June 11, 2010
Depression is nothing new. King Saul in the Old Testament struggled with depression; Greek philosophers, such as Plato and his student Aristotle, examined the mind in depth; and the ancient Greek physician Arateus studied subjects during mania and depression, recognizing characteristics and patterns. The effects, causes and outcomes of depression have been studied since the dawn of time. Major depressive disorder, as well as debilitating amounts of anxiety and other mood disorders, is, unfortunately, common. According to the National Institutes of Health (NIH), mood disordersmajor depressive disorder, dysthymic disorder and bipolar disorderare present in approximately 20.9 million American adults, or about 9.5 percent of the U.S. population age 18 and older in a given year. Major Depressive Disorder is the leading cause of disability in the United States for ages 15 to 44 and affects approximately 14.8 million American adults, or about 6.7 percent of the U.S. population age 18 and older in a given year. It is more prevalent in women than in men. Fortunately, much like Hippocrates approach, the natural products industry has several natural solutions for depression, stress, anxiety and other mood disruptors, so users can avoid the negative side effects of many pharmaceutical-based antidepressants.
Trace minerals, such as chromium are essential to the bodys well-being; and, as more studies are conducted on natural products, researchers are finding many supplements are multi-purposeful and many ailments have a cause-and-effect relationship with other ailments in the body, such as glucose and metabolism.
These efforts have been investigated starting as far back as 1996, when William Eaton of John Hopkins University examined depression and the risk of onset of type 2 diabetes.1 Eaton concluded: Major depressive disorder signals increased risk for onset of type 2 diabetes. Limitations of the findings arise from the difficulty in determining temporal order with two chronic conditions, even when the temporal order of measurement is clear. In addition, even though control variables were introduced for the use of health services, it is possible that the treatment for depression led to an earlier diagnosis of diabetes in this sample.
Recent research further explores the relationship between mood and diabetes. A placebo-controlled, double blind, pilot study of chromium picolinate (as Chromax, from Nutrition 21) was conducted in 15 patients with Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) major depressive disorder, atypical type.2 Patients received 600 mcg of chromium picolinate or matching placebo for eight weeks. Seventy percent of the chromium picolinate patients versus zero placebo patients met responder criteria (P=0.02). Other outcomes were consistent with a greater effect of chromium picolinate. Chromium picolinate showed promising antidepressant effects possibly via 5HT2A downregulation or increased insulin sensitivity.
In a case series of eight patients with refractory mood disorders, chromium supplements (as Chromax) dramatically improved symptoms and functioning.3 The putative antidepressant effects of chromium could be accounted for by enhancement of insulin utilization and related increases in tryptophan availability in the central nervous system, and/or by chromium's effects on norepinephrine release.
In 2005, researchers replicated a pilot trial, in which atypical depression showed a significant positive therapeutic response to chromium picolinate; but what researchers found interesting was the link between depression, decreased insulin sensitivity and subsequent diabetes, and chromium picolinate's insulin-enhancing effect.4 Therefore, a double blind, multicenter, eight-week replication study randomized adult outpatients with atypical depression to receive 600 mug/d of elemental chromium, as provided by chromium picolinate (as Chromax), or placebo. Of the 113 patients, 110 (70 chromium picolinate, 40 placebo) constituted the intent-to-treat (ITT) population (i.e., received at least one dose of study medication and completed at least one efficacy evaluation) and 75 (50 chromium picolinate, 25 placebo) were evaluable (i.e., took at least 80 percent of study drug with no significant protocol deviations). Researchers found no significant difference between the chromium picolinate and placebo groups in both the ITT and evaluable populations on the primary efficacy measures, with both groups showing significant improvement from baseline on total 29-item Hamilton Depression Rating Scale (HAM-D-29) scores during the course of treatment (P<0.0001). However, in the evaluable population, the chromium picolinate group showed significant improvements from baseline compared with the placebo group on 4 HAM-D-29 items: appetite increase, increased eating, carbohydrate craving and diurnal variation of feelings. A supplemental analysis of data from the subset of 41 patients in the ITT population with high-carbohydrate craving showed the chromium picolinate patients had a significantly greater response (65 percent) on total HAM-D-29 scores than the placebo group (33 percent), as well as significantly greater improvements on the following HAM-D-29 items: appetite increase, increased eating, carbohydrate craving and genital symptoms (e.g., level of libido). The results of this study suggested the main effect of chromium was on carbohydrate craving and appetite regulation in depressed patients and 600 mug of elemental chromium may be beneficial for patients with atypical depression who also have severe carbohydrate craving.
Other minerals also play a role in mood disorders. Calcium and magnesium were involved in a 2010 cross-sectional study to determine their association with mental health in relatively healthy, adult women without psychiatric disorders.5 A total of 112 adult women were recruited from the outpatient clinic in a university hospital setting. Serum calcium and magnesium levels were measured, and indicators of mental health such as depression, anxiety and stress were evaluated. Women in the middle tertile of serum calcium/magnesium ratio had significantly lower scores on depression and stress scales and a lower odds ratio (OR) for the risk of depressive mood disorder than those in the highest tertile. The OR for the risk of depressive mood disorder was higher in women in the lowest tertile of serum magnesium than in those in the highest tertile.
Early this year, a paper published online called, The Role of Zinc in Neurodegenerative Inflammatory Pathways in Depression, provided an overview of the clinical and experimental evidence that implicates the role of zinc in the pathophysiology and therapy of depression within the context of the inflammatory and neurodegenerative hypothesis of this disease.6 In Japan, a double blind, placebo-controlled pilot study randomly placed 30 women in equal numbers into two groups and who ingested one capsule containing multivitamins (MVs) or MV and 7 mg/d of zinc for 10 weeks.7 Women who took MV and zinc showed a significant reduction in anger-hostility score (P=0.009) and depression-dejection score (P=0.011) in the Profile of Moods State (POMS), and a significant increase in serum zinc concentration (P=0.008), whereas women who took only MV did not.
Food for a Better Mood
Mood and diabetes are not the only physiological connection. Anxiety, depression and mood are undeniably connected to the food we eat. A review out of Ohio State University found there is a connection among diet, inflammation, stress and mood disorders. Janice K. Kiecolt-Glaser, Ph.D., noted stress influences food choices and can adversely impact metabolic response to unhealthy food choices. Additionally, activation of the vagus nerve adversely affects digestion and nutrient metabolism; depression and stress both have negative effects on vagal activation.8
Many companies are capitalizing on this connection. According to a report from Business Insights, the global growth in the mood/mind health food and drink presents a huge opportunity. Innovations in Mood & Mind Health Food & Drinks investigated the new market within the functional foods and beverages sector, and how new launches are creating consumer buzz. The Business Insights team noted since 2006, a significant change has occurred in the sector, as consumers are interested in products that can address mood, improve cognition and target specific health concerns related to mental health. Products such as confectionery, baked goods and carbonated beverages, traditionally perceived as indulgent, can be reformatted and rebranded with a new marketing strategy targeting consumers looking for mood or mind support products.
Mood affects food choices and food choices affect mood. The proof really is in the pudding chocolate pudding, as chocolate continually makes the top of the food mood list. A survey out of New Hampshire found mood, occasion, time of day and weather all affect chocolate-buying decisions.9 In San Diego, researchers examined the relationship of chocolate consumption to mood in an adult study sample of about 1,000 subjects who were not on antidepressant medications and did not have any known cardiovascular disease (DVC) or diabetes.10 They found both men and women who had higher depression scores consumed almost 12 servings of chocolate per month; those with lesser depression scores ate about eight servings of chocolate per month; and those with no depression had five servings per month. German researchers rated 37 healthy, normal-weight womens subjective state at 5, 30, 60 and 90 minutes after eating a chocolate bar, an apple or nothing.11 Both chocolate and the apple reduced hunger, elevated mood and increased activation, but the effects of the chocolate were stronger. Eating chocolate was also followed by joy; however some women experienced guilt.
Need more proof food affects mood? Fast-forward to the end of the movie SuperSize Me. The main characters mood was so tied to his 30-day McDonalds diet that he only time he felt good was when he was eating McDonalds; otherwise, he felt depressed.
Fatten Your Mood
Lipids come in all shapes and sizes. From fatty acids (FA) such as omega-3s to phospholipids (PL) such as phosphatidylserine (PS), lipids serve many roles in the body, and brain health is one of them. Endless research has been conducted on omega-3s famous duodocosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Israeli researchers at the Ministry of Health Beer Sheva Mental Health Center reviewed three studies of omega-3 fatty acids in the treatment of depression.12 The first study examined EPA versus placebo as an adjunct to antidepressant treatment in 20 unipolar patients with recurrent major depression. Highly significant benefits were found by week three of EPA treatment compared with placebo. The second study used omega-3 fatty acids in childhood major depression; 28 children aged 6 to 12 were randomized to omega-3 fatty acids or placebo as pharmacologic monotherapy. An analysis of variance (ANOVA) showed highly significant effects of omega-3 on each of the three rating scales. The third study was an open-label add-on trial of EPA in bipolar depression. Twelve bipolar outpatients with depressive symptoms were treated with 1.5-2.0 g/d of EPA for up to six months. In the child study, eight of the 10 patients who completed at least one month of follow-up achieved a 50-percent or greater reduction in HAM-D scores within one month. Overall, omega-3 FAs were shown to be more effective than placebo for depression in both adults and children in small controlled studies and in an open study of bipolar depression.
In England, data was collected from women participating in the Avon Longitudinal Study of Parents and Children.13 At 32 weeks' gestation, the mother completed a questionnaire that included symptoms of depression and a food-frequency questionnaire from which the amount of omega-3 FAs from fish was calculated. Unadjusted and adjusted analyses showed lower maternal intake of omega-3 from seafood was associated with high levels of depressive symptoms. Compared with women consuming more than 1.5 g omega-3 from seafood per week, those consuming none were more likely to have high levels of depressive symptoms. Researchers concluded eating seafood during pregnancy may have beneficial effects on mental well-being.
Another study published in the American Journal of Clinical Nutrition assigned women with moderate-to-severe psychological distress (n=120) to randomly receive 1.05 g ethyl-EPA/d plus 0.15 g ethyl-DHA/d (n= 9) or placebo (n=61) for eight weeks.14 At baseline, women with psychological distress were mildly to moderately depressed, and 24 percent met the major depressive episode (MDE) criteria of the DSM. After eight weeks of supplementation, outcomes improved in both groups, but no significant differences were noted between them. Stratification analyses for MDE diagnosis at baseline indicated differences in adjusted eight-week changes between the ethyl-EPA group without MDE (n =46) and the placebo group (n=45) were 8.0 for the Psychological General Well-Being Schedule (PGWB), -0.2 for the 20-item Hopkins Symptom Checklist Depression Scale (HSCL-D-20) and -2.7 for the HAM-D-21. Differences in adjusted eight-week changes between the ethyl-EPA group with MDE (n=13) and the placebo group (n=16) were not significant. In women with psychological distress without MDE at baseline, the eight-week changes in psychological distress and depressive scales improved significantly more with ethyl-EPA than with placebo.
A 2010 study published in Psychiatry Research indicated EPA may help alleviate depression in part by reducing cortisol levels.15 Researchers from Tehran University of Medical Sciences previously found fluoxetine and EPA were equally effective in controlling depressive symptoms, and had a positive synergistic effect, in part due to reduction of inflammatory cytokines and regulating hypothalamus-pituitary-adrenal (HPA) axis activity. The new trial examined plasma cortisol, serum interleukin-1beta (IL-1 beta) and interleukin-6 (IL-6) in 42 patients enrolled in an eight-week study receiving 1,000 mg/d of EPA alone or in combination with 20 mg/d fluoxetine, and compared to patients only taking fluoxetine. After eight weeks, all three treatments significantly decreased plasma cortisol levels, with no significant difference between groups. Serum concentrations of IL-1beta and IL-6 were not changed with any intervention.
But omegas dont always shine. A randomized, double blind, placebo-controlled four-month trial comparing tuna fish oil to placebo was conducted on 83 outpatients with major depression.16 Despite large reductions in depression, researchers found no significant differences at any assessment time point between patients receiving fish oil compared to placebo. Red blood cell incorporation of FAs indicated good compliance with oil supplementation, although this sample was not initially deficient in omega-3s. This particular dose and type of fish oil conferred no additional benefit to conventional treatment of depression in this sample.
PS has also shown promise in the mental health arena. In fact, omega-3s and PL have been shown to work synergistically. Parris M. Kidd, Ph.D., at the University of California, Berkley, reported on clinical findings of DHA and EPA for cognition, behavior, and mood with cell membrane PL.17 He said, Omega-3 PL supplements that combine DHA/EPA and PL into the same molecule have shown marked promise in early clinical trials. PS with DHA/EPA attached has been shown to alleviate attention deficit/hyperactivity disorder (ADHD) symptoms. Krill omega-3 phospholipids, containing mostly phosphatidylcholine (PC) with DHA/EPA attached, markedly outperformed conventional fish oil DHA/EPA triglycerides in double blind trials for premenstrual syndrome/dysmenorrhea and for normalizing blood lipid profiles. Krill omega-3 phospholipids demonstrated anti-inflammatory activity, lowering C-reactive protein (CRP) levels in a double blind trial. Utilizing DHA and EPA together with phospholipids and membrane antioxidants to achieve a triple cell membrane synergy may further diversify their currently wide range of clinical applications.
A study out of Wales reported in young adults, with neuroticism scores above the median, 300 mg/d of soy-derived PS (from ChemiNutra, as SerinAid®) for one month was associated with feeling less stressed and having a better mood.18
German researchers examined the effects of soy lecithin phosphatidic acid and PS supplementation on pituitary adrenal reactivity (ACTH, cortisol) and on the psychological response to a mental and emotional stressor.19 Four groups of 20 subjects were treated for three weeks with either 400 mg/d of PS, 600 mg/d of PS, 800 mg/d of PS or placebo before exposure to the Trier Social Stress Test (TSST). Treatment with 400 mg/d of PS resulted in a pronounced blunting of both serum ACTH and cortisol, and salivary cortisol responses to the TSST, but did not affect heart rate. The effect was not seen with larger doses of PS. With regard to the psychological response, 400 mg/d of PS seemed to exert a specific positive effect on emotional responses to the TSST. While the placebo group showed the expected increase in distress after the test, the group treated with 400 mg/d of PS showed decreased distress.
In an unpublished study at the University of Guadalajara, the effects of half the conventional dose of hormone replacement therapy (HRT) and the inclusion of PS (as SerinAid) were studied. A total of 90 healthy menopausal women (52.8 age and three years of menopause) were assigned randomly in six groups (n=15 each): HRT 2mg estradiol + 1 mg noretisterone, 1/2 dose of HRT, 300 mg 2v/d of PS, HRT+PS, HRT/2+PS or placebo. Scales to evaluate the menopausal symptoms, depression, memory and attention were applied. HRT generated increases of estradiol, cholesterol, low-density lipoprotein (LDL), triglycerides and phosphatase. HRT/2 increased estradiol, cholesterol and LDL, but levels of triglycerides and phosphatase showed a decrease. PS reduced the estradiol, cholesterol and triglyceride numbers, and LDL and high-density lipoprotein (HDL) didnt change. TH/2+PS showed a pattern with tendencies similar to PS. With THR+PS, the triglyceride levels dropped. The cognitive and emotional scale scores showed a slight improvement in all groups. The results obtained with the half dose of HRT suggested women with hormonal supplement requirements, who have some risk for health conditions, can take half the currently recommended dose since they are beneficial, and tend to lessen the adverse cardiovascular effect of the lipids, above all, the triglycerides. With a half dose, there were also benefits in the emotional and cognitive processes. PS added a cardio-protection effect to HRT.
And, a separate unpublished double blind study assessed the influence of plant PS on memory and mood in functioning elderly, aged 60 to 80 years old, and living in the community. A total of 72 subjects, randomly assigned to placebo and therapy groups, were treated for three months with 300 mg/d of PS. Results showed a large and statistically significant positive influence (which was stronger in higher pretreatment memory scores) of treatment on both memory and mood, whereas influence of placebo was small and non-significant. Memorizing information, visual memory and memorizing numbers were the most improved cognitive functions. Mood was also influenced. Winter mood changes developed in the placebo group, but were entirely blocked in those treated with plant PS.
Botanicals and herbal remedies have been studied for their effects on depression, stress and other mood conditions. A proprietary blend of extracts of magnolia bark (Magnolia officinalis) and Phellodendron amurense (as Relora®, from Next Pharmaceuticals) was studied for its effects on anxiety, stress and sleep in healthy premenopausal women.20 The randomized, parallel, placebo-controlled clinical study was conducted with healthy, overweight (BMI 25 to 34.9), premenopausal female adults, between the ages of 20 and 50 years, who typically eat more in response to stressful situations and scores above the national mean for women on self-reporting anxiety. For six weeks, 250-mg capsules of Relora were administered three times daily. No adverse events were reported in the 26 participants that completed the study. Relora was effective, in comparison to placebo, in reducing temporary, transitory anxiety as measured by the Spielberger STATE anxiety questionnaire, but it was not effective in reducing long-standing feelings of anxiety or depression. Salivary cortisol and amylase levels, appetite, body morphology and sleep quality/latency were not significantly changed by Relora in comparison to placebo. Results led researchers to conclude Relora may offer some relief for premenopausal women experiencing mild transitory anxiety.
A formulation of isoflavones (60 mg), lactobacilli (500 million spores), calcium (141 mg) and vitamin D3 (5 mcg) was added to magnolia bark extract (60 mg) and magnesium (50 mg) (as Estromineral serena [ES]) and was given to symptomatic menopausal women with sleep or mood alterations.21 Women received 1 tablet/d of ES or calcium + vitamin D3 for 24 weeks. Flushing, nocturnal sweating, palpitations, insomnia, asthenia, anxiety, mood depression, irritability, vaginal dryness, dyspareunia and libido loss significantly decreased in severity and frequency during ES versus calcium + vitamin D3 treatment. Well-being (good/very good, 66.7 percent versus 20 percent) and acceptability (93.9 percent versus 31.4 percent) were significantly better for ES.
St. Johns wort (Hypericum perforaturm L.) has also shown promise in this arena of brain health. Researchers conducted a double blind, parallel-group comparative study investigating the efficacy of St. Johns wort in the treatment of mild to moderate forms of depression.22 A total of 348 patients were randomized to received one of three different doses for eight weeks, three times daily: 1 tablet of Hyperiforce (from Bioforce) containing natural extract standardized to 0.33 mg of total hypericin; or an identical tablet containing either one-third or one-sixth of the amount of the abstract. At the end of treatment, a reduction in the average score (from the Hamilton Depression Scale) was observed, a relative reduction of about 50 percent. The response rates were 68 percent (high dosage) and 65 percent and 62 percent (low dosages), respectively. Overall, the intergroup comparison revealed no significant changes. Only 2 percent of the patients experienced mild adverse reactions.
A review of 23 randomized trials, including 1,757 outpatients with mild or moderately severe depressive disorders, compared St. Johns wort with another drug treatment. It found the hypericum extracts to be significantly superior to placebo and similarly effective as standard antidepressants. Side effects occurred in 50 (19.8 percent) patients on hypericum and 84 (52.8 percent) patients on standard antidepressants.23
Ashwagandha (Withania somnifera; WS) has historically been used in Asia for treating stress-related health conditions. An unpublished, double blind, placebo-controlled human clinical trial of WS (as Sensoril®, from NutraGenesis) involving 98 participants demonstrated Sensorils ability to reduce stress. Subjects taking Sensoril experienced a 69.9-percent reduction in an overall measure of stress-related symptoms. These subjects also experienced significant reductions in individual symptoms of stress including: irritability, anxiety, sleeplessness, sweating, headaches and muscle pain, and heart palpitations. These results indicated Sensoril treatment contributes to a substantial improvement in mood and feelings of well-being.
Another botanical, isoflavone-rich red clover, effectively reduced depressive and anxiety symptoms among postmenopausal women in a 2010 study.24 A total of 109 postmenopausal women aged 40 or older were randomly assigned to receive two daily capsules of MF11RCE (80 mg of red clover isoflavones) or placebo of equal appearance for a 90-day period. After a washout period of seven days, medication was crossed over and taken for 90 days more.
After receiving the MF11RCE compound the total Hospital Anxiety and Depression Scale (HADS), as well as anxiety and depression subscale scores, and the total Zung's Self Rating Depression Scale (SDS) scores decreased significantly. This effect was equivalent to a 76.9-percent reduction in the total HADS score (76 percent for anxiety and 78.3 percent for depression) and an 80.6-percent reduction in the total SDS score. After placebo, total HADS (anxiety and depression subscale also) and total SDS scores also decreased significantly in comparison to baseline but only equivalent to an average 21.7 percent decline.
Odds and Ends
Just like the old remedy of a warm glass of milk will help you sleep, milk protein hydrolysate is helping consumers sleep better, which reduces stress. A 30-day, double blind, crossover, unpublished study was conducted on 63 female volunteers showing at least one stress symptom. Subjects receiving Lactium (from Pharmachem) had a significantly greater improvement in stress symptoms versus placebo in the following areas: digestive, intellectual, social, cardiovascular and emotional. The effect of Lactium was greater in subjects having a high-intensity score for a major symptom at the beginning of the study. The areas mentioned here are all equally indicative of and responsive to mood.
A second unpublished study was conducted on 44 healthy men and women with difficulty sleeping. Subjects were given Lactium for four weeks. Results showed Lactium improved sleep duration and efficiency, especially in subjects with a moderate anxiety or depression profile. Lactium was also shown to reduce daytime sleepiness.
Even vitamin D has been linked to mood health. This year, a new study published in the Journal of Clinical Endocrinology & Metabolism found older adults who have low levels of vitamin D have a greater risk of developing depression.25 Researchers followed 531 women and 423 men aged 65 years and older who participated in the InCHIANTI Study in Tuscany, Italy. Serum 25(OH)D was measured at baseline. Depressive symptoms were assessed at baseline and at three- and six-year follow-ups using the Center for Epidemiological Studies-Depression Scale (CES-D). Depressed mood was defined as CES-D of 16 or higher. Women with 25(OH)D less than 50 nmol/L compared with those with higher levels experienced increases in CES-D scores of 2.1 and 2.2 points higher at, respectively, three- and six-year follow-up. Women with low vitamin D also had significantly higher risk of developing depressive mood over the follow-up. In parallel models, men with 25(OH)D less than 50 nmol/L compared with those with higher levels experienced increases in CES-D scores of 1.9 and 1.1 points higher at three- and six-year follow-up. Men with low vitamin D also had a higher risk of developing depressed mood.
Natural solutions for depression and anxiety are in demand due to the high numbers of mood disorders prevalent in U.S. consumers, and the negative side effects that often accompany pharmaceutical-grade anti-depressants. The industry needs to continue to pursue scientific substantiation so more efficacious products can ease Americans melancholic woes.
References on the next page
References for Natural Mood Management
1. W W Eaton et al. Depression and risk for onset of type II diabetes. A prospective population-based study Diabetes Care. 1996;19(10):1097-1102
2. Davidson JR et al. Effectiveness of chromium in atypical depression: a placebo-controlled trial Biol Psychiatry. 2003;53(3):261-4
3. Malcolm N. McLeod and Robert N. Golden Chromium treatment of depression Int J Neuropsychopharmacol. 2000; 3(4):311-314
4. Docherty JP et al. A double-blind, placebo-controlled, exploratory trial of chromium picolinate in atypical depression: effect on carbohydrate craving J Psychiatr Pract. 2005;11(5):302-14
5. Jung KI, et al. Associations of Serum Ca and Mg Levels With Mental Health in Adult Women Without Psychiatric Disorders Biol Trace Elem Res. 2010 Feb;133(2):153-61.
6. Szewczyk B, et al. The Role of Zinc in Neurodegenerative Inflammatory Pathways in Depression Prog Neuropsychopharmacol Biol Psychiatry (2010 Feb 13) [Epub ahead of print].
7. Sawada T, Yokoi K Effect of zinc supplementation on mood states in young women: a pilot study Eur J Clin Nutr. 2010;64(3):331-3
8. Janice K. Kiecolt-Glaser Stress, Food, and Inflammation: Psychoneuroimmunology and Nutrition at the Cutting Edge Psychosom Med. 2010 May;72(4):365-9
9. Candy and Snack Today; http://www.candyandsnacktoday.com/archives/2010/05/mood-weather-factors-in-chocolate-buying.shtml
10. Natalie Rose, MD; Sabrina Koperski, BS; Beatrice A. Golomb, MD, PhD, Chocolate and Depressive Symptoms in a Cross-sectional Analysis Arch Intern Med. 2010;170(8):699-703
11. Macht M, Dettmer D Everyday mood and emotions after eating a chocolate bar or an apple Appetite. 2006;46(3):332-6
12. Osher Y, Belmaker RH Omega-3 fatty acids in depression: a review of three studies CNS Neurosci Ther. 2009 Summer;15(2):128-33
13. Golding J et al. High levels of depressive symptoms in pregnancy with low omega-3 fatty acid intake from fish Epidemiology. 2009;20(4):598-603
14. Lucas M et al. Ethyl-eicosapentaenoic acid for the treatment of psychological distress and depressive symptoms in middle-aged women: a double-blind, placebo-controlled, randomized clinical trial Am J Clin Nutr. 2009 Feb;89(2):641-51
15. Shima Jazayeri et al. Effects of eicosapentaenoic acid and fluoxetine on plasma cortisol, serum interleukin-1beta and interleukin-6 concentrations in patients with major depressive disorder Psychiatry Res. ePub 2010 May 11. DOI: 10.1016/j.psychres.2009.04.013
16. Grenyer BF et al. Fish oil supplementation in the treatment of major depression: a randomized double-blind placebo-controlled trial Prog Neuropsychopharmacol Biol Psychiatry. 2007 Oct 1;31(7):1393-6
17. Kidd PM Omega-3 DHA and EPA for cognition, behavior, and mood: clinical findings and structural-functional synergies with cell membrane phospholipids Altern Med Rev. 2007 Sep;12(3):207-27
18. Benton D et al. The influence of phosphatidylserine supplementation on mood and heart rate when faced with an acute stressor Nutr Neurosci. 2001;4(3):169-78
19. Hellhammer J et al. Effects of soy lecithin phosphatidic acid and phosphatidylserine complex (PAS) on the endocrine and psychological responses to mental stress Stress. 2004 Jun;7(2):119-26
20. Douglas S Kalman et al. Effect of a proprietary Magnolia and Phellodendron extract on stress levels in healthy women: a pilot, double-blind, placebo-controlled clinical trial Nutr J. 2008,7:11
21. Mucci M. et al. Soy isoflavones, lactobacilli, Magnolia bark extract, vitamin D3 and calcium. Controlled clinical study in menopause . Minerva Ginecol. 2006 Aug;58(4):323-34.
22. S Lenoir et al. Hyperiforce tablets for the treatment of mild to moderate depression Schweiz Zschr. GanzheitsMedizin 1997;9:226-32; http://www.avogel.ca/download/Studies/Hyperiforce-Tablet-Treatment-of-mild-to-moderate-depression_1997.pdf
23. Linde K et al. St John's wort for depression--an overview and meta-analysis of randomised clinical trials. Behav Brain Res. 1996 Aug 3; 313(7052):253-8
24. Lipovac M et al. Improvement of postmenopausal depressive and anxiety symptoms after treatment with isoflavones derived from red clover extracts Maturitas. 2010;65(3):258-61
25. Yuri Milaneschi et al. Serum 25-Hydroxyvitamin D and Depressive Symptoms in Older Women and Men J Clin Endocrinol Metab. doi:10.1210/jc.2010-0347
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