Back Clinic Depression Chiropractic Therapeutic Team. A (major depressive disorder or clinical depression) is a common but serious mood disorder. It causes severe symptoms that affect how individuals feel, think, and handle daily activities, i.e., sleeping, eating, and working. To be diagnosed with depression, the symptoms must be present for at least two weeks.
Persistent sad, anxious, or empty mood.
Feelings of hopelessness, pessimism.
Feelings of guilt, worthlessness, or helplessness.
Loss of interest or pleasure in activities.
Decreased energy or fatigue.
Moving or talking slowly.
Feeling restless & having trouble sitting still.
Difficulty concentrating, remembering, or making decisions.
Thoughts of death or suicide & or suicide attempts.
Aches or pains, headaches, cramps, or digestive problems without a clear physical cause and/or do not ease treatment.
Not everyone who is depressed experiences every symptom. Some experience only a few symptoms, while others may experience several. Several persistent symptoms in addition to low mood are required for a diagnosis of major depression. The severity and frequency of symptoms and the duration will vary depending on the individual and their particular illness. Symptoms can also vary depending on the stage of the illness.
Doctors understand that people with depression can experience weight gain and over time, it may eventually lead to obesity if left untreated. Depression is also associated with poor eating habits, overeating, and a more sedentary lifestyle. According to the Centers for Disease Control and Prevention (CDC), approximately 43 percent of people with depression have excess weight or obesity. In a 2002 research study, scientists found that children with depression had an increased risk of suffering from obesity. In the following article, we will discuss what you need to know about obesity and depression. �
Understanding Obesity and Depression
Mental health issues, such as anxiety and depression, are associated with obesity. A 2010 research study found that about 55 percent of people with obesity had an increased risk of developing depression and other mental health issues compared to “healthy” people. Moreover, obesity can also cause a variety of other health issues, including joint pain, hypertension, and diabetes, among others. Anxiety, by way of instance, can also ultimately cause depression and obesity. Scientists believe that stress can make people turn to food as a coping mechanism. This can eventually lead to excess weight gain and obesity. �
Scientists were once hesitant to connect obesity and depression, however, further evidence from numerous research studies has demonstrated that excess weight or obesity can cause a variety of mental health issues like anxiety and depression. Many doctors utilize a multi-pronged treatment approach to help improve a patient’s mental and physical health. Scientists still don’t quite understand how obesity is closely associated with depression but it is clear that there’s a connection between obesity and depression. Furthermore, research studies demonstrated that mental health issues may also cause obesity. �
The Connection Between Obesity and Depression
Obesity and depression, as well as any other mental health issues, are can also cause a variety of other health issues if left untreated, including chronic pain, coronary heart disease, hypertension, sleep problems, and diabetes. Fortunately, all of these health issues can be properly diagnosed, treated, and prevented by following a proper treatment program. Treating the underlying source of a patient’s depression, by way of instance, may help restore their energy in order to help them participate in exercise and physical activities. Engaging in exercise and physical activities may, in turn, help patients lose weight. �
Dietary and lifestyle modifications can also be utilized to help treat a variety of mental and physical health issues, including obesity and depression. It’s essential to seek immediate medical attention from qualified and experienced doctors who can help guide patients in the right direction. If you’ve ever experienced any of the following red-flags, symptoms, or side-effects, including loss of all interest in regular activities that you used to enjoy, an inability to get up from bed or leave your house, abnormal sleep patterns, feeling tired or fatigued, and weight gain, talk to your doctor about what you can do. �
Dealing with Obesity and Depression
A strategic treatment plan for obesity and depression can ultimately be different, however, several methods and techniques can also help improve the underlying source of the other health issue. You can reduce your risk of developing obesity and depression by following proper nutritional or dietary guidelines and engaging in exercise or physical activities. Participating in exercise or physical activities is a great way to naturally help boost endorphins as well as neurotransmitters like dopamine and serotonin that help boost and balance mood, ultimately helping you lose weight and feel better. �
Research studies demonstrated that engaging in exercise or physical activities at least once per week can have a considerable effect on symptoms of depression. Doctors also understand that when you have depression, finding the motivation to participate in exercise or physical activities can be challenging. Doctors recommend taking small steps, such as engaging in 10 minutes of exercise or physical activities every day, may help people get in the habit of participating in exercise or physical activities. Talk to your doctor about the right amount of exercise or physical activity that you should do. �
Talking to a therapist or psychologist is a well-known treatment approach for a variety of mental and physical health issues. From anxiety and depression to excess weight and obesity, a therapist or psychiatrist can help you process the emotional factors that may be causing the underlying source of your health issues. They can also help you embrace changes that will help you improve your quality of life. Following a strategic treatment plan and always being honest with your healthcare professional may ultimately help improve obesity and depression as well as any symptoms, side-effects, and complications. �
Obesity and depression are well-known health issues that need long-term care and attention. It�s essential to talk to your doctor regardless of whether you�re following your strategic treatment plan. Being honest about what you are and aren�t doing is the only way for your doctor to understand and help with your underlying health issues. Your doctor is your best resource for information and they�ll work with you to find the best treatment for your needs, help you create a healthier lifestyle, and hold you accountable for the changes you seek. People with obesity and depression can ultimately restore their wellness. �
Research studies demonstrated that obesity is associated with mental health issues like anxiety and depression. Doctors understand that people with depression can experience weight gain and over time, it may eventually lead to obesity if left untreated. Depression is also associated with poor eating habits, overeating, and a more sedentary lifestyle. According to the Centers for Disease Control and Prevention (CDC), approximately 43 percent of people with depression have excess weight or obesity. In a 2002 research study, scientists found that children with depression had an increased risk of suffering from obesity. In the following article, we will discuss what you need to know about obesity and depression, including the connection between obesity and depression as well as dealing with these mental and physical health issues, among others. – Dr. Alex Jimenez D.C., C.C.S.T. Insight
Doctors understand that people with depression can experience weight gain and over time, it may eventually lead to obesity if left untreated. Depression is also associated with poor eating habits, overeating, and a more sedentary lifestyle. According to the Centers for Disease Control and Prevention (CDC), approximately 43 percent of people with depression have excess weight or obesity. In a 2002 research study, scientists found that children with depression had an increased risk of suffering from obesity. In the article above, we will ultimately discuss what you need to know about obesity and depression. �
The scope of our information is limited to chiropractic, musculoskeletal, and nervous health issues or functional medicine articles, topics, and discussions. We use functional health protocols to treat injuries or disorders of the musculoskeletal system. Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We also make copies of supporting research studies available to the board and or the public upon request. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900.�
Curated by Dr. Alex Jimenez �
Holland, Kimberly. �Are Obesity and Depression Related? And 9 Other FAQs.� Healthline, Healthline Media, 11 May 2018, www.healthline.com/health/depression/obesity-and-depression.
The following Neurotransmitter Assessment Form can be filled out and presented to Dr. Alex Jimenez. The following symptoms listed on this form are not intended to be utilized as a diagnosis of any type of disease, condition, or any other type of health issue. �
Additional Topic Discussion: Chronic Pain
Sudden pain is a natural response of the nervous system which helps to demonstrate possible injury. By way of instance, pain signals travel from an injured region through the nerves and spinal cord to the brain. Pain is generally less severe as the injury heals, however, chronic pain is different than the average type of pain. With chronic pain, the human body will continue sending pain signals to the brain, regardless if the injury has healed. Chronic pain can last for several weeks to even several years. Chronic pain can tremendously affect a patient’s mobility and it can reduce flexibility, strength, and endurance. �
Neural Zoomer Plus for Neurological Disease
Dr. Alex Jimenez utilizes a series of tests to help evaluate neurological diseases. The Neural ZoomerTM Plus is an array of neurological autoantibodies which offers specific antibody-to-antigen recognition. The Vibrant Neural ZoomerTM Plus is designed to assess an individual�s reactivity to 48 neurological antigens with connections to a variety of neurologically related diseases. The Vibrant Neural ZoomerTM Plus aims to reduce neurological conditions by empowering patients and physicians with a vital resource for early risk detection and an enhanced focus on personalized primary prevention. �
Food Sensitivity for the IgG & IgA Immune Response
Dr. Alex Jimenez utilizes a series of tests to help evaluate health issues associated with a variety of food sensitivities and intolerances. The Food Sensitivity ZoomerTM is an array of 180 commonly consumed food antigens that offers very specific antibody-to-antigen recognition. This panel measures an individual�s IgG and IgA sensitivity to food antigens. Being able to test IgA antibodies provides additional information to foods that may be causing mucosal damage. Additionally, this test is ideal for patients who might be suffering from delayed reactions to certain foods. Utilizing an antibody-based food sensitivity test can help prioritize the necessary foods to eliminate and create a customized diet plan around the patient�s specific needs. �
Gut Zoomer for Small Intestinal Bacterial Overgrowth (SIBO)
Dr. Alex Jimenez utilizes a series of tests to help evaluate gut health associated with small intestinal bacterial overgrowth (SIBO). The Vibrant Gut ZoomerTM offers a report that includes dietary recommendations and other natural supplementation like prebiotics, probiotics, and polyphenols. The gut microbiome is mainly found in the large intestine and it has more than 1000 species of bacteria that play a fundamental role in the human body, from shaping the immune system and affecting the metabolism of nutrients to strengthening the intestinal mucosal barrier (gut-barrier). It is essential to understand how the number of bacteria that symbiotically live in the human gastrointestinal (GI) tract influences gut health because imbalances in the gut microbiome may ultimately lead to gastrointestinal (GI) tract symptoms, skin conditions, autoimmune disorders, immune system imbalances, and multiple inflammatory disorders. �
Formulas for Methylation Support
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* All of the above XYMOGEN policies remain strictly in force. �
Modern Integrated Medicine
The National University of Health Sciences is an institution that offers a variety of rewarding professions to attendees. Students can practice their passion for helping other people achieve overall health and wellness through the institution’s mission. The National University of Health Sciences prepares students to become leaders in the forefront of modern integrated medicine, including chiropractic care. Students have an opportunity to gain unparalleled experience at the National University of Health Sciences to help restore the natural integrity of the patient and define the future of modern integrated medicine. �
Depression is one of the most common mental health issues in the United States. Current research suggests that depression results from a combination of genetic, biological, ecological, and psychological aspects. Depression is a major psychiatric disorder worldwide with a significant economic and psychological strain on society. Fortunately, depression, even the most severe cases, may be treated. The earlier that treatment can begin, the more effective it is.
As a result, however, there’s a need for robust biomarkers that will aid in improving diagnosis in order to accelerate the drug and/or medication discovery process for each patient with the disorder. These are objective, peripheral physiological indicators which presence can be used to predict the probability of onset or existence of depression, stratify according to severity or symptomatology, indicate predict and prognosis or monitor response to therapeutic interventions. The purpose of the following article is to demonstrate recent insights, current challenges and future prospects regarding the discovery of a variety of biomarkers for depression and how these can help improve diagnosis and treatment.
Biomarkers for Depression: Recent Insights, Current Challenges and Future Prospects
A plethora of research has implicated hundreds of putative biomarkers for depression, but has not yet fully elucidated their roles in depressive illness or established what is abnormal in which patients and how biologic information can be used to enhance diagnosis, treatment and prognosis. This lack of progress is partially due to the nature and heterogeneity of depression, in conjunction with methodological heterogeneity within the research literature and the large array of biomarkers with potential, the expression of which often varies according to many factors. We review the available literature, which indicates that markers involved in inflammatory, neurotrophic and metabolic processes, as well as neurotransmitter and neuroendocrine system components, represent highly promising candidates. These may be measured through genetic and epigenetic, transcriptomic and proteomic, metabolomic and neuroimaging assessments. The use of novel approaches and systematic research programs is now required to determine whether, and which, biomarkers can be used to predict response to treatment, stratify patients to specific treatments and develop targets for new interventions. We conclude that there is much promise for reducing the burden of depression through further developing and expanding these research avenues.
Keywords:mood disorder, major depressive disorder, inflammation, treatment response, stratification, personalized medicine
Challenges in Mental Health and Mood Disorders
Although psychiatry has a disease-related burden greater than any single other medical diagnostic category,1 a disparity of esteem is still apparent between physical and mental health across many domains including research funding2 and publication.3 Among the difficulties that mental health faces is a lack of consensus surrounding classification, diagnosis and treatment that stems from an incomplete understanding of the processes underlying these disorders. This is highly apparent in mood disorders, the category which comprises the single largest burden in mental health.3 The most prevalent mood disorder, major depressive disorder (MDD), is a complex, heterogeneous illness in which up to 60% of patients may experience some degree of treatment resistance that prolongs and worsens episodes.4 For mood disorders, and in the broader field of mental health, treatment outcomes would likely be improved by the discovery of robust, homogeneous subtypes within (and across) diagnostic categories, by which treatments could be stratified. In recognition of this, global initiatives to delineate functional subtypes are now in progress, such as the research domain criteria.5 It has been posited that biologic markers are priority candidates for subtyping mental disorders.6
Improving Response to Treatments for Depression
Despite an extensive range of treatment options for major depression, only approximately a third of patients with MDD achieve remission even when receiving optimal antidepressant treatment according to consensus guidelines and using measurement-based care, and rates of treatment response appear to fall with each new treatment.7 Furthermore, treatment-resistant depression (TRD) is associated with increased functional impairment, mortality, morbidity and recurrent or chronic episodes in the long term.8,9 Thus, obtaining improvements in treatment response at any clinical stage would afford wider benefits for overall outcomes in depression. Despite the substantial burden attributable to TRD, research in this area has been sparse. Definitions of TRD are not standardized, in spite of previous attempts:4 some criteria require only one treatment trial that fails to achieve a 50% symptom score reduction (from a validated measure of depression severity), while others require non-achievement of full remission or nonresponse to at least two adequately trialed antidepressants of different classes within an episode to be considered TRD.4,10 Furthermore, the staging and prediction of treatment resistance is improved by adding the key clinical features of severity and chronicity to the number of failed treatments.9,11 Nevertheless, this inconsistency in definition renders interpreting the research literature on TRD an even more complex task.
In order to improve response to treatments, it is clearly helpful to identify predictive risk factors of nonresponse. Some general predictors of TRD have been characterized, including a lack of full remission after previous episodes, comorbid anxiety, suicidality and early onset of depression, as well as personality (particularly low extraversion, low reward dependence and high neuroticism) and genetic factors.12 These findings are corroborated by reviews synthesizing the evidence separately for pharmacologic13 and psychological14 treatment for depression. Antidepressants and cognitive-behavioral therapies show approximately comparable efficacy,15 but due to their differing mechanisms of action might be expected to have different predictors of response. While early-life trauma has long been associated with poorer clinical outcomes and reduced responses to treatment,16 early indications suggest that people with a history of childhood trauma might respond better to psychological than pharmacologic therapies.17 Despite this, uncertainty prevails and little personalization or stratification of treatment has reached clinical practice.18
This review focuses on the evidence supporting the utility of biomarkers as potentially useful clinical tools to enhance treatment response for depression.
Biomarkers: Systems and Sources
Biomarkers provide a potential target for identifying predictors of response to various interventions.19 The evidence to date suggests that markers reflecting the activity of inflammatory, neurotransmitter, neurotrophic, neuroendocrine and metabolic systems may be able to predict mental and physical health outcomes in currently depressed individuals, but there is much inconsistency between findings.20 In this review, we focus on these five biologic systems.
To attain a full understanding of molecular pathways and their contribution in psychiatric disorders, it is now considered important to assess multiple biologic �levels�, in what is popularly referred to as an �omics� approach.21 Figure 1 provides a depiction of the different biologic levels at which each of the five systems can be assessed, and the potential sources of markers on which these assessments can be undertaken. However, note that while each system can be inspected at each omics level, the optimal sources of measurement clearly vary at each level. For example, neuroimaging provides a platform for indirect assessment of brain structure or function, while protein examinations in blood directly assess markers. Transcriptomics22 and metabolomics23 are increasingly popular, offering assessment of potentially huge numbers of markers, and the Human Microbiome Project is now attempting to identify all microorganisms and their genetic composition within humans.24 Novel technologies are enhancing our ability to measure these, including through additional sources; for example, hormones such as cortisol can now be assayed in hair or fingernails (providing a chronic indication) or sweat (providing a continuous measurement),25 as well as in blood, cerebrospinal fluid, urine and saliva.
Given the number of putative sources, levels and systems involved in depression, it is not surprising that the scale of biomarkers with translational potential is extensive. Particularly, when interactions between markers are considered, it is perhaps unlikely that examining single biomarkers in isolation will yield findings fruitful for improving clinical practice. Schmidt et al26 proposed the use of biomarker panels and, subsequently, Brand et al27 outlined a draft panel based on prior clinical and preclinical evidence for MDD, identifying 16 �strong� biomarker targets, each of which is rarely a single marker. They comprise reduced gray matter volume (in hippocampal, prefrontal cortex and basal ganglia regions), circadian cycle changes, hypercortisolism and other representations of hypothalamic�pituitary�adrenal (HPA) axis hyperactivation, thyroid dysfunction, reduced dopamine, noradrenaline or 5-hydroxyindoleacetic acid, increased glutamate, increased superoxide dismutase and lipid peroxidation, attenuated cyclic adenosine 3?,5?-monophosphate and mitogen-activated protein kinase pathway activity, increased proinflammatory cytokines, alterations to tryptophan, kynurenine, insulin and specific genetic polymorphisms. These markers have not been agreed by consensus and could be measured in various ways; it is clear that focused and systematic work must address this enormous task in order to prove their clinical benefits.
Aims of this Review
As a deliberately broad review, this article seeks to determine the overall needs for biomarker research in depression and the extent to which biomarkers hold real translational potential for enhancing response to treatments. We begin by discussing the most important and exciting findings in this field and direct the reader to more specific reviews pertaining to relevant markers and comparisons. We outline the current challenges faced in light of the evidence, in combination with needs for reducing the burden of depression. Finally, we look ahead to the important research pathways for meeting current challenges and their implications for clinical practice.
The search for clinically useful biomarkers for people with depression has generated extensive investigation over the last half a century. The most commonly used treatments were conceived from the monoamine theory of depression; subsequently, neuroendocrine hypotheses gained much attention. In more recent years, the most prolific research has surrounded the inflammatory hypothesis of depression. However, a large number of relevant review articles have focused across all five systems; see Table 1 and below for a collection of recent insights across biomarker systems. While measured at many levels, blood-derived proteins have been examined most widely and provide a source of biomarker that is convenient, cost-effective and may be closer to translational potential than other sources; thus, more detail is given to biomarkers circulating in blood.
In a recent systematic review, Jani et al20 examined peripheral blood-based biomarkers for depression in association with treatment outcomes. Of only 14 studies included (searched up until early 2013), 36 biomarkers were studied of which 12 were significant predictors of mental or physical response indices in at least one investigation. Those identified as potentially representing risk factors for nonresponse included inflammatory proteins: low interleukin (IL)-12p70, ratio of lymphocyte to monocyte count; neuroendocrine markers (dexamethasone nonsuppression of cortisol, high circulating cortisol, reduced thyroid-stimulating hormone); neurotransmitter markers (low serotonin and noradrenaline); metabolic (low high-density lipoprotein cholesterol) and neurotrophic factors (reduced S100 calcium-binding protein B). Further to this, other reviews have reported on associations between additional biomarkers and treatment outcomes.19,28�30 A brief description of putative markers in each system is outlined in the subsequent sections and in Table 2.
Inflammatory Findings in Depression
Since Smith�s seminal paper outlining the macrophage hypothesis,31 this established literature has found increased levels of various proinflammatory markers in depressed patients, which have been reviewed widely.32�37 Twelve inflammatory proteins have been evaluated in meta-analyses comparing depressed and healthy control populations.38�43
IL-6 (P<0.001 in all meta-analyses; 31 studies included) and CRP (P<0.001; 20 studies) appear frequently and reliably elevated in depression.40 Elevated tumor necrosis factor alpha (TNF?) was identified in early studies (P<0.001),38 but substantial heterogeneity rendered this inconclusive when accounting for more recent investigations (31 studies).40 IL-1? is even more inconclusively associated with depression, with meta-analyses suggesting higher levels in depression (P=0.03),41 high levels only in European studies42 or no differences from controls.40 Despite this, a recent article suggested particular translational implications for IL-1?,44 supported by an extremely significant effect of elevated IL-1? ribonucleic acid predicting a poor response to antidepressants;45 other findings above pertain to circulating blood-derived cytokines. The chemokine monocyte chemoattractant protein-1 has shown elevations in depressed participants in one meta-analysis.39 Interleukins IL-2, IL-4, IL-8, IL-10 and interferon gamma were not significantly different between depressed patients and controls at a meta-analytic level, but have nonetheless demonstrated potential in terms of altering with treatment: IL-8 has been reported as elevated in those with severe depression prospectively and cross-sectionally,46 different patterns of change in IL-10 and interferon gamma during treatment have occurred between early responders versus nonresponders,47 while IL-4 and IL-2 have decreased in line with symptom remission.48 In meta-analyses, small decreases alongside treatment have been demonstrated for IL-6, IL-1?, IL-10 and CRP.43,49,50 Additionally, TNF? may only reduce with treatment in responders, and a composite marker index may indicate increased inflammation in patients who subsequently do not respond to treatment.43 It is notable, however, that almost all of the research examining inflammatory proteins and treatment response utilize pharmacologic treatment trials. Thus, at least some inflammatory alterations during treatment are likely attributable to antidepressants. The precise inflammatory effects of different antidepressants have not yet been established, but evidence using CRP levels suggests individuals respond differently to specific treatments based on baseline inflammation: Harley et al51 reported elevated pretreatment CRP predicting a poor response to psychological therapy (cognitive�behavioral or interpersonal psychotherapy), but a good response to nortriptyline or fluoxetine; Uher et al52 replicated this finding for nortriptyline and identified the opposite effect for escitalopram. In contrast, Chang et al53 found higher CRP in early responders to fluoxetine or venlafaxine than nonresponders. Furthermore, patients with TRD and high CRP have responded better to the TNF? antagonist infliximab than those with levels in the normal range.54
Together, the evidence suggests that even when controlling for factors such as body mass index (BMI) and age, inflammatory responses appear aberrant in approximately one-third of patients with depression.55,56 The inflammatory system, however, is extremely complex, and there are numerous biomarkers representing different aspects of this system. Recently, additional novel cytokines and chemokines have yielded evidence of abnormalities in depression. These include: macrophage inhibitory protein 1a, IL-1a, IL-7, IL-12p70, IL-13, IL-15, eotaxin, granulocyte macrophage colony-stimulating factor,57 IL-5,58 IL-16,59 IL-17,60 monocyte chemoattractant protein-4,61 thymus and activation-regulated chemokine,62 eotaxin-3, TNFb,63 interferon gamma-induced protein 10,64 serum amyloid A,65 soluble intracellular adhesion molecule66 and soluble vascular cell adhesion molecule 1.67
Growth Factor Findings in Depression
In light of the potential importance of non-neurotrophic growth factors (such as those relating to angiogenesis), we refer to neurogenic biomarkers under the broader definition of growth factors.
Brain-derived neurotrophic factor (BDNF) is the most frequently studied of these. Multiple meta-analyses demonstrate attenuations of the BDNF protein in serum, which appear to increase alongside antidepressant treatment.68�71 The most recent of these analyses suggests that these BDNF aberrations are more pronounced in the most severely depressed patients, but that antidepressants appear to increase the levels of this protein even in the absence of clinical remission.70 proBDNF has been less widely studied than the mature form of BDNF, but the two appear to differ functionally (in terms of their effects on tyrosine receptor kinase B receptors) and recent evidence suggests that while mature BDNF may be reduced in depression, proBDNF may be overproduced.72 Nerve growth factor assessed peripherally has also been reported as lower in depression than in controls in a meta-analysis, but may not be altered by antidepressant treatment despite being most attenuated in patients with more severe depression.73 Similar findings have been reported in a meta-analysis for glial cell line-derived neurotrophic factor.74
Vascular endothelial growth factor (VEGF) has a role in promoting angiogenesis and neurogenesis along with other members of the VEGF family (eg, VEGF-C, VEGF-D) and has promise for depression.75 Despite inconsistent evidence, two meta-analyses have recently indicated elevations of VEGF in blood of depressed patients compared to controls (across 16 studies; P<0.001).76,77 However, low VEGF has been identified in TRD78 and higher levels have predicted nonresponse to antidepressant treatment.79 It is not understood why the levels of VEGF protein would be elevated, but it may partly be attributable to proinflammatory activity and/or increases in blood�brain barrier permeability in depressed states that causes reduced expression in cerebrospinal fluid.80 The relationship between VEGF and treatment response is unclear; a recent study found no relationship between either serum VEGF or BDNF with response or depression severity, despite decreases alongside antidepressant treatment.81 Insulin-like growth factor-1 is an additional factor with neurogenic functions that may be increased in depression, reflecting an imbalance in neurotrophic processes.82,83 Basic fibroblast growth factor (or FGF-2) is a member of the fibroblast growth factor family and appears higher in depressed than control groups.84 However, reports are not consistent; one found that this protein was lower in MDD than healthy controls, but reduced further alongside antidepressant treatment.85
Further growth factors that have not been sufficiently explored in depression include tyrosine kinase 2 and soluble fms-like tyrosine kinase-1 (also termed sVEGFR-1) which act in synergy with VEGF, and tyrosine kinase receptors (that bind BDNF) may be attenuated in depression.86 Placental growth factor is also part of the VEGF family, but has not been studied in systematically depressed samples to our knowledge.
Metabolic Biomarker Findings in Depression
The main biomarkers associated with metabolic illness include leptin, adiponectin, ghrelin, triglycerides, high-density lipoprotein (HDL), glucose, insulin and albumin.87 The associations between many of these and depression have been reviewed: leptin88 and ghrelin89 appear lower in depression than controls in the periphery and may increase alongside antidepressant treatment or remission. Insulin resistance may be increased in depression, albeit by small amounts.90 Lipid profiles, including HDL-cholesterol, appear altered in many patients with depression, including those without comorbid physical illness, though this relationship is complex and requires further elucidation.91 Additionally, hyperglycemia92 and hypoalbuminemia93 in depression have been reported in reviews.
Investigations of overall metabolic states are becoming more frequent using metabolomics panels of small molecules with the hope of finding a robust biochemical signature for psychiatric disorders. In a recent study using artificial intelligence modeling, a set of metabolites illustrating increased glucose�lipid signaling was highly predictive of an MDD diagnosis,94 supportive of previous studies.95
Neurotransmitter Findings in Depression
While the attention paid to monoamines in depression has yielded relatively successful treatments, no robust neurotransmitter markers have been identified to optimize treatment based on the selectivity of monoamine targets of antidepressants. Recent work points toward the serotonin (5-hydroxytryptamine) 1A receptor as potentially important for both diagnosis and prognosis of depression, pending new genetic and imaging techniques.96 There are new potential treatments targeting 5-hydroxytryptamine; for example, using a slow-release administration of 5-hydroxytryptophan.97 Increased transmission of dopamine interacts with other neurotransmitters to improve cognitive outcomes such as decision making and motivation.98 Similarly, the neurotransmitters glutamate, noradrenaline, histamine and serotonin may interact and activate as part of a depression-related stress response; this might decrease 5-hydroxytryptamine production through �flooding�. A recent review sets out this theory and suggests that in TRD, this could be reversed (and 5-HT restored) through multimodal treatment targeting multiple neurotransmitters.99 Interestingly, increases in serotonin do not always occur conjunctively with therapeutic antidepressant benefits.100 Despite this, neurotransmitter metabolites such as 3-methoxy-4-hydroxyphenylglycol, of noradrenaline, or homovanillic acid, of dopamine, have often been found to increase alongside reduction in depression with antidepressant treatment101,102 or that low levels of these metabolites predict a better response to SSRI treatment.102,103
Neuroendocrine Findings in Depression
Cortisol is the most common HPA axis biomarker to have been studied in depression. Numerous reviews have focused on the various assessments of HPA activity; overall, these suggest that depression is associated with hypercortisolemia and that the cortisol awakening response is often attenuated.104,105 This is supported by a recent review of chronic cortisol levels measured in hair, supporting the hypothesis of cortisol hyperactivity in depression but hypoactivity in other illnesses such as panic disorder.106 Furthermore, particularly, elevated cortisol levels may predict a poorer response to psychological107 and antidepressant108 treatment. Historically, the most promising neuroendocrine marker of prospective treatment response has been the dexamethasone suppression test, where cortisol nonsuppression following dexamethasone administration is associated with a lower likelihood of subsequent remission. However, this phenomenon has not been considered sufficiently robust for clinical application. Related markers corticotrophin-releasing hormone and adrenocorticotropin hormone as well as vasopressin are inconsistently found to be overproduced in depression and dehydroepiandrosterone is found to be attenuated; the ratio of cortisol to dehydroepiandrosterone may be elevated as a relatively stable marker in TRD, persisting after remission.109 Neuroendocrine hormone dysfunctions have long been associated with depression, and hypothyroidism may also play a causal role in depressed mood.110 Furthermore, thyroid responses can normalize with successful treatment for depression.111
Within the above, it is important also to consider signaling pathways across systems, such as glycogen synthase kinase-3, mitogen-activated protein kinase and cyclic adenosine 3?,5?-monophosphate, involved in synaptic plasticity112 and modified by antidepressants.113 Further potential biomarker candidates that span biologic systems particularly are measured using neuroimaging or genetics. In response to the lack of robust and meaningful genomic differences between depressed and nondepressed populations,114 novel genetic approaches such as polygenic scores115 or telomere length116,117 could prove more useful. Additional biomarkers gaining popularity are examining circadian cycles or chronobiologic biomarkers utilizing different sources. Actigraphy can provide an objective assessment of sleep and wake activity and rest through an accelerometer, and actigraphic devices can increasingly measure additional factors such as light exposure. This may be more useful for detection than commonly used subjective reports of patients and could provide novel predictors of treatment response.118 The question of which biomarkers are the most promising for translational use is a challenging one, which is expanded upon below.
For each of these five neurobiological systems reviewed, the evidence follows a similar narrative: there are many biomarkers that exist that are associated in some respects with depression. These markers are frequently interrelated in a complex, difficult-to-model fashion. The evidence is inconsistent, and it is likely that some are epiphenomena of other factors and some are important in only a subset of patients. Biomarkers are likely to be useful through a variety of routes (eg, those that predict subsequent response to treatment, those indicating specific treatments as more likely to be effective or those that alter with interventions regardless of clinical improvements). Novel methods are required to maximize consistency and clinical applicability of biologic assessments in psychiatric populations.
Variation of biomarkers over time and across situations pertains more to some types (eg, proteomics) than others (genomics). Standardized norms for many do not exist or have not been widely accepted. Indeed, the influence of environmental factors on markers frequently depends on genetic composition and other physiologic differences between people that cannot all be accounted for. This makes the assessment of biomarker activity, and identifying biologic abnormalities, difficult to interpret. Due to the number of potential biomarkers, many have not been measured widely or in a complete panel alongside other relevant markers.
Many factors have been reported to alter the protein levels across biologic systems in patients with affective disorders. Along with research-related factors such as duration and conditions of storage (which may cause degradation of some compounds), these include time of day measured, ethnicity, exercise,119 diet (eg, microbiome activity, especially provided that most blood biomarker studies do not require a fasting sample),120 smoking and substance use,121 as well as health factors (such as comorbid inflammatory, cardiovascular or other physical illnesses). For example, although heightened inflammation is observed in depressed but otherwise healthy individuals compared to nondepressed groups, depressed individuals who also have a comorbid immune-related condition frequently have even higher levels of cytokines than either those without depression or illness.122 Some prominent factors with probable involvement in the relationship between biomarkers, depression and treatment response are outlined below.
Stress. Both endocrine and immune responses have well-known roles in responding to stress (physiologic or psychological), and transient stress at the time of biologic specimen collection is rarely measured in research studies despite the variability of this factor between individuals that may be accentuated by current depressive symptoms. Both acute and chronic psychological stressors act as an immune challenge, accentuating inflammatory responses in the short and longer term.123,124 This finding extends to the experience of early-life stress, which has been associated with adult inflammatory elevations that are independent of stress experienced as an adult.125,126 During childhood traumatic experience, heightened inflammation has also been reported only in those children who were currently depressed.127 Conversely, people with depression and a history of childhood trauma may have blunted cortisol responses to stress, compared to those with depression and no early-life trauma.128 Stress-induced HPA axis alterations appear interrelated with cognitive function,129 as well as depression subtype or variation in HPA-related genes.130 Stress also has short- and long-term impairing effects on neurogenesis131 and other neural mechanisms.132 It is unclear precisely how childhood trauma affects biologic markers in depressed adults, but it is possible that early-life stress predisposes some individuals to enduring stress reactions in adulthood that are amplified psychologically and/or biologically.
Cognitive functioning. Neurocognitive dysfunctions occur frequently in people with affective disorders, even in unmedicated MDD.133 Cognitive deficits appear cumulative alongside treatment resistance.134 Neurobiologically, the HPA axis129 and neurotrophic systems135 are likely to play a key role in this relationship. Neurotransmitters noradrenaline and dopamine are likely important for cognitive processes such as learning and memory.136 Elevated inflammatory responses have been linked with cognitive decline, and likely affect cognitive functioning in depressive episodes,137 and in remission, through a variety of mechanisms.138 Indeed, Krogh et al139 proposed that CRP is more closely related to cognitive performance than to the core symptoms of depression.
Age, gender and BMI. The absence or presence, and direction of biologic differences between men and women has been particularly variable in the evidence to date. Neuroendocrine hormone variation between men and women interacts with depression susceptibility.140 A review of inflammation studies reported that controlling for age and gender did not affect patient-control differences in inflammatory cytokines (although the association between IL-6 and depression reduced as age increased, which is consistent with theories that inflammation generally heightens with age).41,141 VEGF differences between patients and controls are larger in studies assessing younger samples, while gender, BMI and clinical factors did not affect these comparisons at a meta-analytic level.77 However, the lack of adjustment for BMI in previous examinations of inflammation and depression appears to confound highly significant differences reported between these groups.41 Enlarged adipose tissue has been definitively demonstrated to stimulate cytokine production as well as being closely linked to metabolic markers.142 Because psychotropic medications may be associated with weight gain and a higher BMI, and these have been associated with treatment resistance in depression, this is an important area to examine.
Medication. Many biomarker studies in depression (both cross-sectional and longitudinal) have collected baseline specimens in unmedicated participants to reduce heterogeneity. However, many of these assessments are taken after a wash-out period from medication, which leaves the potentially significant confounding factor of residual changes in physiology, exacerbated by the extensive range of treatments available that may have had differing effects on inflammation. Some studies have excluded psychotropic, but not other medication use: in particular, the oral contraceptive pill is frequently permitted in research participants and not controlled for in analyses, which has recently been indicated to increase hormone and cytokine levels.143,144 Several studies indicate that antidepressant medications have effects on the inflammatory response,34,43,49,145�147 HPA-axis,108 neurotransmitter,148 and neurotrophic149 activity. However, the numerous potential treatments for depression have distinct and complex pharmacologic properties, suggesting there may be discrete biologic effects of different treatment options, supported by current data. It has been theorized that in addition to monoamine effects, specific serotonin-targeting medications (ie, SSRIs) are likely to target Th2 shifts in inflammation, and noradrenergic antidepressants (eg, SNRIs) effect a Th1 shift.150 It is not yet possible to determine the effects of individual or combination medications on biomarkers. These are likely mediated by other factors including the length of treatment (few trials assess long-term medication use), sample heterogeneity and not stratifying participants by response to treatment.
Methodological. As alluded to above, differences (between and within studies) in terms of which treatments (and combinations) the participants are taking and have taken previously are bound to introduce heterogeneity into research findings, particularly in biomarker research. In addition to this, many other design and sample characteristics vary across studies, thus augmenting the difficulty with interpreting and attributing findings. These include biomarker measurement parameters (eg, assay kits) and methods of collecting, storing, processing and analyzing markers in depression. Hiles et al141 examined some sources of inconsistency in the literature on inflammation and found that accuracy of depression diagnosis, BMI and comorbid illnesses were most important to account for in assessing peripheral inflammation between depressed and nondepressed groups.
Clinical. The extensive heterogeneity of depressed populations is well documented151 and is a critical contributor to contrasting findings within the research literature. It is probable that even within diagnoses, abnormal biologic profiles are confined to subsets of individuals that may not be stable over time. Cohesive subgroups of people suffering with depression may be identifiable through a combination of psychological and biologic factors. Below, we outline the potential for exploring subgroups in meeting the challenges that biomarker variability and heterogeneity pose.
Subtypes within Depression
Thus far, no homogenous subgroups within depression episodes or disorders have been reliably able to distinguish between patients based on symptom presentations or treatment responsiveness.152 The existence of a subgroup in whom biologic aberrations are more pronounced would help to explain the heterogeneity between previous studies and could catalyze the path toward stratified treatment. Kunugi et al153 have proposed a set of four potential subtypes based on the role of different neurobiological systems displaying clinically relevant subtypes in depression: those with hypercortisolism presenting with melancholic depression, or hypocortisolism reflecting an atypical subtype, a dopamine-related subset of patients who may present prominently with anhedonia (and could respond well to, eg, aripiprazole) and an inflammatory subtype characterized by elevated inflammation. Many articles focusing on inflammation have specified the case for the existence of an �inflammatory subtype� within depression.55,56,154,155 Clinical correlates of elevated inflammation are as yet undetermined and few direct attempts have been made to discover which participants may comprise this cohort. It has been proposed that people with atypical depression could have higher levels of inflammation than the melancholic subtype,156 which is perhaps not in line with findings regarding the HPA axis in melancholic and atypical subtypes of depression. TRD37 or depression with prominent somatic symptoms157 has also been posited as a potential inflammatory subtype, but neurovegetative (sleep, appetite, libido loss), mood (including low mood, suicidality and irritability) and cognitive symptoms (including affective bias and guilt)158 all appear related to biologic profiles. Further potential candidates for an inflammatory subtype involve the experience of sickness behavior-like symptoms159,160 or a metabolic syndrome.158
The propensity toward (hypo) mania may distinguish biologically between patients suffering from depression. Evidence now suggests that bipolar illnesses are a multifaceted group of mood disorders, with bipolar subsyndromal disorder found more prevalently than was previously recognized.161 Inaccurate and/or delayed detection of bipolar disorder has recently been highlighted as a major problem in clinical psychiatry, with the average time to correct diagnosis frequently exceeding a decade162 and this delay causing greater severity and cost of overall illness.163 With the majority of patients with bipolar disorder presenting initially with one or more depressive episodes and unipolar depression being the most frequent misdiagnosis, the identification of factors that might differentiate between unipolar and bipolar depression has substantial implications.164 Bipolar spectrum disorders likely have been undetected in some previous MDD biomarker investigations, and smatterings of evidence have indicated differentiation of HPA axis activity109 or inflammation165,166 between bipolar and unipolar depression. However, these comparisons are scarce, possess small sample sizes, identified nonsignificant trend effects or recruited populations that were not well characterized by diagnosis. These investigations also do not examine the role of treatment responsiveness in these relationships.
Both bipolar disorders167 and treatment resistance168 are not dichotomous constructs and lie on continua, which increases the challenge of subtype identification. Apart from subtyping, it is worth noting that many biologic abnormalities observed in depression are similarly found in patients with other diagnoses. Thus, transdiagnostic examinations are also potentially important.
Biomarker Measurement Challenges
Biomarker selection. The large number of potentially useful biomarkers presents a challenge for psychobiology in determining which markers are implicated in which way and for whom. To increase the challenge, relatively few of these biomarkers have been subject to sufficient investigation in depression, and for most, their precise roles in healthy and clinical populations are not well understood. Despite this, a number of attempts have been made to propose promising biomarker panels. In addition to Brand et al�s 16 sets of markers with strong potential,27 Lopresti et al outline an additional extensive set of oxidative stress markers with potential for improving treatment response.28 Papakostas et al defined a priori a set of nine serum markers spanning biologic systems (BDNF, cortisol, soluble TNF? receptor type II, alpha1 antitrypsin, apolipoprotein CIII, epidermal growth factor, myeloperoxidase, prolactin and resistin) in validation and replication samples with MDD. Once combined, a composite measure of these levels was able to distinguish between MDD and control groups with 80%�90% accuracy.169 We propose that even these do not cover all potential candidates in this field; see Table 2 for a nonexhaustive delineation of biomarkers with potential for depression, containing both those with an evidence base and promising novel markers.
Technology. Due to technologic advances, it is now possible (indeed, convenient) to measure a large array of biomarkers simultaneously at a lower cost and with higher sensitivity than has been the case previously. At present, this capability to measure numerous compounds is ahead of our ability to effectively analyze and interpret the data,170 something that will continue with the rise in biomarker arrays and new markers such as with metabolomics. This is largely due to a lack of understanding about the precise roles of and the interrelationships between markers, and an insufficient grasp of how related markers associate across different biologic levels (eg, genetic, transcription, protein) within and between individuals. Big data using new analytical approaches and standards will assist with addressing this, and new methodologies are being proposed; one example is the development of a statistical approach grounded in flux-based analysis to discover new potential metabolic markers based on their reactions between networks and integrate gene expression with metabolite data.171 Machine learning techniques are already being applied and will assist with models using biomarker data to predict treatment outcomes in studies with big data.172
Aggregating biomarkers. Examining an array of biomarkers simultaneously is an alternative to inspecting isolated markers that could provide a more accurate viewpoint into the complex web of biologic systems or networks.26 Also, to assist with disentangling contrasting evidence in this literature to date (particularly, where biomarker networks and interactions are well understood), biomarker data can then be aggregated or indexed. One challenge is in identifying the optimum method of conducting this, and it may require enhancements in technology and/or novel analytical techniques (see the �Big data� section). Historically, ratios between two distinct biomarkers have yielded interesting findings.109,173 Few attempts have been made to aggregate biomarker data on a larger scale, such as those using principal component analysis of proinflammatory cytokine networks.174 In a meta-analysis, proinflammatory cytokines have been converted into a single-effect size score for each study, and overall showed significantly higher inflammation before antidepressant treatment, predicting subsequent nonresponse in outpatient studies. Composite biomarker panels are both a challenge and opportunity for future research to identify meaningful and reliable findings that can be applied to improve treatment outcomes.43 A study by Papakostas et al took an alternative approach, selecting a panel of heterogeneous serum biomarkers (of inflammatory, HPA axis and metabolic systems) that had been indicated to differ between depressed and control individuals in a previous study and composited these into a risk score which differed in two independent samples and a control group with >80% sensitivity and specificity.169
Big data. The use of big data is probably necessary for addressing the current challenges outlined surrounding heterogeneity, biomarker variability, identifying the optimal markers and bringing the field toward translational, applied research in depression. However, as outlined above, this brings technological and scientific challenges.175 The health sciences have only recently begun using big data analytics, a decade or so later than in the business sector. However, studies such as iSPOT-D152 and consortia such as the Psychiatric Genetics Consortium176 are progressing with our understanding of biologic mechanisms in psychiatry. Machine-learning algorithms have, in very few studies, started to be applied to biomarkers for depression: a recent investigation pooled data from >5,000 participants of 250 biomarkers; after multiple imputation of data, a machine-learning boosted regression was conducted, indicating 21 potential biomarkers. Following further regression analyses, three biomarkers were selected as associating most strongly with depressive symptoms (highly variable red blood cell size, serum glucose and bilirubin levels). The authors conclude that big data can be used effectively for generating hypotheses.177 Larger biomarker phenotyping projects are now underway and will help to advance our journey into the future of the neurobiology of depression.
Biomarker Panel Identification
The findings in the literature to date require replication in large-scale studies. This is particularly true for novel biomarkers, such as the chemokine thymus and activation-regulated chemokine and the growth factor tyrosine kinase 2 which, to our knowledge, have not been investigated in clinically depressed and healthy control samples. Big data studies must assay comprehensive biomarker panels and use sophisticated analysis techniques to fully ascertain the relationships between markers and those factors which modify them in clinical and nonclinical populations. Additionally, large-scale replications of principal component analysis might establish highly correlated groups of biomarkers and could also inform the use of �composites� in biologic psychiatry, which may enhance the homogeneity of future findings.
Discovery of Homogenous Subtypes
Regarding biomarker selection, multiple panels may be required for different potential pathways that research could implicate. Taken together, the current evidence indicates that biomarker profiles are assuredly, but abstrusely altered in a subpopulation of individuals currently suffering from depression. This may be established within or across diagnostic categories, which would account for some inconsistency of findings that can be observed in this literature. Quantifying a biologic subgroup (or subgroups) may most effectively be facilitated by a large cluster analysis of biomarker network panels in depression. This would illustrate within-population variability; latent class analyses could exhibit distinct clinical characteristics based on, for example, inflammation.
Specific Treatment Effects on Inflammation and Response
All commonly prescribed treatments for depression should be comprehensively assessed for their specific biologic effects, also accounting for the effectiveness of treatment trials. This may enable constructs relating to biomarkers and symptom presentations to predict outcomes to a variety of antidepressant treatments in a more personalized fashion, and may be possible in the context of both unipolar and bipolar depression. This is likely to be useful for new potential treatments as well as currently indicated treatments.
Prospective Determination of Treatment Response
Use of the above techniques is likely to result in an improved ability to forecast treatment resistance prospectively. More authentic and persistent (eg, long-term) measures of treatment response may contribute to this. Assessment of other valid measures of patient well-being (such as quality of life and everyday functioning) could provide a more holistic assessment of treatment outcome that may associate more closely with biomarkers. While biologic activity alone might not be able to distinguish treatment responders from nonresponders, concurrent measurement of biomarkers with psychosocial or demographic variables could be integrated with biomarker information in developing a predictive model of insufficient treatment response. If a reliable model is developed to predict response (either for the depressed population or a subpopulation) and is validated retrospectively, a translational design can establish its applicability in a large controlled trial.
Toward Stratified Treatments
At present, patients with depression are not systematically directed to receive an optimized intervention program. If validated, a stratified trial design could be employed to test a model to predict nonresponse and/or to determine where a patient needs to be triaged in a stepped care model. This could be useful in both standardized and naturalistic treatment settings, across different types of intervention. Ultimately, a clinically viable model could be developed to provide individuals with the most appropriate treatment, to recognize those who are likely to develop refractory depression and supply enhanced care and monitoring to these patients. Patients identified as being at risk for treatment resistance may be prescribed a concomitant psychological and pharmacologic therapy or combination pharmacotherapy. As a speculative example, participants with no proinflammatory cytokine elevations might be indicated to receive psychological rather than pharmacologic therapy, while a subset of patients with particularly high inflammation could receive an anti-inflammatory agent in augmentation to standard treatment. Similar to stratification, personalized treatment-selection strategies may be possible in the future. For example, a particular depressed individual might have markedly high TNF? levels, but no other biologic abnormalities, and could benefit from short-term treatment with a TNF? antagonist.54 Personalized treatment may also entail monitoring biomarker expression during treatment to inform possible intervention changes, the length of continuation therapy required or to detect early markers of relapse.
Novel Treatment Targets
There are a huge number of potential treatments that could be effective for depression, which have not been adequately examined, including novel or repurposed interventions from other medical disciplines. Some of the most popular targets have been in anti-inflammatory medications such as celecoxib (and other cyclooxygenase-2 inhibitors), TNF? antagonists etanercept and infliximab, minocycline or aspirin. These appear promising.178 Antiglucocorticoid compounds, including ketoconazole179 and metyrapone,180 have been investigated for depression, but both have drawbacks with their side effect profile and the clinical potential of metyrapone is uncertain. Mifepristone181 and the corticosteroids fludrocortisone and spironolactone,182 and dexamethasone and hydrocortisone183 may also be effective in treating depression in the short term. Targeting glutamate N-methyl-d-aspartate receptor antagonists, including ketamine, might represent efficacious treatments in depression.184 Omega-3 polyunsaturated fatty acids influence inflammatory and metabolic activity and appear to demonstrate some effectiveness for depression.185 It is possible that statins may have antidepressant effects186 through relevant neurobiological pathways.187
In this way, the biochemical effects of antidepressants (see the �Medication� section) have been utilized for clinical benefits in other disciplines: particularly gastroenterological, neurologic and nonspecific symptom illnesses.188 Anti-inflammatory effects of antidepressants may represent part of the mechanism for these benefits. Lithium has also been suggested to reduce inflammation, critically through glycogen synthase kinase-3 pathways.189 A focus on these effects could prove informative for a depression biomarker signature and, in turn, biomarkers could represent surrogate markers for novel drug development.
Dr. Alex Jimenez’s Insight
Depression is a mental health disorder characterized by severe symptoms which affect mood, including loss of interest in activities. Recent research studies, however, have found that it may be possible to diagnose depression using more than just a patient’s behavioral symptoms. According to the researchers, identifying easily obtainable biomarkers which could more accurately diagnose depression is fundamental towards improving a patient’s overall health and wellness. By way of instance, clinical findings suggest that individuals with major depressive disorder, or MDD, have lower levels of the molecule acetyl-L-carnitine, or LAC, in their blood than healthy controls. Ultimately, establishing biomarkers for depression could potentially help better determine who is at risk of developing the disorder as well as help healthcare professionals determine the best treatment option for a patient with depression.
The literature indicates that approximately two-thirds of patients with depression do not achieve remission to an initial treatment and that the likelihood of nonresponse increases with the number of treatments trialed. Providing ineffective therapies has substantial consequences for individual and societal cost, including persistent distress and poor well-being, risk of suicide, loss of productivity and wasted health care resources. The vast literature in depression indicates a huge number of biomarkers with the potential to improve treatment for people with depression. In addition to neurotransmitter and neuroendocrine markers which have been subject to widespread study for many decades, recent insights highlight the inflammatory response (and the immune system more generally), metabolic and growth factors as importantly involved in depression. However, excessive contrasting evidence illustrates that there are a number of challenges needing to be tackled before biomarker research can be applied in order to improve the management and care of people with depression. Due to the sheer complexity of biologic systems, simultaneous examinations of a comprehensive range of markers in large samples are of considerable benefit in discovering interactions between biologic and psychological states across individuals. Optimizing the measurement of both neurobiological parameters and clinical measures of depression is likely to facilitate greater understanding. This review also highlights the importance of examining potentially modifying factors (such as illness, age, cognition and medication) in gleaning a coherent understanding of the biology of depression and mechanisms of treatment resistance. It is likely that some markers will show most promise for predicting treatment response or resistance to specific treatments in a subgroup of patients, and the concurrent measurement of biologic and psychological data may enhance the ability to prospectively identify those at risk for poor treatment outcomes. Establishing a biomarker panel has implications for boosting diagnostic accuracy and prognosis, as well as for individualizing treatments at the earliest practicable stage of depressive illness and developing effective novel treatment targets. These implications may be confined to subgroups of depressed patients. The pathways toward these possibilities complement recent research strategies to link clinical syndromes more closely to underlying neurobiological substrates.6 Apart from reducing heterogeneity, this may facilitate a shift toward parity of esteem between physical and mental health. It is clear that although much work is needed, establishment of the relationship between relevant biomarkers and depressive disorders has substantial implications for reducing the burden of depression at an individual and societal level.
This report represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King�s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Disclosure. AHY has in the last 3 years received honoraria for speaking from Astra Zeneca (AZ), Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen and UK funding agencies (NIHR, MRC, Wellcome Trust). AJC has in the last 3 years received honoraria for speaking from Astra Zeneca (AZ), honoraria for consulting from Allergan, Livanova and Lundbeck, and research grant support from Lundbeck and UK funding agencies (NIHR, MRC, Wellcome Trust).
The authors report no other conflicts of interest in this work.
In conclusion,�while numerous research studies have found hundreds of biomarkers for depression, not many have established their role in depressive illness or how exactly biologic information could be utilized to enhance diagnosis, treatment and prognosis. However, the article above reviews the available literature on the biomarkers involved during other processes and compares the clinical findings to that of depression. Furthermore, new findings on biomarkers for depression may help better diagnose depression in order to follow up with better treatment. Information referenced from the National Center for Biotechnology Information (NCBI).�The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
Curated by Dr. Alex Jimenez
Additional Topics: Back Pain
Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.
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CBD�research currently being conducted is showing its medical potential. This has opened doors for antipsychotic, anticancer and anti-inflammatory�treatmentoptions among a variety of others. Scientists from all over are publishing studies that are proving CBD is one of the most effective and favorable cannabinoids that promotes proper function of the body’s systems.
Five Properties Of CBD
CBD Medical Benefits
1. Inhibits Cancer Cell Growth
Studies have supported this claim. By way of Proapoptotic action or apoptosis, Cannabidiol, Tetrahydrocannabinol, Cannabigerol and Cannabichromene�in this order are extremely effective in tumor growth reduction in rats and cancerous human prostate cells. Research is still ongoing, but understanding that these cannabinoids stimulate the body�s process of killing cells that no longer function properly or at their optimal level. In traditional chemotherapy both�healthy and cancerous cells�are destroyed and only works when the cancer cells are replicating more frequently than healthy cells. CBD treatment promotes the body�s natural immune response to cells that are not functioning properly, which eradicates tumors.
2. Pain Reducer
The most common reason people start using marijuana despite its psychoactive affects, is that it also functions, as a pain reliever! People with chronic pain that are tired of taking pain killing opiates, rely on cannabinoid products to deal with pain and eliminate its source, commonly inflammation. Inflammation is the body�s natural response to injury, which floods the injured area with blood and nutrients to aid in rehabilitation. But inflammation creates secondary problems, among them�pain and discomfort. Through stimulation of nutrients in the area that is injured, CBD creates negative feedback to inflammatory reactions, as the nutrients that came with the inflammation are already there.
3. Treats Anxiety
Anxiety along with PTSD affects over 40 million adults in the U.S. Valium and Xanax is what is normally used to treat these conditions. However, CBD products are becoming the preferred treatment, as they have none of the side effects or dependency issues. The effects of CBD have been observed thoroughly by experts and studies have proved its effectiveness, as a dependable alternative for mental disorders. Two receptors in the human brain responsible for sending out Adrenaline and Serotonin are the�?2-adrenergic receptor agonist and 5-HT1A receptor antagonist. These receptors both are related to anxiety, depression, insomnia, and other mental disorders when imbalanced.
4. Strengthens The Immune System
Phytocannabinoids are able to balance, reinforce and strengthen the immune system. Cannabinoid products taken daily, work in regulating the immune system. This increases the body�s detection of foreign and potentially dangerous organisms, which include cancer cells.
5. Prevents Muscle Spasms
CBD contains�chemically antispasmodic properties. Athletes from all sports love CBD and what it can do. It is a preferred supplement and these oils have proven to prevent muscle spasms and soreness. This is done through�lubricating the potassium and calcium pumps within the muscle tissue.
CBD is finding its place, slowly, but surely. It is one of natures own medicines and it is our job to discover and figure how to utilize these properties. Consult a doctor before beginning any treatment of diagnosed or undiagnosed diseases with CBD. For the more severe diseases like diabetes, schizophrenia, epilepsy, which, CBD can treat, but only when used properly.
One standard hypothesis of depression is that individuals who are depressed have a lack in monoamine receptors within the body, which in turn leads to reduced levels of neurotransmitters, such as serotonin and norephinephrine, in the brain. But growing evidence supports that at least some kinds of depression might also be linked to continuing low-grade inflammation in the body.
Previous research studies have linked depression with higher level of inflammatory markers when compared with people who aren’t depressed. When individuals are given pro-inflammatory cytokines, they report experiencing more symptoms of depression and anxiety. Chronically high levels of inflammation due to health issues, including chronic pain conditions, are also associated with high rates of depression. Even brain imaging of patients with depression show their brain scans have improved neuroinflammation. If your body is in an inflammatory state, fighting off the common cold or influenza, you can experience symptoms overlapping with depression, including, interrupted sleep, depressed mood, fatigue, foggy-headedness and impaired concentration.
A new study published in The Journal of Clinical Psychiatry supports the assumption that an increase in inflammation might play a role in depression. The huge study analyzed data from 14,275 people who have been interviewed between 2007 and 2012 using the Patient Health Questionnaire, or PHQ-9, to screen for depression and had blood samples drawn. They found that people who had depression had 46 percent greater levels of C-reactive protein, or CRP, a marker of inflammatory disease, in their own blood samples. The research study was just able to establish an association between inflammation and depression but not causation, even though it confirms the association of depression with high levels of inflammation as measured through CRP.
The theory that depression might be viewed as a psychoneuroimmunological disorder may also help explain why attempts to reduce chronic inflammation in the body also enhances and helps prevent depression. The purpose of the article below is to demonstrate as well as thoroughly discuss the role of inflammation in depression. Furthermore, the article will describe the evolutionary imperative to the modern treatment target, including a discussion of phytocannabinoids and their association with the treatment of a variety of health issues, including chronic pain symptoms.
The Role of Inflammation in Depression: from Evolutionary Imperative to Modern Treatment Target
Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.
Depression is a devastating disorder, afflicting up to 10% of the adult population in the United States and representing one of the leading causes of disability worldwide1. Although effective treatments are available, approximately one third of all patients with depression fail to respond to conventional antidepressant therapies2, further contributing to the global burden of the disease. Accordingly, there is a pressing need for new conceptual frameworks for understanding the development of depression to develop better treatments. In this Review, we outline emerging data that point to the immune system � and, in particular, the inflammatory response � as a potentially important contributor to the pathophysiology of depression. We first consider the origins of this notion from an evolutionary perspective, examining the advantages of depressive behaviours in the context of host immune responses to pathogens, predators and conspecifics in ancestral environments. The pivotal role of psychosocial stress in the modern world are then examined, highlighting inflammasome activation and immune cell trafficking as novel mechanisms by which stress-induced inflammatory signals can be transmitted to the brain. Neurotransmitters and neurocircuits that are targets of the inflammatory response are also explored followed by an examination of brain�immune interactions as risk and resilience factors for depression. Finally, these interactions are discussed as a foundation for a new era of therapeutics that target the immune system to treat depression, with a focus on how immunological biomarkers can be used to personalize care.
An Evolutionary Perspective
Data from humans and laboratory animals provide compelling evidence that stress-relevant neurocircuitry and immunity form an integrated system that evolved to protect organisms from a wide range of environmental threats. For example, in the context of a laboratory stressor that entails delivering a speech to a judgmental panel of supposed �behavioural experts�, subjects experience a classic �fight or flight� response characterized by increases in heart rate and blood pressure as well as in cortisol and catecholamines. But something else happens within the body that demands a deeper explanation. The stressor activates key inflammatory pathways in peripheral blood mononuclear cells, including activation of the transcription factor nuclear factor�?B (NF-?B), and leads to marked increases in circulating levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6)3,4. In essence, the body mounts an immune response not against a pathogen, but against a threat to the subject�s self-esteem. Moreover, individuals at high risk of developing depression (for example, those who have experienced early-life trauma) show increased inflammatory responses to such laboratory stressors compared with low-risk individuals3. Furthermore, the greater the inflammatory response to a psychosocial stressor, the more probable the subject is to develop depression over the ensuing months5. Two questions immediately present themselves: why should a stimulus devoid of any pathogen induce an inflammatory response, and why should this response promote the development of depression?
Pathogen Host Defense and Depression
No coherent answer to these questions is apparent if immunity is viewed as merely another physiological system within the body. However, when seen against the back-drop of millions of years of co-evolution between mammals and the world of microorganisms and parasites, the human inflammatory bias exposed by laboratory stressors and reflected in the association between immune activation and depression not only makes imminent adaptive sense but also provides insight into a paradox deep within the heart of depression itself; namely, why are the genetic alleles that are most frequently associated with depression so common in the modern gene pool6 (FIG. 1)
Figure 1: Evolutionary legacy of an inflammatory bias. Early evolutionary pressures derived from human interactions with pathogens, predators and human conspecifics (such as rivals) resulted in an inflammatory bias that included an integrated suite of immunological and behavioural responses that conserved energy for fighting infection and healing wounds, while maintaining vigilance against attack. This inflammatory bias is believed to have been held in check during much of human evolution by exposure to minimally pathogenic, tolerogenic organisms in traditional (that is, rural) environments that engendered immunological responses characterized by the induction of regulatory T (TReg) cells, regulatory B (BReg) cells and immunoregulatory M2 macrophages as well as the production of the anti-inflammatory cytokines interleukin-10 (IL-10) and transforming growth factor-? (TGF?). In modern times, sanitized urban environments of more developed societies are rife with psychological challenges but generally lacking in the types of infectious challenges that were primary sources of morbidity and mortality across most of human evolution. In the absence of traditional immunological checks and balances, the psychological challenges of the modern world instigate ancestral immunological and behavioural repertoires that represent a decided liability, such as high rates of various inflammation-related disorders including depression.
Most adaptive theories of depression have focused on the potential benefits of depressive symptoms for relationships with other humans7. However, recent models have shifted the focus away from relationships with people, to relationships � both detrimental and beneficial � with pathogens6,8. These theories, which are supported by converging evidence (BOX 1), posit that modern humans have inherited a genomic bias towards inflammation because this response � and the depressive symptoms it promotes � enhanced host survival and reproduction in the highly pathogenic environments in which humans evolved6. From this theoretical perspective, at least some of the human vulnerability to depression evolved out of a behavioural repertoire � often referred to as �sickness behaviour� � which promoted host survival in the face of infection. Indeed, it has been hypothesized that the social avoidance and anhedonia characteristic of depression serve to shunt energy resources to fighting infection and wound healing, whereas the hypervigilance characteristic of anxiety disorders, commonly comorbid with depression, subserves protection from attack and subsequent pathogen exposure6,9. Even psychological stress can be understood from this theoretical perspective, given that the vast majority of stressors faced by mammals over evolutionary time boiled down to risks inherent in hunting, being hunted or competing for reproductive access or status. In all of these circumstances, the risk of pathogen invasion � and subsequent death from infection � was greatly increased as a result of wounding. In ancestral environments, the association between stress perception and risk of subsequent wounding was reliable enough that evolution favoured organisms that prepotently activated inflammatory systems in response to a wide array of environmental threats and challenges (including psychosocial stressors), even if this activation was often a �false alarm� (REF. 6).
Pathogen Host Defense Hypothesis of Depression
Several lines of evidence support the notion that the evolution and persistence of depression risk alleles and depressive symptoms in human populations are based on their relevance to �pathogen host defence�. This evidence includes:
Until recently, approximately 50% of humans died from infectious causes before adulthood, thereby providing strong selective pressure for genetic alleles that enhance host defence124.
As a result of strong selective pressure, microbial interactions have been a primary driver of human evolution125.
Patterns of inflammatory activation associated with depression promote survival in highly pathogenic environments while increasing mortality in sanitary conditions common in the developed world126.
The best replicated risk alleles for depression have pro-inflammatory and/or anti-pathogen protective effects or have been implicated in social behaviours that are likely to reduce pathogen exposure6.
Environmental risk factors for the development of depression (that is, psychosocial stress, early life adversity, obesity and processed-food diet) are uniformly pro-inflammatory13.
Exposure to pro-inflammatory cytokines produces a sickness syndrome with symptoms that overlap considerably with those seen in depression and that can be ameliorated by treatment with antidepressants23. In addition, the onset of depression is often mistaken with development of sickness, and symptoms
associated with infections are often mistaken with the onset of depression127.
Chronic cytokine exposure produces a combination of withdrawal and/or energy conservation, anxiety and/or hypervigilance behaviours and emotions that commonly coexist in depression6,9.
Symptoms shared by depression and sickness behaviour � such as hyperthermia and reduced iron availability � that lack any conceivable social value have potent anti-pathogen effects6.
The �pathogen host defence� hypothesis of depression may also provide insight into the twofold increase in depression in women compared to men, especially during the reproductive years10. Recent data indicate that women are more sensitive to the behavioural effects of inflammation, demonstrating greater increases in depressed mood than men following endotoxin exposure despite a similar magnitude in cytokine (IL-6 and tumour necrosis factor (TNF)) responses11. Women also exhibit a greater likelihood than men to develop depression in response to standardized doses of interferon-? (IFN?)12. By being more sensitive to inflammation-induced depressive symptoms, women may have benefited more from the protection provided by these symptoms in terms of fighting infection, healing wounds and avoiding subsequent pathogen exposure. Given the potentially negative impact of inflammation on reproductive success (for example, by reducing fertility and impairing lactation), the increase of depressive symptoms in women across evolutionary time may have given women of reproductive age an advantage in coping with and avoiding pathogens and the related inflammation, with increased depressive disorders being the ultimate trade-off in modern times.
Modern Exaggeration of the Inflammatory Bias
The prevalence of autoimmune, allergic and inflammatory diseases has markedly increased in the past 100 years, and rates of these conditions follow a similar upward trajectory in societies transitioning from traditional (that is, rural) to modern (that is, urban) ways of life13. Increasing evidence suggests that this pattern of widespread immune dysregulation may result from disruptions in our relationship and/or contact with a variety of co-evolved, non-lethal immunoregulatory microorganisms and parasites, especially commensals and symbiotes in the microbiotas of the gut, skin and nasal and oral cavities, that were ubiquitous in the natural environments in which humans evolved14. Although widely disparate, these organisms (often referred to as �old friends�) share a tendency to reduce inflammation and suppress effector immune cells through the induction of IL-10 and transforming growth factor-? (TGF?) while promoting the development of anti-inflammatory immune cell populations, such as alternatively activated (also referred to as �M2�) macrophages and regulatory T (TReg) cells and regulatory B cells13,14 (FIG. 1). Owing to various cultural changes, including the loss of exposure to microbial diversity with the advent of sanitation practices, modern humans now lack this immunoregulatory input � especially during infancy and childhood. Consequently, we find ourselves in a condition of an exacerbated inflammatory bias, with the particular conditions afflicting any given individual largely the result of genetic predisposition and environmental (for example, psychosocial) exposures13,14, ultimately accounting for the high co-morbidity between depression and autoimmune, allergic and inflammatory disorders13,15.
Inflammation and Depression
Data supporting the role of inflammation in depression are extensive and include findings that span experimental paradigms. Patients with major depressive disorder exhibit all of the cardinal features of an inflammatory response, including increased expression of pro-inflammatory cytokines and their receptors and increased levels of acute-phase reactants, chemokines and soluble adhesion molecules in peripheral blood and cerebrospinal fluid (CSF)16,17. Peripheral blood gene expression profiles consistent with a pro-inflammatory �M1� macrophage phenotype and an over-representation of IL-6, IL-8 and type I IFN-induced signalling pathways have also been described18�20. In addition, increased expression of a variety of innate immune genes and proteins, including IL-1?, IL-6, TNF, Toll-like receptor 3 (TLR3) and TLR4, has been found in post-mortem brain samples from suicide victims that had depression16,18,19,21. Meta-analyses of the literature conclude that peripheral blood IL-1?, IL-6, TNF and C-reactive protein (CRP) are the most reliable biomarkers of inflammation in patients with depression16. Polymorphisms in inflammatory cytokine genes, including those encoding IL-1?, TNF and CRP, have also been associated with depression and its response to treatment22. Moreover, other genes implicated in depression derived from meta-analyses of genome-wide association studies have been linked to the immune response and the response to pathogens including TNF6 (BOX 1). Administration of inflammatory cytokines (for example, IFN?) or their inducers (for example, endotoxin or typhoid vaccination) to otherwise non-depressed individuals causes symptoms of depression23�26. Furthermore, blockade of cytokines, such as TNF, or of inflammatory signalling pathway components, such as cyclooxygenase 2, has been shown to reduce depressive symptoms in patients with medical illnesses, including rheumatoid arthritis, psoriasis and cancer, as well as in patients with major depressive disorder27�29.
As the field has matured, it has become increasingly apparent that inflammatory markers are elevated not only in a subgroup of patients with depression30,31 but also in patients with other neuropsychiatric disorders including anxiety disorders and schizophrenia32,33. Moreover, as described below, it may be more accurate to characterize the impact of inflammation on behaviour as being associated not wholly with depression but with specific symptom dimensions across diagnoses that align with the Research Domain Criteria framework put forth by the National Institute of Mental Health (US Department of Health and Human Services). These symptoms, including positive and negative valence systems, relate to altered motivation and motor activity (anhedonia, fatigue and psychomotor impairment) and increased threat sensitivity (anxiety, arousal and alarm)34. Finally, inflammation has been associated with antidepressant treatment non-responsiveness9,32,35�37. For example, in a recent study, 45% of patients with non-response to conventional antidepressants exhibited a CRP >3 mg L?1 (REF. 30), which is considered indicative of a high level of inflammation on the basis of widely accepted cut-off points38. Of note, however, the percentage of patients with high CRP levels can vary as a function of the population being studied, with higher percentages in patients with depression and treatment resistance, childhood maltreatment, medical illnesses and metabolic syndrome.
Immune Pathways Involved in Depression
Inflammasomes: Stress in Translation
Exposure to psychosocial stress is one of the most robust and reproducible predictors of developing depression in humans and is the primary experimental pathway to depressive-like behaviour in laboratory animals. Thus, the observation that exposure to a psychosocial laboratory stressor can activate an inflammatory response in humans was a major breakthrough in linking inflammation to depression3,4. An important question for the field, however, is by what mechanism is stress translated into inflammation? Although considerable attention has been paid to stress-induced neuroendocrine pathways, including the hypothalamic�pituitary�adrenal (HPA) axis and the sympathetic nervous system (SNS), both of which have immunomodulatory functions39, recent focus has been shifted towards inflammasomes, which may represent a crucial immunological interface between stress and inflammation40 (FIG. 2). Inflammasomes are cytosolic protein complexes that form in myeloid cells in response to pathogenic microorganisms and non-pathogenic or �sterile� stressors. Assembly of the inflammasome leads to activation of caspase 1, which then cleaves the precursor forms of IL-1? and IL-18 into the active cytokines41. Given the relatively sterile nature of psychosocial stress, primary interest has been directed towards understanding how inflammasome activation in depression may be triggered by endogenous damage-associated molecular patterns (DAMPs), including ATP, heat shock proteins (HSPs), uric acid, high mobility group box 1 (HMGB1) and a variety of molecules linked with oxidative stress. Indeed, all of these DAMPs are induced by the psychological and mixed (that is, psychological and physiological) stressors used in animal models of depression42; an effect that is in part mediated by stress-induced release of catecholamines43. Moreover, studies in laboratory animals indicate that chronic mild-stress activates the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, which is well-known to respond to DAMPs44,45. Blockade of NLRP3 reverses stress-induced increases in IL-1? in the peripheral blood and brain, while also abrogating depressive-like behaviour in mice45. Interestingly, NLRP3 inflammasome upregulation and caspase-mediated cleavage of the glucocorticoid receptor can cause resistance to the effects of glucocorticoids, which are among the most potent anti-inflammatory hormones in the body46,47. Stress-induced glucocorticoid resistance is a well-characterized biological abnormality in patients with major depressive disorder and has been associated with increased inflammation48,49.
Figure 2: Transmitting stress-induced inflammatory signals to the brain. In the context of psychosocial stress, catecholamines (such as noradrenaline) released by activated sympathetic nervous system fibres stimulate bone marrow production and the release of myeloid cells (for example, monocytes) that enter the periphery where they encounter stress-induced damage-associated molecular patterns (DAMPs), bacteria and bacterial products such as microbial-associated molecular patterns (MAMPs) leaked from the gut. These DAMPs and MAMPs subsequently activate inflammatory signalling pathways such as nuclear factor-?B (NF-?B) and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. Stimulation of NLRP3 in turn activates caspase 1, which leads to the production of mature interleukin-1? (IL-1?) and IL-18 while also cleaving the glucocorticoid receptor contributing to glucocorticoid resistance. Activation of NF-?B stimulates the release of other pro-inflammatory cytokines including tumour necrosis factor (TNF) and IL-6, which together with IL-1? and IL-18 can access the brain through humoral and neural routes. Psychosocial stress can also lead to the activation of microglia to a M1 pro-inflammatory phenotype, which release CC-chemokine ligand 2 (CCL2) that in turn attracts activated myeloid cells to the brain via a cellular route. Once in the brain, activated macrophages can perpetuate central inflammatory responses. ASC, apoptosis-associated speck-like protein containing a CARD; HMGB1, high mobility group box 1; HSP, heat shock protein; LPS, lipopolysaccharide; TLR, Toll-like receptor.
Supporting the potential role of the NLRP3 inflammasome in human depression are data demonstrating that increased expression of NLRP3 and caspase 1 in peripheral blood mononuclear cells of patients with depression is associated with increased blood concentrations of IL-1? and IL-18, which in turn correlate with depression severity19,50. In addition, DAMPs that are known to activate NLRP3 are increased in patients with mood disorders, with examples including HSPs, reactive oxygen species and other markers of oxidative stress such as xanthine oxidase, peroxides and F2-isoprostanes51�53. Finally, there is increasing interest in the potential role of the gut microbiome in mood regulation, which may be mediated in part by the inflammasomes54. Indeed, non-pathogenic commensal bacteria and derived microbial-associated molecular patterns (MAMPs) in the gut can leak into the peripheral circulation during stress and activate the inflammasomes55, a process mediated by the SNS and catecholamines56 (FIG. 2). Of note, stress-induced increases in IL-1? and IL-18 were attenuated by treating animals with antibiotics or neutralizing lipopolysaccharide (LPS), demonstrating the importance of the composition of the gut microbiome and gut permeability in stress-induced inflammatory responses55. Taken together, these data support the notion that the inflammasome may be a key immunological point of integration of stress-induced danger signals that ultimately drive inflammatory responses relevant to depression.
Transmitting Inflammatory Signals to the Brain
In addition to increased expression of innate immune cytokines and TLRs in post-mortem brain samples from suicide victims with depression, evidence of microglial and astroglial activation in several brain regions including frontal cortex, anterior cingulate cortex (ACC) and thalamus in post-mortem studies of patients with depression have been described57�59,60. Moreover, a well-controlled neuroimaging study using positron emission tomography (PET) and a radiolabelled tracer for the translocator protein (TSPO) � which is overexpressed in activated microglia, macrophages and astrocytes � revealed increased immune activation in the brains of patients with major depressive disorder compared with control subjects61. Of note, not all studies have revealed increased TSPO binding in patients with depression, possibly owing to effects of medication and/or a paucity of subjects with increased inflammation61,62. However, data from endotoxin administration to healthy volunteers indicates that radiolabelled TSPO ligands can readily identify cellular activation in several regions of the brain following a potent peripheral immune stimulus63.
Work from laboratory animal studies has elucidated several pathways through which inflammatory signals can be transmitted from the periphery to the brain (FIG. 2). These data support the idea that inflammatory responses in peripheral tissues may drive inflammation in the brain leading to depression. Much of the early work focused on how inflammatory cytokines, which are relatively large molecules, could cross the blood�brain barrier (BBB) and influence brain function64. Two major pathways have been described: the �humoral pathway�, which involves cytokine passage through leaky regions in the BBB, such as the circumventricular organs, and the binding of cytokines to saturable transport molecules on the BBB; and the �neural pathway�, which involves the binding of cytokines to peripheral afferent nerve fibres, such as the vagus nerve, that in turn stimulate ascending catecholaminergic fibres in the brain and/or are translated back into central cytokine signals16. More recently, however, attention has shifted to a third pathway referred to as the �cellular pathway�, which involves the trafficking of activated immune cells, typically monocytes, to the brain vasculature and parenchyma. The details of this pathway have been elegantly dissected in the context of behavioural changes in mice that are associated with peripherally induced inflammation in the liver65. In these studies, the release of TNF from inflamed liver was found to stimulate microglial cell production of CC-chemokine ligand 2 (CCL2; also known as MCP1) that then attracted monocytes to the brain65. Blockade of monocyte infiltration to the brain using antibodies specific for the adhesion molecules P-selectin and ?4 integrin abrogated depressive-like behaviour in this animal model65. Of note, cytokine-stimulated astrocytes also may be major producers of chemokines, such as CCL2 and CXC-chemokine ligand 1 (CXCL1), that attract immune cells to the brain66. The cellular pathway additionally has been elucidated in the context of social defeat stress, whereby GFP-labelled monocytes coalesced in several regions of the brain associated with the detection of threat (for example, amygdala) � an effect that was dependent on CCL2 and was facilitated by mobilization of monocytes from the bone marrow as a result of stress-induced release of catecholamines67,68 (FIG. 2). Of note, initial microglial activation during social defeat stress appeared to be a result of neuronal activation by catecholamines and decreased neuronal production of CX3C-chemokine ligand 1 (CX3CL1; also known as fractalkine), which maintains microglia in a quiescent state67,68. Interestingly, this cellular pathway has received intriguing support from post-mortem analyses of brain tissue from patients with depression who committed suicide that showed increased numbers of perivascular macrophages in association with increased gene expression of allograft inflammatory factor 1 (AIF1, also known as IBA1) and CCL2, which are associated with macrophage activation and cellular trafficking59.
This evidence of peripheral myeloid cells trafficking to the brain during depression constitutes some of the first data supporting the existence of a central inflammatory response in human depression that is primarily driven by peripheral inflammatory events. Moreover, data demonstrate that antibodies that are specific for TNF but which do not cross the BBB, can block stress-induced depression in mice69. These findings indicate that peripheral inflammatory responses not only can provide important clues to the immunological mechanisms of inflammation in depression but also may serve as biomarkers and targets of immune-based therapies for depression. Protein biomarkers such as plasma CRP and TNF as well as immunotherapies targeting individual cytokines such as TNF, IL-1 and IL-6 may be most relevant in this regard. Of note, plasma CRP is a strong response predictor in anti-cytokine therapy70.
Cytokines and Neurotransmitters
Given the pivotal importance of neurotransmission to mood regulation, attention has been paid to the impact of inflammation and inflammatory cytokines on the monoamines serotonin, noradrenaline and dopamine, as well as on the excitatory amino acid glutamate (FIG. 3). There are several pathways through which inflammatory cytokines can lead to reduced synaptic availability of the monoamines, which is believed to be a fundamental mechanism in the pathophysiology of depression71. For example, IL-1? and TNF induction of p38 mitogen-activated protein kinase (MAPK) has been shown to increase the expression and function of the reuptake pumps for serotonin, leading to decreased synaptic availability of serotonin and depressive-like behaviour in laboratory animals72. Through the generation of reactive oxygen and nitrogen species, inflammatory cytokines have also been found to decrease the availability of tetrahydrobiopterin (BH4), a key enzyme co-factor in the synthesis of all monoamines that is highly sensitive to oxidative stress73. Indeed, CSF concentrations of BH4 have been shown to be negatively correlated with CSF levels of IL-6 in patients treated with the inflammatory cytokine IFN?74. In addition, the plasma phenylalanine to tyrosine ratio, an indirect measure of BH4 activity, was shown to correlate with CSF concentrations of dopamine as well as symptoms of depression in IFN?-treated patients74. Activation of the enzyme indoleamine 2,3-dioxygenase (IDO) is also believed to be involved in cytokine-induced neurotransmitter alterations, in part by diverting the metabolism of tryptophan (the primary amino acid precursor of serotonin) into kynurenine, a compound that can be converted into the neurotoxic metabolite quinolinic acid by activated microglia and infiltrating monocytes and macrophages in the brain75,76. Of note, increased levels of quinolinic acid have been found in microglia in the ACC of suicide victims who suffered from depression77. Quinolinic acid directly activates receptors for glutamate (that is, N-methyl-D-aspartate (NMDA) receptors) while also stimulating glutamate release and blocking glutamate reuptake by astrocytes78. The effects of quinolinic acid on glutamate converge with the direct effects of pro-inflammatory cytokines on glutamate metabolism that include decreasing the expression of astrocyte glutamate reuptake pumps and stimulating astrocytic glutamate release79, ultimately contributing to excessive glutamate both within and outside the synapse. The binding of glutamate to extrasynaptic NMDA receptors leads to increased excitotoxicity and decreased production of brain-derived neurotrophic factor (BDNF)80. BDNF fosters neurogenesis, an important prerequisite for an antidepressant response, and has been shown to be reduced by IL-1? and TNF and their downstream signalling pathways including NF-?B in stress-induced animal models of depression81,82. Increased levels of glutamate in the basal ganglia and dorsal ACC (dACC) � as measured by magnetic resonance spectroscopy (MRS) � have been described in patients receiving IFN?, and higher levels of glutamate correlated with an increase in depressive symptoms83. More recent data indicate that in patients with depression, increased inflammation as reflected by a CRP >3 mg L?1 is also associated with increased basal ganglia glutamate (compared with patients with a CRP <1 mg L?1) that correlated with anhedonia and decreased psychomotor speed84. Interestingly, blocking glutamate receptors with ketamine or inhibiting IDO activity protects mice from LPS- or stress-induced depressive-like behaviour but leaves the inflammatory response intact85,86. These results indicate that increased activation of glutamate receptors by glutamate and/or quinolinic acid may be a common pathway through which inflammation causes depressive-like behaviour, suggesting that drugs that block glutamate receptor signalling and/or activation of the IDO pathway and its downstream metabolites might have unique applicability to patients with depression and increased inflammation. Importantly, conventional antidepressant medications act by increasing synaptic availability of monoamines and increasing neurogenesis through induction of BDNF87. Therefore, cytokines such as IL-1? and TNF serve to undermine these activities as they decrease the synaptic availability of monoamines while also decreasing BDNF and increasing extracellular glutamate, which is not a target of conventional antidepressant therapy. These cytokine-driven effects may explain the observations that increased inflammation is associated with less robust antidepressant treatment responses and that treatment-resistant patients exhibit increased inflammatory markers88.
Figure 3: Cytokine targets in the brain: neurotransmitters and neurocircuits. Once in the brain, the inflammatory response can affect metabolic and molecular pathways influencing neurotransmitter systems that can ultimately affect neurocircuits that regulate behaviour, especially behaviours relevant to decreased motivation (anhedonia), avoidance and alarm (anxiety), which characterize several neuropsychiatric disorders including depression. On a molecular level, pro-inflammatory cytokines including type I and II interferons (IFNs), interleukin-1? (IL-1?) and tumour necrosis factor (TNF) can reduce the availability of monoamines � serotonin (5-HT), dopamine (DA) and noradrenaline (NE) � by increasing the expression and function of the presynaptic reuptake pumps (transporters) for 5-HT, DA and NE through activation of mitogen-activated protein kinase (MAPK) pathways and by reducing monoamine synthesis through decreasing enzymatic co-factors such as tetrahydrobiopterin (BH4), which is highly sensitive to cytokine-induced oxidative stress and is involved in the production of nitric oxide (NO) by NO synthase (NOS). Many cytokines, including IFN?, IL-1? and TNF, can also decrease relevant monoamine precursors by activating the enzyme indoleamine 2,3-dioxygenase (IDO), which breaks down tryptophan, the primary precursor for serotonin, into kynurenine. Activated microglia can convert kynurenine into quinolinic acid (QUIN), which binds to the N-methyl-D-aspartate receptor (NMDAR), a glutamate (Glu) receptor, and together with cytokine-induced reduction in astrocytic Glu reuptake and stimulation of astrocyte Glu release, in part by induction of reactive oxygen species (ROS) and reactive nitrogen species (RNS), can lead to excessive Glu, an excitatory amino acid neurotransmitter. Excessive Glu, especially when binding to extrasynaptic NMDARs, can in turn lead to decreased brain-derived neurotrophic factor (BDNF) and excitotoxicity. Inflammation effects on growth factors such as BDNF in the dentate gyrus of the hippocampus can also affect fundamental aspects of neuronal integrity including neurogenesis, long-term potentiation and dendritic sprouting, ultimately affecting learning and memory. Cytokine effects on neurotransmitter systems, especially DA, can inhibit several aspects of reward motivation and anhedonia in corticostriatal circuits involving the basal ganglia, ventromedial prefrontal cortex (vmPFC) and subgenual and dorsal anterior cingulate cortex (sgACC and dACC, respectively), while also activating circuits regulating anxiety, arousal, alarm and fear including the amygdala, hippocampus, dACC and insula. BH2, dihydrobiopterin; DAT, dopamine transporter; EAAT2, excitatory amino acid transporter 2; NET, noradrenaline transporter; NF-?B, nuclear factor-?B; SERT, serotonin transporter; TH, tyrosine hydroxylase; TPH, tryptophan hydroxylase. Copyrighted 2015. Advanstar. 120580:1115BN.
Effects of Inflammation on Neurocircuitry
Given the impact of cytokines on neurotransmitter systems that regulate the functional activity of neurocircuits throughout the brain, it is no surprise that neuroimaging studies have revealed cytokine-induced alterations in regional brain activity. Consistent with the evolutionary advantages of the partnership between the brain and the immune system, primary cytokine targets in the CNS involve those brain regions that regulate motivation and motor activity (promoting social avoidance and energy conservation) as well as arousal, anxiety and alarm (promoting hypervigilance and protection against attack) (FIG. 3).
Dopamine has a fundamental role in motivation and motor activity, and cytokines have been shown to decrease the release of dopamine in the basal ganglia in association with decreased effort-based motivation as well as reduced activation of reward circuitry in the basal ganglia, in particular the ventral striatum89�91. Inflammatory stimuli have been associated with reductions in reward responsiveness in the striatum across many neuroimaging platforms, demonstrating the validity and reproducibility of these cytokine-mediated effects on the brain in otherwise non-depressed individuals peripherally administered IFN?, endotoxin or typhoid vaccination and imaged by PET, functional magnetic resonance imaging (fMRI), MRS and quantitative magnetization transfer imaging83,89,90,92,93. Interestingly, recent fMRI studies suggest that inflammation-induced decreases in responsiveness to positive reward are also associated with increased sensitivity to aversive stimuli (that is, negative reinforcement) and reduced responsiveness to novelty in the substantia nigra (which is another dopamine-rich structure in the basal ganglia)93,94. Typhoid vaccination has also been shown to activate the subgenual ACC (sgACC), a brain region implicated in depression, and to decrease connectivity of the sgACC with the ventral striatum, an effect modulated by plasma IL-6 (REF. 26). These fMRI findings have recently been extended to patients with depression whose increased plasma CRP level is associated with decreased functional connectivity within reward-related circuits including the ventral striatum and the ventromedial prefrontal cortex that, in turn, mediates the relationship between CRP and anhedonia95. Indeed, patients with depression with a CRP >3 mg L?1 had little, if any, connectivity within reward-related circuits as measured by fMRI, whereas connectivity in patients with depression with a CRP <1 mg L?1 was similar to healthy controls95. Taken together, these data support the notion that the effect of cytokines on the brain in general and dopaminergic pathways in particular lead to a state of decreased motivation or anhedonia, which is a core symptom of depression.
fMRI studies have demonstrated that increased inflammation is also associated with increased activation of threat- and anxiety-related neurocircuitry, including the dACC as well as the insula and amygdala26,96,97. Of note, the dACC and amygdala are regions that exhibit increased activity in patients with high-trait anxiety and neuroticism98, conditions that often accompany depression and are associated with increased inflammation. For example, increased concentrations of oral IL-6 and soluble TNF receptor 2 (also known as TNFRSF1B) in response to a public speaking stressor was significantly correlated with the response of the dACC to a social rejection task97. In addition, increased oral IL-6 expression in response to a social evaluation stressor was significantly correlated with activation of the amygdala, with subjects who exhibited the highest IL-6 responses to stress demonstrating the greatest connectivity within threat circuitry, including the amygdala and the dorsomedial prefrontal cortex, as measured by fMRI99. Interestingly, these data are consistent with the trafficking of monocytes to the amygdala during social defeat stress in mice68.
Risk and Resilience
Increased Inflammation and the Risk for Depression
Consistent with the emerging recognition that inflammation may cause depression in certain subgroups of individuals, epidemiological studies on large community samples � as well as smaller samples of medically ill individuals � have demonstrated that increased inflammation serves as a risk factor for the future development of depression. For example, increased peripheral blood CRP and IL-6 concentrations were found to significantly predict depressive symptoms after 12 years of follow up in the Whitehall II study of over 3,000 individuals, whereas no association was found between the presence of depressive symptoms and subsequent blood CRP and IL-6 levels100. Similar findings were reported in the English Longitudinal Study of Ageing in which a CRP >3 mg L?1 predicted depressive symptoms and not vice versa101. Of note, however, some studies have found no longitudinal relationship between depression and inflammation, and others have found that depression leads to increased inflammation102. Other factors known to be associated with increased peripheral inflammation, including childhood and adult trauma, have also been shown to be predictive of a greater risk of developing depression103,104.
Both genetic and epigenetic mechanisms may explain why childhood or adult traumas can contribute to exaggerated or persistent inflammation and, ultimately, depression. For example, polymorphisms in CRP were associated not only with increased peripheral blood concentrations of CRP but also with symptoms of post-traumatic stress disorder, especially heightened arousal, in individuals exposed to civilian trauma32. Moreover, gene�environment interactions have been found to influence depression severity in response to chronic interpersonal stress: individuals carrying polymorphisms in IL1B that are associated with higher expression of peripheral IL-1? exhibited more severe depressive symptoms in the context of interpersonal stress than individuals without the IL1B risk allele105. Similarly, mice in which peripheral blood leukocytes produced high concentrations of LPS-induced IL-6 ex vivo before stress exposure showed decreased social exploration after social defeat stress, whereas mice that produced low levels of IL-6 before stress exposure exhibited no behavioural effects in response to social defeat88. Of note, adoptive transfer of bone marrow progenitor cells from mice producing high levels of IL-6 ex vivo to mice that produced low levels of IL-6 made these formerly stress-resilient animals sensitive to the depressive effects of social defeat88.
Epigenetic changes in genes related to inflammation may also affect the risk for depression and anxiety in the context of psychosocial stress. Indeed, the well-documented association of childhood trauma with increased inflammation is linked to stress-induced epigenetic changes in FKBP5, a gene implicated in the development of depression and anxiety as well as in the sensitivity to glucocorticoids106. Allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP5 were found to be associated with decreased sensitivity of peripheral blood immune cells to the inhibitory effects of the synthetic glucocorticoid dexamethasone on LPS-induced production of IL-6 in vitro106. Of note, decreased activation of glucocorticoid receptor-responsive genes in association with increased activation of genes regulated by NF-?B has been found to be a �fingerprint� of the effects of chronic stress in several studies examining a variety of psychosocial stressors39,107.
T Cells and Resilience to Depression
Some of the most intriguing data regarding the role of the immune system in depression come from studies showing that T cells may protect against stress and depression in laboratory animals. For example, the adoptive transfer of T cells from animals exposed to chronic social defeat stress led to an antidepressant behavioural phenotype in stress-naive mice, which was associated with decreased pro-inflammatory cytokines in serum, a shift towards a neuroprotective M2 phenotype in microglia and increased neurogenesis in the hippocampus108. Similar results have been reported following acute stress in mice, in which effector T cell migration to the choroid plexus as a result of glucocorticoid induction of intercellular adhesion molecule 1 (ICAM1) expression in the choroid plexus was associated with reduced anxiety-like behaviour109. Mice with impaired release of glucocorticoids in response to stress were anxiety prone109. Immunization of anxiety-prone animals with a CNS-specific antigen restored T cell trafficking to the brain during stress and reversed anxiety-like behaviour in association with increased neurogenesis109. Immunization with a CNS-specific antigen also blocked stress-induced depression in mice110. The mechanism by which T cells influence resilience is believed to be related to their production of IL-4 within the meningeal space. Through as yet uncharacterized pathways, IL-4 then stimulates astrocytes to produce BDNF, and also promotes the conversion of meningeal monocytes and macrophages from a pro-inflammatory M1 phenotype to a less inflammatory M2 phenotype111. The movement of T cells throughout the brain, including the meningeal space, has become an area of special interest with the recent description of a brain lymphatic system that heretofore had gone unrecognized112. Data also indicate that TReg cells may have a role in reducing inflammation and supporting neuronal integrity during stress113. Similar reports have characterized T cells that are activated by vagal nerve stimulation to produce acetylcholine, which can inhibit NF-?B activation by binding to the ?7 subunit of the nicotinic acetylcholine receptor114.
Relevant to depression, however, peripheral T cell trafficking in response to glucocorticoids has been shown to be impaired in patients with depression, possibly owing to glucocorticoid resistance as a result of genetically mediated (for example, FKBP5) or inflammasome-mediated mechanisms targeting the glucocorticoid receptor46,115. In addition, inflammatory cytokines and their signalling pathways, including p38 MAPK, have direct inhibitory effects on glucocorticoid receptor function116. Moreover, patients with depression have been shown to have increased numbers of peripheral blood myeloid-derived suppressor cells, which inhibit T cell function117. Of note, activation of the NLRP3 inflammasome leads to increased accumulation of myeloid-derived suppressor cells118. Decreased numbers of peripheral blood TReg cells and reduced concentrations of anti-inflammatory cytokines in the blood, including TGF? and IL-10, have also been reported in depression119. Thus, it appears that patients with depression may have impairments in neuroprotective and anti-inflammatory T cell responses.
These findings suggest that therapies that boost such T cell responses could be used in patients with depression. Examples include immunization strategies (with CNS antigens as discussed above) that attract T cells to the brain or administration of bacteria, such as Mycobacterium vaccae, or parasites that stimulate TReg cell responses or T cell production of IL-4 (REFS 14,109,110,120). Indeed, colonization of pregnant dams with helminths attenuated the increase of hippocampal IL-1? in neonatal rats infected with bacteria and protected these animals from the subsequent development of microglial sensitization and cognitive dysfunction in adulthood. This effect was associated with increased ex vivo production of IL-4 and decreased production of IL-1? and TNF by splenic macrophages in response to LPS stimulation120. Finally, vagus nerve stimulation could be used to induce anti-inflammatory acetylcholine-producing T cells121. Although many strategies exist to activate anti-inflammatory T cell responses including the induction of TReg cells by administration of mesenchymal stem cells122, the majority of the approaches discussed above have proof-of-concept data in animal models of depression. Nevertheless, the clinical relevance of these approaches has yet to be determined by randomized clinical trials in patients with depression.
Our increasing understanding of how inflammatory processes contribute to depression, combined with the growing frustration over the lack of discovery of new antidepressants, have stimulated interest in the possibility that various classes of anti-inflammatory medications or other anti-inflammatory strategies (as discussed above) may hold promise as novel �all-purpose� antidepressants. Unfortunately, it appears that anti-inflammatory agents may only demonstrate effective antidepressant activity in subgroups of patients who show evidence of increased peripheral inflammation, for example individuals with medical conditions including osteoarthritis and psoriasis that are characterized by increased levels of peripheral inflammation and patients with depression with increased inflammatory markers29,30. Moreover, in patients with depression who do not show elevated peripheral levels of inflammation, anti-inflammatory treatments may actually impair placebo responses that contribute to the effectiveness of all known antidepressant modalities123. In the only study to date examining the antidepressant effect of a cytokine antagonist in medically healthy adults with treatment-resistant depression, post hoc analysis revealed a dose-response relationship between baseline levels of peripheral inflammation and subsequent antidepressant response to the TNF inhibitor infliximab30. In patients with baseline plasma CRP concentrations ?5 mg L?1, infliximab outperformed placebo with an effect size similar to that observed in studies of standard antidepressants. Patients with a CRP >3 mg L?1, the standard cut-off for high inflammation, also exhibited separation from placebo. Of note, this latter finding along with data demonstrating the relevance of a CRP >3 mg L?1 to altered reward circuitry and glutamate metabolism in depression as well as the prediction of subsequent depressive episodes (described above) aligns well with other diseases in which a CRP >3 mg L?1 is relevant to prediction and pathology including cardiovascular disease and diabetes. These data suggest that the cut-off for high inflammation in depression may be consistent with other disorders (BOX 2). Importantly, however, in patients with lower levels of inflammation, blockade of TNF with infliximab actually impaired the placebo response30, suggesting that anti-inflammatory treatments in patients without inflammation may be detrimental, highlighting the growing recognition that the immune system has an important role in several processes central to neuronal integrity.
Guidelines for Anti-Inflammatory Clinical Trials in Depression
Based on the animal and human literature on the effects of cytokines on the brain, the following guidelines can inform clinical trials designed to test the cytokine hypothesis of depression.
Inflammation only occurs in subgroups of patients with depression30. Clinical trials should enrich for patient populations with evidence of increased inflammation, particularly those identified by a C-reactive protein (CRP) >3 mg L?1, which has been shown to characterize patients with depression with altered reward circuitry and increased basal ganglia glutamate, as well as those who have shown a response to anti-cytokine therapy30,84,95.
Anti-inflammatory drugs may harm patients without increased inflammation. Inflammatory cytokines and the innate immune response have pivotal roles in synaptic plasticity, neurogenesis, long-term potentiation (which is a fundamental process in learning and memory) and possibly antidepressant response123,128.
Primary behavioural outcome variables should include measures of anhedonia and anxiety. Neuroimaging studies coupled with studies administering a variety of inflammatory stimuli, including the inflammatory cytokine interferon-?, endotoxin and typhoid vaccination, have revealed that inflammation targets neurocircuits in the brain that regulate motivation and reward as well as anxiety, arousal and alarm35. In addition, these symptoms have been shown to respond to anti-cytokine therapy in limited studies.
Drugs that specifically target inflammatory cytokines and/or their signalling pathways are preferable. The majority of clinical trials to date have used anti-inflammatory drugs (non-steroidal anti-inflammatory agents and minocycline, a tetracycline antibiotic) that have several off-target effects making the extant data relevant to testing the cytokine hypothesis of depression difficult to interpret31.
Target engagement must be established in the periphery and ultimately the brain. Protein and gene expression markers of inflammation in the peripheral blood can serve as relevant proxies for inflammation in the brain129, especially given evidence of trafficking of activated peripheral immune cells to the brain in stress-induced animal models of depression. Relevant therapeutic interventions should decrease peripheral inflammatory markers in concert with improvement of specific depressive symptoms. Translocator protein neuroimaging ligands may ultimately serve as direct measures of neuroinflammation and its inhibition by anti-inflammatory therapies in future clinical trials61.
We conclude by offering the balanced perspective that anti-inflammatory therapies are unlikely to be all-purpose antidepressants. Perhaps we only think of standard antidepressants as all-purpose agents because we have never succeeded in developing predictive biomarkers that would reliably inform us of who will respond to any given agent. If so, then we view these agents as all-purpose, not because it is true but out of hope and ignorance. Thus, instead of being a negative, perhaps the finding that baseline inflammatory biomarkers such as CRP can predict subsequent symptomatic response to anti-inflammatory strategies is, in fact, the most positive development thus far in our quest to understand how the immune system might be harnessed to improve the treatment of depression.
Dr. Alex Jimenez’s Insight
When you catch a cold, certain symptoms are triggered by inflammatory markers released in response to illness. While sneezing, coughing and a sore throat serve as the most “obvious” signs you may be sick, what truly keeps you in bed when you have a cold is the accompanying fatigue, inattentiveness, loss of appetite, change in sleep pattern, heightened perception of pain and apathetic withdrawal. These symptoms are similar to the wide array of symptoms that define depression. Many research studies have demonstrated that depression may occur due to an inflammatory response to illness, just as in the case of a common cold. The connection between inflammation and depression has long been argued among healthcare professionals and researchers, where new evidence could open the doors to additional treatment approaches which could help better manage this debilitation health issue.
In ancestral times, integration of inflammatory responses and behaviours of avoidance and alarm provided an evolutionary advantage in managing the microbial world. In the absence of the temporizing influence of commensal organisms that were rife in environments in which humans evolved, the inflammatory bias of the human species in the civilized world has been increasingly engaged in the complex world of psychosocial interactions and the inevitable stress it engenders. Responding to these sterile insults with activation of the inflammasome and mobilization of myeloid cells to the brain, the resultant release of inflammatory cytokines impinges on neurotransmitters and neurocircuits to lead to behaviours that are poorly suited for functioning in modern society. This inevitability of our evolutionary past is apparent in the high rates of depression that are seen in society today. There is also an increasing recognition of mechanisms of resilience that derive from our emerging understanding of the neuroprotective effects of a variety of T cell responses ranging from effector T cells that produce IL-4 to TReg cells with anti-inflammatory properties. A better understanding of these neuroprotective pathways and of the inflammatory mechanisms � from inflammasome activation to cell trafficking to the brain � that operate in patients with depression may lead to the development of novel anti-depressant therapies.
The discovery of the body’s endocannabinoid system, or ECS, in the 1980s provided researchers a totally new outlook on the chemicals in marijuana and hemp that had formerly been identified 40 years earlier, including how these chemicals interacted with and acted on a prevalent regulatory system in the human body. The title given to those chemicals was phytocannabinoids, meaning “phyto” for plantlife. Over 80 phytocannabinoids are identified in marijuana and hemp. The psychoactive phytocannabinoid in marijuana, tetrahydrocannabinol, or THC, represents only one of many phytocannabinoids now being extensively studied for its numerous health benefits. The more science learns about the far-reaching effects of the ECS in encouraging brain health, in improving immune function, in keeping a healthy inflammatory response, and in promoting GI health, fertility, bone health, and much more, the more interest there is in locating these phytocannabinoids in nature and learning how they affect human health. Due to this widespread interest, phytocannabinoids have been identified in many plants outside the Cannabis species; for instance, plants such as clove, black pepper, Echinacea, ginseng, broccoli, and carrots, all contain phytocannabinoids.
Phytocannabinoids in Hemp
Although the majority of people have now heard of cannabadiol (CBD), it’s only one of lots of the constituents in hemp which interact with the ECS. Two other notable phytocannabinoids include:
CBC was first analyzed in the 1980s as it was found to modulate a normal inflammatory response in a rat model. More recently CBC has been shown to promote brain health, skin health, and preserve normal motility in the digestive tract.
CBG has been increasingly studied for its capacity to support nervous system health. CBG has multiple roles from the ECS, such as inhibiting the reuptake of anandamide, an extremely beneficial endocannabinoid we make within our own bodies. CBG might also provide help for immune function, skin health, and a positive disposition. CBG is typically found in much higher concentrations in industrial hemp than in marijuana.
Phytocannabinoids in Other Crops
There is also ongoing research in discovering phytocannabionids in many other plants. Some of them include:
Although BCP is located from the flowers and leaves of hemp, since just the hemp stalk is used in nutritional supplements, even BCP content is lost. But, BCP is contained in many other plants, like cloves and black pepper. BCP binds to the CB2 cannabinoid receptor in the body, and by doing so it helps maintain a healthy inflammatory reaction and promotes the overall health of the digestive tract, skin, and liver disease.
DIM is a compound we create in our bodies when we eat cruciferous vegetables like broccoli, cauliflower, cabbage, and Brussels sprouts. DIM is also a readily available nutritional supplement. Much like beta-caryophyllene, DIM binds to the CB2 cannabinoid receptor. Since the immune system is rich with CB2 receptors, this may clarify the immune-supportive health benefits of the foods.
Located in the familiar herb Echinacea, alkylamides are also drawing interest for their part in the ECS. These unique compounds act on the CB2 cannabinoid receptor to regulate cytokine synthesis and also to support immune function. This activity probably helps clarify some of the common uses of Echinacea.
Found in carrots, celery, parsley, and Panax ginseng, this interesting compound may not be one need to touch. Falcarinol binds to the CB1 cannabinoid receptor which also has the reverse effect of anandamide, that the cannabinoid our bodies make that binds to the receptor. Because of this trend, falcarinol can cause an allergic skin reaction that’s regarded because it prevents our very own ECS from modulating local inflammation.
This phytocannabinoid, found from the Kava plant (Piper methysticum), binds to CB1 cannabinoid receptors and also acts on GABA receptors in the nervous system. Although yangonin appears to promote relaxation and modulate responses to stress, it might also be bad for the liver.
Understanding of the endocannabinoid system is growing quickly. As this knowledge does enlarge, science will continue to find more phytocannabinoids in plants and foods that are useful in supporting health in many ways.
In conclusion,�many research studies have found a connection between inflammatory pathways and neurocircuits in the brain which can lead to a variety of behavioral responses, such as avoidance and alarm, however, growing evidence has demonstrated that chronic inflammation can lead to depression. Depression is a debilitating disorder which amounts to one of the leading causes of disability worldwide. The article above describes the connection between inflammation and depression. New insights on the results of the research studies could open the possibilities for new treatments to treat depression, among other associated health issues. Moreover, understanding the role of phytocannabinoids in the human body can function as another treatment approach for inflammation associated with depression.� Information referenced from the National Center for Biotechnology Information (NCBI).�The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at�915-850-0900�.
Curated by Dr. Alex Jimenez
Additional Topics: Back Pain
Back pain is one of the most prevalent causes for disability and missed days at work worldwide. As a matter of fact, back pain has been attributed as the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience some type of back pain at least once throughout their life. The spine is a complex structure made up of bones, joints, ligaments and muscles, among other soft tissues. Because of this, injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.
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Biochemistry of Pain:�All pain syndromes have an inflammation profile. An inflammatory profile can vary from person to person and can also vary in one person at different times. The treatment of pain syndromes is to understand this inflammation profile. Pain syndromes are treated medically, surgically or both. The goal is to inhibit/suppress the production of inflammatory mediators. And a successful outcome is one that results in less inflammation and of course less pain.
Biochemistry Of Pain
Who are the key players
What are the biochemical mechanisms?
What are the consequences?
Why Does My Shoulder Hurt? A Review Of The Neuroanatomical & Biochemical Basis Of Shoulder Pain
If a patient asks �why does my shoulder hurt?� the conversation will quickly turn to scientific theory and sometimes unsubstantiated conjecture. Frequently, the clinician becomes aware of the limits of the scientific basis of their explanation, demonstrating the incompleteness of our understanding of the nature of shoulder pain. This review takes a systematic approach to help answer fundamental questions relating to shoulder pain, with a view to providing insights into future research and novel methods for treating shoulder pain. We shall explore the roles of (1) the peripheral receptors, (2) peripheral pain processing or �nociception�, (3) the spinal cord, (4) the brain, (5) the location of receptors in the shoulder and (6) the neural anatomy of the shoulder. We also consider how these factors might contribute to the variability in the clinical presentation, the diagnosis and the treatment of shoulder pain. In this way we aim to provide an overview of the component parts of the peripheral pain detection system and central pain processing mechanisms in shoulder pain that interact to produce clinical pain.
INTRODUCTION: A VERY BRIEF HISTORY OF PAIN SCIENCE ESSENTIAL FOR CLINICIANS
The nature of pain, in general, has been a subject of much controversy over the past century. In the 17th century Descartes� theory1 proposed that the intensity of pain was directly related to the amount of associated tissue injury and that pain was processed in one distinct pathway. Many earlier theories relied upon this so-called �dualist� Descartian philosophy, seeing pain as the consequence of the stimulation of a �specific� peripheral pain receptor in the brain. In the 20th century a scientific battle between two opposing theories ensued, namely specificity theory and pattern theory. The Descartian �specificity theory� saw pain as a specific separate modality of sensory input with its own apparatus, while �pattern theory� felt that pain resulted from the intense stimulation of non-specific receptors.2 In 1965, Wall and Melzack�s 3 gate theory of pain provided evidence for a model in which pain perception was modulated by both sensory feedback and the central nervous system. Another huge advance in pain theory at around the same time saw the discovery of the specific mode of actions of the opioids.4 Subsequently, recent advances in neuroimaging and molecular medicine have vastly expanded our overall understanding of pain.
So how does this relate to shoulder pain?�Shoulder pain is a common clinical problem, and a robust understanding of the way in which pain is processed by the body is essential to best diagnose and treat a patient�s pain. Advances in our knowledge of pain processing promise to explain the mismatch between pathology and the perception of pain, they may also help us explain why certain patients fail to respond to certain treatments.
BASIC BUILDING BLOCKS OF PAIN
Peripheral sensory receptors: the mechanoreceptor and the �nociceptor�
There are numerous types of peripheral sensory receptors present in the human musculoskeletal system. 5 They may be classified based on their func�tion (as mechanoreceptors, thermoreceptors or nociceptors) or morphology (free nerve endings or different types of encapsulated receptors).5 The dif�ferent types of receptor can then be further subclas�sified based on the presence of certain chemical markers. There are significant overlaps between dif�ferent functional classes of receptor, for example
Peripheral Pain Processing: �Nociception�
Tissue injury involves a variety of inflammatory mediators being released by damaged cells including bradykinin, histamine, 5-hydroxytryptamine, ATP, nitric oxide and certain ions (K+ and H+). The activation of the arachidonic acid pathway leads to the production of prostaglandins, thromboxanes and leuko- trienes. Cytokines, including the interleukins and tumor necrosis factor ?, and neurotrophins, such as nerve growth factor (NGF), are also released and are intimately involved in the facilitation of inflammation.15 Other substances such as excitatory amino acids (glutamate) and opioids (endothelin-1) have also been implicated in the acute inflammatory response.16 17 Some of these agents may directly activate nociceptors, while others bring about the recruitment of other cells which then release further facilitatory agents.18 This local process resulting in the increased responsiveness of nociceptive neurons to their normal input and/or the recruitment of a response to normally subthreshold inputs is termed �peripheral sensitization�.�Figure 1 summarizes some of the key mechanisms involved.
NGF and the transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor have a symbiotic relationship when it comes to inflammation and nociceptor sensitization. The cytokines produced in inflamed tissue result in an increase in NGF production.19 NGF stimulates the release of histamine and serotonin (5-HT3) by mast cells, and also sensitizes nociceptors, possibly altering the properties of A? fibers such that a greater proportion become nociceptive. The TRPV1 receptor is present in a subpopulation of primary afferent fibers and is activated by capsaicin, heat and protons. The TRPV1 receptor is synthesized in the cell body of the afferent fibre, and is transported to both the peripheral and central terminals, where it contributes to the sensitivity of nociceptive afferents. Inflammation results in NGF production peripherally which then binds to the tyrosine kinase receptor type 1 receptor on the nociceptor terminals, NGF is then transported to the cell body where it leads to an up regulation of TRPV1 transcription and consequently increased nociceptor sensitivity.19 20 NGF and other inflammatory mediators also sensitize TRPV1 through a diverse array of secondary messenger pathways. Many other receptors including cholinergic receptors, ?-aminobutyric acid (GABA) receptors and somatostatin receptors are also thought to be involved in peripheral nociceptor sensitivity.
A large number of inflammatory mediators have been specifically implicated in shoulder pain and rotator cuff disease.21�25 While some chemical mediators directly activate nociceptors, most lead to changes in the sensory neuron itself rather than directly activating it. These changes may be early post- translational or delayed transcription dependent. Examples of the former are changes in the TRPV1 receptor or in voltage- gated ion channels resulting from the phosphorylation of membrane-bound proteins. Examples of the latter include the NGF-induced increase in TRV1 channel production and the calcium-induced activation of intracellular transcription factors.
Molecular Mechanisms Of Nociception
The sensation of pain alerts us to real or impending injury and triggers appropriate protective responses. Unfortunately, pain often outlives its usefulness as a warning system and instead becomes chronic and debilitating. This transition to a chronic phase involves changes within the spinal cord and brain, but there is also remarkable modulation where pain messages are initiated � at the level of the primary sensory neuron. Efforts to determine how these neurons detect pain-producing stimuli of a thermal, mechanical or chemical nature have revealed new signaling mechanisms and brought us closer to understanding the molecular events that facilitate transitions from acute to persistent pain.
The Neurochemistry Of Nociceptors
Glutamate is the predominant excitatory neurotransmitter in all nociceptors. Histochemical studies of adult DRG, however, reveal two broad classes of unmyelinated C fiber.
Chemical Transducers To Make The Pain Worse
As described above, injury heightens our pain experience by increasing the sensitivity of nociceptors to both thermal and mechanical stimuli. This phenomenon results, in part, from the production and release of chemical mediators from the primary sensory terminal and from non-neural cells (for example, fibroblasts, mast cells, neutrophils and platelets) in the environment36 (Fig. 3). Some components of the inflammatory soup (for example, protons, ATP, serotonin or lipids) can alter neuronal excitability directly by inter- acting with ion channels on the nociceptor surface, whereas others (for example, bradykinin and NGF) bind to metabotropic receptors and mediate their effects through second-messenger signaling cascades11. Considerable progress has been made in understanding the biochemistry basis of such modulatory mechanisms.
Extracellular Protons & Tissue Acidosis
Local tissue acidosis is a hallmark physiological response to injury, and the degree of associated pain or discomfort is well correlated with the magnitude of acidification37. Application of acid (pH 5) to the skin produces sustained discharges in a third or more of polymodal nociceptors that innervate the receptive field 20.
Cellular & Molecular Mechanisms Of Pain
The nervous system detects and interprets a wide range of thermal and mechanical stimuli as well as environmental and endogenous chemical irritants. When intense, these stimuli generate acute pain, and in the setting of persistent injury, both peripheral and central nervous system components of the pain transmission pathway exhibit tremendous plasticity, enhancing pain signals and producing hypersensitivity. When plasticity facilitates protective reflexes, it can be beneficial, but when the changes persist, a chronic pain condition may result. Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.
Introduction: Acute Versus Persistent Pain
Figure 5. Spinal Cord (Central) Sensitization
Glutamate/NMDA receptor-mediated sensitization.�Following intense stimulation or persistent injury, activated C and A? nociceptors release a variety of neurotransmitters including dlutamate, substance P, calcitonin-gene related peptide (CGRP), and ATP, onto output neurons in lamina I of the superficial dorsal horn (red). As a consequence, normally silent NMDA glutamate receptors located in the postsynaptic neuron can now signal, increase intracellular calcium, and activate a host of calcium dependent signaling pathways and second messengers including mitogen-activated protein kinase (MAPK), protein kinase C (PKC), protein kinase A (PKA) and Src. This cascade of events will increase the excitability of the output neuron and facilitate the transmission of pain messages to the brain.
Disinhibition.�Under normal circumstances, inhibitory interneurons (blue) continuously release GABA and/or glycine (Gly) to decrease the excitability of lamina I output neurons and modulate pain transmission (inhibitory tone). However, in the setting of injury, this inhibition can be lost, resulting in hyperalgesia. Additionally, disinhibition can enable non-nociceptive myelinated A? primary afferents to engage the pain transmission circuitry such that normally innocuous stimuli are now perceived as painful. This occurs, in part, through the disinhibition of excitatory PKC? expressing interneurons in inner lamina II.
Microglial activation.�Peripheral nerve injury promotes release of ATP and the chemokine fractalkine that will stimulate microglial cells. In particular, activation of purinergic, CX3CR1, and Toll-like receptors on microglia (purple) results in the release of brain-derived neurotrophic factor (BDNF), which through activation of TrkB receptors expressed by lamina I output neurons, promotes increased excitability and enhanced pain in response to both noxious and innocuous stimulation (that is, hyperalgesia and allodynia). Activated microglia also release a host of cytokines, such as tumor necrosis factor ? (TNF?), interleukin-1? and 6 (IL-1?, IL-6), and other factors that contribute to central sensitization.
The Chemical Milieu Of Inflammation
Peripheral sensitization more commonly results from inflammation-associated changes in the chemical environment of the nerve fiber (McMahon et al., 2008). Thus, tissue damage is often accompanied by the accumulation of endogenous factors released from activated nociceptors or non-neural cells that reside within or infiltrate into the injured area (including mast cells, basophils, platelets, macrophages, neutrophils, endothelial cells, keratinocytes, and fibroblasts). Collectively. these factors, referred to as the �inflammatory soup�, represent a wide array of signaling molecules, including neurotransmitters, peptides (substance P, CGRP, bradykinin), eicosinoids and related lipids (prostaglandins, thromboxanes, leukotrienes, endocannabinoids), neurotrophins, cytokines, and chemokines, as well as extracellular proteases and protons. Remarkably, nociceptors express one or more cell surface receptors capable of recognizing and responding to each of these pro-inflammatory or pro-algesic agents (Figure 4). Such interactions enhance excitability of the nerve fiber, thereby heightening its sensitivity to temperature or touch.
Unquestionably the most common approach to reducing inflammatory pain involves inhibiting the synthesis or accumulation of components of the inflammatory soup. This is best exemplified by non-steroidal anti-inflammatory drugs, such as aspirin or ibuprofen, which reduce inflammatory pain and hyperalgesia by inhibiting cyclooxygenases (Cox-1 and Cox-2) involved in prostaglandin synthesis. A second approach is to block the actions of inflammatory agents at the nociceptor. Here, we highlight examples that provide new insight into cellular mechanisms of peripheral sensitization, or which form the basis of new therapeutic strategies for treating inflammatory pain.
NGF is perhaps best known for its role as a neurotrophic factor required for survival and development of sensory neurons during embryogenesis, but in the adult, NGF is also produced in the setting of tissue injury and constitutes an important component of the inflammatory soup (Ritner et al., 2009). Among its many cellular targets, NGF acts directly on peptidergic C fiber nociceptors, which express the high affinity NGF receptor tyrosine kinase, TrkA, as well as the low affinity neurotrophin receptor, p75 (Chao, 2003; Snider and McMahon, 1998). NGF produces profound hypersensitivity to heat and mechanical stimuli through two temporally distinct mechanisms. At first, a NGF-TrkA interaction activates downstream signaling pathways, including phospholipase C (PLC), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K). This results in functional potentiation of target proteins at the peripheral nociceptor terminal, most notably TRPV1, leading to a rapid change in cellular and behavioral heat sensitivity (Chuang et al., 2001).
Irrespective of their pro-nociceptive mechanisms, interfering with neurotrophin or cytokine signaling has become a major strategy for controlling inflammatory disease or resulting pain. The main approach involves blocking NGF or TNF-? action with a neutralizing antibody. In the case of TNF-?, this has been remarkably effective in the treatment of numerous autoimmune diseases, including rheumatoid arthritis, leading to dramatic reduction in both tissue destruction and accompanying hyperalgesia (Atzeni et al., 2005). Because the main actions of NGF on the adult nociceptor occur in the setting of inflammation, the advantage of this approach is that hyperalgesia will decrease without affecting normal pain perception. Indeed, anti-NGF antibodies are currently in clinical trials for treatment of inflammatory pain syndromes (Hefti et al., 2006).
Glutamate/NMDA Receptor-Mediated Sensitization
Acute pain is signaled by the release of glutamate from the central terminals of nociceptors, generating excitatory post-synaptic currents (EPSCs) in second order dorsal horn neurons. This occurs primarily through activation of postsynaptic AMPA and kainate subtypes of ionotropic glutamate receptors. Summation of sub-threshold EPSCs in the postsynaptic neuron will eventually result in action potential firing and transmission of the pain message to higher order neurons.
Other studies indicate that changes in the projection neuron, itself, contribute to the dis- inhibitory process. For example, peripheral nerve injury profoundly down-regulates the K+- Cl- co-transporter KCC2, which is essential for maintaining normal K+ and Cl- gradients across the plasma membrane (Coull et al., 2003). Downregulating KCC2, which is expressed in lamina I projection neurons, results in a shift in the Cl- gradient, such that activation of GABA-A receptors depolarize, rather than hyperpolarize the lamina I projection neurons. This would, in turn, enhance excitability and increase pain transmission. Indeed, pharmacological blockade or siRNA-mediated downregulation of KCC2 in the rat induces mechanical allodynia.
Why does my shoulder hurt? A review of the neuroanatomical and biochemical basis of shoulder pain
Benjamin John Floyd Dean, Stephen Edward Gwilym, Andrew Jonathan Carr
Cellular and Molecular Mechanisms of Pain
Allan I. Basbaum1, Diana M. Bautista2, Gre?gory Scherrer1, and David Julius3
1Department of Anatomy, University of California, San Francisco 94158
2Department of Molecular and Cell Biology, University of California, Berkeley CA 94720 3Department of Physiology, University of California, San Francisco 94158
Molecular mechanisms of nociception
David Julius* & Allan I. Basbaum�
*Department of Cellular and Molecular Pharmacology, and �Departments of Anatomy and Physiology and W. M. Keck Foundation Center for Integrative Neuroscience, University of California San Francisco, San Francisco, California 94143, USA (e-mail: firstname.lastname@example.org)
Pain Anxiety Depression�Everyone has experienced pain, however, there are those with depression, anxiety, or both. Combine this with pain and it can become pretty intense and difficult to treat. People that are suffering from depression, anxiety or both tend to experience severe and long term pain more so than other people.
The way anxiety, depression, and pain overlap each other is seen in chronic and in some disabling pain syndromes, i.e. low back pain, headaches, nerve pain and fibromyalgia. Psychiatric disorders contribute to the pain intensity and also increase the risk of disability.
Depression:�A (major depressive disorder or clinical depression) is a common but serious mood disorder. It causes severe symptoms that affect how an individual feels, thinks, and how the handle daily activities, i.e. sleeping, eating and working. To be diagnosed with depression, the symptoms must be present for at least two weeks.
Persistent sad, anxious, or �empty� mood.
Feelings of hopelessness, pessimistic.
Feelings of guilt, worthlessness, or helplessness.
Loss of interest or pleasure in activities.
Decreased energy or fatigue.
Moving or talking slowly.
Feeling restless & having trouble sitting still.
Difficulty concentrating, remembering, or making decisions.
Thoughts of death or suicide & or suicide attempts.
Aches or pains, headaches, cramps, or digestive problems without a clear physical cause and/or that do not ease with treatment.
Not everyone who is depressed experiences every symptom. Some experience only a few symptoms while others may experience several. Several persistent symptoms in addition to low mood are�required�for a diagnosis of major depression. The severity and frequency of symptoms along with the duration will vary depending on the individual and their particular illness. Symptoms can also vary depending on the stage of the illness.
PAIN ANXIETY DEPRESSION
What is the relationship?
What is the neurophysiology behind it?
What are the central consequences?
Brain Changes In Pain
Figure 1 Brain pathways, regions and networks involved in acute and chronic pain
Davis, K. D. et al. (2017) Brain imaging tests for chronic pain: medical, legal and ethical issues and recommendations Nat. Rev. Neurol. doi:10.1038/nrneurol.2017.122
PAIN, ANXIETY AND DEPRESSION
Pain, especially chronic is associated with depression and anxiety
The physiological mechanisms leading to anxiety and depression can be multifactorial in nature
Pain causes changes in brain structure and function
This change in structure and function can alter the ability for the brain to modulate pain as well as control mood.
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