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 Table of Contents  
EDITORIAL
Year : 2018  |  Volume : 6  |  Issue : 1  |  Page : 1-11

The invisible illness of depression: “Never Say Never Mind, Mind the Mind,” and Mind the “Science Gap”


Department of Neurology, Yenepoya Medical College, Mangalore, Karnataka, India

Date of Web Publication11-Jun-2018

Correspondence Address:
Prof. Dr. Bhaskara P Shelley
Department of Neurology, Yenepoya Medical College, Yenepoya (Deemed to be) University, Mangalore - 575 018, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amhs.amhs_55_18

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How to cite this article:
Shelley BP. The invisible illness of depression: “Never Say Never Mind, Mind the Mind,” and Mind the “Science Gap”. Arch Med Health Sci 2018;6:1-11

How to cite this URL:
Shelley BP. The invisible illness of depression: “Never Say Never Mind, Mind the Mind,” and Mind the “Science Gap”. Arch Med Health Sci [serial online] 2018 [cited 2018 Jun 18];6:1-11. Available from: http://www.amhsjournal.org/text.asp?2018/6/1/1/234107



“God, but life is loneliness, despite all the opiates, despite the shrill tinsel gaiety of 'parties' with no purpose, despite the false grinning faces we all wear. And when at last you find someone to whom you feel you can pour out your soul, you stop in shock at the words you utter – they are so rusty, so ugly, so meaningless and feeble from being kept in the small cramped dark inside you so long. Yes, there is joy, fulfillment and companionship – but the loneliness of the soul in its appalling self-consciousness is horrible and overpowering.”

Sylvia Plath

During my doctorhood and fascinating journey through medicine, I have realized many times the imperfect health-care system, the “science gap” that ignores the wholesome emotional and spiritual well-being, and the core essence of “salutogenesis/health-ease” model of health promotion of the patient. Being a “feeling physician,” I give less credence to the conventional stereotype of the rationalistic “cerebral side” of medicine since the current “technocratic” medicine encounters reflect “social-disconnectedness,” a “detached concern,” and “heartlessness” in our clinical and professional encounters. Having a high empathy quotient, I do suffer many a times from subliminal professional alexithymia.

In this editorial, I touch upon the disorder of the mind, namely depression, which is often ignored in many of the disorders of the mind–brain–body axis, and is alarming for me to note that it has assumed proportions of a global crisis where World Health Organization (WHO) has predicted depression to be the leading cause of worldwide disability by 2020. “The greatest mistake in the treatment of diseases is that there are physicians for the body and physicians for the soul, although the two cannot be separated.” The words of Plato should reinvigorate us to “mind the science gap” beyond the “pill therapy” and prompt us to rethink on the foundations of how positive mental health and interdisciplinary approaches could be effectively harnessed to fight the global mental disability of depression. There is a quintessential priority for “wake-up call” for countries on shattering the stigma on mental health and depression, early identification, closing the global treatment gap, and to rethink wholesome approaches to creating and fostering positive mental health and mental capital in general.

I do reminisce the precious and poignant time I spent during my sabbatical at the Institute of Neurology, Queen Square, where I undertook a research clinic for treatment-resistant depression under the guidance of my mentor Professor Trimble for envisaging potential treatment with 'Vagus Nerve Stimulation' (VNS). I still preserve various letters of communication of such patients till today. This gave me a thorough insight into the neurobiology, functional neuroanatomicaly and imaging neuroscience defects in depression as well as the human sufferings of this invisible illness. I could feel their loneliness of the soul, especially when they do feel the appalling self-consciousness of anhedonia, the rustic meaningless, and empty darkness, which makes the illness so intolerably a horrible situation and overpowering. To make matters worse, depression is one of the strongest predictors of suicide, especially when accompanied by hopelessness. People often commit suicide when they perceive that there is no way out of an intolerably painful situation, or when they see no purpose or meaning to a life of seemingly unending suffering.

History has revealed the “existential abyss and emptiness” caused by the plague of the “Black Dog illness” in the lives of Sylvia Plath, Ernest Hemingway, Abraham Lincoln, Ludwig van Beethoven, John Keats, Vincent Van Gogh, Isaac Newton and Leo Tolstoy. Sylvia Plath wrote “I want to kill myself, to escape from responsibility, to crawl back abjectly into the womb,” gassed herself in her kitchen in 1963. In 1961, Ernst Hemmingway put the barrel of his shotgun in his mouth and pulled the trigger. However, I will refrain from not dwelling on the definite neurobiological association (creativity and psychopathology: the neuropsychiatry of creativity) between creativity and mood disorders, and the role of dopamine and fronto-limbic structures in creativity.

The death of Robin Williams and Chester Bennigton is a wake-up call to recognize and fight depression through pluralistic and interdisciplinary approaches since depression is a heterogeneous disorder, rather than being a single disorder. In India, Bollywood actress Deepika Padukone who has fought depression herself is now the new brand ambassador of Indian Psychiatric Society. She is set to de-stigmatize depression, reduce the negative beliefs and stereotypes of mental health illnesses, increase public awareness, and develop outreach programs through innovative partnership of Indian Psychiatric Society with Deepika's Bengaluru-based non-profit organisation, The Live Love Laugh Foundation.

Depression has been associated with humanity since antiquity. The interested reader may peruse the historical perspective and descriptions of depression and melancholia in many ancient documents including The Old Testament, The Book of Job, and Homer's Iliad. Historical documents that were written by healers, philosophers, and writers throughout the ages point to the long-standing existence of depression as a health problem. The history of depression has been well explicated in classic works of Stanley W. Jackson's “Melancholia and Depression: Hippocrates to Modern Times” who was a Professor of Psychiatry and the History of Medicine at the Yale University School of Medicine and Clark Lawlor's “From Melancholia to Prozac,” a cultural exploration of the history of depression and melancholy.

Depression is more than brain neurochemistry and needs to be seen from a biopsychosocial problem, a sociocultural, and a lifestyle perspective. Depression has several subcomponents such as mood, stress/anxiety, and cognition; we should re-look at depression not as a whole, but see it with as many parts and dissect these different parts when we are looking at interdisciplinary treatments, and shape our future research and policy interventions to address this public health crisis. This editorial will not endeavor to explicate the neurobiological, neurochemistry, neuroanatomical, morphofunctional brain alterations and its functional imaging neurosciences perspective of depression. Instead, I would stress the need to be “mindful of the science gap” in our understanding of depression, and re-think about the modern “depressiogenic social milieu,” and various other risk factors. The various risk factors include the 21st-century lifestyle and behavioral environments, growing burden of chronic noncommunicable disorders, the modern cultural mismatches and stresses placed on the human body, consumption of high-energy foods, dietary habits, obesity, the lack of physical activity (PA), declining social capital, lower social connectedness and loneliness, social isolation, long-term working hours producing circadian dysfunction, decreased exposure to sunlight, Vitamin D, and poor sleep patterns, stressful life events, reduced leisure activities, less family connections, smaller social circles, and the deterioration in social cohesion of our current societies.

In our modern societies, there is hardly a congruence of rational intelligent quotient (IQ), emotional IQ, and spiritual IQ intertwined with a low physical intelligence that all spirals down to a low happiness quotient. Another potential explanation for changing rates of depression as a “disease of modernity and civilization” is the excessive “Facebook use,” “internet addiction,” and “workplace depression.” It is quite evident that antidepressant drugs alone will not be able to cure the epidemic of depression, but would need a pluralistic multimodal intervention of biopsychosocial, spiritual-religion based cognitive behavioral therapies, nutritional psychiatry, and various “science gap” strategies. The main thrust of the editorial will be an attempt to fill the glass half empty of this “science gap” to fight the invisible overempowering illness of depression. These holistic avenues would indeed be effective not only in promoting positive emotional and social health instead, but also help reduce reliance on antidepressants in many cases.

“Depression is the most unpleasant thing I have ever experienced... It is that absence of being able to envisage that you will ever be cheerful again. The absence of hope. That very deadened feeling, which is so very different from feeling sad. Sad hurts but it's a healthy feeling. It is a necessary thing to feel. Depression is very different.”

J. K. Rowling 2000


  “Never Say Never Mind, Mind the Mind” Top


We need to “mind the mind” and reinvigorate global health efforts in mental health disorders in order to preserve the “mental health capital” of human diaspora. Well, I would unhesitatingly reiterate that depression is evolving rapidly as a “disease of modernity” on account of the panoply of behavioral-lifestyle-sociocultural milieu of 21st-century civilization. We have put stresses and metabolic and allostatic load beyond the human evolutionary biological adaptations so that our 21st-century lifestyles are now out of synchrony with our “Paleolithic” human body machinery. Rightly so, the World Mental Health Day initiated by the World Federation for Mental Health in 1992 did adopt the theme of depression in 2012. In 2017, the World Health Day's theme was “Depression: Let's Talk” since the WHO estimated that between 2005 and 2015, there has been an 18% increase in people suffering from depression. According to the latest estimates from the WHO in 2015, more than 322 million people are now living with depression worldwide. The WHO estimates that by 2020 depression will be the second leading cause for disability worldwide.[1] Most worryingly, the WHO estimated the “treatment gap” of 50% in high-income countries, while in low-income countries, that number rises to 80%–90%. Untreated depression is the leading cause of over 788,000 suicides that occur worldwide every year, roughly corresponding to one death in every 45 seconds. Hence, depression is now the world's most widespread illness.

An Indian perspective is reflected by a study the National Institute of Mental Health and Neurosciences (NIMHANS) in Bengaluru. The study estimated that the incidence of depression is roughly one in every 20 Indians or 5% of the population.[2] India would find it difficult to tackle this burden since there are only about 4000 psychiatrists as workforce nationwide which is approximately about three psychiatrists per million people.

In my opinion, such alarming figures both globally and nationally should be taken as a wake-up call to re-think on multi-pronged, pluralistic interdisciplinary approaches to enhance mental health and brain health, promote emotional and social well-being, have a strategy to create awareness, de-stigmatize mental health disorders, introduce mental and brain–mind health education in school curriculum, and fight depression beyond the sole well-established and well-known intervention of the “anti-depressant” pill armentatarium. This is especially so when there is limited adherence to care and relatively low remission rates with conventional pharmacotherapies and psychotherapies.


  Mind the Science Gap Top


“Come forth into the light of things; let Nature be your teacher”

William Wordsworth (1770–1858)

Many of the illnesses that we confront today are what evolutionary biologists called “mismatch diseases” such as diabetes, heart diseases, obesity, and depression since the stress we experience today is different from Paleolithic stress in human prehistory. Daniel Lieberman, a Professor of Human Evolutionary Biology at Harvard University, surmises that our 21st century behavioral and lifestyle patterns with high comfort, stress, and cultural evolution of modern living, stress hormone system, hypercortisolism, craving for quick, high-energy sweet foods, and sedentary behavior have ultimately gone beyond the evolutionary adaptations of the Paleolithic human anatomy and physiology resulting in “mismatch diseases.”[3] Never before had we as a society embraced the culture of a astounding increase in the use of antidepressants. Another doubly disturbing flipside of depression is its independent association to a higher susceptibility to ischemic heart disease, stroke, Parkinson's disease, dementia/Alzheimer's disease, obesity, substance abuse, cancer (lung and liver cancers), downregulation and dysfunction of the immune system and immune surveillance through psychoneuroimmunology, and functional somatic syndromes (fibromyalgia syndromes).

To mind the science gap,” we need to be more aware of healthy and harmful lifestyle behaviors. Several of the nonpharmacological and lifestyle interventions are promising. In geriatric depression and late-life depression with comorbid chronic somatic disorders and polypharmacy, evidence-based nonpharmacological treatment options are needed.


  Depression – A Lifestyle Disease Top


I reiterate that the modern 21st-century civilization is certainly contributing to “mismatch diseases” and “lifestyle disorders” at an alarming pace today. In my informed opinion, at a clinical and population level, depression can be conceptualized as a lifestyle disease and as a disease of “modernity.”[4] The etiopathogenesis of depressive disorders is always complex and multifactorial that is dependent on neurobiological, genetic, personality, and psychological underpinnings. However, emphasis needs to be placed on various lifestyle targets such as negative stressful and traumatic events in childhood; inadequate wholesome food habits; physical inactivity; obesity; metabolic syndrome; dysfunctional circadian rhythms; sleep/wake cycle pressures; stress-fatigue-sleep deficiency; urbanization; social isolation and inadequate social networks with the family unit; environmental and workplace stressors (workplace depression); recreational substances such as nicotine, drugs, and alcohol use; psychosocial factors such as more competition and time pressure; and the increasing human interface with technology (Internet, Facebook) and all these exert a cost on mental health.

All these factors associated with the 21st century modernity potentially disrupt the hypothalamic–pituitary–adrenal (HPA) axis and increase cortisol and low-grade systemic inflammation and oxidative stress. It is pivotal to realize that neuroendocrine disruption, inflammation, and oxidative and nitrosative stress may potentially damage mitochondria and mitochondrial DNA and disturb hippocampal neurogenesis which has been linked to the etiology of depression.[5]


  Integrative-Lifestyle Medicine and Holistic Psychiatry Top


To “mind the mind,” and to “mind the science gap,” we need “to go back to the medical conceptual drawing board” and understand the “science gap.” I stress the need for “holistic psychiatry” centered on an evidence-based integrative complementary medicine model, i.e., the “Antidepressant-Lifestyle-Psychological-Social depression treatment model” that integrates nonpharmacological interventions.[6]Integrative Medicine (IM) and Lifestyle Medicine are alterative healing-oriented medicine that takes account of the whole person, including all aspects of lifestyle. Holistic psychiatry lends credence to the patient as a unified whole, comprising of mental, emotional, physical, spiritual, social, and environmental forces that simultaneously and equally affect health and mental well-being. Through the integrative complementary medicine model, nutritional/functional/orthomolecular medicine and mind-body/energy medicine in addition to conventional medicine approaches are utilized to restore a state of optimal mental and physical health, as naturally and efficiently as possible.

Ayurveda says in Sanskrit “Swasthshya swastha rakshitham” meaning “Try to preserve health and well-being,” a salutogenesis health concept of “whole-person healing.” This can be achieved through Lifestyle Medicine, consisting of the evidence-based adoption of PA or exercise, dietary modification, adequate relaxation/sleep and social interaction, use of mindfulness-based meditation techniques, and the reduction of recreational substances such as nicotine, drugs, and alcohol. Such integrative systems to 'mind the mind' could incorporate Ayurveda, Ayurvedic Psychiatry, Anthroposophic medicine (AM), Complementary and Alternative Medicine (CAM). AM has been established in eighty countries worldwide, most significantly in Central Europe.[7] Studies have shown long-term clinical improvement with AM therapies such as art and music therapy, eurythmy movement exercises, rhythmical massage, dance and movement therapy, body-oriented psychotherapy (kinesiotherapeutic interventions), reflexology, mindfulness meditation, yoga, which provide a promising heterogeneous nondrug/ non- pharmacological therapeutic field for the treatment of mental disorders and depression.[8],[9]


  Yoga and Mindfulness Meditation Top


Yoga originated more than 5000 years ago in India as a comprehensive life discipline to harmonize body, mind, and spirit and to transcend suffering by developing an abiding awareness of one's spiritual nature. Hatha yoga emphasizes physical components – such as body postures, breathing (Pranayama) and relaxation techniques, and dietary practices. A recent randomized clinical trial (RCT) pilot study from San Francisco has found promising evidence that 8 weeks of active hatha yoga sessions twice weekly can help treat depression as evidenced by a significant change in General Self-Efficacy Scale and/or Rosenberg Self-Esteem Scale scores.[10] Another study from NIMHANS developed a comprehensive yoga module as an outpatient therapy for depression and was found to be feasible and useful in patients with depression.[11]

Yoga, Ayurveda, and its Medhya rasayanas, Meditation and Pranayama, are “push-ups for the brain” and paths to brain wellness. The neuroscience of meditation does indeed show structural changes in cortical thickness, gray matter density, gray and white matter neuroplasticity, changes in functional connectivity and anatomical connectivity, and changes in electroencephalography patterns. Moreover, the neural mechanisms of mindfulness-based stress reduction did also reveal an increase in gray matter concentrations in areas that were involved in learning and memory processes, emotion regulation, self-referential processing, and perspective taking.


  We Are What We Eat-Food for Thought Top


From gut to behavior-how nutrients affect mental health and the brain

There is unequivocal evidence to reinforce the role of dietary patterns and diet quality in depression and affective disorders.[12],[13]

Major dietary changes consisting of nutrient-insufficient and energy-dense foods, saturated fats, and refined sugar have occurred across the globe in the past century. Diet modulates several key biological processes that underscore mood disorders, including brain plasticity and function, the stress response system, mitochondria, inflammation, and oxidative processes (Indian wholesome diet). A Western dietary pattern is associated with increased markers of systemic inflammation, which corroborates with studies that higher levels of serum high-sensitivity C-reactive protein are an independent risk factor for depression. A deficiency of wholefood diet depletes body resources of essential micronutrients critical in neurochemical function, including B vitamins, zinc, magnesium, Vitamin C, and a range of plant compounds such as flavonoids that are potent antioxidants and anti-inflammatory moieties. Minding our diet and altering dietary patterns does affect a variety of factors influencing the development and trajectory of depression. Mediterranean-style diet, low-carbohydrate diet, omega-3 foods (fish oils, walnuts, avocados, flaxseeds, soybeans, canola, or olive oil), turmeric, and curry dish are all “food for brain and mental health.”

Can yogurt affect the brain and mood and stress-related affective disorders? Could adding twice a day yogurt to your diet could relieve depression? Are probiotics the key to a better antidepressant? Eating yogurt rich in lactobacillus – a probiotic bacteria – may help alleviate symptoms of depression and anxiety through enzymatic fermentology and gut–brain axis (GBA). Regular consumption of fermented milk product (yogurt) that contains Lactobacillus does ameliorate the gut–microbiome dysbiosis by decreasing the circulating level of kynurenine, a metabolite associated with depression, and may actually change the way our brain responds to the environment. Thus, restoring intestinal Lactobacillus levels is sufficient to improve the metabolic alterations and behavioral abnormalities.

Another reflection I have developed over the many years of my doctor hood is that our so called 'evidence based medicine' with its scientific data seem to rest on a 'one-legged stool' and seems imperfect many a times. Many a times our call for decision making demands much certainty when clinical scenarios are riddled with uncertainties and 'terra incognita' of 'known unknowns', and 'unknown unknowns'. This is the ground zero reality of the 'science of medicine'. The 'evidenced-burdened' approach is seen by the dramatic U-turn in the Dietary Guidelines Advisory Committee report in 2015 which stated that “cholesterol is not considered a nutrient of concern for overconsumption”. Nevertheless, I would still reiterate that a more cautious approach to dietary cholesterol intake is warranted, especially in high-risk populations. Similar to the “cholesterol hypothesis” one of the irony of ironies is the propaganda against 'coconut oil' and favoring polyunsaturated sunflower (PUFA)-rich oils. Fats are classified into short chain, medium chain, and long chain fatty acids based on their number of carbon atoms and the length of the chain. Coconut oil is low calorie fat with medium chain fatty acids (MCT) (Lauric acid, capric acid). Lauric acid gets converted inside the human system into Monolaurins which is the best fat that mother's milk has. It is interesting to note that MCT in Virgin Coconut Oil is rich in polyphenols and has been propounded to be a potential antidepressant functional food. I would reiterate that we need formal clinical trials and studies on coconut oil, diet and lifestyle interventions, including vegan diet and Sattvic diet and its effects on mood (anxiety, depression) and neurological disorders like Alzheimer's disease. MCT as in coconut oil is now being used in the treatment of Alzheimer's disease, Parkinson's disease, Huntington's disease, Multiple sclerosis, ALS, and drug resistant epilepsy. These effects are mediated through metabolism of MCT to ketones that readily cross the blood-brain barrier to provide an alternative source of brain fuel.

Recognizing that nutrition as the key to brain health, this forms a fundamental premise of integrative medicine. Instead of focusing on just one type of intervention, integrative medicine tries to address all factors that may contribute to a mental disorder e.g. bringing together nutritional supplements, medicines, psychotherapy, and lifestyle changes. The European PREDIMED study certainly is a welcome study as it found an inverse association between adherence to a Mediterranean diet and the risk of depression.

Although human lithium deficiency disease have not been well defined. Lithium is found in a wide variety of foods, and is highest in seafood, fish, pastured egg yolks, mushroom, organic tomatoes, organic dairy products, and mineral rich foods such as nuts, seeds, and cacao. Lithium is an unaddressed nutritional supplement. The diverse neuroprotective mechanisms are truly remarkable. The scientific literature has shown that lithium modulates GSK-3, up-regulates neurotrophic factors such as BDNF, and promotes epigenetic changes that resets the trajectory of mental illness. In low doses, lithium acts as a nutrient required for B12 and folate transport and uptake, neuromodulation, and maybe yet be another mechanism of the antidepressive and mood elevating action of Lithium at nutritional dosage levels. Professor Timothy Marshall, a holistic neuropharmacologist in the United States does advocate that an optimal, nutritional intake of lithium as 'ultra-trace minerals' may prevent or ameliorate many neurologic and psychiatric conditions.

Another well-known factor for mental disorders is that cells within the brain require omega-3 oils in order to be able to transmit signals that enable proper thinking, regulate mood, and emotions. Several mechanisms of action may explain how eicosapentaenoic acid (EPA) which the body converts into docosahexaenoic acid (DHA), the two omega-3 fatty acids found in fish oil, elicit antidepressant effects in humans.

Looking into an Ayurvedic perspective, it is interesting to note that a holistic system of dietary classification and, Hatha yoga & energetics has been long explicated that is of relevance to nutritional psychiatry. There are three qualities of foods (ahar), namely Sattvic, Rajasic, and Tamasic foods, all of which have effects on the mind, body, and emotions (Mano Vijnana Avum Manasa Roga; Ayurvedic Psychiatry). Healthy eating can also be considered a practice to seek for and attain harmonic body/mind balance. According to yogic philosophy, there are intimate connections of diet with mind, and foods have an unknown subtle essence that is difficult to prove through modern scientific methods. The Sattvic diet (pure and balanced) is believed to increase energy and produce happiness, calmness, and mental clarity. It could enhance longevity, health, and spirituality. All foods included in this diet are fresh, juicy, nutritious, and tasty, thus including the consumption of fresh fruits and vegetables, sprouted grains, roots, tubers, nuts, cow milk, curd, and honey.[14] Sattvic foods promote the mind to be calm and clear, with creative thinking that allows it to easily find effective solutions to life's problems, little quantity of Rajas to implement these creative ideas and solutions, and Tamas in moderation is considered as grounding and promotes stability. It is propounded in Ayurveda to have a judicious balance of the three qualities of food with 70%–80% of foods to be Sattvic (Sattvic diet).

I am amazed at the therapeutic attraction knowing that “anti-depressive foods” could have considerable impact to fight against depression worldwide. Diet is one of the noninvasive approaches that can be used to enhance neural signaling by influencing synaptic transmission and brain plasticity. I believe, India being a pluralistic society, there must be case–control studies and RCTs in traditional medicine (TM) or complementary and alternative systems of medicine (CAM), and Ayurveda, and Yoga to integrate and unite the two philosophies of the Western and traditional systems of medicine paving way for a holistic meta-medicine system of health care (physical, neuropsychiatric, and affective disorders) for positive healing outcomes for the human race and mental health capital rather than curative obsessions. Hence would I certainly advocate for the pursuit of an integrative psychiatric model, with diet as a key element.


  Depression-Brain–Gut–Microbiome Link Top


Connection between gut bacteria and depression

How does the gut as the “Second Brain” or the enteric nervous system influence our mood and well-being? The microbiome, a complex microbial ecosystem containing some 100 trillion microorganisms, functions to establish the intestinal lining and aids in its maintenance that are essential for health. The human mind–body is not an isolated self-sufficient island, instead it is a super-complex intricate multidirectional ecosystem consisting of trillions of bacteria, neurochemical trajectories, and distributed brain neurobehavioral neural networks for maintaining homeostasis (immune, neuroendocrine, and psychoneuroimmunology) and mental-brain health. The microbiome–gut–brain link does not support the reductionist science and Descartian dualism of the mind–body, and is intriguing to fathom the ability of the central nervous system (CNS) to communicate with the gut. Thus, it can be assumed empirically that there exists a close relationship between emotional state, mental and brain health, mood and other neurodevelopmental disorders, and gut function. In recent years, the bidirectional communication between the CNS and gut microbiota, referred to as the GBA, has been an area of significant interest, and one of the most exciting developments in the history of medicine and neurosciences. The gut microbiota, probiotics, and GBA does extend to endocrine, neural, and immune pathways too. The influence of gut microbiota on hormone and neurotransmitter signaling functions that may be modulated by the CNS is now understood to offer major opportunities to improve human health.

Hormones, neurotransmitters, and immunological factors released from the gut are known to send signals to the brain either directly or via autonomic (vagus) neurons, i.e., “microbiota–gut–vagus–brain axis.” The vagal afferent nerves sends the impulses from the gut to the first central relay in the dorsomedial medulla (nucleus tractus solitarius) from which projections are widely distributed to various brain regions such as limbic forebrain and prefrontal cortices occur thus modulating affective behaviour and mood regulation. The gut microbiome can equally influence neural development and cognitive and emotional behavior. Therefore, healthy gut function has been linked to normal CNS function. Dysbiosis and variations in the gut microbiota have been causally linked to CNS disorders and psychopathology such as depression, anxiety disorders, schizophrenia, and autism.[15] Gut microbiota are now an important player in how the body influences the brain, contributes to normal healthy homeostasis, emotional and cognitive processing, and influences the risk of disease, including stress-related disorders, such as anxiety and depression. Neuroscientists are taking cognizance of the GBA and its “bottom-up” influence of microbes themselves, with several studies showing that commensal bacteria are important to CNS function. Hence, the GBA modulation could be used to develop innovative approaches to prevent brain–mind disorders and psychopathologies.

Probiotics are transient entities that colonize the gastrointestinal tract and influence various pathways to impact the CNS by regulating critical neurotransmitters implicated in depression. Probiotics are in the spotlight of enteric neuroscience research that influences brain biochemistry, neural development, and other behavioral phenomenon. A recent systematic review to analyze the current body of research assessing the effects of probiotics on symptoms of depression in humans such as mood, anxiety, and cognition did show robust and compelling positive evidence in alleviating depressive symptoms.[16] Another study did confirm a link between intake of fermented milk product (yogurt) with probiotic (containing Bifidobacterium animalis subsp. Lactis, Streptococcus thermophilus, Lactobacillus bulgaricus, and Lactococcus lactis subsp. Lactis) in healthy women and functional magnetic resonance imaging evidence of modulation of brain activity in brain regions that control central processing of emotion and sensation. This study paves the way forward that gut flora can provide novel targets for the treatment of emotional disorders associated with gut dysbiosis.[17] It seems likely that our evolving knowledge on gut microbiome does add paradigm-transforming insights to our existing understanding of human brain function in health and disease and could provide promising novel therapies in disorders of the mind–brain interface.[18]


  Depression-Nutritional Psychiatry Top


Few people are aware of the connection between nutrition and depression. In recent years, there has been an unprecedented growth of research targeting at the relationship between nutrition and mental health. There has been bidirectional evidence to lend credence to protective effect of healthy diets on depressed mood, as well as the newest research supporting a detrimental impact of unhealthy diets on the mental health young adults. In light of this, the International Society for Nutritional Psychiatry Research (ISNPR) was formed in 2013 to advance research and communication on nutritional medicine in the field of psychiatry. Nutritional psychiatry is an emerging field of psychiatry that explores the relationship between dietary patterns and risk of mental health disorders. The nascent field of nutritional psychiatry targets nutritional interventions taking cognizance of the evolving and recent studies explicating our understanding of the biological pathways that mediate diet–mental health link, the immune system, oxidative biology, brain plasticity, and the microbiome-GBA. This burgeoning field offers promise for a new approach to both the prevention and treatment of brain–mind and psychopathologic disorders that rank in the global burden of disorders.[19] Deficiencies in neurotransmitters such as serotonin, dopamine, noradrenaline, and gamma-aminobutyric acid (GABA) are often associated with depression. Dietary supplements containing neurochemicals such as S-adenosylmethionine, probiotics, omega-3 fatty acids, i.e., eicosapentaenoic acid, docosahexanoic acid, Vitamin D, folate and Vitamin B12, low glycemic index foods, and various other micronutrients (polyphenols, calcium, iron, chromium, selenium, lithium, iodine, and zinc) have clearly shown to modulate brain biochemistry and psychoneuroimmunology. The microbiota-GBA and the role of nutritional factors indeed influence the brain, mental, emotional, and social well-being of an individual.

In 2014, eight European countries funded an innovative project with the acronym “MooDFOOD” standing for “Multi-country cOllaborative project on the rOle of Diet, Food-related behaviour, and Obesity in the prevention of Depression.” As alluded to earlier, targeting food-related behaviours and nutritional status is a novel preventive strategy for depression and obesity.[20] I would advocate nutritional strategies nutraceutical, 'psychobiotic' (prebiotics and probiotics) interventions, multinutrient supplements and change in food-related behavior as an adjunctive treatment of depression. The emerging field of Nutritional Psychiatry will offer a new approach to both the prevention and treatment of mental disorders that account for the leading disability burden globally.


  Exercise and the Prevention of Depression Top


The 21st-century lifestyles have tremendously reduced the amount of work- and leisure-time PA and formalized exercise, increasingly sedentary, with the resultant side effect of obesity currently recognized as another major health problem worldwide. Imaging studies have demonstrated structural changes associated with early-onset depression in the hippocampus, amygdala, striatum, and frontal cortex; areas that are all extensively interconnected. Most consistently associated with depression are the findings of volume loss in the hippocampal formation.

Exercise facilitates neuroplasticity in the brain by promoting the expression of brain neurotrophic factors, improved synaptogenesis, enhanced hippocampal functioning, modified apoptosis, and increased vascular reserve of the brain. Studies have demonstrated that walking maintains brain volume and prevents cognitive impairment and depression. PA and exercise have been shown to induce widespread neurobiological adaptations through the release of endorphins, and as a diversion from negative thoughts and the mastery of a new skill. Exercise is a positive behavioral intervention to enhance brain health and plasticity. These positive benefits on mood occur through activation of molecular, cellular cascades and biological pathways that include inflammatory cytokines, oxidative stress, brain-derived neurotrophic factor (BDNF), and neurotrophins that stimulate neurogenesis; increased levels of endocannabinoids; changes in the HPA axis; and decreased cortisol production.[21]

An innovative study designed to follow up of a “healthy” cohort of 33,908 Norwegian adults for 11 years did document the protective effect of regular leisure-time exercise against new-onset depression.[22] The study findings are exciting because the HUNT study showed that even relatively small amounts of exercise (from 1 h/week) could deliver significant protection against depression. It is also heartening to note that exercise compares favorably to antidepressant medications as a first-line treatment for mild-to-moderate depression and has also been shown to improve depressive symptoms when used as an adjunct to medications.


  Fasting and Calorie Restriction Top


I would initiate this essential area of “spiritual fasting traditions” (Upavasa, Ramadhan fasting, Lent season) by reflecting on the traditional Okinawan lifestyle practices. Okinawans are the inhabitants of the largest of the Ryukyu Islands, a semi-circular archipelago of over 150 islands stretched between southern part of Japan and Taiwan.

Their lifestyle practices included healthy diet comprising of low caloric intake, with lots of fruit, tofu, vegetables, and seaweed, high vegetable/fruit consumption, higher intake of good fats (omega-3, mono-unsaturated fat) and high-fiber diet, high flavonoid intake, regular exercise, practice of tai chi, riding bikes, avoidance of smoking, blood pressure control, rich social network and meaningful bonding, spiritual well-being, and a stress-minimizing psycho-spiritual engagement. Through such lifestyles, it is observed that the rates of cancer, stroke, coronary heart disease, and depression are well below the average of advanced economies and most were centenarians.

Our fasting rituals and traditions are well based on the science of dietary and caloric restriction (CR) and alternate-day fasting (ADF). The nascent literature from both animal and human trials does show beneficial effects of fasting by promoting brain health; healthy brain aging and lifespan and depression through resistance of neurons to neurodegeneration; and chronic disease prevention such as type 2 diabetes mellitus, cardiovascular disease (CVD), and cancer. Observational studies on the Okinawa centenarians revealed that the adult energy intake was 20% less than the Japanese national average. Molecular basis underlying the antidepressant actions of calorie restriction might involve multiple physiological processes, primarily including orexin signaling activation, increased CREB phosphorylation and neurotrophic effects of BDNF, enhanced neurogenesis, release of endorphin, and ketone production.[23] There is some evidence to show that CR could induce antidepressant-like effects in animal model of depression. CR is intertwined with the brain–gut axis, some signal pathways common between the control of CR mitochondrial bioenergetics and regulation of neuroendocrine status, and depression. BDNF is vital for the formation and plasticity of neuronal networks, and of course, these networks are involved in depression as well as cognitive well-being, aging, and brain health. It is astounding to note that ADF and fasting during Ramadhan had been documented to have significantly increased plasma levels of serotonin, BDNF, and NGF.[24] Various studies have showed that fasting/food deprivation can also induce BDNF expression in neuronal circuits involved in cognition by increasing their activity and by shifting cellular energy substrate utilization from glucose to ketones. I would suggest that a better understanding of the neurobiological underpinnings of fasting and calorie restriction, ADF, meal size and frequency, and energy intake may affect brain–mind health since these nondrug interventions may lead to novel approaches for prevention and treatment of disorders at the brain–mind interface.


  Vitamin D and Depression Top


It is astonishing to take note that Vitamin D deficiency prevails in epidemic proportions all over the Indian subcontinent, with a prevalence of 70%–100% in the general population. Vitamin D deficiency is implicated in CVD, primary hypertension, atherosclerosis, diabetes, neurocognitive disorders, Alzheimer's dementia, Parkinson's disease, motor neuron disease-amyotrophic lateral sclerosis, epilepsy, migraine, fibromyalgia syndromes, multiple sclerosis, cancer, systemic inflammatory disorders, and infections (tuberculosis) apart from the well-known bone health and metabolic bone disorders. There has been research examining the relationship of Vitamin D to seasonal affective disorder, schizophrenia, and depression. The possibility of a role of Vitamin D in neuropsychiatric disorders is suggested by region-specific expression of Vitamin D receptors in the cingulate cortex, thalamus, hypothalamus, cerebellum, substantia nigra, amygdala, and hippocampus, all of which may be crucial in neuroendocrine functioning, limbic regulation, and morphofunctional brain development. Studies in the United States have documented that people with serum Vitamin D ≤50 nmol/L are at a significantly higher risk of showing depression than individuals whose serum levels of Vitamin D are ≥75 nmol/L.

To my mind, exercise involving exposure to natural sunlight such as exercise outdoors during daylight hours, eating foods rich in Vitamin D, and/or taking dietary supplements to improve Vitamin D deficiency could improve one's mental well-being; it would be a simple and cost-effective solution for many who are at risk for depression. From the evidence-based medicine (EBM) perspective, I would however highlight the need for more studies to establish the direction of causality in the association between Vitamin D deficiency and depression.[25]


  Developmental Biology and Depression Top


Here, the question I would like to pose is “Is there an association between brains, its development, maturation times, and parenting?” It is prudent to realize that adverse childhood experiences and disturbed childhood relationships have long been implicated as a risk factor for adult depression as a developmental psychopathology. Adverse childhood environments therefore do represent an important risk factor for the development of psychopathology later in life.

Depression is a common, chronic, and debilitating disorder with the first onset often occurring during childhood and adolescence and affecting close to a quarter of all adults during their lifetime. The predominant etiological models used to understand the causes of depression include the psychoanalytic (Freudian psychodynamic theory), cognitive (Beck's cognitive theory), behavioral (helplessness and hopelessness theories), interpersonal, and biological perspectives. Lack of parental support is linked to childhood and teenage depression. It is important to understand that the mammalian brain is designed to be sculpted into its final configuration at the molecular, cellular, neuroendocrine, neurocognitive trajectories, and behavioral level by the effects of early stress. These include psychosocial risk factors, childhood abuse, childhood maltreatment and neglect, adolescent sibling conflict, and peer conflict; the lack of positive and supportive parenting does have an effect on brain development. Nuture (developmental psychology) versus Nature (genes) or the gene–environment interplay dictates the morphofunctional development, neurogenesis, connectomics (axonal and dendritic arborizations and synpatognesis), HPA, stress-response systems of our brain and the intricate myelination process of the corpus callosum and hemispheric integration, and prefrontal lobe that are ultimately responsible for the emergence of our rich behavioral repertoire.

Being a behavioral neurologist, it is crucial for me to undeline state that various early life psychosocial stressors do alter the molecular composition of the GABA-benzodiazepine supramolecular complex, resulting in the attenuated development of central benzodiazepine and high-affinity GABA-A receptors in the amygdala and locus coeruleus and glucocorticoid receptos in the hippocampus. Early childhood and adolescent psychosocial risk factors cause aberrant microstructural cortical development, diminished development of the left hemisphere (including the neocortex, hippocampus, and amygdala), reduced size of the corpus callosum, and attenuated activity in the cerebellar vermis (the cerebellar cognitive affective syndromes).

Across development, studies of adults, adolescents, children, and preschoolers all point to a family history of depression and exposure to stressful life events as the most robust risk factors for depression. I draw particular attention to two studies. One published in the American J Psychiatry in 2007 that demonstrated that poor quality of sibling relationships, interpersonal emotional time and energy, and relational deficits in childhood to be an important psychosocial and specific predictor of major depression in adulthood.[26] Another study published in Developmental Cognitive Neuroscience in 2014 did show the association between positive maternal behaviors on critical neurodevelopmental processes in adolescence.[27] Early childhood sexual abuse, early stress, and lifetime assaultive violence have been linked to cortical maldevelopment and increased electrophysiological abnormalities. Several studies reported that severe early stress and abuse have the potential to alter brain development and cause limbic dysfunction during specific sensitive periods of cortical maturation. The cascade of events is mediated through stress-induced neurohormones of the glucocorticoid, noradrenergic, and vasopressin-oxytocin stress response systems which affect neurogenesis, synaptic overproduction and pruning, and myelination. The aberrant cortical development has been reported to involve the corpus callosum, left neocortex, hippocampus, and amygdala

In summary, I would emphasize on future research in the direction of causality and biopsychosocial risk factors for emotional and behavioral problems in children and adolescents. This will explicate early childhood adverse experiences as an early sign of vulnerability to adult depression and whether these relationships might themselves be appropriate targets for preventive intervention.


  Internet Addiction and Facebook Depression Top


Is social media and electronic communication technology is destroying the quality of human interaction? Aside from the positive aspects of the Internet being an integral part of our everyday life, the negative distressing effects are its significant association with anxiety, stress, and depression in the younger generation, adolescents, and students. Electronic communication and digital social networks through the Internet and Facebook is becoming a growing social issue among adolescents, young adults, and students. As noted with other addictive disorders, an increased level of depression is associated with those who become addicted to the Internet (Internet addiction syndrome) and Facebook.

Facebook depression is one of the risk factors that teens may face with overexposure to social media with fewer “in-person” social outlets. In their Facebook profiles, users communicate abundant social comparison information conveying mainly positive self-portrayals. Thereby, social networking sites such as Facebook provide a fertile ground for envy. They report “subjective/perceived social isolation” where individuals lack a sense of social belonging, true engagement with others, and fulfilling relationships with increasing social media use. In several studies, social comparison or envy mediates a positive association between Facebook use and undesirable affective outcomes such as depression. It is also increasing the propensity toward engaging in risky activities such as substance abuse, unsafe sex, or self-destructive behaviors.

Social isolation, from a neurobiological perspective, affects gene expression, negatively impacting vascular and mental health. It is associated with unnatural increases in cortisol patterns, and these aberrant patterns can disrupt sleep, immune function, and cognition. Therefore, it is not surprising that social isolation can substantially increase the risk for all-cause mortality. I feel that the Internet and mobile technology seem to be subtly destroying the meaningfulness of social interactions and in-depth meaningful and rich bonding social connectivity (perceived social isolation), thereby in real life disconnecting us from the world around us and leading to an imminent sense of isolation in today's society. To me, it is not any surprise that face-to-face interaction is proven to comfort us and provide us with some important sense of well-being and prevent erosion of strong ties.


  Bibliotherapy Top


The therapeutic value of reading

“Great books help you understand and they help you feel understood”

John Green

Reading, the therapeutic use of literature, has been established as a means of improving mental health and well-being, popularly known as “book therapy” or in psychiatric lexicon as bibliotherapy. The term bibliotherapy originates from Greek that is biblus which means books, and therapy which means psychological assistance efforts. In fact, storytelling is an ancient art form, an integral part of human existence, and the most enduring part of education, it is an accessible and creative and reflective form of experiences of communicating both imagined and real as explained by Teresa Grainger in her book Traditional Storytelling, 1997.

Bibliotherapy is an expressive therapy in which there is an individual relationship with the content or essence of books, poems, and other writings as a therapy. It is believed to influence the attitudes, feelings, and behaviors of individuals as expected and may stimulate readers to think. Reading from poems to novels and nonfiction (bibliotherapeutic resource) can certainly cause positive effect in those with depression. Depressed people markedly imbibe their negative experiences (Beck's cognitive triad) due to their adverse life experiences, events, and dysfunctional cognitive appraisals. Therefore, self-directed reading is positive; can comfort, inspire, provide validation of emotions and self-recognition (insight), self-development and reflection; be cathartic; and help to provide information to cope with life.[28],[29] Finding a connection between personal experiences and those of characters in the book does create a sense of connection that validated emotions. This reading therapy does ameliorate depressive symptoms in the long term, improvements in mood and psychological well-being, and could be an affordable treatment that reduces the need for medications.

Cognitive bibliotherapy (CBT)-based bibliotherapy through appropriate guidance helps motivated patients with mild-to-moderate depression or subthreshold depressive symptoms to identify and understand their own destructive thought and behavioral patterns and to re-modify them resulting in more rational and realistic thinking and behavior. This may be a sole or supplementary adjunct to individual psychotherapy, interpersonal psychotherapy, or cognitive behavioral therapy. Cognitive bibliotherapeutic intervention stimulates critical thinking and provides insight to human behavior and motives; promotes self-evaluation, problem-solving, and decision making; and stimulates high-level reasoning, to realize that problems can have many alternative solutions, and that an individual can make choices in solving their problems.[30]

Affective bibliotherapy is dependent on psychodynamic theories referring to Sigmund and Anna Freud. The positive value behind affective bibliotherapy has underpinnings in better self-understanding and an awareness of the universality and uniqueness of the problems they face. This promotes empathy, creates positive attitudes, personal and social adjustments and adaptations, develops positive self-image, and increases emotional resilience. Through reading and listening to other people's stories, one will find a healing method that fulfills the basic human needs for finding and understanding the truth, finding an explanation of bad experiences, and even for challenging injustices. In this respect, I refer to Bollywood superstar Anupam Kher's book “The Best Thing about You is You.” The book reaffirms the truism that “everyone is unhappy in their own way” and reinforces the realization of self-therapy, rediscovering the real self and finding self-contentment, emotional sustainability, peace, and raising our “happiness quotient.” I am sure that our very own ancient Hindi stories/folklores can be employed to design a self-help bibliotherapeutic for childhood and adolescent depression in India.

Bibliotherapy in depression has stood the test of EBM. I am reminded of two recent studies that showed the proof of the pudding. In 2017, systematic review of RCT of ten studies from the University of Turin, Italy, did irrevocably document that bibliotherapy to be effective in the reduction of adults depressive symptoms in the long-term period, providing an affordable prompt treatment that could reduce further medications.[31] The study also shed promising therapeutic effects through interventions such as behavioral activation using “individual life-review,” exercise on depressive symptoms, problem-solving therapy (PST), PST with engagement in social activities, behavioral therapy, brief psychodynamic therapy, and cognitive therapy (CBT). The second 2017 study conducted by the University of Groningen in the Netherlands did unequivocally confirm bibliotherapy to be effective in the reduction of adult depressive symptoms in the long-term period.[32]

Depression is among the most common of psychological disorders, such that it has been called the “common cold” of psychopathology. Considering the demographic shifts of people having less cohesive and meaningful social connectedness, being independent, and having less family-oriented lives, the time has come for an evidence-based model of integrative lifestyle medicine, technology-enhanced digital psychiatry, and holistic psychiatry which would be the only sustainable, therapeutic, and preventative approach for depression and promoting well-being at the mind–brain interface. I am quite certain that drugs alone will not be able to cure the epidemic of depression at the dawn of the “neurocentric age” employing “healthy brain lifestyle 2020” and “brain-well-being” strategies. The best medical intervention is not segregation. Instead, it is the time for experimentation to integrate and unite the two philosophies of the Western and traditional systems of medicine. I stress the need to embrace an integrative medical system, a holistic health paradigm, as an extension of conventional medicine incorporating a “salutogenic and holistic” approach through a multimodal treatment system taking into account all dimensions: physical, emotional, mental, spiritual, and social, I reiterate the need for critical engagement between Western medicine and its neglected allies (TM and CAM). This will amalgamate the “best of the best” of the Western medicine, yet integrating the ancient wisdom of traditional systems ensuring an economic, sustainable, cost-effective, and accessible health care to India's “Bharat” and other developing nations to preserve the “mental capital” and “brain health.” Lifestyle medicine for depression should be an integral part of treatment and preventative efforts. While medication and psychological interventions are first-line treatments for depression, Lifestyle Medicine offers a potentially safe and low-cost option for augmenting the management of the condition. To my mind, the application of Lifestyle Medicine should be considered in the context of long-term sustainability.

The Internet, mobile-based interventions, and smartphone apps designed for mental health information, early diagnosis, and brief patient-administered depression questionnaires for depression are certainly economically affordable and sustainable e- and m- based digital psychiatry technologies to address depression in India. As India is poised for a smartphone revolution and with over 1 billion mobile users, I feel that technological solutions (smartphone/mobile apps) would indeed be innovative in India for behavioral health problems such as depression. Researchers from Australia's National Institute of Complementary Medicine, Harvard Medical School, the University of Manchester, and the Black Dog Institute in Australia have also examined the efficacy of smartphone-based treatments for depression. As a part of Integrative Medicine, the digital psychiatry intervention could translate to a safe and accessible intervention for people in India and around the world to help people monitor, understand, and manage their mental health. After reviewing some of the studies on social networks, and Facebook Depression, I do realize that the relationship between Facebook and depression is still inconclusive. On the contrary, Facebook can also be used as an important tool in early screening and online intervention for depression in young adults.

As a cognitive behavioral neurologist with passionate interest in the disorders of the brain–mind interface, I would ultimately surmise that it is quintessential to “mind the science gap”. This would include the intricate web of “nature” versus “nurture” relationships between the brain, brain development, microstructural maturation, neuroendocrine system, HPA system, the second brain of GBA, and the panoply of diverse biopsychosocial risk exposures and susceptibilities to many of the human afflictions affecting brain and mental health. There must be a renewed impetus for research into evidence-based depression prevention strategies, campaigns to promote mental well-being and brain well-being to lessen the global disease burden. Looking through the eyepiece of globalism of our nations, the social scientists and econometrists use the 'World Happiness Index' as a surrogate marker of self reported happiness and life satisfaction. India ranks 133rd out of 156 countries in the World Happiness Report. Public health policies from a human health perspective that reinforces a “culture of health” centered at healthy lifestyle, promotion of population-wide healthy dietary patterns, effective nutrition, and physical activity behaviour change would go a long way to maintain the 'mental well being', 'happiness quotient', and 'life quotient' of our global human capital on planet earth.

“If you are that depressed reach out to someone. And remember, suicide is a permanent solution, to a temporary problem”

Robin Williams

An Ode to Depression



    Since I could ever remember down my memory lane

    Always wondered- “Who will I be?”

    “Que sera sera, Whatever will be, will be”

    What will I be? How will I be remembered?



    A Victim of human insensitiveness, an unhappy childhood

    Raw wounds that are not healed, memories linger on

    I am strong on the exterior, quite fragile deep inside

    Disheartened now at human wickedness, deceit, & human shallowness

    Trust, Love and Humaneness are now 'empty' laconic words



    Did God make a mistake?

    Sad that God maketh man, so deceitful and wicked

    Tragically struck at society's humane-less wilderness and freewill

    The farce, illusion of our human society

    The lack of human brotherhood



    Is it worth the journey in this world, why should I cling on to life?

    What makes it worthwhile to live in this sea of confusion, tyranny, deceit, mistrust?

    Adam and Eve made a choice in the Garden of Eden to eat the forbidden apple

    So Should I stay? Should I leave? Am I lost?

    I am tired of the meaningless reality

    I wonder what makes life worth living!

    Is there hope? I am tired of wearing my “social-mask”



    Alas, my journey through darkness

    The loneliness- the cold absence of feelings, the hollowed-out feeling

    I have lost my mental compass and hope

    Can I have the freewill to make a decision to “leave” this world? Let me go 'home' now

    Show me some reasons that I am wrong

    The “black dog” is growling at me now

    Anonymous



 
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  In this article
Mind the Science Gap
Integrative-Life...
Yoga and Mindful...
We Are What We E...
Depression-Nutri...
Exercise and the...
Fasting and Calo...
Vitamin D and De...
Developmental Bi...
Internet Addicti...
Bibliotherapy
“Never Say...
“Never Say...
Mind the Science Gap
Integrative-Life...
Yoga and Mindful...
We Are What We E...
Depression-Nutri...
Exercise and the...
Fasting and Calo...
Vitamin D and De...
Developmental Bi...
Internet Addicti...
Bibliotherapy
Depression ̵...
Depression-Brain...
References

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