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Essential Nutrients and Psychopathology

Mark R. Zuccolo

The integration of multiple pathways of approach to the diagnosis and treatment of mental illness provided by the adoption of the biopsychosocial model is gaining greater acceptance. Concurrently, greater attention is being paid to the adjuvant role of nutrition in the management of mental disorders as well as to the more general phenomenon of self-medication with unregulated nutritional supplements. The important role of certain nutritional substances in the maintenance of good health and its restoration is increasingly being studied from a preventive and therapeutic point of view (Ciliska, Robinson, Armour, Ellis, Brouwers, Gauld, Baldassarre, & Parminder, 2005). Generic symptoms such as fatigue, headache, mood changes are not only addressed with prescribed or over the counter medication but also through the assumption of more or less natural products (Breakey, 1997).

The food most people consume is not as rich in nutritional value due to industrial processing or to the effects of pollution in the air, water and soil (Horrigan, Block, & Edelblute, 2003). Therefore, the human body, especially in industrialized societies, receives fewer of the vitamins and minerals that are necessary for optimal health (McGregor, 1992). Moreover, additional energy expenditures and therefore caloric consumption are required to cope with the stress that is so pervasive in our societies (Flach, 2005).

In 1968, the two-time Nobel Prize winner Linus Pauling pioneered scientific research on vitamins and coined the term orthomolecular to describe a therapy that included large doses of nutritional substances (Pauling, 1968). His research built on to the previous work of two Canadian psychiatrists, Abram Hoffer and Humphry Osmond, who in 1952 began to use very large doses of vitamins, in particular those of the B group, for the treatment of psychiatric disorders (Hoffer & Osmond, 1960). Pauling attempted to demonstrate the effectiveness of taking very large doses of vitamins in prevention and in therapy. Its studies focused on the antiradical effects of ascorbic acid (vitamin C) and of the liposoluble vitamins A and E in the stimulation of the immune system. Other pioneers in the field were Carl Pfeiffer (1987), Roger Williams (1971) and Hans Selye (1973), the Austrian researcher most famous for his studies on stress and its repercussions on the immune system.

It is rare that only one cause is sufficient to explain any specific psychopathology. Most determinant in psychopathology are situations of physical and emotional stress, family and work challenges, the challenges of daily life, and genetic predispositions. In addition to biological, psychological and societal agents, orthomolecular medicine takes into consideration the effects of substances that are voluntarily or involuntarily introduced into the body (Pauling, 1968). Among nutritional substances, the most important are vitamins, minerals, fats, amino acids and essential fatty acids. The body is not capable of producing them and therefore it synthesizes most of these substances from food or from nutritional supplements. Currently, there are 45 substances that are considered as essential nutrients (Lichtenstein & Russell, 2005). A nutritional substance may help cure a disease already in progress, or prevent a future one, thanks to its stimulatory action on cellular metabolism. Individuals who, for example, begin in adult age to assume a appropriate amounts of calcium, magnesium and vitamin D, can achieve an optimal level of these minerals in their bones (Sahota, Mundey, San, Godber, & Hosking, 2006). This contributes to maintaining a cohesive and resistant skeletal structure, and to diminishing the risk of brittleness and osteoporosis. Beneficial effects are obtained with the assumption of vitamin B6 which, taken as a supplement, improves the functions of the immune system and thus improves resistance to infections. R. J. Williams (1971), an American chemist who discovered two vitamins (pantothenic acid and folic acid), was one of the “founding fathers” of orthomolecular medicine. He introduced the concept of differentiating pharmaceutical substance into two types: to the first type belong those substances that are foreign to the human body and that cannot be found in natural foods, which often discovered by chance or through experimentation have been proven to be effective in the treatment of certain diseases. Aspirin, penicillin and first generation tranquilizers belong to this type of medications. To the second type belong those nutritional substances that occur naturally in our body and that can be found in natural foods. Nutritional substances such as vitamins, fatty acids and minerals belong to this group.

Stress affects the mind and the body (Selye, 1973). It is a syndrome that disturbs the body’s equilibrium and causes a homeostasis-seeking reaction that may include muscular tension, high blood pressure, increased cardiac frequency, increased release of the stress hormone adrenalin, a weakening of the immune system, allergies of various type, digestive tract symptoms, nervousness and difficulty in concentrating, and depression. These symptoms have the tendency to become chronic and their origin is often not attributable to a physical cause, but to a situation that affects the individual psychologically.

Against high blood pressure the intake of essential fatty acids has been shown to be beneficial, especially those synthesized from salt water fish (Ladwig, Marten-Mittag, Loewel, Doering, & Koenig, 2003). Vitamins of the B group have been shown to be beneficial against fatigue, nervousness, irritability, difficulty in concentration (Sachdev, Parslow, Lux, Salonikas, Wen, Naidoo, Christensen, & Jorm, 2005). To strengthen the immune system, large doses of vitamin C, zinc and vitamin A, and those of the B group have also proven beneficial (Robles, Glaser, & Kiecolt-Glaser, 2005; Segerstrom & Miller, 2004). To relieve muscular tension, as well as in cardio-circulatory diseases, magnesium, calcium and potassium are recommended (Blomhoff, Holven, & Brosstad, 2004). Foods that are helpful in fighting stress are whole-grain cereals, because they contain vitamins of the B group; vegetables and fruits, as they contain vitamin C and minerals; dairy products and eggs, thanks to their high content of vitamins A and E; cold pressed nuts and oils, rich in essential omega-3 fatty acids; iron-rich meats from healthy animals; most sea fish, which is rich in omega-3 fatty acids (Cunningham-Rundles, Ahrn, Abuav-Nussbaum, & Dnistrian, 2002; Stephensen, 2001).

The use of drugs does not always promote healing, often simply disguising the symptoms or converting them in other sordid and more dangerous ones. Researchers have concluded that in the digestive system there are receptors for a substance called vasoactive intestinal peptide, found in the central nervous system where it acts as a neuropeptide and is released by specific interneurons, and it is said to affect the behavior of cells of the immune system (Gerhold & Wise, 2006; Huang, Miller, Wang, Kong, Paul, & Goetzl, 2006). In other words, the intestine exchanges information with the brain, and vice versa, through these messenger proteins that travel in the blood stream.

Oxidative stress caused by free radicals is one of the factors that contribute to accelerate the normal process of aging and may have a part in the pathogenesis of many disorders. Stress adaptation requires numerous homeostatic adjustments that involve hormones, neurotransmitters, oxidizing substances and other mediators (Cooney, 1998; Pardoll, 2001; Vivier, Nunès, & Vély, 2004). An imbalance of the delicate homeostatic mechanism can increase the production of oxidizing substances and cause molecular damage. This damage is added to that caused by normal aerobic metabolism, which in itself generates free radicals, causing an accumulation of oxidation in the mitochondria and contributing to accelerate the normal process of aging (D’Mello, 1998; Fugakawa, 1999). Such process appears to be crucial in the etiology of severe neurological disorders, such as Alzheimer’s and dementia (Hurwitz, 2004), Parkinson’s, lateral amyotrophic sclerosis (Haag, 2003), schizophrenia and mood disorders (NHFA, 2003; Noriyuki, Yoshiharu, & Nozomu, 2001).

Free radicals are highly reactive molecules that are produced in both normal and pathological processes. They are proven or suspected agents of tissue damage in a wide variety of circumstances including radiation (Balabanli, Turkozkan, Akmansu, & Polat, 2006), damage from environment chemicals (Mathers, Fraser, McMahon, Saunders, Hayes, & McLellan, 2004), and aging (Harman, 2006). The deficiency of antioxidants can render cellular membranes particularly susceptible to damage from free radicals. A reduced availability of essential fatty acids, which promote neuronal growth and maintenance, can lead to an alteration in the operation of NMDA, a glutamate receptor implicated in many important brain functions including long-term potentiation (Rancillac, Rossier, Guille, Tong, Geoffroy, Amatore, Arbault, Hamel, & Cauli, 2006). The brain, rich in polyunsaturated essential fatty acids, is particularly vulnerable to the damage caused by free radicals, with physiological and pathological consequences (Averback, 1981; Miyakawa, Sumiyoshi, & Deshimaru, 1972). Free radicals have been implicated in the development of schizophrenia (Reddy, Mahadik, Mukherjerr, & Murthy, 1991) and of tardive dyskinesia (Cadet, Lohr, & Jeste, 1986).

Oxidative stress is therefore in a position to modify the properties of cellular membranes, by modifying their content of fatty acids and cholesterol. In particular, the brain of adult mammals has a high content of DHA, a polyunsaturated long chain fatty acid particularly susceptible to oxidative damage, and the deficiency of this substance in the course of intrauterine development is correlated to neurological disorders in the fetus (Green & Yavin, 1998). In adult life, DHA content is reduced substantially with aging and with exposure to the free radicals of oxygen (Urano, Sato, Otonari, Makabe, Suzuki, & Ogata, 1998).

Epidemiological observations and clinical data suggest that a variation in the composition in fatty acids in cellular membranes can also be correlated with major depression (Hallahan & Garland, 2005; Maes, Christophe, Delanghe, Altamura, Neels, & Meltzer, 1999). Recent studies have focused the attention on the depletion of eicosapentaenoic omega 3-epoxygenase (EPA) and docosahexaenoic acid (DHA) in the cellular membranes of depressed patients (Keck, Mintz, McElroy, Freeman, Suppes, Frye, Altshuler, Kupka, Nolen, Leverich, Denicoff, Grunze, Duan, & Post, 2006). EPA and DHA have been shown in numerous studies to be significantly reduced in depressed individuals (Peet, Murphy, Shay, & Horrobin, 1998). Adams et al. (1996) have studied the percentage of polyunsaturated fatty acids in the red cell membranes of 20 patients affected by major depression, estimating their lipid intake in the three previous months by means of a questionnaire. The plasma level of fatty acids was not statistically different than that found in a group of healthy subjects, but there were meaningful negative correlations between the erythrocyte levels of EPA and the severity of the symptoms as measured by the Hamilton Depression Rating Scales (HDRS), between the levels of plasma DHA and HDRS ratings, as well as a significant positive correlation in the ratio arachidonic acid(AA)/EPA in erythrocytes and plasma. In the patients participating in the study the loss of appetite was not prominent; therefore the authors suggested that the erythrocyte imbalance between AA (ubiquitous in most foods) and EPA (much less represented) is not due simply to lower caloric intake (Adams et al., 1996). Maes et al. (1999) have found a deficiency of omega-3 fatty acids and a compensatory increase of monounsaturated omega-6 fatty acids in the phospholipids of depressed patients as compared to control subjects, a meaningful positive correlation between serum zinc and the ratio omega-6/omega-3, and no meaningful variation in fatty acid levels after antidepressant treatment.

The presence of fatty acids in cellular membranes determines their characteristics. The physical properties of receptors and enzymes, such as adenylate cyclase and phospholipase, are influenced by the properties of cellular membranes and these effects appear to be meaningful in depression, since the response to neurotransmitter stimulation depends on the membrane’s chemical equilibrium (Stoll, Locke, Marangell, & Severus, 1999a). Structurally, omega-3 fatty acids have a folded-over structure, occupy a greater volume and render the cell membranes more permeable (Kalat, 2004). Such characteristics partially explains the rationale by which these compounds may have effectiveness as antidepressants and mood stabilizers (Peet & Mellor, 1998). These data correlate with the neurochemical theories of depressive pathology, which focus on the involvement of various neurotransmitter systems. Recent studies have drawn attention on the possible effects of a deficiency of omega-3 on the dopaminergic and serotonin neurotransmission and the consequent altered function of cerebral areas involved in the regulation of behavior and emotions (Keck et al., 2006). Chalon et al. (2001) have hypothesized that the influences of polyunsaturated fatty acids on behavior may be due to effects on cortical and limbic dopaminergic neurotransmission.

Pathological alterations due to the action of free radicals of oxygen can be improved through two mechanisms: the inactivation of the O2 radicals by means of anti-oxidants that are introduced with a diet rich in vitamins A and C, ubiquinones and ß-carotene; and the substitution of essential polyunsaturated fatty acids with a dietary supplement (Ratnam, Ankola, Bhardwaj, Sahana, & Kumar, 2006). A better control of oxidative stress could contribute to avoid the deterioration of certain mental disorders. It is well documented that the typical American diet is seriously deficient in anti-oxidant compounds; moreover a highly caloric diet and an elevated consumption of red meats increases the rate of oxidation (Kant, 2003; Norman, Go, & Butrum, 2004). Additionally, elevated cigarette consumption and an excessive assumption of alcoholic drinks, also implicated in the increase of free radical oxidation, are common among patients suffering from schizophrenia and mood disorders (Hibbeln, Linnoila, Umhau, Rawlings, George, & Salem, 1998). Vitamin E has been used in the treatment of tardive diskinesia, with positive results when administered for long periods of time (at least 6 months). Peet et al. (1993) have found a statistically significant response with 1200/UI of vitamin E per day, with a sustained therapeutic effect for 7-13 months after the interruption of treatment (110). More than a dozen studies have been conducted on the use of vitamin E (800-1600 UI/day) in schizophrenic patients with TD (Mahadik, Evans, & Lal, 2001),

Christensen & Christensen (1988) have investigated the correlation between the course of schizophrenia and national statistics relative to fat consumption. They have found that countries with better prognosis for schizophrenia were those in which the national diet included a higher proportion of fat from fish and from vegetables. In essence, the patients who consumed greater amounts of omega-3 fatty acids showed less severe symptoms, a finding supported by a variety of other studies (Mellor, Laugharne, & Peet, 1995; Peet, Laugharne, Mellor, & Ramchand, 1996; Peet & Mellor, 1998; Shah, Vankar, Telang, Ramchand, & Peet, 1998). If anti-oxidant agents can help in blocking the damage caused by free radicals, the treatment with these food supplements could restore cellular structure. Such a therapy, along with counseling on dietetic factors and lifestyle, could beneficially influence the prognosis of schizophrenia (Mahadik & Scheffer, 1996).

New research is also focusing attention on the role that anti-oxidants in the diet may play in the treatment of other mood disorders (Sachdev et al., 2005). It is hypothesized that fatty acids may have stabilizing effects on mood with a mechanism similar to that of lithium and of valproic acid, by modifying the pathways of transmission of neuronal signals (Rybakowsky & Lehmann, 1991). In their action on bipolar disorder, they appear to mimic lamotrigine’s mood stabilizing and antidepressant properties (Stoll et al., 1999b). The mechanisms of action must be further clarified, as it is still unclear whether fatty acids show a specific pharmacological effect or a mere compensation of nutritional deficits. The concomitant assumption of anti-oxidants vitamins (vitamins C and E) may optimize the effect of fatty acids, further preventing oxidation. A double-blind 4-month clinical study of 30 patients with bipolar disorder has shown the effectiveness of fatty acid supplements in comparison to a placebo (olive oil), added to the usual therapies. The experiment group of patients had a significantly longer period of remission as compared to the control group (Stoll et al., 1999a; Stoll et al., 1999b).

Adjuvant nutritional therapies have also been studied in patients who showed a relapse despite continuing antidepressant treatment. A double-blind study that added omega-3 or a placebo to the conventional treatment has shown statistically significant improvements in the experiment group in as little as three weeks (Nemets, Stahl, & Belmaker, 2002). Also, melatonin seems to perform as a scavenger of free radicals beyond its well-known properties of regulation of gonadal function and of biological rhythms (Lipartiti, Franceschini, Zanoni, Gusella, Giusti, & Cagnoli, 1996). Research data suggest that melatonin may positively influence neurodegenerative processes that are involved in the formation of free radicals and the release of excitatory aminoacid (Lipartiti et al., 1996).

Scientific investigators in the 1970s began to ask if a correlation existed between food and behavior. Nowadays, new and more sophisticated studies have revealed the effective existence of this food-behavior correlation in children (Lamberg, 2005) and older adults (Maiman, Hildreth, Cox, & Greenland, 1992). In a review of studies conducted between 1985 and 1995, Breakey (1997) has found evidence that there is a clear relationship between what children eat and the way in which they behave. “The most important discovery” he asserts “has been the presence - in nearly all studies - of one statistically meaningful variation of behavior as a result of a dietary change” (p. 193). Moreover, these studies have revealed a consistency of response to dietary variations which is also statistically significant. Although it is reported that the changes in the diet can improve a wide spectrum of behavioral problems, including hyperactivity and insomnia, Breakey asserts that an important and unexpected discovery is that the parameter primarily influenced by the intake of certain foods is mood, most of all irritability. Recent research gives prominence to a strong connection between depression and dietary deficiencies, in particular that of B9 vitamin (folic acid). From the beginning of the 1980s, a series of studies have demonstrated that low levels of folic acid are correlated with the onset and maintenance of depression (Sachdev et al., 2005).

References

Adams, P. B., Lawson, S., Sanigorski, A., & Sinclair, A. J. (1996). Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression. Lipids, 31, 157-161.

Andreasen, N. C. (1997). Linking mind and brain in the study of mental illnesses: A project for a scientific psychopathology. Science, 275(5306), 1586.

Averback, P. (1981). Structural lesions of the brain of young schizophrenics. Canadian Journal of Neurological Science, 8, 73-76.

Badaracco, M. A. (2006). Psychiatry, psychoanalysis, and the new biology of mind. The American Journal of Psychiatry, 163(1), 165.

Balabanli, B., Turkozkan, N., Akmansu, M., & Polat, M. (2006). Role of free radicals on mechanism of radiation nephropathy. Molecular Cell Biochemistry 12, 213-220.

Blomhoff, S., Holven, K. B., & Brosstad, F. (2004). Psychological factors and cardiovascular disease. Journal of Thrombosis & Haemostasis, 2, 201-203.

Bordens, K. S., & Abbott, B. B. (2004). Research design and methods: A process approach (5th ed.). New York: Gardners Books.

Breakey, J. (1997). The role of diet and behavior in childhood. Journal of Pediatrics and Child Health, 33(3), 190-194.

Cadet, J. L., Lohr, J. B., & Jeste, J. V. (1986). Free radicals and tardive dyskinesia. Trends in Neurosciences, 9, 107-108.

Carlson, L. E. (2005). Introduction to psychoneuroimmunology. Canadian Psychology, 46(1), 53-55.

Chalon, S., Vancassel, S., Zimmer, L., Guilloteau, D., & Durand, G. (2001). Polyunsaturated fatty acids and cerebral function: Focus on monoaminergic neurotransmission. Lipids, 36, 937-944.

Christensen, O., & Christensen, E. (1988). Fat consumption and schizophrenia. Acta Psychiatrica Scandinavica, 78, 587-591.

Chrousos, G. P. (1985). Corticotrophin releasing factor: Basic studies and clinical applications. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 9(4), 349-359.

Ciliska, D., Robinson, P., Armour, T., Ellis, P., Brouwers, M., et al. (2005). Diffusion and dissemination of evidence-based dietary strategies for the prevention of cancer. Nutrition Journal, 4(13).

Cooney, J. M. (1998). Stress, stress hormones and the immune system. The International Journal of Social Psychiatry, 44(2), 156.

Cunningham-Rundles, S., Ahrn, S., Abuav-Nussbaum, R., & Dnistrian, A. (2002). Development of immunocompetence: Role of micronutrients and microorganisms. Nutrition Reviews, 60(5), S68.

D’Mello, S. R. (1998). Molecular regulation of neuronal apoptosis. Current Topics in Developmental Biology, 39, 187-213.

Flach, F. (2005). Trauma and health: Physical consequences of exposure to extreme stress. The American Journal of Psychiatry, 162(9), 1769.

Fugakawa, N. K. (1999). Aging: Is oxidative stress a marker or is it causal? Proceedings of the Society of Exploratory Biological Medicine, 222, 293-298.

Gerhold, L. M., & Wise, P. M. (2006). Vasoactive intestinal polypeptide regulates dynamic changes in astrocyte morphometry: Impact on gonadotropin-releasing hormone neurons. Endocrinology, 147(5), 2197-2202.

Green, P., & Yavin, E. (1998). Mechanisms of docosahexaenoic acids accretion in the fetal brain. Journal of Neuroscience Research, 52, 129-136.

Haag, M. (2003). Essential fatty acids and the brain. Canadian Journal of Psychiatry, 48(3), 195-203.

Hallahan, B., & Garland, M. R. (2005). Essential fatty acids and mental health. British Journal of Psychiatry, 186(4), 275-277.

Harman, D. (2006). Free radical theory of aging, an update: Increasing the functional life span. Annals of the New York Academy of Sciences, 1067, 10-21.

Hibbeln, J. R., Linnoila, M., Umhau, J. C., Rawlings, R., George, D. T., et al. (1998). Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset alcoholics. Biological Psychiatry, 44, 235-242.

Hoffer, A., & Osmond, H. (1960). Chemical basis of clinical psychiatry. Springfield, IL: Thomas.

Horrigan, B., Block, B., & Edelblute, J. (2003). World Health Organization list top 20 risks to a healthy life. Alternative Therapies in Health and Medicine, 9(1), 32.

Huang, M. C., Miller, A. L., Wang, W., Kong, Y., Paul, S., et al. (2006). Differential signaling of T cell generation of IL-4 by wild-type and short-deletion variant of type 2 G protein-coupled receptor for vasoactive intestinal peptide (VPAC2). Journal of Immunology, 176(11), 6640-6646.

Hurwitz, T. A. (2004). Neuropsychiatry: Grasping the body-mind and mind-body problems. Canadian Journal of Psychiatry, 49(3), 155-156.

Kalat, J. W. (2004). Biological Psychology (8th ed.). Belmont, CA: Thomson Wadsworth.

Kandel, E. R. (1999). Biology and the future of psychoanalysis: A new intellectual framework for psychiatry revisited. The American Journal of Psychiatry, 156(4), 505.

Kandel, E. R., & Squire, L. R. (2000). Neuroscience: Breaking down scientific barriers to the study of brain and mind. Science, 290(5494), 1113.

Kant, A. K. (2003). Reported consumption of low-nutrient-density foods by American children and adolescents: Nutritional and health correlates, NHANES III, 1988 to 1994 Archives of Pediatric & Adolescent Medicine 157(8), 789-796.

Keck, P. J., Mintz, J., McElroy, S., Freeman, M., Suppes, T., et al. (2006). Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder. Biological Psychiatry, 61, 675-681.

Ladwig, K.-H., Marten-Mittag, B., Loewel, H., Doering, A., & Koenig, W. (2003). Influence of depressive mood on the association of CRP and obesity in 3205 middle aged healthy men. Brain, Behavior and Immunity, 17(4), 268-275.

Lamberg, L. (2005). New mind/body tactics target medically unexplained physical symptoms and fears. JAMA: Journal of the American Medical Association, 294(17), 2152-2154.

Lichtenstein, A. H., & Russell, R. M. (2005). Essential Nutrients: Food or supplements? Where should the emphasis be? JAMA, 294, 351-358.

Lipartiti, M., Franceschini, D., Zanoni, R., Gusella, M., Giusti, P., et al. (1996). Neuroprotective effects of melatonin. Advances in Experimental Medicine and Biology, 396, 315-321.

Lundblad, R. L. (2005). The evolution from protein chemistry to proteomics. Chicago: CRC Press.

Maes, M., Christophe, A., Delanghe, J., Altamura, C., Neels, H., et al. (1999). Lowered omega-3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients. Psychiatry Research, 85, 275-291.

Mahadik, S. P., Evans, D., & Lal, H. (2001). Oxidative sress and role of antioxidant and w-3 essential fatty acid supplementation in schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 25, 463-493.

Mahadik, S. P., & Scheffer, R. E. (1996). Oxidative injury and potential use of antioxidants in schizophrenia. Prostaglandins, Leukotrienes and Essential Fatty Acids, 55, 45-54.

Maiman, L. A., Hildreth, N. G., Cox, C., & Greenland, P. (1992). Improving referral compliance after public cholesterol screening. American Journal of Public Health, 82(6), 804-809.

Mathers, J., Fraser, J. A., McMahon, M., Saunders, R. D., Hayes, J. D., et al. (2004). Antioxidant and cytoprotective responses to redox stress. Biochemical Society Symposia, 71, 157-176.

McGregor, A. (1992). WHO: Health and environment. The Lancet, 339(8793), 605.

Mellor, J. E., Laugharne, J. D., & Peet, M. (1995). Schizophrenic symptoms and dietary intake of n-3 fatty acids. Schizophrenia Research, 18(85-86).

Miyakawa, T., Sumiyoshi, S., & Deshimaru, M. (1972). Electron microscopic study on schizophrenia: Mechanisms of pathological change. Acta Neuropathologica, 20, 67-77.

Nemets, B., Stahl, Z., & Belmaker, R. H. (2002). Addition of omega-3 fatty aid to maintenance medication treatment for recurrent unipolar depressive disorder. American Journal of Psychiatry, 159, 477-479.

NHFA. (2003). Stress and coronary heart disease: Psychosocial risk factors. Journal of The National Heart Foundation of Australia, 178 (6), 272-276.

Noriyuki, K., Yoshiharu, K., & Nozomu, A. (2001). Suppression of cellular immunity in men with a past history of posttraumatic stress disorder. The American Journal of Psychiatry, 158(3), 484.

Norman, H., Go, V., & Butrum, R. (2004). Review of the International Research Conference on Food, Nutrition, and Cancer. Journal of Nutrition 134(12 Suppl), 3391S-3393S.

Pardoll, D. M. (2001). Stress, NK receptors, and immune surveillance. Science, 294(5542), 534.

Pauling, L. (1968). Orthomolecular psychiatry: Varying the concentrations of substances normally present in the human body may control mental disease. Science, 160(3825), 265-271.

Peet, M., Laugharne, J., Rangarajan, N., & Reynolds, G. P. (1993). Tardive dyskinesia, lipid peroxidation, and sustained amelioration with vitamin E treatment. International Journal of Clinical Psychopharmacology, 8, 151-155.

Peet, M., Laugharne, J. D., Mellor, J., & Ramchand, C. N. (1996). Essential fatty acid deficiency in erythrocyte membranes from chronic schizophrenic patients, and the clinical effects of dietary supplementation. Prostaglandins, Leukotrienes and Essential Fatty Acids, 55, 71-75.

Peet, M., & Mellor, J. (1998). Double-blind placebo-controlled trial of n-3 polyunsaturated fatty acids as an adjunct to neuroleptics. Paper presented at the Ninth Schizophrenia Winter Workshop, Davos, Switzerland.

Peet, M., Murphy, B., Shay, J., & Horrobin, D. (1998). Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients. Biological Psychiatry, 43, 315-319.

Pfeiffer, C. C. (1987). Nutrition and mental illness: An orthomolecular approach to balancing body chemistry. Rochester, Vermont: Healing Arts Press.

Rancillac, A., Rossier, J., Guille, M., Tong, X. K., Geoffroy, H., et al. (2006). Glutamatergic control of microvascular tone by distinct GABA neurons in the cerebellum. Journal of Neuroscience Research, 26, 6997-7006.

Ratnam, D., Ankola, D., Bhardwaj, V., Sahana, D., & Kumar, M. (2006). Role of antioxidants in prophylaxis and therapy: A pharmaceutical perspective. Journal of Control Release, 113(3), 189-207.

Reddy, R., Mahadik, S. P., Mukherjerr, M., & Murthy, J. N. (1991). Enzymes of the antioxidant system in chronic schizophrenic patients. Biological Psychiatry, 30, 409-412.

Robles, T. F., Glaser, R., & Kiecolt-Glaser, J. K. (2005). Out of balance: A new look at chronic stress, depression, and immunity. Current Directions in Psychological Science, 14(2), 111.

Rybakowsky, J. K., & Lehmann, W. (1991). Abnormalities of lithium transport across the erythrocyte membrane in depression and schizophrenia. Biological Psychiatry, 44, 123-128.

Sachdev, P., Parslow, R., Lux, O., Salonikas, C., Wen, W., et al. (2005). Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-aged community sample Psychological Medicine 35(4), 529-538.

Sahota, O., Mundey, M. K., San, P., Godber, I. M., & Hosking, D. J. (2006). Vitamin D insufficiency and the blunted PTH response in established osteoporosis: The role of magnesium deficiency. Osteoporosis International, 7, 1013-1021.

Segerstrom, S. C., & Miller, G. E. (2004). Psychological stress and the human immune system: A meta-analytic study of 30 years of inquiry. Psychological Bulletin, 130(4), 601.

Selye, H. (1973). The evolution of the stress concept. American Scientist, Vol. 61(6), 692-699.

Shah, S., Vankar, G. K., Telang, S. D., Ramchand, C. N., & Peet, M. (1998). Eicosapentaenoic acid (EPA) as an adjunct in the treatment of schizophrenia. Paper presented at the Ninth Schizophrenia Winter Workshop, Davos, Switzerland.

Stephensen, C. B. (2001). Examining the effect of a nutrition intervention on immune function in healthy humans: What do we mean by immune function and who is really healthy anyway? The American Journal of Clinical Nutrition, 74(5), 565.

Stoll, A. L., Locke, C. A., Marangell, L. B., & Severus, W. E. (1999a). Omega-3 fatty acids and bipolar disorder: A review. Prostaglandins, Leukotrienes and Essential Fatty Acids, 50, 329-337.

Stoll, A. L., Severus, E., Freeman, M. P., Rueter, S., Zboyan, H. A., et al. (1999b). Omega-3 fatty acids in bipolar disorder: A preliminary double-blind, placebo-controlled trial. Archives of General Psychiatry, 56, 407-412.

Urano, S., Sato, Y., Otonari, T., Makabe, S., Suzuki, S., et al. (1998). Aging and oxidative stress in neurodegeneration. Biofactors, 7, 103-112.

Vivier, E., Nunès, J. A., & Vély, F. (2004). Natural killer cell signaling pathways. Science, 306(5701), 1517.

Williams, R. (1971). Nutrition against disease. New York: Pitman Publishing.