Depression is characterized by sadness, purposelessness, irritability, and impaired body functions. Depression can be serious and often requires professional help or medication. Depression remains a significant health and economic challenge globally irrespective of increased investment in its recognition and treatment. According to World Health Organization (WHO), unipolar depression is expected to become one of the most leading causes of disease burden by 2030. Hence, the discovery of antidepressive foods is fascinating and could have significant impact globally. Indeed noncommunicable diseases are one of the most significant challenges health decision makers currently facing in Eastern Mediterranean countries where the transition is increasing morbidity of depression and mental diseases, cardiovascular diseases, diabetes, cancer, and respiratory diseases with a significant impact on the least disadvantaged populations.
Current treatment strategies focus primarily on biological and psychological pathways, ignoring the key contribution of lifestyle and dietary patterns. Metabolic syndrome (MetS) and depression are becoming most prevalent diseases globally, whose interaction needs further investigation. Dietary treatment for weight loss in patients with MetS may improve depressive symptoms, however, the precise pathways remain unknown.
There is emerging evidence to suggest that diet and nutrition play an important role in the risk, and the genesis of depression. However, there are limited studies regarding the therapeutic impact of dietary interventions on existing mental illness. Studies of single nutrients on depression have generated inconsistent results, and have failed to consider the complex interactions between nutrients. Several studies are now investigating the association of various dietary patterns and depression.
This book aims to accomplish the primary goal of health promotion by preventing depression among young adolescent women with pre and post-menstrual syndrome, pregnancy, hypothyroidism, diabetes, obesity, coelic diseases, drug addiction, and elderly patients with progressive neurodegenerative disorders, cardiovascular disorders, post-traumatic stress disorders, chronic pain, rheumatoid arthritis, fibromyalgia, cancer, and several other chronic illnesses. Diet, which targets multiple disease etiologies, can prevent the development of depressive and neurodegenerative disorders and the cognitive deficits. Increased prevalence of depressive and neurodegenerative diseases combined with the lack of effective pharmaceutical treatments and their deleterious side effects, has created a dire need for the development of effective therapies. As these disorders are multifactorial in origin; treatments directed to interfere at different mechanistic levels may be more effective than the traditional single-targeted pharmacological approach. A diet composed of zinc, melatonin, curcumin, piperine, eicosapentaenoic acid (EPA, 20:5, n-3), docosahexaenoic acid (DHA, 22:6, n-3), uridine, and choline has shown ameliorating effects on olfactory bulbectomized animals; a well-established experimental model of depression (Borre et al., 2013).
This book motivates to learn beyond diet and depression as diet alone may not be sufficient to completely cure a particular victim of severe depression. The chapters described in this book are based on the author's own research experience of over 30 years and from other internationally-recognized scientists. There are numerous risk factors associated with depression, which have been described in detail. The book provides an up to date knowledge about the therapeutic potential of dietary interventions, including Tryptophan-rich diet, Vitamin-B6, Melatonin, Coenzyme Q10, Antioxidants, Zinc, Iron, Folate, Vitamin B1, Vitamin B12, Vitamin D, Antioxidants, Moderate Exercise, and Natural Light to accomplish synergistic effect during the treatment of depression.
The primary objective of dietary interventions is to minimize the requirement of expansive pharmaceutical agents such as specific serotonin-reuptake inhibitors (SSRIs), Fluoxetine and other antidepressants with serious adverse effects including anorexia, weight loss, osteoporosis, and suicidal ideations.
There is now sufficient evidence to suggest that dietary manipulation can alleviate various symptoms of depression alone or in combination with well-established antidepressants. Each chapter brings new knowledge and recent references to the reader. This book is being introduced at an appropriate time and will be extremely useful for the prevention/treatment of depression by simple non-pharmacological dietary interventions with minimum or no adverse effects alone and/or in combination with well-established antioxidants and antidepressants currently available in the market as well as in our daily diet. It is envisaged that specific dietary interventions may either eliminate or reduce the requirement of antidepressant drugs with numerous deleterious adverse effects and cost in chronic diseases associated with severe depression.
This book will be a valuable source of information for the early management of depression in several clinical conditions including chronic psychiatric diseases, neurodegenerative diseases of aging, cancer, diabetes, cardiovascular diseases, neuropsychoendorcinological diseases, post-traumatic stress disorders, stroke, diabetes, eating disorders, chronic drug addiction, obesity, celiac disease, hypothyroidism, rheumatoid arthritis, fibromyalgia, chronic multi-drug-resistant malignancies, infections, and several other diseases where depression plays a significant impact on the health, wellbeing, and productivity of a victim.
In general, physicians try a battery of antidepressants for the clinical management of patients with MDD with limited success as the conventional antidepressant treatment may not be completely successful in every patient. On several occasions these patients may suffer from the adverse effects of the antidepressants including, anorexia, weight loss, and osteoporosis as mentioned earlier. Hence considerable attention is being focused on simple non-pharmacological dietary approaches for the clinical management of depression. A brief description of these dietary interventions is provided below as a general background information.
Tryptophan. Although several neurotransmitters including serotonin (5-HT), dopamine (DA), norepinephrine (NE) and γ-amino butyric acid (GABA) and their receptors may participate in the pathogenesis of depression; serotonergic mechanism proved highly significant in the clinical management of depression. Serotonin is synthesized in the CNS by its precursor, Tryptophan. Tryptophan can easily cross the blood twain barrier and converted to serotonin by enzymes, tryptophan hydroxylase and 5-HTP decarboxylase in the presence of pyridoxal phosphate, derived from vitamin B_6. As tryptophan is naturally less abundant in various protein-rich diets, it is important to select foods specifically rich in essential amino acid, tryptophan. Craving for fat and carbohydrate-rich diet particularly among obese persons is to enhance insulin secretion which augments tryptophan bioavailability in the CNS in order to augment 5-HT synthesis and hence alleviates symptoms of depression. Brain regional serotonin in the dorsal raphe and periaqueductal grey regions is significantly reduced in patients with depression. Recently we and other investigators reported that decreased level of brain region-specific 5-hydroxytryptamine (5-HT) is a major pathogenic factor in depression and its symptoms can be alleviated by consuming tryptophan-rich diet (Wurtman and Wurtman., 1995; Wurtman, 1995; Shabbir et al., 2013). Hence tryptophan-rich diet can be prescribed to patients with depression. As a matter of fact various healthy foods are rich in tryptophan. As such serotonin does not cross the blood brain barrier and has shorter half-life hence cannot be directly used for the treatment of depression. This concept arose from the observation that drugs augmenting extracellular levels of 5-HT have antidepressant action. Whether such drugs rectify a primary deficit of depression, remains unknown. A number of impairments in biomarkers of central 5-HT function have been reported in depressive patients, indicating that 5-HT deficiency could be present in depression, particularly in severely ill Parkinson's disease (PD) patients. The literature on putative 5-HT biomarker abnormalities and depression has been corroborated by demonstrating that such impairments occur as a consequence of reduced 5-HT(Ext) in a mouse model of 5-HT deficiency, the tryptophan hydroxylase 2 His(439) knockin (Tph2KI) mouse. These studies have provided further evidence for 5-HT deficiency in depression and the role of polymorphisms in the Tph2 gene as a factor in 5-HT deficiency (Jacobsen et al., 2012). (A detailed description of Tryptophan-rich food in alleviating depression is provided in one of the chapter in this book)
Kema et al., (1995) developed a high performance liquid chromatographic method with quaternary gradient elution and fluorometric detection for estimating tryptophan (TRP), 5-hydroxytryptophan, serotonin (5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) in urine, platelet-rich plasma and (tumor) tissue of patients with carcinoid tumors. Prior to injection, urine samples are diluted and filtered. Platelet-rich plasma and tissue homogenates are pre-purified by C18 solid phase extraction. Detection limits are ~2 pmol. Results of urinary 5-HT and 5-HIAA compared with those of single component analyses. No consistent diurnal variations were found for TRP, 5-HT and 5-HIAA in 12-h urine samples from 15 healthy adults. Abstinence of 5-HT-rich foods reduced urinary levels of 5-HT and 5-HIAA. C18 extraction of indoles from protein-containing matrices was studied in platelet-rich plasma. This approach offers distinct advantages over single component analyses in the study of TRP metabolism in patients with carcinoid tumors and depression.
We have reported that depression is characterized by sadness, purposelessness, irritability, and impaired body functions. Depression causes severe symptoms for several weeks, and dysthymia, which may cause chronic, low-grade symptoms. Treatment of depression involves psychotherapy, medications, or phototherapy (Shabbir et al., 2013). Clinical and experimental evidence indicates that a healthy diet can reduce symptoms of depression. The neurotransmitter, serotonin (5-HT), synthesized in the brain, plays an important role in mood alleviation, satiety, and sleep regulation. Although certain fruits and vegetables are rich in 5-HT, it is not easily accessible to the CNS due to blood brain barrier. However the serotonin precursor, tryptophan, can readily pass through the blood brain barrier. Tryptophan is converted to 5-HT by tryptophan hydroxylase and 5-HTP decarboxylase, respectively, in the presence of pyridoxal phosphate, derived from vitamin B_6. Hence diets poor in tryptophan may induce depression as this essential amino acid is not naturally abundant even in protein-rich foods. Tryptophan-rich diet is important in patients susceptible to depression such as certain females during pre and postmenstrual phase, post-traumatic stress disorder, chronic pain, cancer, epilepsy, Parkinson's disease (PD), Alzheimer's disease (AD), schizophrenia, and drug addiction. Carbohydrate-rich diet triggers insulin response to enhance the bioavail ability of tryptophan in the CNS which is responsible for increased craving of carbohydrate diets. Although serotonin reuptake inhibitors (SSRIs) are prescribed to obese patients with depressive symptoms, these are incapable of precisely regulating the CNS serotonin and may cause life-threatening adverse effects in the presence of monoamine oxidase inhibitors (MAOIs). However, CNS serotonin synthesis can be controlled by proper intake of tryptophan-rich diet. We highlighted the clinical significance of tryptophan-rich diet and vitamin B_6 to boost serotonergic neurotransmission in depression observed in various neurodegenerative diseases. However pharmacological interventions to modulate serotonergic neurotransmission in depression, remains clinically significant. Depression may also involve several other molecular mechanisms as yet remain to be further explored.
There is increasing evidence demonstrating that sleep has an influence on dietary choices. Both cross-sectional and epidemiologic studies have shown that those who sleep less are more likely to consume energy-rich foods (such as fats or refined carbohydrates), fewer portions of vegetables, and have more irregular meal patterns. The purpose of this book is to discuss the evidence linking diet and sleep and to determine whether what we eat and nutrients we obtain from the food before bed time matters. In addition, scientific evidence behind traditional sleep-promoting foods such as milk and some herbal products has been described. These are reviewed using data from clinical trials, mostly in healthy subjects. In addition, the author has discussed the possible mechanisms and summarized their findings that confirm a link between diet and sleep. Overall, foods impacting the availability of tryptophan, as well as the synthesis of serotonin and melatonin, may be helpful in promoting sleep. Although there are physiological connections, the clinical relevance needs to be studied further (Peuhkuri et al., 2012). Brain serotonin function promotes sleep regulation and cognitive processes, whereas sleep abnormalities and behavioral decline are attributed to deficient brain serotoninergic neurotransmission particularly in the aging subjects. Brain uptake of the serotonin precursor, tryptophan is dependent on nutrients that influence the availability of tryptophan via a change in the ratio of plasma tryptophan to the sum of the other large neutral amino acids (Trp: LNAA). It was tested whether evening consumption of α-lactalbumin protein with an enriched tryptophan content of 4.8 g/100 g increases plasma Trp: LNAA and improves alertness and performance on the morning after sleep, particularly in individuals with sleep abnormalities. Healthy subjects with or without mild sleep complaints participated in a double-blind, placebo-controlled study. The subjects slept for 2 separate nights so that morning performance could be evaluated after an evening diet containing either tryptophan-rich α-lactalbumin or tryptophan-low placebo protein. Evening dietary changes in plasma Trp: LNAA were measured. Behavioral measures of attention were recorded during a continuous performance task. Evening α-lactalbumin intake caused a 130% increase in Trp: LNAA before bed time and reduced sleepiness and improved sustained attention the following morning. Only in poor sleepers was accompanied by improved behavioral performance. Evening dietary increases in plasma tryptophan availability for uptake into the brain enhance alertness early in the morning after an overnight sleep, because of improved sleep (Markus et al., 2005). It is now known that sleep depends on the quantity and quality of the diet. Food deprivation results in a reduction in sleep duration. It has also been demonstrated that in the newborn, the supply of certain essential amino acids improves sleep through their action on the synthesis of specific neurotransmitters. A study was performed to test if the quantity and/or quality of dietary protein could improve the recovery of sleep during re-feeding after caloric deprivation. Sleep parameters were compared in rats fed ad libitum, food restricted during 4 days, or reefed isocalorically after food restriction with three dietary regimens varying in the amount (14% versus 30%) or quality (milk protein or α-lactalbumin) of protein. Sleep recovery, in particular slow-wave sleep, was improved in rats re-fed with a-lactalbumin, confirming the close relationship between feeding and sleep and that α-lactabumin could be used to improve sleep quality with nutritional disturbances such as food restriction, shift work, and Ramadan etc (Minet-Ringuet et al., 2004).
Vitamin B_6. We reported that vitamin B_6 is also equally important as an antidepressant as it is involved in the synthesis of several neurotransmitters including serotonin, dopamine, and GABA required for the normal CNS function. Vitamin B_6 (pyridoxine) from different dietary sources is converted to pyridoxal by pyridoxine oxidase, and pyridoxal is converted to pyridoxal phosphate by pyridoxal kinase. Pyridoxal phosphate (PLP) serves as a coenzyme for the metabolic activation of various decarboxylases including 5-HTP decarboxylase for the synthesis of serotonin. More specifically the neuroprotective role of pyridoxine is its involvement in the brain-regional synthesis of serotonin, dopamine, taurine, and GABA by acting as a coenzyme in the decarboxylation step (Dakshinamurti et al., (1990). Treatment of normal adult Tats with pyridoxine or B-vitamin mixture resembling Neurobion (E-Merck, Germany) increased the synthesis of brain regional serotonin (Dakshinamurti et al., 2003). The author has several publications in this direction. (A detailed description of Vitamin B_6-rich food in alleviating depression is provided in this book)
Melatonin. Melatonin is synthesized by pineal gland and regulates the circadian rhythm and sleep-wakeful cycle. Recently its role as an antioxidant has also been reported. Serotonin is the precursor for the synthesis of melatonin which is derived from N-acetyl serotonin. Hence tryptophan in the diet and its metabolism remains of central importance for alleviating depression. Melatonin can also serve as anti-inflammatory, anti-apoptotic, and antidepressant agent and is being further explored for its clinical usefulness in depression in addition to its well-established role as a regulator of sleep-wake cycle. In fact subjects with sleep disorders also suffer from depression. Recent studies have demonstrated that Melatonin prevents methamphetamine-induced autophagy in cultured glioma cell lines (Nopparat et al; 2010; Jumnongprakhon et al., 2013). Hence Melatonin may be used as an antidepressant with no or minimum adverse effects. (A detailed description of tryptophan-rich food and melatonin in alleviating various symptoms of depression is provided in this book)
Mitochondrial Bioenergetics in Depression: The author discovered Charnoly body (CB) which is formed as a result of mitochondrial degeneration due to nutritional and/or neurotoxic insult. Charnoly bodies are electron-dense, multi-lamellar, pleomorphic structures and are involved in apoptosis and neurodegeneration. Charnoly body formation occurs in the CNS (particularly hippocampus and hypothalamus) in depression. We have recently reported that CB formation can be inhibited by MTs as these metalloproteins serve as free radical scavengers in the CNS and cultured human dopaminergic (SK-N-SH and SHY-5Y) neurons (Sharma et al., 2013a; Sharma et al., 2013b). Free radicals are formed due to oxidative and nitrative stress in the mitochondria as a result of oxidative phsophorylation. (A detailed description of foods supplemented with Zn~2+ in alleviating depression through MTs induction is provided in this Book)
Coenzyme Q_10. Coenzyme Q_10 serves as a rejuvenator of the mitochondrial bioenergetics as it is required for the synthesis of rate limiting enzyme, ubiquinone-NADH oxidoreductase (complex-1). This enzyme complex is rate limiting and is involved in the mitochondrial oxidative phosphorylation for the synthesis of ATP. We discovered that CoQ_10 can serve as an antioxidant and anti-inflammatory agent as it inhibits TNFα and NFκβ expression in homozygous weaver (wv/wv) mice exhibiting progressive neurodegeneration (Ebadi et al., 2004). CoQ_10 stabilizes mitochondria in PD associated with severe depression (Ebadi et al., 2007). Furthermore, vitamin E and CoQ_10 are localized primarily in the inner mitochondrial membrane to scavenge free radicals and reactive oxygen species (ROS) formed during oxidative phosphorylation and during oxidative stress. CoQ_10 rejuvenates vitamin E during oxidative stress, hence both CoQ_10 and Vitamin E act synergistically to provide neuroprotection. Hence additional supplementation of vitamin E and CoQ_10 could be beneficial in depression. That induction of pro-inflammatory cytokines, NFκβ is suppressed by CoQ_10 and MTs enhance CoQ_10 synthesis, established the free radical theory of neurodegeneration and the therapeutic potential of CoQ_10 and vitamin E (Ebadi and Sharma, 2006). Since MTs provide neuroprotection by boosting mitochondrial bioenergetics and monoaminergic neurotransmission, therapeutic interventions augmenting brain regional MTs may provide neuroprotection in depression (Sharma and Ebadi., 2008; Sharma and Ebadi., 201 la ; Sharma et al., 2013). We have recently reported that MTs provide neuroprotection by acting as a free radical scavenger to prevent CB formation implicated in apoptosis and progressive neurodegeneration. In addition to MTs and CoQ_10, several other potent antioxidants, anti-inflammatory, and antiapoptotic agents exist in our healthy diets about which very limited information is as yet available. Intensive studies are going on in this direction which will provide better therapeutic interventions for the clinical management of depression. The author has recently written a detailed chapter on "Antioxidants and Potential Therapeutics in Neurodegeneration" (Sharma and Ebadi, 2014). (A detailed description regarding CB formation and its involvement in major depressive disorders is provided in volume-2 of this book)
Antioxidants and Depression. Recently we and others have written an extensive reviews on the therapeutic potential of various antioxidants in progressive neurodegenerative disorders including PD, AD, HD, ALS, MS, and depression (Sharma and Ebadi 2014; Wurtman, 2013; Lang and Borgwardt, 2013). (A detailed description of various antioxidants-rich food in alleviating depression is also provided in this book)
Zinc. The bioavailability of Zn~2+ is 50% among old subject >60 years of age due to improper mastication and irregular intestinal absorption. Physiological concentrations of Zn~2+ provide advantage by augmenting MTs with anti-inflammatory, anti-apoptotic, and antioxidant properties. A detailed description of Zn~2+ and MTs is provided in our recent publications (Ebadi et al., 2001; Sharma and Ebadi 2003; Ebadi and Sharma 2003; Sharma et al., 2004; Klongpanichapak et al., 2006; Sharma and Ebadi. 2013). Hence physiological supplementation of Zn~2+ in the diet may alleviate depression. (A detailed description of Zn~2+- supplemented diet in alleviating depression particularly among aging subjects is provided in this book)
Phototherapy. Photo-therapy can be effectively used for augmenting brain regional serotonin synthesis and hence alleviate depression in seasonal affective disorders (SAD). Natural sun light augments the synthesis of CNS serotonin, hence has significant impact on mood alleviation (Conti. 2008). Therefore, subjects suffering from SAD during winter can be effectively treated with a combination of tryptophan-rich diet and phototherapy without prescribing expansive antidepressants with serious adverse effects. Although phototherapy lamps are available to alleviate symptoms of depression in people suffering from seasonal affective disorders, a better option will be to visit tropical countries and/or Caribbean islands with lot of sunshine during winter for couple of weeks as a tourist. It is important to point out that the duration of the direct light and its intensity must be adjusted in a delicate way so that it does not cause impairment in vision. Particularly psoriasis patients should be very careful about direct exposure of their skin to sunlight. Using sun glasses and proper hydration are recommended during visit to the tropical countries or Caribbean islands even during winter (A detailed description of the therapeutic potential of phototherapy as a booster of serotonergic neurotransmission in depression is provided in one of our publications)
The last chapters are devoted to differential diagnosis and the significant beneficial effects of combined therapies with dietary interventions, natural light, and pharmacological agents in order to accomplish synergistic benefits for the clinical management of depression. A brief mention of electroconvulsive therapy (ECT) is also provided, where dietary interventions may have synergistic effect on the clinical outcome of patients with MDDs. There are several unknown neuroprotective agents and antioxidants in our diet which remain unknown and as yet undiscovered although we consume them routinely through our diet without even knowing their exact clinical significance. Hence a detailed future study on diet and its therapeutic potential in depression will go a long way in the clinical management of several patients of depression in future. Recently curcumin has emerged as a potent antidepressant; however its bioavalability in the CNS is a major challenge which is being resolved by employing modern nanotechnological approaches.
It is envisaged that the book will be a valuable source of recent knowledge about depression, emerging disease-specific biomarkers of depression and its alleviation by nonpharmacological dietary interventions with minimum and/or no adverse effects. Indeed dietary intervention is an economical therapeutic approach with allmost full compliance unlike conventional antidepressants associated with noncompliance, significant cost, and severe adverse effects. However one should not be carried away with an elusive idea that diet is the only solution to combat this complex disorder. In fact antidepressants have their own clinical significance in MDDs. Several potential synergistic or antagonistic interactions with diet may occur when antidepressant drugs are taken alone or in combination with specific diets. A limited information is as yet available in this direction. Although there are various types of balanced diets, Mediterranean diet has shown significant promise and universal acceptance as the healthiest diet to alleviate depression.
It is envisaged that this book will be a valuable source of recent knowledge about depression, emerging disease-specific biomarkers of depression and its alleviation by nonpharmacological dietary interventions with minimum and/or no adverse effects. Indeed dietary intervention is an economical and unique therapeutic approach with all most full compliance unlike conventional antidepressants associated with noncompliance, significant cost, and severe adverse effects. Hence it will gain more acceptance and popularity in the management of depression.
The above picture represents the in-vivo model of mitochondria! complex-1 inhibitor, 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP)- (10mg/kg, i.p)-induced neurotoxicity in metallothioneins transgenic (MT_trans) and metallothioneins double gene knock out (M_Trans) Mouse after 7 days of treatment. MT_dko mouse was moderately obese, lethargic, and completely immbolized; whereas MT_trans mouse could still walk with its stiff legs and erect tail, confirming that MTs provide mitochondrial neuroprotection by inhibiting Charnoly body (CB) formation and by serving as free radical scavengers associated with numerous progressive neurodegenerative disorders including major depressive dorders (MDDs). (Original contribution: Sharma & Ebadi; 2014)

Preface vii

Acknowledgment xvii

About the Author xix

About this Book xxi

Words of Wisdom xxiii

Abbreviations xxv

Chapter 1 History of Depression 1

Chapter 2 Dietary Requirements and Depression 9

Chapter 3 Tryptophan-Rich Diet and Depression 21

Chapter 4 Natural Diets and Depression 35

Chapter 5 Diet, Exercise, and Depression 53

Chapter 6 Disease-Specific Antidepressant Diets 61

Chapter 7 Disease-Specific Depression and Diet (Recent Update) 79

Chapter 8 Antidepressant Diets 131

Chapter 9 Diets to Prevent Primary Depression 139

Chapter 10 Clinical Symptoms and Treatment of Depression 151

Index 175

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