Further Studies on Nutrients and Mental Health

A study of 13,000 Spanish university graduates free of depression at baseline reported an inverse association between magnesium intake and depression incidence 6 years later.[1] Zinc deficiency has also been implicated in the endocrine pathway of depression. Another possible reason for the antidepressant effects of zinc may be the anti-inflammatory and antioxidant properties of zinc supplementation.

A large cross-sectional study[2] assessed the association between dietary magnesium intake and risk of depression in a nationally representative sample of 17,730 adults from the 2007-2014 National Health and Nutrition Examination Survey.  The inverse association between dietary magnesium intake and risk of depression was statistically significant among all age groups. A linear relationship was found between dietary magnesium intake and risk of depression in dose-response analysis.

A 2016 study found vitamin D deficiency was 4.7x more common among patients with bipolar disorder, schizophrenia, or schizoaffective disorder than among the Dutch general population. The researchers advised that annual measurement of vitamin D levels in psychiatric patients with these disorders seems to be justified especially as it will help to maintain bone health, muscle strength and to prevent osteoporosis.[3]


 What Causes Mental Illness?

Among the biological and psychological theories explaining the causes of depression, the hypothesis involving an active inflammatory process is becoming increasingly important. Inflammation markers:

  • Inflammatory enzymes (e.g., manganese superoxide dismutase (MnSOD), myeloperoxidase (MPO), inducible nitric oxide synthase).

  • Proinflammatory and anti-inflammatory cytokines.

  • Oxidative stress biomarkers- malondialdehyde and glutathione.

Through the kynurenine pathway, these factors lead to a deficit in serotonin and melatonin, which is considered one of the main reasons of depression.[4]


 Nutrients and Mental Illness

  • When used with antipsychotics, B vitamins may be effective for improving symptomatic outcomes of schizophrenia, by restoring nutritional deficits, reducing oxidative stress, or modulating neurological pathways. A systematic review of 18 Randomised Control Trials - 832 pts found vitamin B supplementation (including B6, B8 and B12) reduced psychiatric symptoms significantly more than control conditions. Meta-regression analyses showed that shorter illness duration was associated with greater vitamin B effectiveness.[5]

  • Serotonin synthesis, release and function in the brain are all modulated by vitamin D as well as EPA and DHA. Brain serotonin is synthesized from tryptophan by tryptophan hydroxylase 2, which is transcriptionally activated by vitamin D. Inadequate levels of vitamin D (∼70% of the population) and omega-3 fatty acids are common, suggesting that brain serotonin synthesis is not optimal. EPA increases serotonin release from presynaptic neurons by reducing E2 series prostaglandins. DHA influences serotonin receptor action by increasing cell membrane fluidity in postsynaptic neurons. Thus, low vitamin D, EPA or DHA, in combination with genetic factors and at key periods during development, could lead to dysfunctional serotonin activation and function and may be one underlying mechanism that contributes to neuropsychiatric disorders and depression. Optimizing vitamin D and Omega-3 fatty acid intake may help prevent and modulate the severity of brain dysfunction.[6]

  • Magnesium is involved in >350 different biochemical processes crucial for the proper functioning of the cardiovascular, alimentary, endocrine and musculoskeletal systems.[7]

  • Missing key nutrients can be bad for your mental health. A study of 14834 adults found those who met the recommended daily intake for zinc (OR: 0.74; 95% CI: 0.56-0.99), copper (OR: 0.68; 95% CI: 0.56-0.82) and selenium (OR: 0.52; 95% CI: 0.39, 0.71) had significantly lower odds of depression.[8][9]

  • B vitamins are essential for neuronal function, and severe deficiencies have been linked to increased risk of neurodevelopmental disorders, psychiatric disease and dementia. Gene polymorphisms involved in B vitamin absorption, metabolism and function, such as CβS, TCN2 and MTRR have also been linked to increased incidence of psychiatric and cognitive disorders.[10]

  • Nutrients can even impact the risk of auto immune thyroid disease. Severely low serum magnesium was shown to be associated with increased risks of positive anti-thyroglobulin antibodies and hypothyroidism![11]

  • Physical health is often linked with mental health and both can be impacted by nutrients. The co-administration of probiotics and vitamin D for 12 weeks to women with Polycystic ovarian syndrome had beneficial effects on mental health.[12][1]

  • Probiotics and selenium for Polycystic Ovarian Syndrome found improvements in hormonal and mental health parameters. In a Randomised Control Trial (RCT) – double blinded, placebo-controlled clinical trial: 60 subjects, aged 18-40 years old, participants were randomly allocated into two groups to intake 8 × 109 CFU/day probiotic plus 200 μg/day selenium supplements (n = 30) or placebo (n = 30) for 12 weeks. Hormonal and inflammatory parameters were measured at baseline and after the 12-week intervention. Probiotic and selenium co-supplementation resulted in a significant improvement in depression and anxiety and stress scale scores compared with the placebo. Furthermore, probiotic and selenium co-supplementation significantly reduced total testosterone, hs-CRP and malondialdehyde (MDA) and significantly increased total antioxidant capacity total GSH compared with the placebo. [13] No medication can do that!

  • Diabetes, mental health and selenium are also linked. A 12-week Randomised Control Trial (double blinded, placebo-controlled) of diabetics with Coronary Heart Disease found that consuming a probiotic plus selenium lowered fasting plasma glucose, serum insulin levels, insulin resistance, and enhanced insulin sensitivity compared with the placebo. Additionally, co-supplementation reduced triglycerides, total cholesterol and hsCRP and increased nitric oxide, total antioxidant capacity and total GSH compared with the placebo. [14]

  • Significantly lower levels of calcitriol (vitamin D) are found in men and women with depression as well as anxiety disorders. The SiAnxiety score was inversely correlated with vitamin D level and dietary calcium intake (p < .01). Development of non-cardiac chest pain (NCCP) can be predicted from an increased anxiety score which in turn can be predicted from low vitamin D levels. This suggests physicians should consider anxiety and vitamin D deficiency as possible causes for NCCP.[15]

  • Potassium, calcium, magnesium, phosphorus, iron, zinc, and copper were significantly and negatively correlated with depressive symptoms among female participants, but not male participants in study of 1423 participants older than 65 years old. [16] Nutrient therapy therefore needs to be tailored to the patient.

  • Magnesium deficiency can result in serious neurological and psychological disruptions, with some of the most common clinical findings being personality changes (32.7%), depression (22.4%), and stupor (20.4%), among other conditions such as apathy, agitation, confusion, dementia, malaise, sensory disturbances, anxiety and delirium.

  • Magnesium influences the neurotransmission involved in emotional processes, including the serotonergic, noradrenergic, dopaminergic, GABAergic and glutamatergic systems. Magnesium deficiency has been shown to lead to changes in the functioning of the central nervous system (CNS), especially in the glutamatergic transmission in the limbic system and cerebral cortex—brain regions that play important roles in the etiopathogenesis of depression. Decreased Magnesium levels have been correlated with impaired protein and DNA synthesis and thereby decreased serotonin levels.[17] A 2005 study that leveraged dietary surveys suggested that 68% of Americans consume less than the recommended daily allowance of magnesium.[18] Because only about 1% of total body magnesium is typically found extracellularly in the serum, serum magnesium levels are not necessarily representative of total body magnesium or the concentration of magnesium found intracellularly that is available for cellular use.

  • Magnesium a GABA antagonist and an angiotensin II-antagonist - systems that have all been implicated in the pathophysiology of depression. Magnesium is an important modulator of NMDA-receptor activity and increased levels of Magnesium `are known to inhibit NMDA receptors. Magnesium is well known for its importance as an NMDA glutamate Receptor antagonist which has long been understood as a key player in synaptic potentiation, learning and memory. While the exact mechanism has yet to be elucidated, animal studies have demonstrated that the ameliorative effects of Magnesium on depressive symptoms can be reversed by NMDA-receptor agonists, thus pointing to a possible interaction between magnesium and the NMDA receptor as a therapeutic target for the treatment of depression. NMDA-receptor antagonists are known to increase brain concentrations of serotonin and thereby potentially combat depression.[19]

  • Magnesium chloride is as effective in the treatment of depressed, hypomagnesemic elderly as 50 mg of daily imipramine. Studies report that highly depressed, drug-free patients have the highest RBC Magnesium values, suggesting a shift of intracellular magnesium to extracellular compartments and a translocation of magnesium from the brain to the blood. Case histories have shown rapid recovery (<7 days) from major depression using 125 to 300 mg of magnesium (glycinate) with each meal and at bedtime, while restricting calcium, glutamates, and aspartates. Clinical trials support the efficacy and safety of Magnesium in the treatment of depression. [20]

  • Homocysteine is significantly increased in Bipolar patients and first degree relatives. In contrast, folate and B12 were sig lower in patients and relatives. Patients and relatives carrying TT and/or AA and AC genotypes had elevated Homocysteine and reduced folate and B12 levels. High Homocysteine, low folate and B12 may be a risk factor for development of BPD.[21]

  • Glutamate overexpression in the brain can be explained by Manganese deficiency, and is associated with autism, Alzheimer’s, depression, anxiety syndrome, Parkinson's disease, and prion diseases. Manganese is an important nutrient required in small amounts for multiple essential functions in the body. A recent study on cows fed genetically modified Roundup™ ready feed revealed a severe depletion of serum Manganese. Glyphosate, the active ingredient in Roundup™ has also been shown to severely deplete Manganese levels in plants. This 2015 paper investigated the impact of Manganese on physiology, and its association with gut dysbiosis as well as neuropathologies. [22]

  • Excess exposure or deficiency of Manganese was associated with ADHD in a study of 40 children with ADHD and 43 controls in Korea aged 6-15 years old. Manganese in abnormal ranges was significantly higher in ADHD compared to controls. Butyrylcholinesterase (BChE) activity levels may serve as a reliable new plasma biomarker of Manganese -induced neuro behavioural changes. [23]

  • Low Vitamin D was associated with depressive symptoms and anxiety disorders in schizophrenia. Low Vitamin D associated with suicide risk, agoraphobia, negative symptoms and antidepressant use in schizophrenia. Supplementation with Vitamin D has been associated with lower depressive and anxiety symptoms and improved cognition.[24]

  • Neonatal vitamin D deficiency is associated with an increased risk for schizophrenia in later life. Environmental risk factors, such as latitude, migration, and those born in Winter and Spring have an increased risk of schizophrenia. In a large Danish case-control study (n = 2602), 25(OH)D3 was assessed from neonatal dried blood samples. Those in the lowest quintile (<20.4 nmol/L) had a significantly increased risk of schizophrenia (IRR = 1.44, 95%CI: 1.12-1.85).  The biological mechanism is most likely related to vitamin D's action on the regulation of inflammatory and immunological processes, consequently affecting the manifestation of clinical symptoms and treatment response of schizophrenia.[25]

  • Low Vitamin D is also associated with reduced brain volume in both animals and humans! Reduced whole brain and increased ventricular volume are reported in schizophrenia. Vitamin D levels have been found to be significantly positively associated with peripheral grey matter volume in patients with schizophrenia. A prospective association has been found between higher baseline Vitamin D levels and lower total psychotic symptoms and negative symptoms of psychosis at 12 months in first episode psychosis.[26]

  • Following an 8-week open label trial with Vitamin D3, adolescent patients with Bipolar exhibiting symptoms of mania demonstrated improvement in their mood symptoms in conjunction with their brain neurochemistry (decreased Anterior cingulate glutamate, and increased Anterior cingulate GABA).[27]

  • Patients in acute manic episodes have been found to have significantly lower vitamin D than healthy controls (respectively 15.16 ± 7.48 and 22.31 ± 8.8) but the remission group’s Vit D levels (18.40 ± 7.30) did not differ significantly from healthy controls. It is recommended that serum vitamin D levels should be measured in patients with bipolar disorder especially in long term care.[28]

  • Recent studies have confirmed that low B12 seems to be associated with depression in the aged. There was a specific positive association of low B12 with depression among older women. Similarly, a cross-sectional analysis in subjects over 20 years demonstrated positive associations between B12 and depression in females.[29]

  • Results from a recent systemic review provided evidence for an association between vitamin D insufficiency and clinical depression. Similarly, a recent meta-analysis demonstrated Vitamin D supplementation favourably impacted depression ratings in major depression with a moderate effect size.[30]

  • Vitamin D supplementation (plus increased dairy-product) intake had a significant positive impact on physical and mental health status in psychiatric outpatients. The researchers suggested that screening for vitamin D deficiency should be routine for psychiatric evaluation.[31]

  • Randomised Control Trials and 2 meta-analyses found SAMe was significantly more efficacious than placebo and equivalent to TCAs (Tricyclic antidepressants), in the treatment of depression. The use of SAMe has been evaluated both by parenteral pathway at a dose of 150-400 mg/day, and by oral pathway at a dose of 1600 mg/day, with studies that are not inferior compared to 150 mg of imipramine.

  • SAMe administered with escitalopram compared with placebo shows greater antidepressant efficacy, but only in the case of male patients. Numerous clinical trials have confirmed its efficacy in treating depression. 800-1600mg SAMe/day has been shown to be an effective adjunctive treatment strategy for SSRI non-responders with major depressive disorder. (For example, a RCT of 73 SSRI non responders found adding SAMe 800mg BD caused remission rates to improve to 25.8% compared to 11.7% with minimal side effects).[32]

  • SAM-e increases COMT enzyme activity, which may ameliorate aggressive symptoms. 18 patients with chronic schizophrenia and low activity COMT polymorphism were randomly assigned to receive either SAM-e (800 mg) or placebo for 8 weeks in double-blind fashion. Results indicated some reduction in aggressive behaviour and improved QOL following SAM-e administration. Female patients showed improvement of depressive symptoms.[33]

  • A Cochrane review of 29 studies of Major Depression, involving 5,489 patients randomised and double blind found St John's Wort was superior to placebo in treating patients with major depression and are "similarly effective" as standard anti-depressants and has “fewer side effects". However, it can interact with medication so it is important to tell your health care provider if you take it.[34]

  • An 8-week RCT with 200 patients with mild to moderate depression found significant reduction in Atypical Depression using a St John’s Wort extract, compared to placebo. However, it can interact with medication so it is important to tell your health care provider if you take it.[35]

  • Researchers have suggested 800 ug/day folic acid and 1mg/day B12 should be tried to improve treatment outcome in depression.[36]

  • A study of 112 patients with Bipolar disorder showed a significant prevalence of high Homocysteine during an acutely depressed phase. Interestingly, a significant inverse correlation between Homocysteine level and concentration of folic acid and vitamin B12 as well as with E-selectin and ICAM-1 (markers of endothelial function/inflammation) was observed.[37] It is known that elevated serum homocysteine, decreased folate, and low vitamin B12 serum levels are associated with poor cognitive function, cognitive decline, and dementia. Current literature shows that some psychiatric disorders, mainly affective and psychotic ones, can be related to the levels of vitamin B12, folate, and homocysteine. This study found that vitamin B12 levels were decreased and homocysteine levels were increased in OCD patients.[38,39,40]

  • Studies have found that both high and low Selenium levels have been linked with dysregulation of oxidative and inflammatory pathways. Selenoproteins, such as glutathione peroxidases, thioredoxin reductases and selenoprotein P, are known to provide protection against lipoperoxidation and oxidative cell damage. A low selenium concentration has been associated with an increased level of pro-inflammatory cytokines, such as interleukin-6 (IL-6), C-reactive protein, and growth differentiation factor-5 (GDF-5).

  • Selenium has been found to have significant modulatory effects on the dopaminergic, serotonergic, and noradrenergic systems, which are all involved in the physiopathology of depression and other psychiatric illnesses. Similarly, dopaminergic neurons vulnerable to oxidative stress have been shown to be modulated by selenoprotein, thus allowing selenium to play a preventative role in neurodegeneration.

  • A study found an association between selenium deficiency and decreased BDNF concentrations (Brain Derived Neurotrophic Factor). As a neurotrophic factor that has been extensively associated with the pathophysiology of major depressive disorder[41], it is possible that BDNF concentrations could mediate the relationship between selenium deficiency and depression. In an intervention study performed on mice, a multi-target selenium-based compound, reduced depressive symptoms in female mice, suggesting a potential antidepressant effect of selenium.

  • A Cross-sectional study found that total zinc, iron, copper and selenium intakes may all be inversely associated with depression. [42]

  • Copper levels being too out of range can cause problems. There are sizeable negative correlation between increase in Cu/Zn ratio and educational attainment in children. Cu/Zn ratio should be approximately 1:1 in adults and children for best mental function. [43]. Children with ASD show a significantly lower Zn/Cu (ie higher Cu/Zn) ratio than neurotypical cohorts. [44]

  • Increased Copper levels in blood may be associated with depression, and may be a biomarker for depression. [45] Higher copper has been noted in women with post-natal depression women, and an elevated Cu/Zn ratio observed in these women. [46]


You Need Our Precision Approach

We can change a person’s epigenetic expression using the right targeted nutritional treatment, thereby improving their mental health.

Though as Dr.Walsh says: “After clinical experience with thousands of mental health patients, I was surprised to learn that nutrient overloads usually cause more mischief than deficiencies. This explains why most multivitamin/mineral products are ineffective for mentally ill patients and can cause more harm than good. Patients with an overload of copper, methionine, folic acid or iron are likely to deteriorate if they take supplements containing these nutrients. In most cases, mentally ill persons cannot become well using a special diet or indiscriminately stuffing themselves with amino acids, vitamins and minerals.

“The challenge is to carefully identify the specific nutrient overloads and deficiencies possessed by an individual and to provide treatments that normalise blood and brain levels of these chemicals with rifle-shot precision. This is the essence of biochemical therapy.” (Nutrient Power: Heal your biochemistry and heal your brain”, William Walsh, PhD)


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