- 1 Section A
- 2 Definition, Challenge, Location and Depression’s General Characteristics
- 3 Where is Depression located ?
- 4 Constituent Characteristics or Symptomatology
- 5 Types of depression
- 6 Section B
- 7 The Pathophysiology & Etiology of Depression
- 8 Neuro-Inflammation, Immunological & Nutritional Dysfunctions
- 9 Diet affects the Inflammation pathway in Depression
- 10 Gluten, the Immune System and Brain Inflammation
- 11 The MicroBiome, inflammation and Depression
- 12 The Blood Brain Barrier, Blood Sugar, inflammation and Depression
- 13 Oxidative Stress and Depression
- 14 Mitochondrial Dysfunction and Depression
- 15 Glutathione Depletion, Nrf2 and Depression
- 16 The NRf2 Pathway
- 17 MTOR, Animal Protein and Depression
- 18 Methylation, Folate, Vitamin B-12 Deficiency and Depression
- 19 Circadian rhythm (Sleep Deprivation and Light therapy)
- 20 HPA Axis Abnormalities
- 21 Monoamine neurotransmitter Imbalances and Depression
- 22 Below, three short simplified video clips
- 23 Precision and Reference Notes
- 24 Share this:
- 25 Like this:
- 26 Related
Mental Diseases are not caused by an insufficiency of prescribed synthetic psychiatric drugs. In this blog-article, i will delve into a common mental and physiological imbalance symptom, known as depression, by first examining it’s characteristics (Section A). Thereafter, i will review a few of depression’s biochemical mechanisms of action and pathways (Section B). Another blog-article will examine different natural and holistic techniques that can durably fix this health problem. (See Article on Holistic Solutions for Mental Disorders and unhappiness). It may be useful to first read the blog-article on how we were genetically designed to eat. (See this article)
Definition, Challenge, Location and Depression’s General Characteristics
The Happiness Medicine Institute’s Working Definition
From the viewpoint of Holistic and Happiness medicine, depression is less a disease then a symptom of a more general pathological state that can be defined as a general physiological deviation from homeostasis, characterized by the misfiring of neurotransmitters’ signals, a break-down of the neuron and neuropeptide communication network combined to hormonal & antioxidant depletion, neuro-genesis inhibition, nutritional degradation, oxidative and electrophilic stress, redox disturbances, systemic inflammation, emotional trauma and JDV (joie de vivre) Lifestyle neglect. (*)
On the other hand, for most conventional and integrative medical doctors, depression is a disease by itself that is classified in the official DMS V mental disease reference book as a mental health disorder, (1) rampant with over a dozen symptoms, from being persistently low mood and having feelings of sadness, to loss of interest for people and Life, entertaining suicidal thoughts, anorexia and more. (2) (See also below)
At this juncture, it may be useful to confirm that Depression, whether it be defined as a symptom or a disease, is a serious state of being that has condemned the person to life without Joie de Vivre in a durable way and whose major risks are self-harm and suicide.
Contrary to mood swings, depression is thus a persistent problem, not a passing “down in the dumps” one. The depression psychiatrist experts have computed the average length of a depressive episode to be 6-8 months (3). The longer these depressive episodes exist, the more cash-flow conventional psychiatrists make. The evidence does suggest that most allopathic medical doctors don’t have an interest in finding and treating the constituent causes that lead to depression and most other mental disorders, they would be losing too much cash-flow. (Cf the Institute’s blog on this) Hence, conventional psychiatry’s and allopathic medicine’s symptomatic and sectorial approach to this health condition.
Yet, this approach has been a relative and prolonged failure. For the last few decades, the only symptomatic treatments that have been systematically retained have been the neurotransmitter reuptake inhibitors. However, in between 30 to 40 % of patients do not respond to these drugs (Source) and 60 to 70% of patients do not experience remission. (Source).
Worse, according to Professor Cohen, there is no credible evidence that shows that antidepressants or any other drugs produce long-term elevation of mood or other effects that are particularly useful in treating depression (Cf, Moncrieff J., Cohen D., Do antidepressants cure or create abnormal brain states?, in «PLoS Medicine» 3, e240 (2006). P. 961) And even worse, these addictive psychiatric drugs can permanently damage the brain and hinder its own recovery. (Cf. Moncrieff J., Why is it so difficult to stop psychiatric drug treatment? It may be nothing to do with the original problem, in «Medical Hypotheses» 67, 517-523 (2006).
Furthermore, most of these synthetic drugs take a long time to show symptomatic results, while their toxicity (side effects) put in place multiple complications. (See Section C)
In the absence of Holistic and Happiness Medicine, these drugs can nonetheless help severely depressed patients from significant harm and suicide.
But for the “best interests” of the patient and to be consistent with Science, the challenge would be to replace most of conventional medical protocols with new legally binding standards of care coming first from integrative medicine as a transition and then durably crowning the Health-Care system with holistic and happiness medicine.
Top: The Amygdala is one of the key Areas of the brain that is affected by depression. The amygdala is part of the limbic system, a group of structures deep in the brain that’s associated with emotions such as anger, pleasure, sorrow, fear, and sexual arousal. (Source: Harvard University)
Where is Depression located ?
The current knowledge indicates that the pathophysiology of depression (4) may be distributed across multiple brain regions and connectivity circuits. These are composed of the anterior cingulate, dorsolateral, medial and inferior prefrontal cortex, insula, superior temporal gyrus, basal ganglia and the cerebellum, to which the olfactory bulb may also play a role. (5)
The Hippocampus Connection with Depression
Many factors contribute to major depressive disorder (MDD) such as the misfiring of neurotransmitter signals to the brain. The hippocampus in the limbic area houses a key circuitry system. It is thus relevant to all forms of depression and mental disorders.
The hippocampus is located near the center of the brain. It stores memories and regulates the production of a hormone called cortisol, a hormone which releases cortisol during times of physical and mental stress, including during times of depression. (6)
When the depression gets chronic, the hippocampus shrinks. And when the chronically depressed person recovers her-his JDV (joie de vivre), the hippocampus returns to its normal size.
“Research shows that the hippocampus is smaller in some depressed people. For example, in one fMRI study published in The Journal of Neuroscience, investigators studied 24 women who had a history of depression. On average, the hippocampus was 9% to 13% smaller in depressed women compared with those who were not depressed. The more bouts of depression a woman had, the smaller the hippocampus. Stress, which plays a role in depression, may be a key factor here, since experts believe stress can suppress the production of new neurons (nerve cells) in the hippocampus (.…) (Source)
Even an onslaught of drug-based neurotransmitters introduced into the limbic system can not prosper without neurogenesis, new nerve growth and connections that have been lost with chronic stress and depression. This is why the Holistic Happiness solution to depression is to first focus on neurogenesis so that the neuronal circuits can correctly process neurotransmitters’ signals. (See ultra).
Constituent Characteristics or Symptomatology
To be officially labeled depressive, the patient needs to be burdened by at least five of the following criteria, with the first two as a permanent features of all types of depressions.
DMS V Criteria
A. 1. Depressed mood most of the day, almost every day, indicated by your own subjective report or by the report of others. This mood might be characterized by sadness, emptiness, or hopelessness.
2. Markedly diminished interest or pleasure in all or almost all activities most of the day nearly every day.
3. Significant weight loss when not dieting or weight gain.
4. Inability to sleep or oversleeping nearly every day.
5. Psychomotor agitation or retardation nearly every day.
6. Fatigue or loss of energy nearly every day.
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day.
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day.
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.
Additional Distinction Criteria
B. Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
C. The episode is not due to the effects of a substance or to a medical condition
D. The occurrence is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders
E. There has never been a manic episode or a hypomanic episode
Types of depression
Some of the more frequent bouts of depression are briefly describe in this non exhaustive list below.
Clinical Depression or Major Depressive Disorder with psychotic features (MDD)
This condition is characterized by depression accompanied by psychosis. Psychosis can involve delusions, like false beliefs and detachment from reality, or hallucinations, in other words, the patient appears to be sensing things that do not exist, like pink elephants climbing up the bedroom wall.
The DSM-IV-TR recognizes five further subtypes of MDD, called specifiers, in addition to noting the length, severity and presence of psychotic features:
Melancholic depression is characterized by a loss of pleasure in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early-morning waking, psychomotor retardation, excessive weight loss (not to be confused with anorexia nervosa), or excessive guilt. (7)
Atypical depression is characterized by mood reactivity (paradoxical anhedonia) and positivity, significant weight gain or increased appetite (comfort eating), excessive sleep or sleepiness (hypersomnia), a sensation of heaviness in limbs known as leaden paralysis, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection. 8
Catatonic depression is a rare and severe form of major depression involving disturbances of motor behavior and other symptoms. Here, the person is mute and almost stuporous, and either remains immobile or exhibits purposeless or even bizarre movements. Catatonic symptoms also occur in schizophrenia or in manic episodes, or may be caused by neuroleptic malignant syndrome. 9
Postpartum depression, or mental and behavioral disorders associated with the puerperium,refers to the intense, sustained and sometimes disabling depression experienced by women after giving birth. Postpartum depression has an incidence rate of 10–15% among new mothers. The DSM-IV mandates that, in order to qualify as postpartum depression, onset occur within one month of delivery. It has been said that postpartum depression can last as long as three months. 10
Seasonal affective disorder (SAD) is a form of depression in which depressive episodes come on in the autumn or winter, and resolve in spring. The diagnosis is made if at least two episodes have occurred in colder months with none at other times, over a two-year period or longer. (11) Previously called seasonal affective disorder (SAD), this condition is related to the reduced daylight of winter – the depression occurs during this season but lifts for the rest of the year and in response to light therapy. Countries with long or severe winters seem to be affected more by this condition. (Source)
Unipolar versus bipolar depression If the predominant feature is a depressed mood, it is called unipolar depression. However, if it is characterized by both manic and depressive episodes separated by periods of normal mood, it is referred to as bipolar disorder (previously called manic depression). Unipolar depression can involve anxiety and other symptoms – but there are usually no manic episodes. However, research shows that for around 40 percent of the time, individuals with bipolar disorder are depressed, making the two conditions difficult to distinguish. (Source)
Subthreshold depression (StD) refers to clinically relevant depressive symptoms that do not meet the criteria for a major depressive disorder (MDD). Although the symptoms of StD are less severe than the symptoms of MDD, StD is associated with a greater health service burden than MDD, due to its higher prevalence rate in population. Subthreshold depression is associated with impaired resting-state functional connectivity of the cognitive control network. (12)
The Pathophysiology & Etiology of Depression
Whether we categorize Depression as a disease or a syndrome or a symptom, a corrective intervention will need to anchor itself on causation. One can not reverse an illness without understanding its causes. The main objective of etiology and epidemiology is to uncover the constellation of causes that lead to a diseased state. Once the cause is identified, then we can proceed to remove it. When we speak of causation, we necessarily delve into the constituent elements that make up the chain of causality, including, but not limited to correlations and biochemical mechanisms of action that lead to the targeted pathology.
In this perspective, pathophysiology or physiopathology is a convergence of pathology with physiology. Pathology is the medical discipline that describes abnormal conditions typically observed during a disease state, whereas physiology is the biological discipline that describes processes or action mechanisms operating within an organism whereas pathophysiology seeks to explain the physiological processes or mechanisms whereby abnormal “dis-eased” conditions develop. From the viewpoint of holistic medicine, we especially look at the body’s deviation and compensatory mechanisms to homeostasis. Homeostasis is the body’s tendency toward a relatively stable equilibrium between interdependent elements, especially as maintained by physiological processes. Within this process, the reality of the “bio-terrain” and “milieu” (i.e., microenvironment) in combination with epigenetics is key. Epigenetics is the study of changes in organisms caused by environmental modification of gene expression rather than alteration of the genetic code itself. While genetic determinism tends to be the the key centralizing concept of conventional medicine, in holistic medicine, epigenetics and the bio-terrain are the two centralizing processes that determine most diseases.
In this realm, one of the problems with conventional medicine is that it distinguishes myriad of correlations and then formulates theories and proclaims that the disease is idiopathic, meaning “of unknown cause”. Conventional medicine’s proponents formulate these theories without paying sufficient attention to all of the structural causes of the illness, emotional, environmental and epigenetic. This is why this type of medicine is a symptomatic one, it will usually only address the symptomatology of the disease state, with little emphasis on prevention, let alone on causation.
From the Holistic Medicine viewpoint, the conventional bio-medical model of diseases in not consistent with the rigor of Science, let alone with the exigencies of an efficient, safe and cost friendly public health and standard of care system.
Be that as it may, tens of thousands of helpful research papers and published studies in medicine are classified in the PubMed system, thanks to which holistic and independent-minded researchers can put together coherent and credible medical theories, thanks to which we can better control and reverse chronic diseases like depression and schozophrenia.
In this realm, scientific studies have found that numerous brain tissues show altered activity in patients suffering from depression, and this has encouraged advocates of various theories to identify a biochemical origin of the disease, (as opposed to theories that emphasize psychological or situational causes). Several theories concerning the biologically based cause of depression have been suggested over the years, including theories revolving around inflammation and immunological dysfunction, oxidative stress, gut dysbiosis, nutritional and sunshine deficiencies, mitochondrial dysfunctins, methylation problems, monoamine neurotransmitters, HPA axis dysfunction, structural abnormalities of emotional circuits, neuroplasticity (neurogenesis), toxemia (including prescription drug toxemia), trauma, lifestyle factors and genes.
Each of these theories merit much more analysis than what i can give them in this blog-article. I will nonetheless attempt to substantiate most of them with credible evidence and conclude with a working causation model that will help to guide us toward the appropriate remedial treatment plan that has the potential to reverse just about any type of Depression. I have willingly minimized a genetic analysis of depression, first because genes are way downstream in terms of causative factors and need to be expressed by exogenous and environmental factors. Second, a purely genetic analysis of diseases disempowers the patient from proactive remedical correction. And third, i have treated genes and mental disorders in another blog.
Neuro-Inflammation, Immunological & Nutritional Dysfunctions
Neuroinflammation combined to auto-immunity constitutes a twin significant synergistic element in my quest to uncover the deep structural causes to mental disorders. In this perspective, multiple meta analysis on cytokine levels in depressed patients have demonstrated increased levels of inflammatory IL-1, IL-6, C-reactive protein in depressed patients. (13)
Increased numbers of T-Cells presenting activation markers, levels of neopterin, IFN gamma, sTNFR, and IL-2 receptors have been observed in depression. (14)
Various sources of inflammation in depressive illness have been hypothesized and include trauma, sleep problems, diet, smoking and obesity. (15)
Cytokines, (16) by manipulating neurotransmitters, are involved in the generation of sickness behavior, which shares some overlap with the symptoms of depression.
Neurotransmitters hypothesized to be affected include dopamine and serotonin, which are common targets for antidepressant drugs. Induction of indolamine-2,3 dioxygenease by cytokines has been proposed as a mechanism by which immune dysfunction causes depression. (17)
Immune system abnormalities have been observed, including increased levels of cytokines involved in generating sickness behavior (which shares overlap with depression). (18)
Individuals with depression have been shown to have higher levels of inflammatory cytokines in their neurological tissue (19) (Source A and Source B), so this too is evidence that there is some semblance of immune dysfunction that is part of the depression process. Furthermore, there is growing evidence that specific cytokines, once in imbalance or out of synch with the body’s innate intelligence, signal the brain to generate not only neuroimmune alterations, but also neurochemical, neuroendocrine and behavior changes within the central nervous system (CNS) and beyond. (20) (Source A) & (Source b)
Diet affects the Inflammation pathway in Depression
New research has indicated that this imbalance is not a genetic flaw as was once thought but instead is due to a heavy onslaught of toxicity and nutritional and lifestyle based deficiencies and abuses that cause massive brain inflammation that disrupts normal neurological processing.
“Current research in psychoneuroimmunology and brain biochemistry indicates the possibility of communication pathways that can provide a clearer understanding of the association between nutritional intake, central nervous system, and immune function thereby influencing an individual’s psychological health status”. (21) (Source)
The evidence is compelling: there is more then a correlation between inflammatory diets and depression.
“Our study is the first to observe an association between an inflammatory prone dietary pattern (derived from reduced-rank regression) and depression risk. Conclusions: The inflammatory dietary pattern is associated with a higher depression risk. This finding suggests that chronic inflammation may underlie the association between diet and depression”. (22). (Source)
This relationship between an inflammatory diet and depression has also be shown in children and their mothers, a published study in the American Journal of Clinical Nutrition corroborates this claim.
“Given that poorly nourished adults may be less able to actively cope with stressors, nutritional deficiencies may accentuate the negative impact of stress exposure on mental health”. (23) (Source)
Other pieces of evidence that show the effectiveness of applying an anti-inflammatory strategy to reverse depression and normalize the immune system come from this published study. These studies show that an anti-inflammatory treatment normalizes cytokine levels. (24)
Gluten, the Immune System and Brain Inflammation
Among other food molecules like animal foods, casein from milk, sugar, sodas and many chemical additives, gluten is another inflamatory components that comes from different grains, in particular from wheat. Gluten is a sticky storage protein that binds to the small intestinal wall where it often causes digestive and immune system disorders.
There is extensive research about gluten sensitivity and inflammatory disorders in just about every part of the neurological system. For example:
“Short-term exposure to gluten specifically induced current feelings of depression with no effect on other indices or on emotional disposition. Gluten-specific induction of gastrointestinal symptoms was not identified. Such findings might explain why patients with non-coeliac gluten sensitivity feel better on a gluten-free diet despite the continuation of gastrointestinal symptom”. (25) (Source)
The biochemical pathway for the inflammatory process is characterized as the “gluten-mediated immune response”, which is a highly inflammatory process.
“Converging and accumulating evidence suggests that the gluten-mediated immune response is frequently associated with neurological and psychiatric manifestations, and GS represents a unique condition with a potentially different mechanism and different manifestations than celiac disease” (26) (Source)
Because gluten is a significant trigger in psychiatric disorders such as anxiety, bipolar disorder, depression and schitzophrenia, the HMI’s recommends to avoid wheat and white flower and to go gluten-free (See ultra in the Holistic Solutions) section.
The MicroBiome, inflammation and Depression
During the last ten years, there has been an extensive amount of relevant research linking the gut microbiome (i.e., microbiota) and inflammation to neurological health, including depression.
One reason why this is so is because the gut bacteria produce hundreds of neurochemicals that the brain uses to regulate basic physiological processes as well as mental processes such as learning, memory and mood. For example, gut bacteria manufacture about 95 percent of the body’s supply of serotonin, which influences both mood and GI activity.
“The recognition that the gut microbiota interacts bidirectionally with other environmental risk factors, such as diet and stress, suggests promise in the development of interventions targeting the gut microbiota for the prevention and treatment of common mental health disorders”. (27) (Source)
The discovery that unequivocably showed trillions of bacteria in mammalian microbiome (ie, intestinal flora) toiling to contribute in making key chemicals like serotonin in the gut was effectuated over ten years ago. Yet allopathic conventional medicine still prefers to administer monoamine neurotransmitters like serotonin via side-effect causing drugs, instead of getting the body to produce it via spore-forming bacteria allies and via the Vegas nerve axis connection. From the viewpoint of science, the patient’s best interest and holistic medicine, this is a serious malpractice-type of mistake.
“The gastrointestinal (GI) tract contains much of the body’s serotonin (5-hydroxytryptamine, 5-HT), but mechanisms controlling the metabolism of gut-derived 5-HT remain unclear. Here, we demonstrate that the microbiota plays a critical role in regulating host 5-HT. Indigenous spore-forming bacteria (Sp) from the mouse and human microbiota promote 5-HT biosynthesis from colonic enterochromaffin cells (ECs), which supply 5-HT to the mucosa, lumen, and circulating platelets. Importantly, microbiota-dependent effects on gut 5-HT significantly impact host physiology, modulating GI motility and platelet function. We identify select fecal metabolites that are increased by Sp and that elevate 5-HT in chromaffin cell cultures, suggesting direct metabolic signaling of gut microbes to ECs. Furthermore, elevating luminal concentrations of particular microbial metabolites increases colonic and blood 5-HT in germ-free mice. Altogether, these findings demonstrate that Sp are important modulators of host 5-HT and further highlight a key role for host-microbiota interactions in regulating fundamental 5-HT-related biological processes” (Source).
Reinforcing this above-mentioned argument, research has confirmed that low levels of healthy lactobacillus and bifidobacterium are linked with increased brain excitability and neurological inflammation. (28) (Source)
“In conclusion, the emerging concept of a gut microbiota-brain axis suggests that the modulation of the gut microbiota may provide a novel therapeutic target for the treatment and/or prevention of mood and anxiety disorders”. (29)
Among thousands of other super useful tasks, these friendly microbes also help to break down the excititory neurotransmitter glutamate into the inhibitory neurotransmitter GABA. Low levels of GABA production are associated with anxiety, seizures, depression, dementia, autism and Alzheimer’s.
“In this study, I reveal the discovery of a novel previously uncultured bacteria, Flavonifractor sp., and its growth factor,, the neurotransmitter γ-aminobutyric acid (GABA). I also show that abundant members of the gut microbiome produce large amounts of GABA. This data suggest that GABA-modulating bacteria could be impacting mental health, as decreased levels of GABA are associated with a variety of mental health disorders, including depression, anxiety, and autism. Consequently, therapeutics could be designed around their introduction/removal” See, GABA Modulating Bacteria in the Human Gut Microbiome (30) (Source)
Additionally, in the right balance and under the appropriate conditions, the good bacteria can better control and neutralize the less good pathogenic microbes which secrete toxic metabolites that cause, among other nefarious substances and processes, an increased excititory responses in the brain and increase inflammatory cytokine activity. In particular, a substance from gram-negative bacteria (E coli, Salmonella, Shigella, etc.) have a waste product called lipopolysaccharide (LPS) that inflames the brain and creates depressive like behavior. (31). (Source)
“Transient stimulation of the innate immune system by an intraperitoneal injection of lipopolysaccharide (LPS) activates peripheral and central expression of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase (IDO) which mediates depressive-like behavior. (…) These data establish that activation of the innate immune system in the brain is sufficient to activate IDO and induce depressive-like behavior in the absence of detectable IFN gamma. Targeting IDO itself may provide a novel therapy for inflammation-associated depression”. (32) (Source)
Hence, the need to better control these pathogenic microbes and regulate the gut with prebiotics, probiotics in combination with healthy, holistic & happy living, the impact of which can significantly help to boost many important “brain-gut” chemicals, one of which is key for depression and mental disorders, serotonin. As shown above, serotonin levels in the gastrointestinal tract (GI tract or gut), blood platelets, and the central nervous system (CNS) of animals, including humans, are signficantly modulated by the gut bacteria. In Holistic & Happiness medicine, we have many ways to encourage the body to produce its own key signaling molecules and chemicals without taking synthetic side-effct causing drugs. Cf., Young SN (2007). “How to increase serotonin in the human brain without drugs”. Rev. Psychiatr. Neurosci. 32 (6): 394–99).
The Blood Brain Barrier, Blood Sugar, inflammation and Depression
n blood brain barrier (BBB) is a tight network of blood vessels that is designed to only allow small nutrients to pass into the brain. The BBB is a mechanism the body uses to protect the brain from oxidative stress, infectious microbes, infectious microbes and chronic inflammation.
When blood sugar is thrown off balance it leads to openings in the BBB that allow for toxins to cross into the brain and increased inflammatory activity in the brain. This inflammation reduces neurotransmitter levels and leads to increased states of anxiety and depression.
“Depression was significantly associated with time to first severe hypoglycemic episode and number of hypoglycemic episodes. Research assessing whether recognition and effective treatment of depression among persons with diabetes prevents severe hypoglycemic episodes is needed”. (33) (Source)
Blood sugar imbalances also lead to nutrient deficiencies in key B vitamins, trace minerals and magnesium that further weaken the BBB and increase oxidative stress and inflammation in the brain
Top: Paired electrons gravitating around its proton-neutron nucleus. When electrons get unpaired, they create havoc, what is called “oxidative stress” (See below the Video explanation)
Oxidative Stress and Depression
Increased markers of oxidative stress relative to controls have been found in patients with MDD. A marker of DNA oxidation, 8-Oxo-2′-deoxyguanosine, has been found to be increased in both the plasma and urine of depressed patients. This along with the finding of increased F2-isoprostanes levels found in blood, urine and cerebrospinal fluid indicate increased damage to lipids and DNA in depressed patients. Studies with 8-Oxo-2′ Deoxyguanosine varied by methods of measurement and type of depression, but F2-Isoprostane level was consistent across depression types. Authors suggested lifestyle factors, dysregulation of the HPA axis, immune system and autonomics nervous system as possible causes. (34)
Another meta-analysis found similar results with regards to oxidative damage products as well as decreased oxidative capacity. (35) Oxidative stress is one of the key mechanisms of action insofar as most psychiatric diseases are concerned, including schizophrenia, bipolar and depression. (35 bis) Oxidative stress with its cousin electrophilic stress are also drivers of cognitive decline that we observe with the conventional aging process of human tissues.
Mitochondrial Dysfunction and Depression
Every cell of the body has mitochondria within it that produce energy for the cell. The mitochondria are the battery packs of the cell and they are extremely important on many fronts. High levels of oxidative stress wear down the mitochondria and cause a dysfunctional state.
In this perspective, studies have found that individuals with major depressive disorder have an advanced state of mitochondrial dysfunction.
“There is controversy about depression being a physical illness, in part because a reproducible, sensitive, and specific biologic marker is not available. However, there is evidence that mitochondrial dysfunction and oxidative stress may be associated with abnormal brain function and mood disorders, such as depression. This paper reviews selected human and animal studies providing evidence that intracellular mitochondrial metabolic dysfunction in specific brain regions is associated with major depressive disorder. This supports the hypothesis that chronic mitochondrial dysfunction in specific tissues may be associated with depression. Evaluation of mitochondrial dysfunction in specific tissues may broaden the perspective of depression beyond theories about neurotransmitters or receptor sites, and may explain the persistent signs and symptoms of depression” (36) (Source)
Abnormal mitochondrial morphology, size and density have all been reported in the brains of individuals with major depressive disorder and schizophrenia Research has shown that this is initiated by a profound glutathione (GSH) decrease and a mitochondrial dysfunction. (37)
Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neurodegenerative disorders. One of the results of this damage is both the depletion of gluthatione and a sustained overproduction of NO (nitric oxide). (Ibid) This pathway also accounts for the oxidative stress found so many mental disorders.
All of these new findings lead us to tentatively conclude that mental disorders like depression and schizophrenia tend to be metabolic in nature, where the mitochondria and its electron transport chain system are damaged.
A growing body of evidence suggests that mitochondrial dysfunction is important in patients with psychiatric disorders. The evidence include impaired energy metabolism in the brain detected using results of magnetic resonance spectroscopy, electron microscopy, co-morbidity with mitochondrial diseases, the effects of psychotropics on mitochondria, increased mitochondrial DNA (mtDNA) deletion in the brain, and association with mtDNA mutations/polymorphisms or nuclear-encoded mitochondrial genes. It is possible that the new information will lead to a focus on psychiatric disorder as a metabolic disease. Treatment with psychotropics might ultimately enhance energy metabolism and reduce the damage of oxidative stress. The next step in the study of mitochondrial dysfunction in patients with psychiatric disorders should be clarification of how mitochondrial dysfunction, a nonspecific risk factor, causes specific symptoms. Further study of mitochondrial dysfunction in patients with psychiatric disorder is expected to be useful for the development of cellular disease markers and new psychotropics. (38) (Source)
With these pieces of strong evidence, we are getting to the crux of mental disorders’ biochemical mechanisms of action, most of which stem from dysfunctional mitochondria combined with oxidative stress. As a consequence, we are dealing with metabolic and systemic diseases. This is why holistic and happiness medicine is clinically superior to the modern allopathic “a pill for every ill” approach, which can never be metabolic. See below the HMI’s metabolic and holistic approach for the details, ultra.
Mitochondrial dysfunction and defects in oxidative metabolism are a characteristic feature of many chronic illnesses not currently classified as mitochondrial diseases. Examples of such illnesses include bipolar disorder, multiple sclerosis, Parkinson’s disease, schizophrenia, depression, autism, and chronic fatigue syndrome. (…) This paper details mechanisms by which elevated levels of reactive oxygen and nitrogen species together with elevated pro-inflammatory cytokines could conspire to pave a major road to the development of mitochondrial dysfunction and impaired oxidative metabolism seen in many patients diagnosed with these disorders “ (39) (Source)
Glutathione Depletion, Nrf2 and Depression
Glutathione (GSH), the body’s master endogenous detoxification molecule and anti-oxidative stress antioxidant, is a key player in many chronic pathologies, from atherosclerosis to cancer and the dramas of mental illnesses.
“The GSH level was measured in the cerebral cortex, cerebellum, brain stem, and the hypothalamus (…) There was an appreciable depletion of cortical GSH in shocked mice that was corrected to varying degrees by the different antidepressants. The results suggest a close link between stress-induced behavioral depression, increased monoaminergic utilization, oxidative stress, and brain GSH. (40) (Source)
In certain mental disorders like Parkinson Disease and AD, the cells are under so much stress that their main protective shield made from Glutathione (GSH) gets worn down and the oxidative stress process damages the mitochondria and the DNA leading to cell death. In this realm, poor blood sugar control and high environmental toxin exposure are known to deplete glutathione levels and impair mitochondrial function, all the more so that the antioxidants that we take in will usually not mitigate the oxidative stress the mitochondria is subject to..
“Oxidative stress is believed to contribute to the pathogenesis of Parkinson’s disease. One of the indices of oxidative stress is the depletion of the antioxidant glutathione (GSH), which may occur early in the development of Parkinson’s disease. (…) Our studies have shown that the depletion of GSH causes a cascade of events, which ultimately may result in cell death. An early event following GSH depletion is a phospholipase A(2)-dependent release of arachidonic acid. Arachidonic acid can cause damage to the GSH-depleted cells through its metabolism by lipoxygenase. The generation of superoxide radicals during the metabolism of arachidonic acid is likely to play an important role in the toxic events that follow GSH depletion.”(41). (Source)
The NRf2 Pathway
Recent research has found a new signaling pathway that plays a key role in amplifying the anti oxidative stress effects of anti-oxidants in the body. When the body is confronted with major stressors the cells must quickly modulate their antioxidant capacity to counteract the increased oxidative stress. Among other mechanisms of action, it uses the Nrf2 pathway to do this. (42)
Nrf2 (NF-E2-related factor 2) is a transcription factor in humans encoded by a specific gene that regulates the expression of a set of antioxidant and detoxifying genes regarding which gluthatione is important. This pathway is activated under times of oxidative stress to enhance the expression of a multitude of antioxidant and phase II liver detoxification enzymes that restore homeostasis to the ox/redox cycles in the body (43).
As we mentioned, mood disorders such as depression, bipolar, addictions, have shown to be linked to chronic inflammation, and oxidative stress and poor neurotransmitter regulation. The Nrf2 pathway has been found to be useful in these realms, (44) including with electrophilic stress.
The Keap1-Nrf2 pathway regulates the expression of antioxidant enzymes such as glutathione perioxidase and NAD(P)H-quinone oxidoreductase 1. As a consequence, the liver works better, toxins get ejected including toxic estrogen metabolites (45).
Knowing that the weakening of this anti-depression pathway is part of causation, Holistic and Happiness medicine will therefore recommend Nrf2 Activators, including, but not limited to key curcumin, stilbenes, catechins, and sulforaphane. These molecules can be found in turmeric (curcumin), resveratrol (wine), berries (stilbenes), green tea and dark chocolate (catechins) and cruciferous veggies (sulforaphane). (See section C) Glutathione is a major modulator within this mechanism of action. (46)
MTOR, Animal Protein and Depression
MTOR is a newly discovered signaling pathway that is millions of years old (ie, also found in bacteria). This protein can modulate muscle growth, homeostasis and diseases, depending on whether it is over-activated or not. Called mammilian or mechanistic target of rapamycin, (mTOR for short), this biological process integrates a variety of environmental cues to regulate many cellular processes, from autophagy, muscle growth, cell differentiation, inflammation to nutrition sensing. (46 bis)
However, when hyper-activated, this mTOR pathway is also implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, depression and neurodegeneration, one effect of which is the acceleration of senescence (aging). (Source)
Different scientists are working on identifying the exact mechanisms of action that would better explain why overactivation of mTOR promotes these symptoms, from accelerated aging, depression and neurodegeneration to cancer. (46 ter).
On the other hand, what we know is that an unholistic diet made from killed animals will strongly activate an inflammed mTOR process provking the emergence of diseases and syndromes like Alzheimers, schizophrenia and depression. (46 quadro)
Methylation, Folate, Vitamin B-12 Deficiency and Depression
Science has shown that patients with depression have altered methylation processes due to genetic polymorphyisms (MTHFR, MTRR and COMT among others) and nutrient deficiencies, like folate and vitamin B-12.
“Folate and vitamin B12 are required both in the methylation of homocysteine to methionine and in the synthesis of S-adenosylmethionine. S-adenosylmethionine is involved in numerous methylation reactions involving proteins, phospholipids, DNA, and neurotransmitter metabolism. Both folate and vitamin B12 deficiency may cause similar neurologic and psychiatric disturbances including depression, dementia, and a demyelinating myelopathy. A current theory proposes that a defect in methylation processes is central to the biochemical basis of the neuropsychiatry of these vitamin deficiencies. Folate deficiency may specifically affect central monoamine metabolism and aggravate depressive disorders. In addition, the neurotoxic effects of homocysteine may also play a role in the neurologic and psychiatric disturbances that are associated with folate and vitamin B12 deficiency”. (47) (Source)
Methylation is a controlled transfer of a methyl group (one carbon and three hydrogen atoms) onto proteins, amino acids, enzymes and DNA in every cell and tissue of the body to regulate healing, cell energy, genetic expression of DNA, liver detoxification, immunity and neurology. Adapting to stress and the challenges of life is an aspect that methylation provides the body. Without adequate methylation processes the individual cannot adapt to stress effectively.
“Folate deficiency is also relatively common in depressed people, with approximately one-third of depressed individuals having an outright deficiency. Folate is a water-soluble B-vitamin necessary for the proper biosynthesis of the monoamine neurotransmitters serotonin, epinephrine, and dopamine. The active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF, L-methylfolate), participates in re-methylation of the amino acid metabolite homocysteine, creating methionine. S-adenosylmethionine (SAMe), the downstream metabolite of methionine, is involved in numerous biochemical methyl donation reactions, including reactions forming monoamine neurotransmitters. Without the participation of 5-MTHF in this process, SAMe and neurotransmitter levels decrease in the cerebrospinal fluid, contributing to the disease process of depression. SAMe supplementation was shown to improve depressive symptoms. 5-MTHF also appears to stabilize, enhance production of, or possibly act as a substitute for, tetrahydrobiopterin (BH4), an essential cofactor in monoamine neurotransmitter biosynthesis. There are few intervention studies of folic acid or 5-MTHF as a stand-alone treatment for depression related to folate deficiency; however, the studies that have been conducted are promising. Depressed individuals with low serum folate also tend to not respond well to selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Correcting the insufficiency by dosing folate along with the SSRI results in a significantly better antidepressant response”. (48) (Source)
Key methylation elements include the methylated B vitamins (riboflavin, B6, folate and B12 in particular), magnesium, selenium, zinc and various trace minerals. Individuals with depression are often deficient in these key nutrients and need nutritional and supplemental strategies to address these key methylating agents. See Section C for HMI’s recommendations in this realm.
Circadian rhythm (Sleep Deprivation and Light therapy)
Depression may also be related to the same brain mechanisms that control the cycles of sleep and wakefulness. As a result, when there are abnormalities in the circadian rhythm, or biological clock, depression is usually associated to this imbalance. (49) For example, rapid eye movement (REM) sleep (ie, which is the dream stage) may be quick to arrive and intense in depressed people. This is because REM sleep depends on decreased serotonin levels in the brain stem and depressed patients have decreased levels of serotonin. (50)
Overall, the serotonergic system is least active during sleep and most active during wakefulness. Prolonged wakefulness due to sleep deprivation activates serotonergic neurons, leading to processes similar to the therapeutic effect of antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), but without the drug’s side effects. In this regard, depressed patients can exhibit a significant lift in mood after a night of sleep deprivation. (51) Hence the HMI’s recommendation to enjoy an “all night party”, in combination with heliotherapy and the HMI’s other holistic techniques. (See Section C.)
Research on the effects of light therapy on seasonal affective disorder suggests that light deprivation is related to decreased activity in the serotonergic system and to abnormalities in the sleep cycle, particularly insomnia. Exposure to light also targets the serotonergic system, providing more support for the important role this system may play in depression. (52)
Thus, sleep deprivation and light therapy both target the same brain neurotransmitter system and brain areas as antidepressant drugs, and are now used clinically to treat depression. (53). However, sleep deprivation should not be done regularly. Sleep is also very curative. But to kick-start the recovery mechanism, it can be indicated to try at least one night of full sleep deprivation. Seen Section C.
Light therapy, sleep deprivation and also sleep time displacement (sleep phase advance therapy) are being used today in a few clinics. This strategy has good results for severe depressed hospitalized patients. (54)
Furthermore, increased and decreased sleep length appears to be a risk factor for depression. (55) Patients with MDD sometimes show diurnal and seasonal variation of symptom severity, even in non-seasonal depression. Diurnal mood improvement was associated with activity of dorsal neural networks. Increased mean core temperature was also observed. One hypothesis proposed that depression was a result of a phase shift. (56).
HPA Axis Abnormalities
HPA corresponds to the Hippocampus Pituirary Adrenal axis. HPA axis abnormalities have been suggested in depression given the association of CRHR1 with depression.(57)
These stress-related abnormalities have been hypothesized to be the cause of the Hippocampus’ volume reductions seen in depressed patients. (58)
Top: The Serotonin (a monoamine neuro-transmitter) Brain pathway
Monoamine neurotransmitter Imbalances and Depression
Monoamines are neurotransmitters that include serotonin, dopamine, norepinephrine, and epinephrine. Many antidepressant drugs increase synaptic levels of the monoamine neurotransmitter, serotonin, but they may also enhance the levels of two other neurotransmitters, norepinephrine and dopamine while producing side or toxic effects. The observation of some chemical rebalancing via monoamine intervention led to the monoamine hypothesis of depression, which postulates that the deficit of certain neurotransmitters is responsible for the corresponding features of depression.
The monoamine theory is thus based on the brain’s chemical neurotransmitters imbalances and is derived from the established correlation between monoaminergic drugs and symptomatology mitigation. This theory and its subsequent clinical application has been the dominant conventional “business as usual” model. It is empirically based on different pieces of evidence. For example, acute depletion of tryptophan, a necessary precursor of serotonin can cause depression in those in remission or relatives of depressed patients. This correlation this suggests that decreased serotonergic neurotransmission is important in depression. (59)
Furthermore, the proponents of this monoamine theary invoke the correlation between the risk of acquiring depression and the reality of polymorphism in the 5-HTTLPR gene, which codes for serotonin receptors. Polymorphism of dopamine receptor genes also implicates dopamine, another monoamine, in depression. (60) In addition, increased activity of monoamine oxidase, which degrades monoamines, has been associated with depression. (61)
The proponents of this pharmaceutical-based model recommend choosing the antidepressant with the mechanism of action impacting the most prominent symptoms. For this school, anxious or irritable patients should be treated with SSRIs or norepinephrine reuptake inhibitors, and the ones with the loss of energy and enjoyment of life should be given norepinephrine and dopamine enhancing drugs. Other proponents have also proposed monoamine norepinephrine in dysphoria, fatigue, apathy, cognitive dysfunction as well as dopamine in the loss of motivation and psychomotor symptoms.(62)
While the monoamine imbalance hypothesis has been oversimplified, (63) it nonetheless has some validity to it. Especially when there are emergencies, like suicidal, epilepsy or paranoia attacks, in which case drugs that can quickly correct the chemical brain imbalance may be indicated, even if this is a short term palliative intervention. Thereafter, it’s important to go back to a more holistic approach, if only to gently accustom the patient’s brain, gut and endocrine glands to restore homeostasis and the body’s own self-repair mechanisms.
It is on the basis of this above-mentioned pathophysiological and etiology analysis that i can now propose many holistic evidence-based depression reversal strategies.
Christian Joubert CSO and Director of HMI
For the proposed holistic and naturopathic solutions to Depression and most mental disorders, an eBOOK is pending. See Ebook Store for details.
Below, three short simplified video clips
Top: neurotransmitters misfiring and not flowing smoothly accross the synapse. Synapses are gaps between nerve cells. These cells convert their electrical impulses into bursts of chemical relayers, called neurotransmitters, which travel across the synapses to receptors on adjacent cells, triggering electrical impulses to travel down the latter cells.
Short Video Training on Oxidative Stress, Depression and Holistic Solutions like Joie de Vivre (JDV) emotional work
Top Picture: All people including mammals (like this cat above) have an amygdala, and thus feel emotions. The amygdala is a small almond-shaped structure in the brain involved in basic emotions like joy, fear, sadness, surprise, anger and frustration
Precision and Reference Notes
(1). Depression is not stress or being moody. even the feeling of grief resulting from the death of someone close is not itself depression if it does not persist. Depression can, however, be related to bereavement – when depression follows a loss, psychologists call it a “complicated bereavement.” www.ncbi.nlm.nih.gov/pmc/articles/PMC1414693/
4 Neuroimaging studies indicate that although many regions of the brain have been repeatedly implicated in the pathophysiology of depression. In recent times, the focus of neuroimaging has shifted from regional brain abnormalities to circuit level connectivity abnormalities. However, connectivity models are inherently more complicated, and the validity of these models remains to be tested.In future studies, this distributed nature of depression needs to be further investigated, primary and secondary areas affected need to be identified, and new paradigms to explain complex mental functions need to be explored.
(5). Paul B. Fitzgerald, Angela R. Laird, Jerome Maller, Zafiris J. Daskalakis (2008). A meta-analytic study of changes in brain activation in depression Human Brain Mapping, 29 (6), 683-695.
(6). Cf. Curr Psychiatry Rep. 2012 Dec; 14(6): 634–642. Problems can occur when excessive amounts of cortisol are sent to the brain due to a stressful event or a chemical imbalance in the body. In a healthy brain, brain cells are produced throughout a person’s adult life in a part of the hippocampus called the dentate gyrus. In people with MDD, however, the long-term exposure to increased cortisol levels can slow the production of new neurons and cause the neurons in the hippocampus to shrink
(7). American Psychiatric Association 2000a, pp. 419–20
(8). American Psychiatric Association 2000a, pp. 421–22
(9). American Psychiatric Association 2000a, pp. 417–18
(10). Nonacs, Ruta M (4 December 2007). “Postpartum depression”. eMedicine. Retrieved 30 October 2008.
(11). American Psychiatric Association 2000a, p. 425
(12). Translational Psychiatry (2015) 5, e683; doi:10.1038/tp.2015.174
Published online 17 November 2015 Subthreshold depression is associated with impaired resting-state functional connectivity of the cognitive control network
(13) Wright SL, Persad C (2007). “Distinguishing between depression and dementia in older persons: Neuropsychological and neuropathological correlates”. Journal of Geriatric Psychiatry and Neurology. 20 (4): 189–98. IL-10 appears to not be relevant in this process.
(14) Sadock 2002, p. 260
15). Hahn, Tim; Marquand, Andre F.; Ehlis, Ann-Christine; Dresler, Thomas; Kittel-Schneider, Sarah; Jarczok, Tomasz A.; Lesch, Klaus-Peter; Jakob, Peter M.; Mourao-Miranda, Janaina; Brammer, Michael J.; Fallgatter, Andreas J. (April 2011). “Integrating Neurobiological Markers of Depression” (PDF). JAMA Psychiatry. 68 (4): 361–368.
(16). In this perspective, One major inflammatory mediator is called a cytokine. Cytokines are cell signalling molecules that aid cell to cell communication in immune responses and stimulate the movement of cells towards sites of inflammation, infection and trauma. Examples of cytokines include interleukins and interferons which are found in abundance in sites of inflammation.
(17). ”Mental and behavioural disorders: Mood [affective] disorders”. World Health Organization. 2010.
(18). Krishnadas, Rajeev; Cavanagh, Jonathan (1 May 2012). “Depression: an inflammatory illness?”. Journal of Neurology, Neurosurgery, and Psychiatry. 83 (5): 495–502. Cf. Patel, Amisha (1 September 2013). “Review: the role of inflammation in depression”. Psychiatria Danubina. 25 Suppl 2: S216–223. Cf. Dowlati, Yekta; Herrmann, Nathan; Swardfager, Walter; Liu, Helena; Sham, Lauren; Reim, Elyse K.; Lanctôt, Krista L. (1 March 2010). “A meta-analysis of cytokines in major depression”. Biological Psychiatry. 67 (5): 446–457.
(19). www.ncbi.nlm.nih.gov/pubmed/19258033 www.ncbi.nlm.nih.gov/pubmed/23644052
(20) www.ncbi.nlm.nih.gov/pubmed/12469936 www.ncbi.nlm.nih.gov/pubmed/22681170
(21) Indian J Psychiatry. 2008 Apr-Jun; 50(2): 77–82. Understanding nutrition, depression and mental illnessesT. S. Sathyanarayana Rao, M. R. Asha,1 B. N. Ramesh,2 and K. S. Jagannatha Rao2
(22).Diet, Inflammation and the Brain Inflammatory dietary pattern and risk of depression among women Michel Lucas, Patricia Chocano-Bedoya, Matthias B. Schulze, Fariba Mirzaei, Éilis J. O’Reilly, Olivia I. Okereke, Frank B. Hu, Walter C. Willett, Alberto Ascherio Brain Behav. Immun. 36 (2014) 46–53] Brain, Behavior, and Immunity, Volume 46, May 2015, Pages 327 www.sciencedirect.com/science/article/pii/S0889159113004698
(23). The American Journal of Clinical Nutrition The American Journal of Clinical NutritionModels linking nutritional deficiencies to maternal and child mental health Theodore D Wachs1,2,3 1 From Purdue University, Department of Psychological Sciences, Purdue University, West Lafayette, Presented at the symposium “Maternal and Child Mental Health: Role of Nutrition,” held at Experimental Biology 2008, San Diego, CA, 8 April 2008. ajcn.nutrition.org/content/89/3/935S.full
(24). Raedler, Thomas J. (1 November 2011). “Inflammatory mechanisms in major depressive disorder”. Current Opinion in Psychiatry. 24 (6): 519–525. Cf, Köhler, Ole; Benros, Michael E.; Nordentoft, Merete; Farkouh, Michael E.; Iyengar, Rupa L.; Mors, Ole; Krogh, Jesper (1 December 2014). “Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials”. JAMA Psychiatry. 71 (12): 1381–1391. Cf, Sadock 2002, p. 288
(25). Aliment Pharmacol Ther. 2014 May;39(10):1104-12. doi: 10.1111/apt.12730. Epub 2014 Apr 1.Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity – an exploratory clinical study.Peters SL1, Biesiekierski JR, Yelland GW, Muir JG, Gibson PR. www.ncbi.nlm.nih.gov/pubmed/24689456
(26).Psychiatr Q. 2012 Mar; 83(1): 91–102.Neurologic and Psychiatric Manifestations of Celiac Disease and Gluten Sensitivitywww.ncbi.nlm.nih.gov/pmc/articles/PMC3641836/
(27). Curr Opin Psychiatry. 2015 Jan;28(1):1-6. The gut microbiome and diet in psychiatry: focus on depression. www.ncbi.nlm.nih.gov/pubmed/25415497
(28). CNS Neurol Disord Drug Targets. 2014;13(10):1770-86. Gut emotions – mechanisms of action of probiotics as novel therapeutic targets for depression and anxiety disorders. Slyepchenko A, Carvalho AF, Cha DS, Kasper S, McIntyre RS1. https://www.ncbi.nlm.nih.gov/pubmed/25470391
(30). GABA Modulating Bacteria in the Human Gut Microbiome Philip Strandwitz1, Ki-Hyun Kim2, Eric Stewart1, Jon Clardy2, and Kim Lewis1 1AAntimicrobial Discover Center, Department of Biology, Northeastern University, Boston, MA, USA Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
(31). Mol Psychiatry. 2009 May;14(5):511-22. doi: 10.1038/sj.mp.4002148. Epub 2008 Jan 15.Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice.O’Connor JC1, Lawson MA, André C, Moreau M, Lestage J, Castanon N, Kelley KW, Dantzer R. www.ncbi.nlm.nih.gov/pubmed/18195714
(32). J Neuroinflammation. 2010 Aug 2;7:43. doi: 10.1186/1742-2094-7-43.Central administration of lipopolysaccharide induces depressive-like behavior in vivo and activates brain indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures.Fu X1, Zunich SM, O’Connor JC, Kavelaars A, Dantzer R, Kelley KW. www.ncbi.nlm.nih.gov/pubmed/20678226
(33) Ann Fam Med. 2013 May-Jun;11(3):245-50. doi: 10.1370/afm.1501.
Association of depression with increased risk of severe hypoglycemic episodes in patients with diabetes. Katon WJ1, Young BA, Russo J, Lin EH, Ciechanowski P, Ludman EJ, Von Korff MR.www.ncbi.nlm.nih.gov/pubmed/23690324
(34) Gruenberg, A.M., Goldstein, R.D., Pincus, H.A. (2005). “Classification of Depression: Research and Diagnostic Criteria: DSM-IV and ICD-10” (PDF). Biology of Depression: From Novel Insights to Therapeutic Strategies (eds J. Licinio and M.-L. Wong). Wiley-VCH Verlag GmbH. doi:10.1002/9783527619672.ch1. Retrieved 30 October 2008.
(35) ”The ICD-10 Classification of Mental and Behavioural Disorders: Clinical descriptions and diagnostic guidelines” (PDF). World Health Organization. 2010.
Decreased leukocyte telomere lengths were found. Cf., Clinical description and diagnostic guideline. Geneva: World Health Organization, 1992
(35 bis). Case in point: “The evidence behind oxidative stress mechanisms in schizophrenia can be grouped into three categories: first, those studies that illustrate disturbed oxidative homeostasis through oxidative enzyme genetic poly- morphism and quantification of antioxidants, free radicals and markers of oxidative damage; second, those demonstrating antioxidant mechanisms of es- tablished antipsychotic drugs; third, those showing benefits from antioxidant therapies”. (Source)
(36) Neuropsychiatr Dis Treat. 2013;9:567-73. doi: 10.2147/NDT.S44282. Epub 2013 Apr 26.Mitochondrial dysfunction, oxidative stress, and major depressive disorder.www.ncbi.nlm.nih.gov/pubmed/23650447
(37). Neuropsychopharmacology (2001) 24, 420–429. Glutathione Depletion, Lipid Peroxidation and Mitochondrial Dysfunction Are Induced by Chronic Stress in Rat BrainJose LM Madrigal BSc1, Raquel Olivenza BSc1, Maria A Moro Ph.D1, Ignacio Lizasoain MD, Ph.D1, Pedro Lorenzo MD, Ph.D1, Jose Rodrigo MD, Ph.D2 and Juan C Leza MD, Ph.D1
(38) Chang Gung Med J. 2009 Jul-Aug;32(4):370-9. Mitochondrial dysfunction and psychiatric disorders.www.ncbi.nlm.nih.gov/pubmed/19664343 See also BMC Med. 2015 Apr 1;13:68. Mitochondria are intracellular organelles crucial in the production of cellular energy. Mitochondrial diseases may result from malfunctions in this biochemical cascade. Several investigators have proposed that mitochondrial dysfunction is related to the pathophysiology of bipolar disorder (BD), major depressive disorder (MDD) and schizophrenia (SZ). The authors reviewed recent study findings and tried to delineate the current understanding of the correlation between mitochondrial dysfunction and psychiatric disorders.
(39). The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders.Morris G1, Berk M2,3,4,5. https://www.ncbi.nlm.nih.gov/pubmed/25889215
(40). Pharmacol Biochem Behav. 1994 Aug;48(4):845-51.Glutathione as a cerebral substrate in depressive behavior. https://www.ncbi.nlm.nih.gov/pubmed/7972287
(41). Parkinsonism Relat Disord. 2002 Sep;8(6):385-7.
Glutathione depletion and oxidative stress.
(42). Kang KW, Lee SJ, Kim SG. Molecular mechanism of nrf2 activation by oxidative stress. Antioxid Redox Signal. 2005 Nov-Dec;7(11-12):1664-73. PMID: 16356128
(43). Katoh Y, Iida K, Kang MI, Kobayashi A, Mizukami M, Tong KI, McMahon M, Hayes JD, Itoh K, Yamamoto M. Evolutionary conserved N-terminal domain of Nrf2 is essential for the Keap1-mediated degradation of the protein by proteasome. Arch Biochem Biophys. 2005 Jan 15;433(2):342-50. See also Surh YJ, Kundu JK, Na HK. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals.Planta Med. 2008 Oct;74(13):1526-39.
(44). Miller DM, Singh IN, Wang JA, Hall ED. Nrf2-ARE activator carnosic acid decreases mitochondrial dysfunction, oxidative damage and neuronal cytoskeletal degradation following traumaticbrain injury in mice.Exp Neurol. 2014 Nov 26;264C:103-110. Cf., Kärkkäinen V, Pomeshchik Y, Savchenko E, Dhungana H, Kurronen A, Lehtonen S, Naumenko N, Tavi P, Levonen AL, Yamamoto M, Malm T, Magga J, Kanninen KM, Koistinaho J. Nrf2regulates neurogenesis and protects neural progenitor cells against Aβ toxicity. Stem Cells. 2014 Jul;32(7):1904-16. Cf. Sandberg M, Patil J, D’Angelo B, Weber SG, Mallard C. NRF2-regulation in brain health and disease: implication of cerebral inflammation. 2014 Apr;79:298-306.
(45). Cf., Li J, Stein TD, Johnson JA.Geneticdissectionof systemic autoimmune disease in Nrf2-deficient mice. Physiol Genomics. 2004 Aug 11;18(3):261-72. Cf. Lee JM, Chan K, Kan YW, Johnson JA. Targeted disruption of Nrf2 causes regenerative immune-mediated hemolytic anemia.Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9751-6.
(46). In the vast majority of patients with chronic illnesses, there’s one consistent finding: a lack of adequate glutathione. Glutathione is one of the most important elements in the body. It protects us from oxidative stress, helps us detoxify, and plays a key role in the regulation of our neurotransmitters. Lack of glutathione is associated with virtually all chronic neurological degenerative diseases, diabetes, heart disease, migraines, depression, cancer, and autoimmune diseases. The government’s medical database, pubmed.gov, and put in glutathione, you’ll find 110,000 citations. There are more than 700 citations discussing glutathione and depression, 500 references discussing glutathione and Parkinson’s disease, and 3,300 references related to diabetes and glutathione. Oxidative stress is a result of energy production in the body, and we can’t live without oxidation. If it isn’t controlled, it can also destroy our body. The process of making energy results in heat and exhaust and chemical byproducts that need to be released. Up to 25 percent of ROS comes from oxidative phosphoration. Vitamin C, vitamin E, and CoQ10 when used with glutathione helps to recycle and renew the body. The other purpose of glutathione is to remove toxins from the body. When glutathione removes a toxin, it binds to that toxin and leaves the body with the toxin. Consequently, we have to replace (or the body has to produce) the glutathione in order for us to maintain healthy levels.
(46 bis). The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.
(46 ter). Kennedy BK, Lamming DW (June 2016). “The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging”. Cell Metabolism. 23 (6): 990–1003.
(46 quadro). Beevers CS, Li F, Liu L, Huang S (August 2006). “Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells”. International Journal of Cancer. 119 (4): 757–64.
(47). Nutr Rev. 1996 Dec;54(12):382-90.
Folate, vitamin B12, and neuropsychiatric disorders. Bottiglieri T1. www.ncbi.nlm.nih.gov/pubmed/9155210
(48). Altern Med Rev. 2008 Sep;13(3):216-26. Cf. The methylation, neurotransmitter, and antioxidant connections between folate and depression.Miller AL1. www.ncbi.nlm.nih.gov/pubmed/18950248
(49). Carlson, Neil R. (2013). Physiology of behavior (11th ed.). Boston: Pearson. pp. 578–582. ISBN 978-0-205-23939-9.
(50). Adrien J.. Neurobiological bases for the relation between sleep and depression. Sleep Medicine Review. 2003;6(5):341–51.
(51). op cit, Carlson)
(52). Terman M. Evolving applications of light therapy. Sleep Medicine Review. 2007;11(6):497–507. doi:10.1016/j.smrv.2007.06.003.
(53). Benedetti F, Barbini B, Colombo C, Smeraldi E. Chronotherapeutics in a psychiatric ward. Sleep Medicine Review. 2007;11(6):509–22. doi:10.1016/j.smrv.2007.06.004. PMID 17689120
(54). Op cit, Terman.
(55). Zhai, Long; Zhang, Hua; Zhang, Dongfeng (1 September 2015). “SLEEP DURATION AND DEPRESSION AMONG ADULTS: A META-ANALYSIS OF PROSPECTIVE STUDIES”. Depression and Anxiety. 32 (9): 664–670.
(56). Germain, Anne; Kupfer, David J. (6 December 2016). “CIRCADIAN RHYTHM DISTURBANCES IN DEPRESSION”. Human psychopharmacology. 23 (7): 571–585.
(57). Arana, George W. (1 December 1985). “The Dexamethasone Suppression Test for Diagnosis and Prognosis in Psychiatry”. Archives of General Psychiatry. 42 (12): 1193–204
(58). Varghese, Femina P.; Brown, E. Sherwood (1 January 2001). “The Hypothalamic-Pituitary-Adrenal Axis in Major Depressive Disorder: A Brief Primer for Primary Care Physicians”. Primary Care Companion to The Journal of Clinical Psychiatry. 3 (4): 151–155.
(59). Ruhe, HG; Mason, NS; Schene, AH (2007). “Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies”. Molecular Psychiatry. 12: 331–359.
(60) HASLER, GREGOR (4 December 2016). “PATHOPHYSIOLOGY OF DEPRESSION: DO WE HAVE ANY SOLID EVIDENCEOF INTEREST TO CLINICIANS?”. World Psychiatry. 9 (3): 155–161. PMC 2950973 . Cf. Dunlop, Boadie W.; Nemeroff, Charles B. (1 April 2007). “The Role of Dopamine in the Pathophysiology of Depression”. Archives of General Psychiatry. 64 (3): 327–37.
(61). Meyer JH, Ginovart N, Boovariwala A, et al. (November 2006). “Elevated monoamine oxidase a levels in the brain: An explanation for the monoamine imbalance of major depression”. Archives of General Psychiatry. 63 (11): 1209–16. Cf. Kenneth L. Davis; et al. (2002). Neuropsychopharmacology : the fifth generation of progress : an official publication of the American College of Neuropsychopharmacology (5th ed.). Philadelphia, Pa.: Lippincott Williams & Wilkins. pp. 1139–1163.
(62) Nutt DJ (2008). “Relationship of neurotransmitters to the symptoms of major depressive disorder”. Journal of Clinical Psychiatry. 69 Suppl E1: 4–7.
Cf also, Marchand; Valentina; Jensen. “Neurobiology of Mood disorders”. Hospital physician: 17–26.
(63). Lacasse, Jeffrey R.; Leo, Jonathan (8 November 2005). “Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature”. PLoS Medicine. 2 (12)
(*). In this working definition as well as in the text, there are multiple concepts that may need clarification:
Neuropeptides are small protein-like molecules (peptides) used by neurons to communicate with each other. They are neuronal signaling molecules that influence the activity of the brain and the body in specific ways. Different neuropeptides are involved in a wide range of brain functions, including analgesia, reward, food intake, metabolism, reproduction, social behaviors, learning and memory. Neuropeptides are essentially related to peptide hormones, and in some cases peptides that function in the periphery as hormones also have neuronal functions as neuropeptides. The distinction between neuropeptide and peptide hormone has to do with the cell types that release and respond to the molecule; neuropeptides are secreted from neuronal cells (primarily neurons but also glia for some peptides) and signal to neighboring cells (primarily neurons). In contrast, peptide hormones are secreted from neuroendocrine cells and travel through the blood to distant tissues where they evoke a response. Both neuropeptides and peptide hormones are synthesized by the same sets of enzymes. (Neuropeptides and Other Bioactive Peptides: From Discovery to Function, L.D.Fricker, Morgan & Claypool Publishers, 2012)
Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group that is connected to an aromatic ring by a two-carbon chain (-CH2-CH2-). All monoamines are derived from aromatic amino acids like phenylalanine, tyrosine, tryptophan, and the thyroid hormones by the action of aromatic amino acid decarboxylase enzymes. Monoaminergic systems, i.e., the networks of neurons that utilize monoamine neurotransmitters, are involved in the regulation of cognitive processes such as emotion, arousal, and certain types of memory. It has been found that monoamine neurotransmitters play an important role in the secretion and production of neurotrophin-3 by astrocytes, a chemical which maintains neuron integrity and provides neurons with trophic support. Cf. Carlson, Neil R. (2005). Foundations of Physiological Psychology (6th ed.). Boston: Pearson A and B. p. 108. Nutt DJ (2008). “Relationship of neurotransmitters to the symptoms of major depressive disorder”. Journal of Clinical Psychiatry. 69 Suppl E1: 4–7. Marchand; Valentina; Jensen. “Neurobiology of Mood disorders”. Hospital physician: 17–26.
Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract (GI tract), blood platelets, and the central nervous system (CNS) of animals, including humans. It is popularly thought to be a contributor to feelings of well-being and happiness. Approximately 90% of the human body’s total serotonin is located in the enterochromaffin cells in the GI tract, where it is used to regulate intestinal movements.[The serotonin is secreted luminally and basolaterally which leads to increased serotonin uptake by circulating platelets and activation after stimulation, which gives increased stimulation of myenteric neurons and gastrointestinal motility. (Source)http://www.cell.com/cell/abstract/S0092-8674(15)00248-2The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants. Young SN (2007). “How to increase serotonin in the human brain without drugs”. Rev. Psychiatr. Neurosci. 32 (6): 394–99. Cf also King MW. “Serotonin”. The Medical Biochemistry Page. Indiana University School of Medicine. Berger M, Gray JA, Roth BL; Gray; Roth (2009). “The expanded biology of serotonin”. Annu. Rev. Med. 60: 355–66
The genotype of an organism is defined as the sum of all its genes. The phenotype of an organism is the observable physical or biochemical characteristics of an organism, determined by both genetic make-up and environmental influences.
Redox (short for reduction–oxidation reaction) is a chemical reaction in which the oxidation states of atoms are changed. Any such reaction involves both a reduction process and a complementary oxidation process, two key concepts involved with electron transfer processes. Redox reactions include all chemical reactions in which atoms have their oxidation state changed; in general, redox reactions involve the transfer of electrons between chemical species. The chemical species from which the electron is stripped is said to have been oxidized, while the chemical species to which the electron is added is said to have been reduced. It can be explained in simple terms: Oxidation is the loss of electrons or an increase in oxidation state by a molecule, atom, or ion. Reduction is the gain of electrons or a decrease in oxidation state by a molecule, atom, or ion. As an example, during the combustion of wood, oxygen from the air is reduced, gaining electrons from the carbon. Although oxidation reactions are commonly associated with the formation of oxides from oxygen molecules, oxygen is not necessarily included in such reactions, as other chemical species can serve the same function. The reaction can occur relatively slowly, as in the case of rust, or more quickly, as in the case of fire. There are simple redox processes, such as the oxidation of carbon to yield carbon dioxide (CO2) or the reduction of carbon by hydrogen to yield methane (CH4), and more complex processes such as the oxidation of glucose (C6H12O6) in the human body.
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalysed by protein kinases, which ultimately results in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding (or signal sensing) in a receptor give rise to a signaling cascade, which is a chain of biochemical events along a signaling pathway. When signaling pathways interact with one another they form networks, which allow cellular responses to be coordinated, often by combinatorial signaling events. At the molecular level, such responses include changes in the transcription or translation of genes, and post-translational and conformational changes in proteins, as well as changes in their location. These molecular events are the basic mechanisms controlling cell growth, proliferation, metabolism and many other processes. In other words, signal transduction pathways have evolved to regulate cell communication in a wide variety of ways.