Anxiety & Depression

This is not a comprehensive list, simply some articles I have found along the way.

Ever hear people talk about their need for Xanax to relax or calm their anxiety? Xanax and other benzodiazepine pharmaceutical options (Valium works similarly) help to temporarily restore balance between glutamate and GABA by artificially increasing GABA. This increase in GABA calms the over excitation from excess  glutamate, acting as a mild sedative. Unfortunately, artificially increasing GABA through the use of these pharmaceuticals will actually decrease natural production of GABA, only intensifying the problem. One of the best ways to naturally increase GABA and balance these neurotransmitters is to work on lowering glutamate levels.

“Lack of GABA can be felt in many different ways. Anxiety and panic disorders are common issues associated with lack of GABA. Having high levels of fear, a sense of something bad is going to happen/dooms day feeling is another manifestation. Often the symptoms increase when you are trying to relax, i.e. the mind goes on the gerbil wheel or rumination occurs. There may be problems with racing thoughts. There are often episodes of explosive behavior – temper tantrums or unstable mood in children or adults. There is poor organization to detail and problems with distraction. It can be hard to get to work or appointments on time, or trouble managing homework. There is inner tension or excitability that doesn’t allow relaxation or it’s hard to unwind. It can manifest with needing to fall asleep with the TV on, or needing to have a little “night cap.”

“Compelling research has linked excess glutamate stimulation and/or elevations of proinflammatory cytokines to a number of neuropsychiatric and behavioral conditions, many of which are seen with CTE. These include panic attacks, aggressive behavior, suicide, obsessive-compulsive disorder, anxiety, and depression.[,,,,,]”

“Anxiety, stress, and trauma-related disorders are a major public health concern in the United States. Drugs that target the gamma-aminobutyric acid or serotonergic system, such as benzodiazepines and selective serotonin reuptake inhibitors, respectively, are the most widely prescribed treatments for these disorders. However, the role of glutamate in anxiety disorders is becoming more recognized with the belief that drugs that modulate glutamatergic function through either ionotropic or metabotropic glutamate receptors have the potential to improve the current treatment of these severe and disabling illnesses. Animal models of fear and anxiety have provided a method to study the role of glutamate in anxiety. This research has demonstrated that drugs that alter glutamate transmission have potential anxiolytic action for many different paradigms including fear-potentiated startle, punished responding, and the elevated plus maze. Human clinical drug trials have demonstrated the efficacy of glutamatergic drugs for the treatment of obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, and social phobia. Recent data from magnetic resonance imaging studies provide an additional link between the glutamate system and anxiety. Collectively, the data suggest that future studies on the mechanism of and clinical efficacy of glutamatergic agents in anxiety disorders are appropriately warranted.”

“Because the density of NMDA (glutamate receptor) and muscarinergic M1 receptors also correlated negatively with the two factors, these receptors had a positive effect on general activity. In contrast, correlations of GABAA, serotonin, and kainate receptors had the opposite sign as compared to closed arm entries. It is concluded that hereditary variations in the amygdala, particularly in kainate and serotonin receptors, play a role for the baseline and fear-sensitized ASR, whereas the general activity is influenced by many neurotransmitter receptor systems.”

“Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, and G-protein-coupled metabotropic glutamate (mGlu) receptors function to regulate excitability via pre- and postsynaptic mechanisms. Various mGlu receptor subtypes, including group I (mGlu1 and mGlu5), group II (mGlu2 and mGlu3), and group III (mGlu4, mGlu7 and mGlu8) receptors, specifically modulate excitability within crucial brain structures involved in anxiety states.” “These studies indicate that metabotropic glutamate receptors are interesting new targets to treat anxiety disorders in humans.”

“The article concludes with further support for the role of the GABA system in anxiety by summarizing the current evidence supporting the use of novel GABAergic agents including tiagabine in the treatment of anxiety disorders”

“Depressed patients with signs of systemic inflammation have elevated levels of glutamate in regions of the brain that are important for motivation, the researchers have found. Our results suggest that inflammation markers can guide us to which depressed patients respond best to glutamate blockers,”

Depression and glutamate GREAT article: “Recent growing evidence suggests that glutamatergic neurotransmission, the major excitatory system in the brain, plays a criti-cal role in the pathophysiology and treat-ment of neuropsychiatric disorders. The glutamatergic system is interconnected with GABAergic and monoaminergic pathways, and it has been shown that approximately 80% of neurons in the neocortex are excita-tory glutamatergic neurons [4] . In the last several years, a number of clinical and preclinical studies demonstrated that mala-daptive changes in excitatory/inhibitory cir-cuitry, particularly in glutamate homeo stasis and neurotransmission, have a primary role in mood and anxiety disorders.”

“Depressed patients with signs of systemic inflammation have elevated levels of glutamate in regions of the brain that are important for motivation, the researchers have found.”Our results suggest that inflammation markers can guide us to which depressed patients respond best to glutamate blockers,” says lead author Ebrahim Haroon, MD, assistant professor of psychiatry and behavioral sciences at Emory University School of Medicine and Winship Cancer Institute. “This could be an important step toward personalizing treatment for depression.””

“Inflammatory cytokines interfere with the regulation of the neurotransmitter, glutamate. Glutamate is an excitatory neurotransmitter that, if left to go wild, can pound our NMDA receptors in the brain and wreak major havoc. No one wants overexcited NMDA receptors, and clinical depression is one among many nasty brain issues that can be caused by overexcitement. Astrocytes, little clean-up cells in the brain, are supposed to mop up excess glutamate to keep it from going nutso on the NMDA. Turns out inflammatory cytokines interfere with the clean-up process. The horse tranquilizer (and club drug) ketamine, when administered IV, can eliminate symptoms of severe depression pretty much immediately in some cases (do NOT try this at home) (2). Ketamine helps the astrocytes mop up glutamate, and it is assumed that this is how ketamine instantly cures depression. Unfortunately, the effects of ketamine don’t last, otherwise it would be a nifty tool, indeed.”

“In addition, newer studies have shown a strong correlation between brain glutamate levels and major depression, thus making a case for immunoexcitotoxicity in addictive disorders as well as associated neurodegeneration.[,] These studies also explain the link between immunoexcitotoxicity and neuropsychiatric and behavioral disorders associated with CTE.”

“A large number of clinical studies suggest that pathophysiology is associated with dysfunction of the predominant glutamatergic system, malfunction in the mechanisms regulating clearance and metabolism of glutamate, and cytoarchitectural/morphological maladaptive changes in a number of brain areas mediating cognitive-emotional behaviors. Concurrently, a wealth of data from animal models have shown that different types of environmental stress enhance glutamate release/transmission in limbic/cortical areas and exert powerful structural effects, inducing dendritic remodeling, reduction of synapses and possibly volumetric reductions resembling those observed in depressed patients. Because a vast majority of neurons and synapses in these areas and circuits use glutamate as neurotransmitter, it would be limiting to maintain that glutamate is in some way ‘involved’ in mood/anxiety disorders; rather it should be recognized that the glutamatergic system is a primary mediator of psychiatric pathology and, potentially, also a final common pathway for the therapeutic action of antidepressant agents. A paradigm shift from a monoamine hypothesis of depression to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the working hypothesis that drives research for new drugs and therapies. Importantly, despite the availability of multiple classes of drugs with monoamine-based mechanisms of action, there remains a large percentage of patients who fail to achieve a sustained remission of depressive symptoms. The unmet need for improved pharmacotherapies for treatment-resistant depression means there is a large space for the development of new compounds with novel mechanisms of action such as glutamate transmission and related pathways.”

“We describe a new term: glutamate-based depression (GBD). GBD is defined as a chronic depressive illness associated with environmental stress and diseases associated with altered glutamate neurotransmission. We hypothesize that glutamate-induced over-activation of extrasynaptic NMDA receptors in the subgenual cingulate area called Brodmann’s 25 plays an important role in the etiology of depression and may be responsible for the high incidence of co-morbid depression associated in diseases with glutamate etiology. While depression is a syndrome with multiple possible etiologies, we propose that a disruption in glutamatergic neurotransmission may underline a substantial proportion of clinically observed depression. The high rates of depressive symptoms associated with various disorders in which altered glutamatergic functions have been identified, may suggest a common pathophysiological mechanism is underlying the diverse clinical presentations.”

“Multiple lines of evidence suggest that inflammation and glutamate dysfunction contribute to the pathophysiology of depression. Peripheral inflammation leads to microglial activation which could interfere with excitatory amino acid metabolism leading to inappropriate glutamate receptor activation”

“Using magnetic resonance spectroscopy, the team also found that levels of GABA—the main chemical that inhibits signals in the brain—in participants’ hippocampi predicted their ability to suppress thoughts. “If you have more GABA to work with, you’re better at controlling your thoughts,” Anderson says. In other words, if the PFC contains the mental brake pedal, hippocampal GABA levels are the brake pads that determine how effectively the brain stops.
The study helps to bridge the gap between molecular neuroscience and human behavior—and how the process goes awry in disease. “It’s a great step,” says neuroscientist Brendan Depue of the University of Louisville, who was not involved in the work. “The next step is to do a drug study,” Anderson says. “Could we make people better [at suppressing thoughts] by giving them drugs that enhance GABA?””

“Our findings suggest that altered glutamate levels may be implicated in MDD, which provides further evidence of glutamatergic dysfunction in MDD.” Elevated peripheral blood glutamate levels in major depressive disorder.

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