Anxiety, Depression, and Insomnia: A Look at Potential Physiological Mediators
Dr Carrie Decker ND, reviews these common conditions and explores strategies and treatments.
Supporting patients who experience anxiety, depression, insomnia often is a long arduous task for both the patient and provider. Although these conditions have standard labels, there often are many changing factors as contributors, never mind that supplements which have been introduced also can change the playing field. With the information that is now available with genetic assessment, specific nutrient supplementation or nutrient forms such as methylated folate or methylcobalamin are more thoughtfully directed at supporting the biological pathways which impact neurotransmitter balance and symptoms such as these. Even though these nutrients may help facilitate enzymatic function and neurotransmitter metabolism, it still is worthwhile to consider other aspects of physiology which may be dysfunctional in these clinical settings, and how supplemental therapies may be directed at addressing them.
A dysfunctional HPA axis
Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and increased basal cortisol levels are commonly found in patients with depression. Studies have shown that there is a reduced sensitivity of the glucocorticoid receptor at the level of the hypothalamus and pituitary, leading to impaired negative feedback as demonstrated by the dexamethasone suppression test., Animal studies have shown that cortisol inhibits melatonin synthesis in settings of stress, while human studies showing similar effects with prednisolone therapies corroborate this finding. Given these findings, it may not be surprising that sleeping difficulties are associated with depression. On the other hand, in long-standing anxiety disorders, a lower cortisol awakening response has been observed, although findings from studies investigating total cortisol response are inconsistent. None-the-less, sleep difficulties are common with anxiety disorders and associated with descriptions such as “active brain” or “difficulty turning off,” i.e. mental activity or worrying.
Are brain wave patterns to blame?
The alpha rhythm of brain wave patterns, known as alpha waves, predominantly occur during wakeful relaxation with closed eyes, and are present during activities such as meditation. Mixed findings exist concerning the alpha wave activity in conditions of anxiety, depression, and insomnia likely due to the existence of slower and faster alpha waves, different regions of centralization, and other coexisting conditions., Interestingly, alpha wave activity also may be inversely associated with systemic cortisol levels, as a study of individuals practicing yoga suggests. In this study of seasoned yoga practitioners, it was found that during their yoga practice alpha wave activity increased, associated with a decrease in cortisol. An increase in alpha wave activity overall is associated with an alert yet relaxed state and improved concentration, both of which are often impacted in depression and anxiety.
A glutamate or GABA issue?
Neurotransmitters most broadly discussed in relation to anxiety and depression are serotonin, dopamine, and norepinephrine. However, other neurotransmitters such as glutamate and γ-aminobutyric acid (GABA) also play an important role. Glutamate receptor subtypes have been shown to modulate excitability associated with anxiety, while in depression, a hyperfunctioning glutaminergic system also may be an issue., Treatment with glutaminergic receptor antagonists such as ketamine or memantine have been shown to have positive effects in both conditions, including treatment resistant depression. Increased inflammation has been observed to co-exist in individuals who are responsive to glutamate antagonists, and inflammatory cytokines have been shown to affect glutamate metabolism. Concentrations of GABA, an inhibitory neurotransmitter, have been shown to be lower in major depressive disorder, however the impact of GABA-promoting pharmaceutical agents on depression varies. In individuals with post-traumatic stress disorder (PTSD), lower levels of GABA were found in the insular cortex, a region of the brain associated with emotional response, and the lower insula GABA levels were associated with significantly higher trait and state anxiety. Lower GABA concentrations in individuals with PTSD have also been shown to be associated with poor sleep quality. Meta-analysis of individuals with PTSD, social anxiety disorder, and specific phobias have also shown greater activity in regions of the insula and amygdala, the regions of the brain associated with an emotional responses such as fear in the presence of threatening stimuli. GABA, as an inhibitory neurotransmitter, is one of the mediators responsible for reducing the response to fear or anxiety-provoking stimuli.
What about oxidative stress?
Increased oxidative and nitrosative stress has been shown to contribute to depression via numerous mechanisms. Individuals with unipolar and bipolar depression have been observed to have increased levels of markers of oxidative damage such as malondialdehyde and 8-iso-prostaglandin F2, markers of oxidative damage to lipids., Lipid peroxidation and oxidative damage are associated with cellular membrane fluidity and mitochondrial dysfunction, which also may play a role in the pathogenesis of depression. Increased oxidative stress is inherently associated with inflammation, and perhaps not surprisingly higher levels of pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor α (TNF-α) have been observed in a meta-analysis in patients with depression, as well as elevated levels acute phase reactants such as C-reactive protein (CRP). Although antidepressants are most well-known for their impacts on neurotransmitter availability, they also may impact depression by having anti-inflammatory and antioxidative effects.,
A case for melatonin?
Melatonin is primarily produced in the pineal gland, although other tissues such as the retina and lens of the eye, gonads, bone marrow, and gut also produce it. Melatonin not only has impacts on sleep as a regulator of the circadian rhythm, but also is a neuroprotective antioxidant. Many studies have found decreased melatonin production and disrupted rhythms with age,,, while other factors such as electromagnetic pollution also may have an influence. Decreased levels of melatonin and an altered circadian rhythm have been observed in depressed subjects,, possibly associated with increased cortisol levels. As the biosynthesis of melatonin is from serotonin, lower levels of serotonin, and its precursor tryptophan, also may play a role. Single nucleotide polymorphisms associated with the rate-limiting melatonin synthesis enzyme, acetylserotonin methyltransferase, also are associated with recurrent depressive disorder.
Melatonin has been shown to be protective against central nervous system oxidative damage, reducing lipid peroxidation and oxidative damage to nuclear DNA while stimulating mRNA levels of superoxide dismutase and the activities of glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase., Anti-inflammatory effects of melatonin also have been demonstrated in the central nervous system, with both experimental data and clinical studies showing melatonin to reduce pro-inflammatory cytokines including IL-6, IL-8, and TNF-α. As a protective agent against lipid peroxidation, melatonin also plays a role in maintaining the fluidity of biological membranes, which is necessary for cellular signaling and mitochondrial function.
Melatonin receptor agonists such as agomelatine and prolonged-release melatonin have been studied for the treatment of insomnia and depression. Agomelatine, a melatonin-receptor agonist and a weak selective serotonergic receptor (5-HT2C) antagonist, has been shown improve depression and sleep quality, and may positively impact associated anxiety. Melatonin has been shown in a variety of clinical settings to positively impact depression,, both as a monotherapy and adjunctive therapy in combination with antidepressants., Improvements in depression-related insomnia and fatigue have also been seen with prolonged-release melatonin. A reduction of anxiety associated with surgical procedures also has been observed with the use of melatonin.
Green tea: more than antioxidants
Green tea is well known for its high amounts of antioxidants, particularly one known as epigallocatechin gallate or EGCG. However, green tea also contains a high amount of an amino acid known as L-theanine. L-theanine is widely used and studied in Japan, a culture particularly known for their tea consumption. L-theanine has been observed to promote relaxation and reduction of stress, possibly by increasing alpha-wave activity as well as by blocking the binding of L-glutamic acid to excitatory glutamate receptors in the central nervous system.,,
L-theanine also has been shown to impact neurotransmitter balance. L-theanine has been shown in animal studies to pass through the blood-brain barrier and to significantly increase serotonin and dopamine levels in the brain, particularly in the regions of the striatum, hypothalamus and hippocampus. A decrease in serum corticosterone has also been observed in conjunction with the rise of serotonin and dopamine in regions of the pituitary and hippocampus with high doses of L-theanine. Additionally, continuous administration of L-theanine has been shown to increase expression of brain-derived neurotrophic factor (BDNF) protein, a protein which is plays a role in neural plasticity and neurogenesis, including that of dopaminergic and serotonergic neurons. Increased BDNF levels also may be one mechanism by which pharmaceuticals, supplements, and exercise have a positive impact on anxiety and depression.,,
In clinical settings, supplementation with L-theanine has been shown to have a relaxing effect in a resting state,  reduce heart rate and salivary immunoglobulin A (sIgA) secretion in acute stressful events,  reduce anxiety and attenuate blood-pressure in a setting of mental task challenge,  and reduce salivary α-amylase activity and subjective experience of stress during academic challenges. These physiological changes and symptomatic experience of stress are suggested to be mediated via reduced sympathetic nervous system activity, as measured by heart-rate variability and salivary α-amylase activity. As stress and the physiological response to it is known to affect anxiety, depression, and patterns of sleep, these findings support the consideration of L-theanine as an adjunctive support for individuals who experience these issues. Concerning sleep, L-theanine has been shown to improve aspects of sleep quality in boys with attention-deficit/hyperactivity disorder, as well as caffeine-induced decreases in slow-wave sleep in animals. Although L-theanine has not been studied for the treatment of depression in humans, animal studies suggest an antidepressant-like effect.
A word or two on GABA
Similarly to L-theanine, supplemental administration of GABA has been shown to significantly increase alpha wave patterns in the brain in humans, accompanied by reduced levels of anxiety. Under conditions of mental stress, GABA administration also has been shown to support alpha wave activity. GABA can also be found in foods as a product of fermentation, which is why teas such as Pu-Erh and kimchi are potential food-sources of GABA.,,
A primary question about GABA as a supplemental therapy is the ability of GABA to cross the blood-brain barrier (BBB), in which endothelial cells of capillaries are more tightly connected to protect the brain from harmful substances. Transport through the BBB occurs via specialised transporter molecules or diffusion through the cellular lipid bilayer. Evidence has been found for a GABA transporter in the BBB, however in animal models the efflux rate has been shown to be considerably higher than influx. In some individuals, the junctions of the BBB may allow for greater transport as biological compounds such as histamine and bradykinin may increase BBB permeability. It also has been proposed that the observed effects are associated with binding to GABA receptors of the enteric nervous system, and are modulated by the vagus nerve.  Additionally, liposomal delivery systems have been shown to facilitate transport across the BBB and increase availability of therapeutic agents in the central nervous system. 
Dr. Decker is a certified Naturopathic Doctor, graduating with honors from the National College of Natural Medicine (now the National University of Natural Medicine) in Portland, Oregon. Prior to becoming a naturopathic physician, Dr. Decker was an engineer, with graduate degrees in biomedical and mechanical engineering from the University of Wisconsin-Madison and University of Illinois at Urbana-Champaign respectfully. Dr. Decker sees patients at her office in Portland, OR, as well as remotely, with a focus on gastrointestinal disease, mood imbalances, eating disorders, autoimmune disease, chronic fatigue, thyroid dysfunction, and skin conditions.
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