Immunoneurodepressive Disorder: The Pandemic Right in Front of Our Eyes

This article includes a special message from Dr. Russell Blaylock on compounds and supplements that may reduce the impact of chronic microglial activation.

A significant percentage of psychiatric patients may be suffering due to disrupted neuroimmunity. Current symptom-based diagnostic and treatment paradigms are insufficient for addressing the complex etiology of major depression and related disorders. A shift towards understanding and treating the underlying pathological processes could not only improve patient outcomes but also potentially reduce the societal and economic burden of these conditions.

The Hidden Pandemic

In an era where medical advancements are touted as evidence of our massive investment in biomedical research, a silent pandemic lurks right under our noses. This pandemic is not caused by a virus or bacteria but by a complex interplay between our nervous and immune systems. This condition encompasses a range of ailments including Chronic Fatigue Syndrome (CFS), Bipolar Disorder (BD), and Major Depressive Disorder (MDD). Combined, these syndromes and disorder can be considered under the more causal-focused "Immunoneurodepressive Disorder".

The most recent statistics indicate a significant rise in the incidence of major depression. According to a Gallup News report from 2023, 29.0% of Americans have been diagnosed with depression in their lifetime, with 17.8% currently experiencing depression [Gallup News]. This is a marked increase from previous years; for instance, in 2020, 18.4% of U.S. adults reported having ever been diagnosed with depression [CDC].

The incidence of related conditions varies but is alarmingly high. For instance, Major Depressive Disorder affects approximately 21% of women and 11%–13% of men in the United States. Bipolar Disorder has a lifetime prevalence of about 2.8% among adults, while Chronic Fatigue Syndrome is estimated to affect up to 2.5 million Americans. These statistics are even more concerning when one considers that a significant number of cases likely go undiagnosed; estimates suggest that as many as 84-91% of people with CFS are not yet diagnosed.

The symptoms of these disorders are as varied as they are debilitating. Major Depressive Disorder often manifests as persistent sadness, loss of interest in activities, and a profound sense of hopelessness. Bipolar Disorder is characterized by mood swings that include depressive episodes and periods of mania. Chronic Fatigue Syndrome, on the other hand, primarily involves extreme fatigue that fails to improve with rest and may worsen with physical or mental activity.

Diagnosis and treatment for these conditions are generally approached through a combination of psychiatric evaluation, symptom tracking, and sometimes, neuroimaging tests. Treatments often involve neurochemistry-focused pharmacotherapy with antidepressants for MDD, mood stabilizers for BD, and symptom management strategies for CFS, which may include cognitive-behavioral therapy and graded exercise therapy.

Immunoneurodepressive Disorder as a Systemic Syndrome

Unlike traditional diseases that affect a single organ or system, Immunoneurodepressive Disorder impacts both the brain and the immune system, making it a particularly insidious and misunderstood condition. The disorder is characterized by chronic microglial activation (CMA), a state where the brain's immune cells are stuck in the "on" state, leading to a cascade of harmful effects. This activation is often triggered by neuronal death, which can be caused by a variety of factors such as toxins, trauma, or even normal aging. Once activated, microglia produce substances like glutamate and Interleukin-6 (IL-6), which can lead to further cascades of signals leading to chronic microglial activation, further damage to brain cells and perpetuate a vicious cycle of inflammation and cell death.

Understanding this disorder requires a multi-disciplinary approach, combining insights from neurology, immunology, and psychology. The intricate mechanisms behind Immunoneurodepressive Disorder are clearly known, but the condition is almost never actually treated - because it has not been properly identified by the psychiatric community as a systemic disorder in spite of a robust bolus of studies and literature clearly implicating immunoneuroexcitotoxicity as a root cause.

Microglia are the immune cells of the central nervous system, acting as the first line of defense against pathogens and injuries. However, when these cells are chronically activated, they can become a source of neurotoxicity, releasing pro-inflammatory molecules that can damage neurons[1][2]. This is a double-edged sword; while microglia are essential for clearing away debris and pathogens, their prolonged activation can lead to a vicious cycle of neuronal death and further microglial activation[4].

One of the key players in this cycle is glutamate, a neurotransmitter that, in excess, can lead to excitotoxicity, a form of neuronal death. Excitotoxicity is often a result of increased glutamate release following initial neuronal damage. This excess glutamate can activate microglia, leading to the release of inflammatory cytokines like IL-6[5]. The presence of these cytokines can then cause more neuronal death, perpetuating the cycle.

Dr. Russell Blaylock has, with colleagues, published extensively on immunoexcitotoxicity and immunoneuroexcitotoxicity, which play a central role in my understanding of the causes of autism disorder.

• Blaylock RL, Maroon J. Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy-A unifying hypothesis. Surg Neurol Int. 2011;2:107. doi: 10.4103/2152-7806.83391 https://pubmed.ncbi.nlm.nih.gov/21886880/

• Blaylock RL. A possible central mechanism in autism spectrum disorders, part 2: immunoexcitotoxicity. Altern Ther Health Med. 2009 Jan-Feb;15(1):60-7. PMID: 19161050. https://pubmed.ncbi.nlm.nih.gov/19161050/

• Blaylock, RL. 2023. The biochemical basis of neurodegenerative disease: The role of immunoexcitotoxicity and ways to possibly attenuate it. Surg Neurol Internat 14:141 https://pubmed.ncbi.nlm.nih.gov/37151454/

A critical aspect of immunoneuroexcitotoxicity is the role of persistent toxins like aluminum and mercury, both of which cause death cell, endoplasmic reticulum stress (ER-Stress), and chronic microglial activation. These biologically persistent toxins, which clear slowly from the brain, act on the brain in a pernicious manner via serial neuronal destruction.

See IPAK-EDU Information Sheets on Aluminum and on Mercury

At the same time, in our increasingly toxic world, repeated exposures to excitotoxic chemicals can also contribute to chronic microglial activation, creating a state of perpetual neuroinflammation and neuronal death[3]. This is particularly concerning because it suggests that even low-dose chronic exposure to such toxins could lead to lifelong issues related to chronic microglial activation.

Pathogenic Microglial Priming

Chronic microglial activation and neuronal death are tightly interlinked through a cascade of neuroimmune signaling. This involves a complex interplay of neurotransmitters like glutamate, inflammatory cytokines like IL-6, and even environmental toxins (Table 1).

Table 1. Works Citing CMA and Environmental Toxins That Can Cause It (Including Aluminum)

1. Environment Matters: Microglia Function and Dysfunction in a Changing World. (n.d.). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732848/

2. Microglial Activation in Metal Neurotoxicity. (n.d.). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9904912/

3. Environmental Toxins Linked to Neurodegeneration and Autism. (n.d.). Retrieved from https://fisherpub.sjf.edu/cgi/viewcontent.cgi?article=1025&context=pharmacy_facpub

4. Environmental Signals on Microglial Function during Brain Development and Disease. (n.d.). Retrieved from https://www.mdpi.com/1422-0067/21/6/2111

5. Microglial Activation in Metal Neurotoxicity: Impact in Neurodegenerative Diseases. (n.d.). Retrieved from https://www.hindawi.com/journals/bmri/2023/7389508/

6. Astrocytes, another type of glial cell, also play a crucial role in this chronic microglial activation (CMA). They are involved in the regulation of neurotransmitter systems and immune responses, adding another layer of complexity to CMA. Specifically, astrocytes contribute to this cycle by releasing pro-inflammatory cytokines and chemokines, further activating microglia and perpetuating inflammation. They also regulate glutamate homeostasis; an imbalance can lead to excitotoxicity, exacerbating neuronal damage. Moreover, astrocytes can undergo reactive astrogliosis, a state of hyperactivity that can either be neuroprotective or contribute to neurodegeneration, depending on the context. The result is a self-perpetuating cycle that can lead to various neurodegenerative and neuropsychiatric disorders.

The traditional approach to diagnosing neuropsychiatric disorders like major depression often relies on symptom-based criteria, which can be a significant limitation. This method fails to recognize the underlying causal factors and actual pathological processes at play. For example, treatments with neurochemically focused neurotropic medications like SSRIs or antipsychotics often target symptoms (“neurotransmitter imbalance”) rather than the root causes, such as chronic microglial activation or excitotoxicity and chronic inflammation. Over time, the effectiveness of these pharmaceutical approaches tends to diminish, leading physicians to experiment by changing the patients’ medicine, with some actually potentially exacerbating symptoms due to the cumulative effects of chronic microglial activation.

Emerging research suggests that a more effective approach would involve diagnoses and treatments aimed at these root causes. For instance, studies have shown that chronic microglial activation is tightly interlinked with neuronal death through a cascade of neuroimmune signaling involving neurotransmitters like glutamate and inflammatory cytokines like IL-6.

There is Hope

Routine scans for brain inflammation and signs of immune imbalance in people exhibiting bipolar disorder, major depressive disorder and chronic fatigue syndrome by psychiatrists and psychologists would help many people understand the biological basis of their conditions. Addressing these underlying factors could lead to more effective and sustainable treatment outcomes. For example, agents that attenuate excitotoxicity or neuroinflammation could prove beneficial for treating major depression, as they target the root causes rather than just alleviating symptoms. This approach is supported by biomedical literature, such as studies that have found mood stabilizers like lithium to decrease markers of brain arachidonic acid metabolism, which is upregulated in conditions involving excitotoxicity and neuroinflammation [Medline]. Integrative approaches with compounds that reduce microglial activation, such as foods and supplements rich in luteolin, might be found to reduce the severity and frequency of psychiatric episodes.

Dr. Blaylock:

Thank you for your return engagement at IPAK-EDU. The students enjoyed your presentation immensely. As promised, I would like to ask you to provide a brief description of potential clinical approaches to modulating chronic microglial activation. We understand these are speculative areas requiring research, and that your response is not medical advice. Thank you for any information you’d care to share.

Sincerely,

James Lyons-Weiler

Dear James,

“Thank you very much. The papers you attached on psychiatric effects of, basically, immunoexcitoxicity, in psychiatric disease, were excellent. They and other literature strongly point out the relation to excitotoxicity as well as immune alteration. Danzer has been a leader in this drive, at least as regards the immune aspect. I look forward to your upcoming paper. You are a great writer and innovative thinker. Thank you for the attachments--especially your autoimmune lecture. Bless you all.

Your friend,

Russell

Russell L. Blaylock, M.D.

Theoretical Neuroscience Research, LLC

Associate Editor-in-Chief; Neuroinflammation Section

Surgical Neurology International

PS: I finished the paragraph, that actually extended to a page. It was as much as I could cut it down. 

Ways To Inhibit Microglial Activation and Excitotoxicity

 Fortunately, there are several ways to accomplish this without dangerous medications. Mainly, scientists have discovered several natural products that accomplish this. As a side note, it was discovered that using a rather simple medication, ketamine, even in a single, low dose, could correct severe, medication-resistant depression that lasted for a considerable period after the medication was stopped. Ketamine is a rather powerful ionic glutamate receptor blocker.

In larger, more prolonged doses it can cause a brain lesion in the cingulate cortex. It is the toxicity and strength of medicinal glutamate blockers that make them less useful. In addition, many completely block the glutamate receptor, and one must appreciate that glutamate transmission makes up 90% of cortical transmission and 50% transmission of the brain overall. Hence, one does not want total blockage of this transmitter or its receptors.

 Nano-grape seed extract is the only natural product known to block the calcium-permeable AMPA receptors (the most destructive).

As a result, attention has focuses on two things, partially blocking or selective blocking of certain glutamate receptors or using things that alter the activity of the metabotropic receptors. These special types of receptors either enhance excitotoxicity or decrease excitotoxicity. Thus far there are no medication or natural products that have been identified to do this.

A second method is to reduce microglial activation. This is rather tricky, as the activated microglial also have a reparative function. In general, it is about timing, as chronic microglial activation is harmful. Repair occurs early—usually days.

Here are natural products known to reduce microglial activation: Nano-Curcumin, resveratrol, baicalein, luteolin, apigenin, taurine, Nano-grapeseed extract, saffron, tocotrienol, fisetin, Nano-andrographide, Shandra, EGCG (green and white tea extract), and hawthorn. Taurine is a neuromodulator, but it must be taken with meals as it is powerfully hypoglycemic. Nano-Curcumin slight anticoagulates blood (a good thing) and it chelates iron (in many cases a good thing but must be watched.) Tocotrienol, is a form of vitamin E, that is much more powerful as an antioxidant and protects astrocytes in the brain, the main repository of glutamate and supplied nutrient to brain cells. Forskolin increase glutamate transports EAAT1 and 2, the most important ones. The following increase brain derived neurotrophic factor (BDNF) a major healing products in the brain: Nano-Curcumin, hesperidin, Nano-bacopa, saffron and nano-triphala.

Nitric oxide (NO) is an important product, but also quite dangerous in excess. It plays a major role in excitotoxicity. These things lower excess NO: Nano-Curcumin, EGCG, luteolin, taurine, Nano-grape seed extract, saffron, tocotrienol and Nano-Bacopa.

These things lower the pro-inflammatory cytokine TNF-a: Nano-triphala, CoQ10, EGCG, luteolin, hawthorn (improves blood flow and heart pumping, but lowers blood pressure as a vasodilator), Nano-Bacopa, and especially vinpocetine, Nano-quercetin (must be taken with meals—is a hypoglycemic) and apigenin. Vinpocetine also combats tinnitus and improves brain blood flow.

The B-vitamins also inhibit excitotoxicity especially thiamine, riboflavin, methyl colbamin and pyridoxine.

There are several things that increase mitochondrial function: L-carnitine and/or acetyl-L-carnitine, R-lipoic acid, CoQ10, taurine, Nano-grape seed extract, Nano-bacopa, Nano-curcumin, EGCG, carnosine, baicalein and quercetin. Vitamins that enhance mitochondrial function include vitamin B1 (thiamine), riboflavin-5-phosphate, pyridoxine-5-phospate (don’t take more than 25mg a day), methyl-folate and sublingual vitamin B12 (methyl cobalamin).

You don’t need to take them all, just the main ones. Do not overdose as most are very safe but a few will cause problems.”

And of course, check with your physician before starting or stopping any medications and have them check for potential interactions with any medications they may have prescribed for you.

Blaylock RL, Maroon J. Natural plant products and extracts that reduce immunoexcitotoxicity-associated neurodegeneration and promote repair within the central nervous system. Surg Neurol Int. 2012;3:19. doi: 10.4103/2152-7806.92935. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307240/

Blaylock RL, Maroon J. Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy-A unifying hypothesis. Surg Neurol Int. 2011;2:107. doi: 10.4103/2152-7806.83391. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157093/

CITATIONS AND RELATED READING

[1]: [Microglial activation and chronic neurodegeneration - PMC - NCBI](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951017/)

[2]: [Microglial activation and its implications in the brai diseases](https://pubmed.ncbi.nlm.nih.gov/17504139/)

[3]: [Microglia in Neuroinflammation and Neurodegeneration - Frontiers](https://www.frontiersin.org/articles/10.3389/fnins.2021.742065)

[4]: The semantics of microglia activation - Journal of Neuroinflammation](https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02309-6)

[5]: [Microglia in Neurological Diseases: A Road Map to Brain ... - Frontiers](https://www.frontiersin.org/articles/10.3389/fncel.2018.00488)

1. NIMH: An estimated 21.0 million adults in the United States had at least one major depressive episode, representing 8.3% of all U.S. adults. [Source](https://www.nimh.nih.gov/health/statistics/major-depression)

2. CDC: The age-standardized prevalence of depression among U.S. adults was 18.5%. [Source](https://www.cdc.gov/mmwr/volumes/72/wr/mm7224a1.htm)

3. JAMA Psychiatry: The 12-month and lifetime prevalences of major depressive disorder were 10.4% and 20.6%, respectively. [Source](https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2671413)

4. Our World in Data: One in three women (33%) and one in five men (19%) have major depression by the age of 65 in the United States. [Source](https://ourworldindata.org/depression-lifetime-risk)

5. NCBI Bookshelf: Major depressive disorder has a lifetime prevalence of about 5 to 17 percent. [Source](https://www.ncbi.nlm.nih.gov/books/NBK559078/)

U.S. Depression Rates Reach New Highs (gallup.com)

https://news.gallup.com/poll/505745/depression-rates-reach-new-highs.aspx

National, State-Level, and County-Level Prevalence Estimates of Adults Aged ≥18 Years Self-Reporting a Lifetime Diagnosis of Depression — United States, 2020 | MMWR (cdc.gov)

https://www.cdc.gov/mmwr/volumes/72/wr/mm7224a1.htm

NIMH » Major Depression (nih.gov)

https://www.nimh.nih.gov/health/statistics/major-depression

National, State-Level, and County-Level Prevalence Estimates of Adults Aged ≥18 Years Self-Reporting a Lifetime Diagnosis of Depression — United States, 2020 | MMWR (cdc.gov)

https://www.cdc.gov/mmwr/volumes/72/wr/mm7224a1.htm

Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States | Depressive Disorders | JAMA Psychiatry | JAMA Network

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2671413

What is the lifetime risk of depression? - Our World in Data

https://ourworldindata.org/depression-lifetime-risk

Major Depressive Disorder - StatPearls - NCBI Bookshelf (nih.gov)

https://www.ncbi.nlm.nih.gov/books/NBK559078/

T cells: an emerging cast of roles in bipolar disorder | Translational Psychiatry (nature.com)

https://www.nature.com/articles/s41398-023-02445-y