Menopause and Mental Health


gg61214755Menopause is a natural developmental transition in every woman’s life.  It refers to the discontinuation of the function of the ovaries and is associated with the cessation of menstruation, which explains the name.  While the average age of menopause is 51, many women may begin menopause in their 40’s.  Menopause is artificially triggered when a woman has her ovaries surgically removed.  The impact on hormones associated with menopause can affect mood and mental health as well as cardiovascular risk, cancer risk, and the risk of bone loss.

Depression in menopause is linked both to the psychological effect of the loss of fertility and the hormonal changes associated with menopause, but there may be additional factors to consider. [1]  Menopause may increase systemic inflammation. [2]  This may be the result of the changes in body fat distribution and insulin receptivity associated with menopause. [3]  Oxidative stress may increase with estradiol depletion through menopause. [4]  As you know, inflammation and oxidative stress are factors involved in depression and dementia as well as other mental health concerns.

Acute anxiety triggered by menopause has been reported [5-8], as has bipolar disorder [9, 10].  Schizophrenia may worsen in menopausal women.  This has been associated with the protective effects of estrogenic hormones[11] as well as structural changes in the brain that occur during menopause.[12]

Oophorectomy (ovary removal) before menopause has been associated with an increased risk of age related cognitive decline and dementia [13],  and early menopause may be a risk factor for eventual development of dementia in women with Down Syndrome.[14]  Insulin resistance and changes in the immune system are also linked to menopause and a variety of conditions from metabolic syndrome to depression.  I have explored the link between metabolic syndrome and depression in a previous paper.  So what evidence is there that nutritional interventions may be useful to address menopausal mental health?

The link between inflammation and oxidative stress suggests that an anti-inflammatory diet may be a safe and appropriate intervention.  While pharmaceutical anti-inflammatory medications may present serious side effect risk, anti-inflammatory botanicals may be a safe and effective consideration.[15]

The literature has reported Vitamin E to address vasomotor effects (hot flashes) of menopause since the late 1940’s.[16-18]  Vitamin D has also been explored. Calcium and Vitamin D help to reduce bone loss secondary to menopause. [19, 20] Additionally there are numerous herbs and botanicals historically used for menopausal symptoms.

Black Cohosh may be one of the most widely used herbs for this purpose in the US.  This native North American plant has been widely used over the past 100 years for women’s health issues, including its ancient use by Native Americans for menopausal symptoms. Many studies report it to be safe and effective.[21-23]  However, other studies suggest it may be no more effective than placebo.[24]  And there is controversy about whether it can cause liver damage.  One study suggests that pure standardized Black Cohosh may be safe but that adulterants found in many preparations may be hepatotoxic. [25]  Other studies conclude that reports of liver damage may have erroneously concluded that the liver problems were caused by Black Cohosh.[26]  At this point, it appears that while people with risk factors for liver disease may be wise to avoid Black Cohosh, it is likely to be effective and safe for the vast majority of people if sourced from a reliable supplier in a standardized and pure form. [26]

Other herbs such as Dong Quai and Chaste tree berries have been used for menopausal symptoms.  Dong Quai addresses hot flashes, sleep quality and fatigue.[27]  Chaste berry may have an effect on the dopaminergic nervous system, which can assist in menopausal symptom reduction. [28]

Soy isoflavones have also been widely used to reduce symptoms associated with menopause. However, the mechanism of action and efficacy remain unclear.[29, 30] Some suggest that phytoestrogens can replace estrogen function without increasing the risk of estrogenic cancers, while other research suggests that this is not correct.  Other approaches to sidestep estrogen such as DIM (Diindolylmethane), a component found in cruciferous vegetables, may activate estrogen receptor sites rather than provide estrogen alternatives. [31]

Magnolia extract and magnesium have been reported to be helpful for the psychological symptoms of menopause, while soy isoflavones have been more linked to the vasomotor symptoms. [32]   Soy isoflavones have been reported in a single study to be helpful for cognitive issues of menopause including memory and learning, but these have not been replicated. [33]

As is often the case in the natural product arena, the science lags the application in the area of menopausal relief.  It is wise to avoid products that do not have clear quality assurance throughout the chain of custody and to look for products that have good scientific support of their formulation.  That said, natural products may offer considerable relief for both the vasomotor and psychological symptoms of menopause.

Dr. Richard A. Wyckoff, PhD
Founder, The Alliance for nutrition and Mental Health
September 2013

1.            Judd, F.K., M. Hickey, and C. Bryant, Depression and midlife: are we overpathologising the menopause? J Affect Disord, 2012. 136(3): p. 199-211.

2.            Abu-Taha, M., et al., Menopause and ovariectomy cause a low grade of systemic inflammation that may be prevented by chronic treatment with low doses of estrogen or losartan. J Immunol, 2009. 183(2): p. 1393-402.

3.            Sites, C.K., et al., Menopause-related differences in inflammation markers and their relationship to body fat distribution and insulin-stimulated glucose disposal. Fertil Steril, 2002. 77(1): p. 128-35.

4.            Sanchez-Rodriguez, M.A., et al., Menopause as risk factor for oxidative stress. Menopause, 2012. 19(3): p. 361-7.

5.            Chung-Park, M., Anxiety attacks following surgical menopause. Nurse Pract, 2006. 31(5): p. 44-9.

6.            Woods, N.F., E.S. Mitchell, and C. Landis, Anxiety, hormonal changes, and vasomotor symptoms during the menopause transition. Menopause, 2005. 12(3): p. 242-5.

7.            Chung-Park, M., Anxiety attacks following surgical menopause: a case report. Holist Nurs Pract, 2005. 19(5): p. 236-40.

8.            Toriizuka, K., M. Mizowaki, and T. Hanawa, [Menopause and anxiety: focus on steroidal hormones and GABAA receptor]. Nihon Yakurigaku Zasshi, 2000. 115(1): p. 21-8.

9.            Khan, A.Y., et al., Menopause manifesting as bipolar symptoms. J Psychiatr Pract, 2007. 13(5): p. 339-42.

10.          Ishimaru-Tseng, T.V., Evaluation of late onset bipolar illness during menopause. Hawaii Med J, 2000. 59(2): p. 51-3.

11.          Gupta, R., I. Assalman, and R. Bottlender, Menopause and schizophrenia. Menopause Int, 2012. 18(1): p. 10-4.

12.          Fukuta, H., et al., Effects of menopause on brain structural changes in schizophrenia. Psychiatry Clin Neurosci, 2013. 67(1): p. 3-11.

13.          Rocca, W.A., et al., Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology, 2007. 69(11): p. 1074-83.

14.          Coppus, A.M., et al., Early age at menopause is associated with increased risk of dementia and mortality in women with Down syndrome. J Alzheimers Dis, 2010. 19(2): p. 545-50.

15.          Sampalis, J.S. and L.A. Brownell, A randomized, double blind, placebo and active comparator controlled pilot study of UP446, a novel dual pathway inhibitor anti-inflammatory agent of botanical origin. Nutr J, 2012. 11: p. 21.

16.          Rubenstein, B.B., Vitamin E diminishes the vasomotor symptoms of menopause. Fed Proc, 1948. 7(1 Pt): p. 106.

17.          Finkler, R.S., The effect of vitamin E in the menopause. J Clin Endocrinol Metab, 1949. 9(1): p. 89-94.

18.          Mc, L.H., Vitamin E in the menopause. Br Med J, 1949. 2(4641): p. 1378-82, illust.

19.          Di Daniele, N., et al., Effect of supplementation of calcium and vitamin D on bone mineral density and bone mineral content in peri- and post-menopause women; a double-blind, randomized, controlled trial. Pharmacol Res, 2004. 50(6): p. 637-41.

20.          Kitatani, K., [Calcium and vitamin D intake after menopause]. Clin Calcium, 2004. 14(1): p. 98-101.

21.          Ross, S.M., Menopause: a standardized isopropanolic black cohosh extract (remifemin) is found to be safe and effective for menopausal symptoms. Holist Nurs Pract, 2012. 26(1): p. 58-61.

22.          Nasr, A. and H. Nafeh, Influence of black cohosh (Cimicifuga racemosa) use by postmenopausal women on total hepatic perfusion and liver functions. Fertil Steril, 2009. 92(5): p. 1780-2.

23.          Lieberman, S., A review of the effectiveness of Cimicifuga racemosa (black cohosh) for the symptoms of menopause. J Womens Health, 1998. 7(5): p. 525-9.

24.          Geller, S.E., et al., Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial. Menopause, 2009. 16(6): p. 1156-66.

25.          Teschke, R., et al., Herb induced liver injury presumably caused by black cohosh: a survey of initially purported cases and herbal quality specifications. Ann Hepatol, 2011. 10(3): p. 249-59.

26.          Teschke, R., W. Schmidt-Taenzer, and A. Wolff, Spontaneous reports of assumed herbal hepatotoxicity by black cohosh: is the liver-unspecific Naranjo scale precise enough to ascertain causality? Pharmacoepidemiol Drug Saf, 2011. 20(6): p. 567-82.

27.          Kupfersztain, C., et al., The immediate effect of natural plant extract, Angelica sinensis and Matricaria chamomilla (Climex) for the treatment of hot flushes during menopause. A preliminary report. Clin Exp Obstet Gynecol, 2003. 30(4): p. 203-6.

28.          Wuttke, W., et al., Chaste tree (Vitex agnus-castus)–pharmacology and clinical indications. Phytomedicine, 2003. 10(4): p. 348-57.

29.          Vincent, A. and L.A. Fitzpatrick, Soy isoflavones: are they useful in menopause? Mayo Clin Proc, 2000. 75(11): p. 1174-84.

30.          North American Menopause, S., The role of soy isoflavones in menopausal health: report of The North American Menopause Society/Wulf H. Utian Translational Science Symposium in Chicago, IL (October 2010). Menopause, 2011. 18(7): p. 732-53.

31.          Leong, H., et al., Potent ligand-independent estrogen receptor activation by 3,3′-diindolylmethane is mediated by cross talk between the protein kinase A and mitogen-activated protein kinase signaling pathways. Mol Endocrinol, 2004. 18(2): p. 291-302.

32.          Mucci, M., et al., Soy isoflavones, lactobacilli, Magnolia bark extract, vitamin D3 and calcium. Controlled clinical study in menopause. Minerva Ginecol, 2006. 58(4): p. 323-34.

33.          Santos-Galduroz, R.F., et al., Effects of isoflavone on the learning and memory of women in menopause: a double-blind placebo-controlled study. Braz J Med Biol Res, 2010. 43(11): p. 1123-6.

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Energy Drinks: What is the truth?


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Energy Drinks: What is the truth?

Dr. Richard A. Wyckoff, PhD

Founder, The Alliance for Nutrition & Mental Health

The rapid growth of the energy drink industry is a public health concern for numerous reasons.  Energy drinks continue to be promoted as “functional foods” and claim to improve physical and mental performance.   In fact, many research publications since 2001 have purportedly documented the efficacy of these foods for improved driving performance [1, 2],  improved mood and cognition [3-6], enhanced motor evoked potentials [7], Muscle endurance [8-10], Soccer performance [11] and other performance related issues.  In general, this research does not include measures of safety nor address the long-term effect of over-zealous consumption of “energy” drinks.  As such, it is questionable whether the researchers were engaged in science or in marketing.

Such studies conclude that caffeine, glucose, taurine, guarana and inositol appear to be the effective ingredients. [12]   The mechanism of the effect appears to be the activation of the pituitary, hypothalamus and adrenal  glands.[13] That is, the activation of a stress response.  It is well known that acute stress can trigger a short-term improvement in cognitive and physical performance as part of the general adaptation syndrome. [14]   It is also generally understood that additional stress is not what the doctor orders for performance enhancement in today’s chronically stressful environment.  In fact, prolonged stress causes a degradation in performance.  Apropos to this point, a recent study documents that not all people will experience a boost in performance from acute stress.  Individual performance styles may be more important than the stress itself. [15]

Since the energy drink industry has used the early-published science to promote the idea that such drinks are safe and effective, the consumption of energy drinks has increased in vulnerable populations such as preteens and adolescents.[16]  But reports of illness and/or death associated with these drinks has prompted public health concerns. Reports have associated energy drinks with heart disease and death. [17-22]  Many pediatric hospitals across the US have published concerns or policy statements encouraging that children should not consume such beverages.

Another trending public health concern is the combination of alcohol and energy drinks.  This occurs when people drink alcohol and energy drinks separately or when manufacturers combine alcohol with caffeine, taurine etc. in a novel single product.  These drinks are promoted as helpful in sobering up but the fact is that they simply cause a false perception of sobriety. [23]  This effect increases the actual risk of driving (or other impulsive behaviors) while intoxicated. [24]

Public health concerns regarding the proliferation of these products appear to be well founded.  This is partly due to the false promotions of these products as safe and effective.  Overuse by athletes, medical students, night shift workers, sleepy drivers and intoxicated youth is harmful and a serious discussion of the nature of human bioenergetics and valid supplementation strategies appears to be desperately needed in our pop culture.

1.            Horne, J.A. and L.A. Reyner, Beneficial effects of an “energy drink” given to sleepy drivers. Amino Acids, 2001. 20(1): p. 83-9.

2.            Reyner, L.A. and J.A. Horne, Efficacy of a ‘functional energy drink’ in counteracting driver sleepiness. Physiol Behav, 2002. 75(3): p. 331-5.

3.            Kennedy, D.O. and A.B. Scholey, A glucose-caffeine ‘energy drink’ ameliorates subjective and performance deficits during prolonged cognitive demand. Appetite, 2004. 42(3): p. 331-3.

4.            Scholey, A.B. and D.O. Kennedy, Cognitive and physiological effects of an “energy drink”: an evaluation of the whole drink and of glucose, caffeine and herbal flavouring fractions. Psychopharmacology (Berl), 2004. 176(3-4): p. 320-30.

5.            Smit, H.J., et al., Mood and cognitive performance effects of “energy” drink constituents: caffeine, glucose and carbonation. Nutr Neurosci, 2004. 7(3): p. 127-39.

6.            Giles, G.E., et al., Differential cognitive effects of energy drink ingredients: caffeine, taurine, and glucose. Pharmacol Biochem Behav, 2012. 102(4): p. 569-77.

7.            Specterman, M., et al., The effect of an energy drink containing glucose and caffeine on human corticospinal excitability. Physiol Behav, 2005. 83(5): p. 723-8.

8.            Ivy, J.L., et al., Improved cycling time-trial performance after ingestion of a caffeine energy drink. Int J Sport Nutr Exerc Metab, 2009. 19(1): p. 61-78.

9.            Candow, D.G., et al., Effect of sugar-free Red Bull energy drink on high-intensity run time-to-exhaustion in young adults. J Strength Cond Res, 2009. 23(4): p. 1271-5.

10.          Forbes, S.C., et al., Effect of Red Bull energy drink on repeated Wingate cycle performance and bench-press muscle endurance. Int J Sport Nutr Exerc Metab, 2007. 17(5): p. 433-44.

11.          Del Coso, J., et al., Effects of a caffeine-containing energy drink on simulated soccer performance. PLoS One, 2012. 7(2): p. e31380.

12.          Peacock, A., F.H. Martin, and A. Carr, Energy drink ingredients. Contribution of caffeine and taurine to performance outcomes. Appetite, 2013. 64: p. 1-4.

13.          Xu, D., et al., Caffeine-induced activated glucocorticoid metabolism in the hippocampus causes hypothalamic-pituitary-adrenal axis inhibition in fetal rats. PLoS One, 2012. 7(9): p. e44497.

14.          Vedhara, K., et al., Acute stress, memory, attention and cortisol. Psychoneuroendocrinology, 2000. 25(6): p. 535-49.

15.          McKay, K.A., et al., Determining the relationship of acute stress, anxiety, and salivary alpha-amylase level with performance of student nurse anesthetists during human-based anesthesia simulator training. AANA J, 2010. 78(4): p. 301-9.

16.          Buxton, C. and J.E. Hagan, A survey of energy drinks consumption practices among student -athletes in Ghana: lessons for developing health education intervention programmes. J Int Soc Sports Nutr, 2012. 9(1): p. 9.

17.          Berger, A.J. and K. Alford, Cardiac arrest in a young man following excess consumption of caffeinated “energy drinks”. Med J Aust, 2009. 190(1): p. 41-3.

18.          Steinke, L., et al., Effect of “energy drink” consumption on hemodynamic and electrocardiographic parameters in healthy young adults. Ann Pharmacother, 2009. 43(4): p. 596-602.

19.          Worthley, M.I., et al., Detrimental effects of energy drink consumption on platelet and endothelial function. Am J Med, 2010. 123(2): p. 184-7.

20.          Rottlaender, D., et al., Cardiac arrest due to long QT syndrome associated with excessive consumption of energy drinks. Int J Cardiol, 2012. 158(3): p. e51-2.

21.          Sadowska, J., Evaluation of the effect of consuming an energy drink on the concentration of glucose and triacylglycerols and on fatty tissue deposition. A model study. Acta Sci Pol Technol Aliment, 2012. 11(3): p. 311-8.

22.          Usman, A. and A. Jawaid, Hypertension in a young boy: an energy drink effect. BMC Res Notes, 2012. 5: p. 591.

23.          Ferreira, S.E., et al., Effects of energy drink ingestion on alcohol intoxication. Alcohol Clin Exp Res, 2006. 30(4): p. 598-605.

24.          Riesselmann, B., F. Rosenbaum, and V. Schneider, [Alcohol and energy drink–can combined consumption of both beverages modify automobile driving fitness?]. Blutalkohol, 1996. 33(4): p. 201-8.

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Update of Nutrition & Bipolar Disorder


Comedy Tragedy

Bipolar Disorder and Nutrition Update

Dr. Rick Wyckoff, PhD

Founder, The Alliance for Nutrition and Mental Health

Bipolar disorder is a condition characterized by cyclic mood swings, varying from mania (expansive mood, high energy, impulsivity, often involving regretful actions) to depression (depressed mood, low energy, social withdrawal, possible suicidal thoughts or impulses).  These cycles may be over  long periods of time (months) or they may be rapid cycling over days or weeks.

Bipolar disorder is actually a group or cluster of disorders collectively referred to as the bipolar spectrum.  There is good evidence that  a genetic component involving the ANK3,CACNA1C, and CLOCK genes are involved in the predisposition to the disorder.  However, people with this genotype may not show symptoms until a major stress event triggers or activates the gene. 

Bipolar disorder is being researched aggressively today, but  only a small percentage of current research involves nutrition.  However, there are hundreds of studies that suggest that various vitamins, minerals, fatty acids and amino acids may be involved in the pathophysiology of the disorder.

Proper medical management of this disorder is essential because each time an episode occurs it increases the likelihood of further occurrences.   Current medications are usually effective at managing the manic symptoms and may also manage the depressive symptoms as well.  Many people don’t like the effect of the medication because they feel it flattens their mood or reduces their creativity.  But the truth is that it is so important to prevent occurrences that they really should use medications as their prescriber recommends.   I am often asked  if there are nutritional alternatives to such medications.  This paper will address that question as of today’s date: July 29, 2013.

Evidence suggests that repeated occurrences are connected with increasing levels of inflammation.  C-reactive protein levels (a marker of systemic inflammation) increase with each episode of mania.   Systemic inflammation also increases levels of Beta Amyloid precursors following mania as well.[1, 2]  Beta Amyloid is associated with the risk of dementia.  Nutritional products that address systemic inflammation may be very helpful to use daily  for these reasons. 

There is some strong evidence that omega-3 fatty acids can help prevent the depression component of bipolar disorder  but not necessarily the manic component.[3]  Trace minerals have been found to be helpful in many studies. [4]  Vitamin D and B12 vitamins including folate have also been reported to be helpful.  [5, 6]

Mitochondrial dysfunction has been implicated in bipolar disorder.[7-9]  Nutrients that support mitochondrial function include ornithine[10],  glutamate [11],  lysine [12] , arginine [13, 14],  ribose , Coenzyme Q10 [15, 16], Vitamins D [17, 18], E [19, 20] and others.

Research suggests that depleted levels of some amino acids in the frontal cortex are associated with cognitive loss in bipolar disorder. [21]  Although there is limited support for amino acid therapies to date,  some studies of  supplements containing amino acids can be found.  [22, 23]  Supplementation of individual amino acids such as tryptophan [24], taurine [25], gaba[26], and /or lecithin/choline [27, 28] may be helpful to consider with support of a good naturopathic physician.  It may be dangerous to supplement with single amino acids without professional advice since they often affect each other’s actions.  High quality natural proteins or balanced protein isolates are a safe alternative for people who can metabolize proteins well.

In addition to medication and nutritional support, people with bipolar disorder can benefit greatly from developing good sleep habits, regular exercise, eating regularly, emotional self-regulation training, and stress management.  Counseling to address the effects of the experience of bipolar symptoms on self-esteem and identity can also be very helpful.  Living a well regulated lifestyle may help stabilize circadian rhythms that are deregulated by bipolar disorder.

Dr. Rick Wyckoff, PhD

 

 

 

1.            Jakobsson, J., et al., Altered concentrations of amyloid precursor protein metabolites in the cerebrospinal fluid of patients with bipolar disorder. Neuropsychopharmacology, 2013. 38(4): p. 664-72.

2.            Vucurovic, K., et al., Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion. Eur J Med Genet, 2012. 55(11): p. 625-9.

3.            Montgomery, P. and A.J. Richardson, Omega-3 fatty acids for bipolar disorder. Cochrane Database Syst Rev, 2008(2): p. CD005169.

4.            Kaplan, B.J., et al., Effective mood stabilization with a chelated mineral supplement: an open-label trial in bipolar disorder. J Clin Psychiatry, 2001. 62(12): p. 936-44.

5.            Ozbek, Z., et al., Effect of the methylenetetrahydrofolate reductase gene polymorphisms on homocysteine, folate and vitamin B12 in patients with bipolar disorder and relatives. Progress in neuro-psychopharmacology & biological psychiatry, 2008. 32(5): p. 1331-7.

6.            Ahmadi, S., et al., Vitamin D receptor FokI genotype may modify the susceptibility to schizophrenia and bipolar mood disorder by regulation of dopamine D1 receptor gene expression. Minerva Med, 2012. 103(5): p. 383-91.

7.            Konradi, C., S.E. Sillivan, and H.B. Clay, Mitochondria, oligodendrocytes and inflammation in bipolar disorder: evidence from transcriptome studies points to intriguing parallels with multiple sclerosis. Neurobiol Dis, 2012. 45(1): p. 37-47.

8.            Washizuka, S., et al., Expression of mitochondria-related genes in lymphoblastoid cells from patients with bipolar disorder. Bipolar Disord, 2005. 7(2): p. 146-52.

9.            Iwamoto, K., M. Bundo, and T. Kato, Altered expression of mitochondria-related genes in postmortem brains of patients with bipolar disorder or schizophrenia, as revealed by large-scale DNA microarray analysis. Hum Mol Genet, 2005. 14(2): p. 241-53.

10.         Metoki, K. and F.A. Hommes, A possible rate limiting factor in urea synthesis by isolated hepatocytes: the transport of ornithine into hepatocytes and mitochondria. Int J Biochem, 1984. 16(11): p. 1155-7.

11.         Tujioka, K., et al., Role of N-acetylglutamate concentration and ornithine transport into mitochondria in urea synthesis of rats given proteins of different quality. J Agric Food Chem, 2002. 50(25): p. 7467-71.

12.         Hommes, F.A., L. Kitchings, and A.G. Eller, The uptake of ornithine and lysine by rat liver mitochondria. Biochem Med, 1983. 30(3): p. 313-21.

13.         Soetens, O., et al., Transport of arginine and ornithine into isolated mitochondria of Saccharomyces cerevisiae. Eur J Biochem, 1998. 258(2): p. 702-9.

14.         Saavedra-Molina, A. and E. Pina, Ornithine uptake by rat liver mitochondria: effect of calcium and arginine. Biochem Int, 1987. 15(1): p. 81-6.

15.         Battino, M., et al., Coenzymes Q9 and Q10, vitamin E and peroxidation in rat synaptic and non-synaptic occipital cerebral cortex mitochondria during ageing. Biol Chem, 2001. 382(6): p. 925-31.

16.         Ibrahim, W.H., et al., Dietary coenzyme Q10 and vitamin E alter the status of these compounds in rat tissues and mitochondria. J Nutr, 2000. 130(9): p. 2343-8.

17.         Campbell, G.R., Z.T. Pallack, and S.A. Spector, Vitamin D Attenuates Nucleoside Reverse Transcriptase Inhibitor Induced Human Skeletal Muscle Mitochondria DNA Depletion. AIDS, 2013.

18.         Bouillon, R. and A. Verstuyf, Vitamin D, mitochondria, and muscle. J Clin Endocrinol Metab, 2013. 98(3): p. 961-3.

19.         Lauridsen, C. and S.K. Jensen, alpha-Tocopherol incorporation in mitochondria and microsomes upon supranutritional vitamin E supplementation. Genes Nutr, 2012. 7(4): p. 475-82.

20.         Mao, G., et al., Effect of a mitochondria-targeted vitamin E derivative on mitochondrial alteration and systemic oxidative stress in mice. Br J Nutr, 2011. 106(1): p. 87-95.

21.         Sobczak, S., et al., Cognition following acute tryptophan depletion: difference between first-degree relatives of bipolar disorder patients and matched healthy control volunteers. Psychol Med, 2002. 32(3): p. 503-15.

22.         Frazier, E.A., M.A. Fristad, and L.E. Arnold, Feasibility of a nutritional supplement as treatment for pediatric bipolar spectrum disorders. J Altern Complement Med, 2012. 18(7): p. 678-85.

23.         Frazier, E.A., M.A. Fristad, and L.E. Arnold, Multinutrient supplement as treatment: literature review and case report of a 12-year-old boy with bipolar disorder. Journal of child and adolescent psychopharmacology, 2009. 19(4): p. 453-60.

24.         Cooke, R.G. and R.D. Levitan, Tryptophan for refractory bipolar spectrum disorder and sleep-phase delay. J Psychiatry Neurosci, 2010. 35(2): p. 144.

25.         Lorenzo, M.P., et al., Optimization and validation of a capillary electrophoresis laser-induced fluorescence method for amino acids determination in human plasma: application to bipolar disorder study. Electrophoresis, 2013. 34(11): p. 1701-9.

26.         Petty, F., et al., Low plasma GABA is a trait-like marker for bipolar illness. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 1993. 9(2): p. 125-32.

27.         Bogarapu, S., et al., Complementary medicines in pediatric bipolar disorder. Minerva Pediatr, 2008. 60(1): p. 103-14.

28.         Moore, C.M., et al., Choline, myo-inositol and mood in bipolar disorder: a proton magnetic resonance spectroscopic imaging study of the anterior cingulate cortex. Bipolar Disord, 2000. 2(3 Pt 2): p. 207-16.

 

 

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The Aging Brain


neuron2

The developmental changes in the brain from birth through senescence are extremely interesting and recent research suggests that there are many things we can do to encourage healthy brain aging and perhaps even avoid neurodegenerative disease.

At birth we have a great deal more neurons in our brain than later in life.  As a matter of fact, the systematic ‘pruning’ of under-stimulated brain cells seems to be a natural and even desirable feature of the developing brain.

This pruning occurs through a process called apoptosis which is the way our body kills cells that need to be removed.  Apoptosis appears to make room for the remaining neurons to create networks of neurons which are hard wired together to perform certain functions.

These neural networks become more complex as we repeat patterns of behavior.  You can think of this as “neurons that fire together wire together.”

So children who are well stimulated by enriched environments may grow brains that are more complex both by sparing apoptosis and by neurogenesis, which is the process of generating new neurons.  You can think of this as the balance between damage (Apoptosis) and repair (Neurogenesis).  When there is more damage than repair, the brain deteriorates.  When there is more repair than damage, the brain grows in complexity.

Neurogenesis is stimulated by challenging the brain just as muscle development is stimulated by challenging muscles.  We challenge our brain by new experiences and learning new things.  This doesn’t always mean that we create new neurons to accommodate the learning.  More often it means that the existing neurons will grow new branches called ‘dendrites’ which associate to other neurons in a complex system of dendritic density.  Think of this as a tree with many branches and sub branches and twigs creating a dense display of complexity blocking out the sky vs. another tree where the branches are sparse and you can see the sky easily through it.

As we age, we learn and grow and our healthy brain becomes very complex.  This requires good nutrition, blood flow and complex biochemical functions we are only now beginning to understand.  At the same time our brain encounters catabolic forces which create some damage.   Injury, trauma and infection are obviously potential sources of damage to the brain.  But more subtle sources of damage include oxidative stress from free radicals, excessive systemic inflammation, cortisol overload from chronic stress, alcohol and drug effects, and blood sugar imbalances.  Even more subtle are the damaging effects of nutritional deficiencies such as Vitamin D3, B- complex, Omega-3 fatty acids and many other vitamins and minerals potentially lacking in the standard American diet. 

Generally for infants and children, these damaging forces are minimal; and, the restorative power of the human body is sufficient to neutralize the potential harm.  But, by the time we reach adulthood the damage our brain is addressing on a daily basis becomes more of an issue.  At this stage in life, the damage and repair are essentially equal in most people.  However, every decade past thirty, damage accumulates and the ability to repair decreases setting the stage for neurodegeneration. 

Most mental health problems like depression and other mood disorders, anxiety, schizophrenia, and obsessive-compulsive disorders generally show up before middle age.  There is ample research demonstrating that these conditions are rooted in neurobiological processes such as inflammation, oxidative stress and prolonged cortisol exposure in addition to neurotransmitter imbalances and genetic predisposition.  In the young adult brain, it is rare to see neurocognitive deficits such as memory, disinhibition, or marked executive functioning deficits.

As the brain ages, certain neurocognitive changes in attention, memory and information processing speed are observed in otherwise healthy seniors.  Older people may also rely on different brain structures than they used when they were younger for the same purpose.  While there is considerable debate about the structural and functional causes of these changes, in my opinion there is a growing body of knowledge about mitochondrial function, inflammation and oxidative stress that suggests that these may set the stage for increasing apoptosis well before any signs or symptoms of frank dementia are seen.  Over enough time, however, these factors may damage the brain to a point that dementia occurs and progresses.

So what can we do to protect our aging brains?  The answers probably won’t surprise you.  Regular exercise helps to maintain a healthy vascular system in the brain.  So, get off the couch! Maintaining healthy blood sugar levels helps protect the proper functioning of insulin receptors in the brain.   Practicing regular stress management not only reduces excessive cortisol levels but also helps maintain DHEA levels essential for brain functioning.  Great sleep hygiene is essential for brain health.  Learn to sleep without depending on pharmaceuticals.  Supplementation can be very valuable.  Consider fish oil, coconut oil, Ornithine-α-keto-glutarate, vitamin D3, B-complex, a good balanced mineral supplement and bio-available protein supplements.  Finally, use your brain!  Stimulation is as essential for the aging brain as it is for newborns.  So learn something exciting everyday!

Let’s not outlive our brain or our money; and thrive to 105.

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Metabolic Fitness & Mental Health


Benefits-of-Physical-Fitness

Everyone wants to be in great shape, healthy and happy.  So why do so many of us miss that mark?  Peak health or optimal wellness is more than the absence of illness —  it requires many components working together to optimize wellness.  One factor, often overlooked in the past, is metabolic fitness.  To understand what metabolic fitness really means, we can look at the other side of the coin, metabolic syndrome.

Metabolic syndrome is a cluster of metabolic indicators, such as slightly elevated blood sugar, blood pressure that is rising but not high enough to diagnose hypertension, mildly elevated lipids, and increasing abdominal fat.  Until recently, these factors were not deemed to be serious enough for diagnosis of a disease state, so physicians typically monitored from year to year.   When their patients ultimately developed a disease, such as diabetes, hypertension, heart disease, etc., physicians then “managed” that disease. 

What we now know is that these factors are not only risk factors for the development of these and many other diseases but also an indication of poor metabolic fitness.  They are perhaps the first indication that an individual is declining into a state of poor health that will ultimately lead to turbo aging and decrepitude and …death.

The logical expectation is that we all will run to the gym and workout or grab our running shoes and enter a 5k.  However, it’s not that simple.  If it were, we would all “just do it,” as the ad slogan says.  The truth is that when we slide toward metabolic syndrome, there are numerous biological factors that make it unlikely we can just rebuild metabolic fitness through physical effort.

The first is our old nemesis — adiposity, or fat.  The majority of us living today have a natural genetic tendency toward a fat storing metabolism.  Living in a land of abundant and cheap carbohydrates makes fat storing easy and inevitable.  And excess fat, especially abdominal fat, creates high levels of pro-inflammatory cytokines. 

Think of these pro-inflammatory cytokines as inflammation that circulates through our body, triggering other cells to generate more pro-inflammatory cytokines.  It’s like a fire that burns in one part of the forest.  Then the wind carries a spark to a nearby patch of trees, where they catch fire and create sparks, which spread the fire, and so on and so on.  Eventually, the fire is consuming the whole forest.  Systemic inflammation, a consequence of adiposity, then becomes one of the pillars of metabolic syndrome. 

Another factor that works against us is the vast amount of oxidative stress our cells must deal with on a daily basis.  Free radicals are side effects from the metabolic processes of cellular energy creation needed for our body to function.  It takes a lot of fruits and vegetables to get the anti-oxidants needed to neutralize these free radicals and render them harmless.  Today we also have additional oxidative stress from environmental pollution, stress, food additives and even the highly processed food we eat.  This makes managing oxidative stress very difficult for the average person.  Prolonged oxidative stress is another pillar of metabolic syndrome.

Further compounding the problem, when we are not metabolically fit, exercise tends to hurt.  We don’t have enough exercise tolerance to experience the benefits and exercise becomes something to avoid at all costs.  This leads to sedentary lifestyle, increased fat and inflammation and oxidative stress.

Get the picture?  Nearly two-thirds of all Americans are overweight or obese. That means that for most people metabolic syndrome is inevitable.  And that means a huge burden of circulating inflammation and oxidative stress.

So what does this have to do with mental illness?  You will appreciate this when you think about what happens when inflammation and / or free radicals pass through the blood brain barrier and enter the brain.  Simply put, the brain doesn’t function well when inflamed.  As a matter of fact, neuroinflammation leads to neurodegeneration and apoptosis.  Apoptosis is the term used when a cell is destroyed by the body’s immune defenses.

Inflammation affects the brain at many levels.  When blood vessels are involved, the inflamed blood vessels cannot transport nutrients or oxygen as effectively, and the involved area of the brain becomes less functional.  As time passes, the inflammation progresses into the nerves and connective tissues of the brain, and the nerves lose more function.  As the level of damage grows and the capacity to repair diminishes, the brain’s function becomes more and more impaired.

Depression and anxiety are signs of such metabolic problems in the early stages.  Dementia is of course a much more serious mental illness that may have a foundation in the neuroinflammatory processes that first show up as depression.  There is also a body of knowledge linking bipolar disease, schizophrenia and other conditions to inflammation, oxidative stress, and other metabolic pathways.

So, when we think of metabolic syndrome and metabolic fitness, maybe we should expand our focus beyond heart disease, stroke and diabetes and start thinking about mental health too.  After all, the brain is an essential part of our body.  What do you think?  Please comment and create dialogue.

 

 

 

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Antioxidants and Depression


Depression and Oxidative Stress

Dr. Richard A. Wyckoff, PhD

The Alliance for Nutrition & Mental Health

March 11, 2013

 

The link between major depression and nutritional status is becoming clearer as we progress into the 21st century.  Oxidative stress is a catabolic effect of free radical damage, which affects neurons on many levels.  A free radical is an ionized molecule that is chemically unstable due to the lack of an electron or electrons.  These occur in huge numbers in the brain and body during normal activity.  Additional free radical load can come from pollution, stress and countless other common factors.

Free radicals are chemically compelled to merge with molecules within the cell to stabilize, and in doing so they damage the cellular structures providing the electron.  This occurs within the cell membrane, cytoplasm, organelles and even in the structure of the DNA deep inside the nucleus.

The natural defense from oxidative stress occurs when antioxidant molecules attach to the free radicals, thus rendering them powerless to harm the cell.  There are many types of antioxidants.  Lipophilic antioxidants generally protect the cell membrane and other fatty structures of the brain.  Hydrophilic antioxidants protect neural cytoplasm, and some antioxidants have a protective effect on other antioxidants, recycling them to defend again.

The relationship between oxidative stress and depression is a relatively new topic in the medical literature.   In 2000, Maes reported that patients with major depressive disorder showed significantly lower vitamin E levels than controls.[1]  In 2001, Widner et al. postulated that disturbed homocysteine and folate metabolism, both linked to depression, may be related to excessive oxidative stress. [2]  One year later, Lukash reported improvement in oxidative status following successful treatment of depression. [3]  Also in 2002, Srivastava studied the levels of nitrous oxide in depressed patients before and after treatment, suggesting an effect. [4]  Then in 2003, a publication by Khanzode reports the relationship between common SSRI treatment and oxidative stress status of patients.  Many of these studies appear to argue that one of the effects of drug treatment is to improve oxidative stress status.  That is, SSRI’s may be potent antioxidants or facilitate the function of antioxidants.

However, in 2008, Miller reports the importance of Folate, a B vitamin in the methylation process in the biosynthesis of monoamines such as dopamine and serotonin and epinephrine.  In that article, he states that Folate deficiencies may play a role in the failure of SSRI’s in the treatment of depression. [5]  Then again, in 2009 Cumurcu looked at the impact of successful drug treatment of depression on total antioxidant status. [6] Finally in 2010, Tacet et al. studied the antioxidant parallels of successful trans cranial magnetic therapy on depressed patients and found that “our data show that TMS induced a protection against cell and oxidative damage induced by OBX, as well as they support the hypothesis that oxidative stress may play an important role in depression.” [7]

This line of research leads to Maes et al. in 2012 concluding that there is sufficient evidence to support a new type of drug for depression that addresses inflammation and oxidative stress as a direct treatment for depression. [8]  Also in 2012 Leonard and Maes published an interesting article exploring the mechanism of how free radical damage may lead to elevations in pro-inflammatory cytokines and metabolic dysregulation or even apoptosis of neurons. [9]

 

But what about nature’s natural anxtioxidants?  Fruits and vegetables are not discussed until Payne et al. observed in 2012 that the intake of fruits and vegetables in the diets of depressed older adults is significantly lower than in comparable older adults who are not depressed. [10]

It is likely that oxidative stress is an intermediating factor, which leads to an increase in systemic inflammation in Major Depression. [11, 12]  Neuronal Inflammation has been Implicated in major depression, dementia and other neurodegenerative diseases in multiple reports.  [13, 14]  At this writing there does not appear to be an evidence base to support a prescriptive diet or supplementation strategy.  This may be because research is dependent upon funding and big pharma does not generally fund research to demonstrate the efficacy of natural products or diet on disease states such as depression.

Clearly, there is a bias in the research literature in favor of drugs, but it seems obvious that increasing consumption of fruits and vegetables as well as consuming supplementation with high levels of antioxidants might be wise; at least until the science catches up with common sense!

What do you think?

 

Dr. Richard Wyckoff, PhD

Founder, The Alliance for nutrition & Mental Health

 

1.            Maes, M., et al., Lower serum vitamin E concentrations in major depression. Another marker of lowered antioxidant defenses in that illness. J Affect Disord, 2000. 58(3): p. 241-6.

2.            Widner, B., et al., Does disturbed homocysteine and folate metabolism in depression result from enhanced oxidative stress? J Neurol Neurosurg Psychiatry, 2001. 70(3): p. 419.

3.            Lukash, A.I., et al., [Free radical processes and antioxidant system in depression and treatment efficiency]. Zh Nevrol Psikhiatr Im S S Korsakova, 2002. 102(9): p. 41-4.

4.            Srivastava, N., et al., A study on nitric oxide, beta-adrenergic receptors and antioxidant status in the polymorphonuclear leukocytes from the patients of depression. J Affect Disord, 2002. 72(1): p. 45-52.

5.            Miller, A.L., The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev, 2008. 13(3): p. 216-26.

6.            Cumurcu, B.E., et al., Total antioxidant capacity and total oxidant status in patients with major depression: impact of antidepressant treatment. Psychiatry Clin Neurosci, 2009. 63(5): p. 639-45.

7.            Tasset, I., et al., Antioxidant-like effects and protective action of transcranial magnetic stimulation in depression caused by olfactory bulbectomy. Neurochem Res, 2010. 35(8): p. 1182-7.

8.            Maes, M., et al., New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates–Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology, 2012. 20(3): p. 127-50.

9.            Leonard, B. and M. Maes, Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev, 2012. 36(2): p. 764-85.

10.          Payne, M.E., et al., Fruit, vegetable, and antioxidant intakes are lower in older adults with depression. J Acad Nutr Diet, 2012. 112(12): p. 2022-7.

11.          Rawdin, B.S., et al., Dysregulated relationship of inflammation and oxidative stress in major depression. Brain Behav Immun, 2012.

12.          Wolkowitz, O.M., et al., Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress – preliminary findings. PLoS One, 2011. 6(3): p. e17837.

13.          Gardner, A. and R.G. Boles, Beyond the serotonin hypothesis: Mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders. Progress in neuro-psychopharmacology & biological psychiatry, 2010.

14.          Phani, S., J.D. Loike, and S. Przedborski, Neurodegeneration and Inflammation in Parkinson’s disease. Parkinsonism & related disorders, 2012. 18 Suppl 1: p. S207-9.

 

 

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PUFAs and Mental Health


Fish is brain food?

Fish oil is a major source of omega-3 (EPA) and Omega-6 (DHA) two long chain fatty acids that have been implicated in many mental health conditions.  EPA and DHA are also synthesized in the body from alpha-linolenic acid (ALA), which is a shorter molecule from plant sources.  ALA sources are primarily seed and nut oils including walnut, flax seed, rape seed and soybeans.   Collectively these fatty acids are called PUFAs or polyunsaturated fatty acids.  Even though EPA and DHA are synthesized from ALA, there may be a concern for vegetarians, since only about 5% of ALA is converted into omega-3, leaving the possibility of deficiency of omega-3 in the vegan diet.[1]

The importance of PUFAs emerged in the context of cardiac  health[2-4], muscle and bone health[5, 6], immune health[7, 8], cancer [9, 10] and other disparate medical conditions.  Brain health and mental health conditions, including depression[11-13], anxiety[14-16], schizophrenia [17], bipolar depression [18] and dementia [19-21], have been shown to have associations with PUFA levels as well.  Perhaps because of the ubiquitous role of PUFAs in so many health conditions  and the fact that omega-3 fatty acids are essential, i.e., not adequately synthesized internally, PUFA supplementation is commonly encouraged even by major hospital websites. [22, 23]

Recent studies provide us with an exceptional understanding of the mechanisms of PUFAs and brain health as well as a deeper understanding of metabolic syndrome. [24-26]  Vegetarians will be pleased that supplementation with ALA modulated the incidence of metabolic syndrome independent of either EPA or DHA.  It seems that ALA intake was inversely associated with metabolic syndrome in adults, independent of the intake of omega-6 PUFAs. [24]

The consumption of sugar in the American diet has increased 33% since the 1960s.  However, the consumption of cane sugar has decreased in the same period.  The increase in consumption is due primarily to the astronomical increase in high fructose corn syrup, which is added to most processed foods.  Consumption of this hidden sugar has increased over 1,000% since the 60s.   Interestingly, this correlates with the increase in obesity and metabolic syndrome.

The impact of high sugar diets on insulin resistance in the brain sheds light on the association between diabetes and depression.[25]  This is also a function of memory and learning issues.  Such negative cognitive effects of the standard American diet (SAD) appear to be due to the changes in insulin receptors in the hippocampus.  One article suggests that schizophrenia may even be metabolically related to insulin signaling effects of metabolic syndrome. [26]

The good news is that laboratory evidence is emerging that suggest that supplementation with omega-3 may mitigate or even partially reverse the effects of high fructose diets on the brain. [25]

1. Burdge, G.C. and P.C. Calder, Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults. Reproduction, nutrition, development, 2005. 45(5): p. 581-97.

2. Vedtofte, M.S., et al., Dietary alpha-linolenic acid, linoleic acid, and n-3 long-chain PUFA and risk of ischemic heart disease. The American journal of clinical nutrition, 2011. 94(4): p. 1097-103.

3. Singer, P. and M. Wirth, Can n-3 PUFA reduce cardiac arrhythmias? Results of a clinical trial. Prostaglandins, leukotrienes, and essential fatty acids, 2004. 71(3): p. 153-9.

4. Pepe, S., et al., PUFA and aging modulate cardiac mitochondrial membrane lipid composition and Ca2+ activation of PDH. The American journal of physiology, 1999. 276(1 Pt 2): p. H149-58.

5. Hess, T.M., et al., Effects of two different dietary sources of long chain omega-3 highly unsaturated fatty acids on incorporation into the plasma, red blood cell, and skeletal muscle in horses2. Journal of animal science, 2012.

6. Dangardt, F., et al., High physiological omega-3 Fatty Acid supplementation affects muscle Fatty Acid composition and glucose and insulin homeostasis in obese adolescents. Journal of nutrition and metabolism, 2012. 2012: p. 395757.

7. Simopoulos, A.P., Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr, 2002. 21(6): p. 495-505.

8. Haw, M.P., et al., The effect of dietary polyunsaturated fatty acids (PUFA) on acute rejection and cardiac allograft blood flow in rats. Transplantation, 1995. 60(6): p. 570-7.

9. Touvier, M., et al., Modulation of the association between plasma intercellular adhesion molecule-1 and cancer risk by n-3 PUFA intake: a nested case-control study. The American journal of clinical nutrition, 2012. 95(4): p. 944-50.

10. Dumas, J.F., et al., n-3 PUFA-enriched diet delays the occurrence of cancer cachexia in rat with peritoneal carcinosis. Nutrition and cancer, 2010. 62(3): p. 343-50.

11. Tajalizadekhoob, Y., et al., The effect of low-dose omega 3 fatty acids on the treatment of mild to moderate depression in the elderly: a double-blind, randomized, placebo-controlled study. European archives of psychiatry and clinical neuroscience, 2011. 261(8): p. 539-49.

12. Levant, B., N-3 (omega-3) Fatty acids in postpartum depression: implications for prevention and treatment. Depression research and treatment, 2011. 2011: p. 467349.

13. Lesperance, F., et al., The efficacy of omega-3 supplementation for major depression: a randomized controlled trial. The Journal of clinical psychiatry, 2011. 72(8): p. 1054-62.

14. Vinot, N., et al., Omega-3 fatty acids from fish oil lower anxiety, improve cognitive functions and reduce spontaneous locomotor activity in a non-human primate. PLoS One, 2011. 6(6): p. e20491.

15. Kiecolt-Glaser, J.K., et al., Omega-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial. Brain, behavior, and immunity, 2011. 25(8): p. 1725-34.

16. Ferraz, A.C., et al., Chronic omega-3 fatty acids supplementation promotes beneficial effects on anxiety, cognitive and depressive-like behaviors in rats subjected to a restraint stress protocol. Behavioural brain research, 2011. 219(1): p. 116-22.

17. McNamara, R.K., Omega-3 fatty acid deficiency: a preventable risk factor for schizophrenia? Schizophrenia research, 2011. 129(2-3): p. 215-6.

18. Balanza-Martinez, V., et al., Therapeutic use of omega-3 fatty acids in bipolar disorder. Expert review of neurotherapeutics, 2011. 11(7): p. 1029-47.

19. Kroger, E., et al., Omega-3 fatty acids and risk of dementia: the Canadian Study of Health and Aging. The American journal of clinical nutrition, 2009. 90(1): p. 184-92.

20. Cole, G.M., Q.L. Ma, and S.A. Frautschy, Omega-3 fatty acids and dementia. Prostaglandins Leukot Essent Fatty Acids, 2009. 81(2-3): p. 213-21.

21. Palmblad, J., et al., [Omega-3-fatty acids protect against dementia. Also early symptoms of mild Alzheimer disease seem to be inhibited]. Lakartidningen, 2007. 104(44): p. 3268-71.

22. Abete, P., et al., PUFA for human health: diet or supplementation? Current pharmaceutical design, 2009. 15(36): p. 4186-90.

23. Marton, C., Omega-3 and Fish Oil Information. Representation of the Most Popular CAM Therapy on the Web Sites of Top U.S. Hospitals. Journal of Consumer Health on the Internet, 2012. 16(1): p. 93-100.

24. Mirmiran, P., et al., Association between interaction and ratio of omega-3 and omega-6 polyunsaturated fatty acid and the metabolic syndrome in adults. Nutrition, 2012.

25. Agrawal, R. and F. Gomez-Pinilla, ‘Metabolic syndrome‘ in the brain: deficiency in omega-3 fatty acid exacerbates dysfunctions in insulin receptor signalling and cognition. The Journal of physiology, 2012. 590(Pt 10): p. 2485-99.

26. Peet, M., The metabolic syndrome, omega-3 fatty acids and inflammatory processes in relation to schizophrenia. Prostaglandins Leukot Essent Fatty Acids, 2006. 75(4-5): p. 323-7.

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