and dehydroepiandrosterone modulate resting-state amygdala connectivity. Hum Brain Mapp. 2014 Jul;35(7):3249-61.

Neurotransmitters, Mood & the Perception of Stress

Fri, 06 Apr 2018 10:07:00 -0700

This is part one of Dr. Guilliams' Neurotransmitters & Mood series. Part two can be found here. Part three can be found here.

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. [1]

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. [2]

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. [3] 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. [4]

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. [4] 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. [5] 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. [6] 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). [7] Furthermore, GR regulation is now considered to be a major mechanism for several classes of antidepressants. [8]

Along with GR-related feedback inhibition common to depressive disorders, increased inflammatory signaling is also considered to drive the depression/HPA axis activation. [9] 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). [10] Nonetheless, blunted feedback inhibition and inflammatory signaling are considered to be major pathways that bridge depression with HPA axis dysfunctions. [11]

For more on stress and depression, refer to Dr. Guilliams’ book The Role of Stress and the HPA Axis in Chronic Disease Management.

Related Resources

References

[1] 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.

[2] Data from Anxiety and Depression Association of America website: www.adaa.org/about-adaa/press-room/facts-statistics accessed 5-12-2015.

[3] 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.

[4] Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008 Sep;31(9):464-8.

[5] 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.

[6] 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

[7] 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

[8] 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.

[9] 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.

[10] 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.

[11] 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

Re-assessing the Notion of "Pregnenolone Steal"

Wed, 21 Jun 2017 13:03:00 -0700

When clinicians measure salivary cortisol and DHEA (DHEA-S) to assess stress and HPA axis function, it is common to find DHEA levels below the reference range in a number of individuals. A common explanation for the depletion of DHEA and other hormones (e.g., progesterone, testosterone) due to chronic stress is the phenomenon known as "pregnenolone steal."

The pregnenolone steal notion states that since all steroid hormones use pregnenolone (derived from cholesterol) as a precursor, the elevated secretion of cortisol caused by acute or chronic stress will inevitably result in less available pregnenolone to serve as a precursor for the production of DHEA and other down-stream hormones.

In other words, according to this theory, the need for cortisol synthesis "steals" pregnenolone away from other hormone pathways, reducing the potential synthesis and secretion of other necessary hormones, resulting in some of the pathophysiological changes related to stress. While a rise in cortisol levels and a concomitant drop in DHEA is one of the clinical characteristics of early and mid-stage chronic stress progression, this phenomenon is not caused by diminished adrenal pregnenolone availability or "pregnenolone steal." The most obvious reason is the fact that the conversion of cholesterol to pregnenolone occurs in the mitochondria of each respective adrenal cortex cell type that is responsible for producing these hormones.

Simply put, there is no known adrenal pool of pregnenolone for one cell to steal away from another, and no known mechanism has been described that could facilitate the transfer of pregnenolone between the mitochondria of different cells (in this case, from the mitochondria of cells within the zona reticularis to those within the zona fasciculata). Unfortunately, the most common figures used to teach steroidogenesis show a common pathway and typically do not specify the differential regulation of available enzymes between different steroidogenic tissues. This leads many to incorrectly assume there is a single "pool" of pregnenolone available for all steroid hormone synthesis within the adrenal. A much better way to teach this is to show the different enzymes available to each cell within the adrenal cortex, showing that each is capable of converting cholesterol to pregnenolone; then to the various needed hormones. The following figure is excerpted from The Standard Road Map, The Role of Stress and the HPA Axis in Chronic Disease Management. It demonstrates a better way to teach this concept, one that avoids showing a single "pool" of pregnenolone for all down-stream hormones.

In addition, the ACTH-driven adrenal synthesis of cortisol is orders of magnitude higher than that of DHEA, and fluctuates radically within a 24-hour period. If there were an adrenal “pregnenolone pool” that contained enough pregnenolone precursors for elevated cortisol production in the morning (or during stress), this "pool" would then also be available for the much smaller amount of needed DHEA production when cortisol synthesis drops even a little.

Research has shown the control of adrenal hormone output is regulated mostly by cell-specific enzyme concentrations and external signals coming from outside the adrenal gland.

Finally, as decades of steroidogenesis research has shown, the control of adrenal hormone output is regulated mostly by cell-specific enzyme concentrations and external signals coming from outside the adrenal gland (See our latest book for specifics). What, then, does this mean in relation to cortisol and DHEA output which, when measured, appears to confirm this phenomenon? What about the role of oral pregnenolone therapy for supporting adrenal DHEA production? Well, it’s a bit complicated. While HPA axis stress and subsequent cortisol synthesis and secretion may be related to the acceleration of reduced DHEA production (i.e., a stress-induced down-regulation of DHEA), this relationship is facilitated by regulatory processes (e.g., feedback inhibitions, receptor signaling, genomic regulation of enzymes, etc.), not an intra-adrenal depletion of pregnenolone as a precursor to downstream hormones. For instance, experimentally induced hyperglycemia and hyperinsulinemia has been shown to affect DHEA and androstenedione production in human subjects. [1] [2]

In one study of poorly-controlled type 2 diabetic subjects with elevated cortisol and low DHEA levels, the enzyme necessary for DHEA formation in the zona reticularis (17,20 lyase) was shown to limit the production of DHEA. The enzyme activity was corrected (along with near normalization of cortisol, DHEA and DHEA-S levels) after six months of diet or pharmacotherapy to improve blood glucose control. [3] Additionally, cell-culture studies suggest that under inflammatory stress (IL-4 and other cytokines), the zona reticularis will down-regulate DHEA production when ACTH is present. [4] [5] These and many other factors (e.g., aging) are likely the driving influences affecting the dynamic relationship between cortisol (activated by the HPA axis) and measured DHEA and/or DHEA-S levels. By re-assessing the specific mechanisms that drive the stress-related changes in adrenal hormone output, and moving away from older and incorrect explanations, we are able to seek (and perhaps address) the various signals that are actually responsible for modulating adrenal hormone secretion during the progression of chronic stress.

If you are interested in learning more about this subject and how oral pregnenolone and DHEA may improve outcomes in subjects with stress-related dysfunctions, please consider purchasing The Role of Stress and the HPA Axis in Chronic Disease Management.

Related Resources

References

[1] Boudou P, Sobngwi E, Ibrahim F et al. Hyperglycaemia acutely decreases circulating dehydroepiandrosterone levels in healthy men. Clin Endocrinol (Oxf). 2006 Jan;64(1):46-52.

[2] Vásárhelyi B, Bencsik P, Treszl A, et al. The effect of physiologic hyperinsulinemia during an oral glucose tolerance test on the levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) in healthy young adults born with low and with normal birth weight. Endocr J. 2003 Dec;50(6):689-95.

[3] Ueshiba H, Shimizu Y, Hiroi N et al. Decreased steroidogenic enzyme 17,20-lyase and increased 17-hydroxylase activities in type 2 diabetes mellitus. Eur J Endocrinol. 2002 Mar;146(3):375-80.

[4] Woods AM, Judd AM. Interleukin-4 increases cortisol release and decreases adrenal androgen release from bovine adrenal cells. Domest Anim Endocrinol. 2008 May;34(4):372-82.

[5] Woods AM, McIlmoil CJ, Rankin EN. Et al. Leukemia inhibitory factor protein and receptors are expressed in the bovine adrenal cortex and increase cortisol and decrease adrenal androgen release. Domest Anim Endocrinol. 2008 Aug;35(2):217-30.

Is It Adrenal Fatigue? Reassessing the Nomenclature of HPA Axis Dysfunction.

Tue, 25 Apr 2017 09:54:00 -0700

Sometimes, when we endeavor to understand and describe complicated medical topics, there is a temptation to find a simple explanation to cut through the complexity. These explanations can help bridge the knowledge gap for a while, but as our knowledge grows, they lose some of their original usefulness (e.g., the notion of “good” and “bad” cholesterol).

In some cases, those over-simplified explanations actually become a hindrance to helping clinicians and patients understand the important mechanisms and solutions related to chronic conditions. The use of terms like “adrenal fatigue” and “adrenal exhaustion” to summarize the complex dysfunctions related to the stress response is one such explanation. Though these terms have helped dispel the notion that only extreme issues related to adrenal function (Addison’s disease or Cushing’s disease) are of clinical importance, and have become surrogate descriptions for stress-related outcomes, they should now be replaced by more accurate and medically appropriate terms, like HPA axis dysfunction, adrenal insufficiency, or where applicable, hypocortisolism.

The Stress Response System(s). Beginning in the brain, stress signals are communicated by direct innervation to the adrenal medulla to cause a nearly immediate release of catecholamine’s (the fight or flight response) and through neuro-hormone signals within the HPA axis that influence the release of cortisol, DHEA(S) and aldosterone.

Does Nomenclature Reassessment Matter?

While it is true that the most common laboratory method to assess the function of the HPA axis is through the measurement of hormones secreted by the adrenal glands, primarily cortisol and DHEA(S), the mechanisms that control the level of these hormones resides mostly outside of the adrenal gland. Low cortisol and DHEA(S) levels may indeed be related to chronic stress, but as a result of HPA axis adaption (down-regulation) to protect tissues from excess cortisol, have little to do with the inherent capability of the adrenal gland to produce these hormones (see adrenal insufficiency below). While many clinicians (and laboratories) still refer to this as “testing the adrenals,” it is much more accurate to say that such testing is assessing the status of the HPA axis using adrenal hormone measurements as surrogate markers. So, why does this nomenclature reassessment matter?

Using descriptive and accurate terms helps clinicians and patients better understand the pathophysiology caused by stress and the stress response system.

First of all, using descriptive and accurate terms helps clinicians and patients better understand the pathophysiology caused by stress and the stress response system. In most cases, issues related to perceived stress, glycemic control, circadian rhythm, cortisol feedback control (in the hypothalamus and/or pituitary), inflammatory signaling, or tissue-specific glucocorticoid effects will have much more to do with a treatment protocol than direct support of adrenal function.

For instance, many adaptogenic herbs and nutrients that were once thought to function primarily by supporting adrenal function have been shown to have mechanism that modulate non-adrenal HPA axis or glucocorticoid signaling functions. Related to this is the ability of the clinician to interface appropriately with the vast amount of literature that describes patient outcomes related to stress and HPA axis function. The term “adrenal fatigue” is virtually absent from the peer-reviewed literature and has even caused the Endocrine Society to warn the public against the diagnostic “myth” of adrenal fatigue and to cast suspicion upon clinicians using such terms. While I generally agree with the Endocrine Society that the term “adrenal fatigue” is problematic, I do not agree with them that there is little evidence to connect chronic stress with adverse health outcomes, or that testing adrenal hormone output is of no value beyond diagnosing extreme adrenal disease conditions.

An increasing body of research links a variety of chronic dysfunctions with specific patterns of adrenal hormone output (basal or provoked). By avoiding the use of oversimplified (and incorrect) terminology to describe these relationships and instead choosing more appropriate descriptive terms, the clinician will enhance the credibility of this important phenomenon and be better equipped to incorporate therapies that address the complexity of the whole stress response system.

What are More Appropriate Terms?

HPA Axis Dysfunction (or Maladaption): This term is much more appropriate to describe the many consequences that link stress (allostasis) with the myriad of measurable negative outcomes related to the stress response. The majority of these outcomes can be linked in some manner to processes controlled by the HPA axis. Alternatively, some refer to these as “disorders of the stress system” or the “consequences of the maladaption to stress.”

Hypocortisolism: This is the most descriptive term to use when measured cortisol is well below the laboratory reference range. Still, it is a relative term and does not necessarily implicate dysfunction or “fatigue” of the adrenal gland. Extreme hypocortisolism is associated with Addison’s disease and other forms of primary and secondary adrenal insufficiency. Reduced HPA axis function resulting in low cortisol levels is common in PTSD, fibromyalgia, chronic fatigue syndrome, certain affective disorders, and individuals with high psychosocial “burnout.” Other specific terms for different stress-related HPA axis phenomena include hypercortisolism, loss of HPA circadian function, and low circulating DHEA(S).

Adrenal Insufficiency: This is a clinical manifestation that results in a deficient production or action of glucocorticoids, a condition that has potential life-threatening consequences. Primary adrenal insufficiency (i.e., Addison’s disease) describes diseases intrinsic to the adrenal cortex primarily caused by autoimmune adrenalitis. Secondary adrenal insufficiency relates to insufficient pituitary ACTH or intrinsic defects in the adrenal responsiveness to ACTH. Tertiary adrenal insufficiency results from impaired synthesis of hypothalamic CRH or AVP. The most common cause of tertiary adrenal insufficiency is the chronic use of exogenous glucocorticoids (pharmacotherapy), leading to the suppression of hypothalamic secretions of CRH. True adrenal insufficiency will almost always require hydrocortisone replacement therapy (often life-long). For a complete review of the etiology, pathophysiology, clinical presentation, diagnosis and treatment approaches to adrenal insufficiency, see Charmandari, et al.¹

¹Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014 Jun 21;383(9935):2152-67.