Rich Western Diet Reprograms Immune Cells in Mice
A 2018 article by Anette Christ and colleagues in the journal Cell describes the process by which a Western diet can trigger changes to the immune system in mice. The mice fed a calorically rich Western diet started to show systemic inflammation. Blood measures of inflammation returned to normal after the mice resumed their regular diet, but their immune responses remained heightened, as if the immune system had been trained to overreact.
The vast majority of deaths in Western cultures are caused by noncommunicable diseases such as type 2 diabetes and cardiovascular disease, which have been linked to lifestyle factors such as diet and exercise. The immune system has two wings: one that responds to specific pathogens, and one that mounts general protection against infection and is triggered by immune signaling receptors. However, according to Christ and colleagues, in addition to reacting when microbes are present, this second wing may also respond to “sterile” danger signs, such as consumption of a Western diet. The immune system may become trained to react this way chronically, something that the researchers believe may trigger inflammation in noncommunicable diseases.
The Western diet triggered epigenetic changes to the mice’s immune system. Epigenetic changes are ones that affect the structure of DNA, for example how tightly it is packaged. In the case of the Western diet, these changes resulted in a heightened immune system that launched strong inflammatory responses in reaction to even small stimuli. Myeloid cells from bone marrow were reprogrammed to proliferate and provide a stronger immune response.
The researchers also took human monocyte cells trained with LDL (“bad”) cholesterol and stimulated them with lipopolysaccharide (an inflammatory compound made of fat and sugar). The cells showed a heightened immune reaction similar to that seen in the mice.
Mice genetically engineered to lack the inflammasome NLRP3, which activates inflammatory responses, did not show the systemic inflammation or the enhanced myeloid activity when fed the Western diet, so Christ and colleagues believe NLRP3 may play an important role in mediating the immune response to the Western diet.
Eating Walnuts and Other Tree Nuts May Lower Cholesterol
In a 2018 meta-analysis and systematic review published in the American Journal of Clinical Nutrition, researcher Marta Guasch-Ferré and colleagues shared their analysis of 26 studies of the effects of diets rich in walnuts on blood lipids and cardiovascular health. The studies included a total of 1059 participants. The walnut-heavy diets were associated with lower total cholesterol, lower LDL (“bad”) cholesterol, and lower triglyceride concentrations. They were also associated with lower apolipoprotein B, a component of LDL.
When walnut-enriched diets were compared to American diets and Western diets, the benefits of the added walnuts on total cholesterol and LDL cholesterol were even more dramatic. The researchers described a Western diet as high in red and processed meats, high-fat dairy products, processed and artificially sweetened foods, and with little intake of fruits, vegetables, fish, legumes, or whole grains.
Compared to control diets, the diets rich in walnuts did not cause weight gain or an increase in body mass index (BMI), and they also did not affect blood pressure.
The studies included in the meta-analysis lasted from four weeks to one year, with a mean length of 8 weeks. The amount of walnuts ranged from 15 to 108 grams per day. In most cases, participants were given whole walnuts to incorporate into whatever daily meal plan they were following, which in some cases was their usual diet and in others was an intervention diet such as a Mediterranean diet or a low-fat diet.
Another meta-analysis published in the American Journal of Clinical Nutrition in 2015 by Liana C. Del Gobbo and colleagues analyzed 61 studies about the effects of tree nuts on cholesterol and related measures, and similarly found that eating tree nuts lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. Del Gobbo and colleagues wrote, “The major determinant of cholesterol lowering appears to be nut dose rather than nut type.” Tree nuts include walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, and Brazil nuts.
Vitamin Methyl B12 Improved Autism Symptoms in Randomized, Placebo-Controlled Study
In a 2016 article in the Journal of the American Academy of Child and Adolescent Psychiatry, Robert L. Hendren and colleagues described an 8-week study in which the vitamin methyl B12 improved symptoms of autism spectrum disorders in children.
Fifty-seven children were randomized to receive either 75??g/kg of methyl B12 injected under the skin every three days or saline injections as a placebo instead. Methyl B12 improved the children’s autism symptoms compared to placebo. The improvements correlated with increases in levels of the amino acid methionine in the blood and improvements in cellular methylation capacity. Children with autism spectrum disorders have reduced ability to methylate (i.e. add methyl groups to) DNA. The methylation process helps convert the toxic amino acid homocysteine into beneficial methionine. The children who received methyl B12 showed a reduction in homocysteine and a better ratio of methionine to homocysteine.
Homocysteine is bad for the heart, for cognition, and for fetal development, while methionine can help improve depression and is important to many cellular reactions. Converting homocysteine to methionine requires vitamin B12 and folate, another B vitamin found in foods such as green vegetables and beans.
Taking folate supplements can help make antidepressants more effective by aiding the methylation process. However, some people have a common variation in the MTHFR gene that makes it difficult for the body to make use of folate. These people would need to take the nutritional supplement L-methylfolate instead of regular folate to help in the conversion of homocysteine to s-adenosylmethionine (SAMe, which acts as an antidepressant).
Vitamin D Has More Benefits Than Previously Thought
Vitamin D has long been known as an important vitamin for bone health, preventing conditions such as osteoporosis and rickets. More recently, research suggests that vitamin D may also protect against conditions such as cancer, heart failure, diabetes, respiratory tract infections, and autoimmune disease.
Many Americans have low vitamin D or a vitamin D deficiency. The human body produces vitamin D in large amounts when the skin is exposed to ultraviolet B rays in sunlight. Vitamin D can also be absorbed from vitamin D–fortified foods such as dairy products, some orange juice, and cereals. Some foods such as fatty fish, beef liver, and egg yolks naturally contain some vitamin D, but it is difficult to get enough vitamin D just from consuming these foods.
Low mood or seasonal affective disorder (SAD), in which people feel depressed during winter periods of limited exposure to sunshine, have been linked to low vitamin D.
Other symptoms of low vitamin D vary but can include pain in the joints, bones, or muscles; fatigue; and breathing problems.
Editor’s Note: A few small studies have suggested that 1,500 IU per day of vitamin D supplements can help depressed mood, even in those with normal vitamin D levels. Several studies have indicated that children or adolescents with psychiatric disorders are especially likely to be vitamin D–deficient. Another study found that higher amounts of vitamin D (4,000 IU) could improve cognition in healthy volunteers more than lower doses could. Vitamin D also improved cognition in people with multiple sclerosis and in those with the autoimmune disease Hashimoto’s thyroiditis.
Vitamin D Deficiency in Newborns Linked to Higher Risk of Schizophrenia in Adulthood
A 2018 study by Darryl W. Eyles in the journal Scientific Reports found that newborns with vitamin D deficiency were more likely to develop schizophrenia later in life. The study made use of several Danish data depositories and had a large sample size of 2,602 participants. In this case control study, registries of patients treated for schizophrenia were matched up to preserved dried blood samples collected at their births, and these were compared to other dried blood samples from people without schizophrenia who shared the same sex and birthdate.
The researchers divided participants into quintiles based on vitamin D levels at birth. Compared to those who fell into the fourth quintile, those in the lowest quintile were 44% more likely to be diagnosed with schizophrenia in adulthood. The researchers also determined polygenic risk scores for each participant, that is, they calculated schizophrenia risk based on the presence of various genes. The two processes together explained 1.2% of the variance in schizophrenia diagnoses.
Risk factors for vitamin D deficiency include being born in the winter or spring, living in high-latitude locations, spending early life in an urban setting, and being darker-skinned (especially in high-latitude locations). These risk factors are all correlated with decreased skin absorption of UV rays from the sun, which is how the human body produces vitamin D. The vitamin D receptor is expressed in the brain in areas that are relevant to schizophrenia, such as areas with a lot of dopamine activity, and each of the above risk factors also applies to schizophrenia.
As expected, participants born in the winter and spring had lower vitamin D levels. Participants whose parents had immigrated to Denmark had lower vitamin D than those with parents native to Denmark.
Newborns’ vitamin D levels depend completely on their mothers’ vitamin D levels, so Eyles and colleagues suggest that ensuring pregnant women have adequate vitamin D levels could prevent some cases of schizophrenia.
Adolescents with Bipolar Disorder May Have Higher Levels of Vitamin D–Binding Protein
Vitamin D binding protein. Illustration: Emw [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)]
A 2018 article by Brawnie Petrov and colleagues in the journal Translational Psychiatry suggests that adolescents with bipolar disorder have higher levels of vitamin D–binding protein than adolescents without a mood disorder. The researchers wrote that vitamin D–binding protein “responds early to cellular damage by binding…structural proteins and activating inflammatory cells.”
This pilot study suggests that measuring levels of vitamin D–binding protein could be a useful marker of bipolar disorder. The study was small, with only 12 participants who had bipolar disorder, 11 who had unipolar depression, and 13 with no mood disorder. The researchers hope to follow up with larger studies in adolescents and adults using blood that has already been collected from people with bipolar disorder.
Vitamin D–binding protein is not measured by a standard blood test. The study authors used a technique where they “fished” for inflammatory factors that might be linked to mood disorders. The researchers began by looking for a link between other inflammatory markers in the blood and bipolar disorder, which have repeatedly been found in other studies, but they did not find any such association. There also did not seem to be a link between bipolar illness and vitamin D levels in the blood, only vitamin D–binding protein levels.
It can be especially difficult to distinguish early bipolar disorder from unipolar depression, and if the results of this small study are replicated, a blood test might eventually help to identify people with bipolar disorder earlier.
Meta-Analysis Finds Omega-3 Fatty Acids Do Not Reduce Cardiovascular Disease Risk
In a 2018 meta-analysis published in the journal JAMA Cardiology, researcher Theingi Aung and colleagues found that across 10 studies including a total of 77,197 participants, omega-3 fatty acid supplementation did not reduce risk of coronary heart disease in people at high risk. This newer finding conflicts with a 2017 advisory from the American Heart Association that suggested omega-3 fatty acid supplementation might prevent cardiovascular disease.
When it comes to mood disorders, it has been similarly difficult to pin down whether omega-3 fatty acids are helpful. Data on omega-3 fatty acid supplements for the prevention of depression have been ambiguous, with small numbers of studies and variations in study design that make it difficult to draw strong conclusions about whether these supplements can improve or prevent depression.
A 2016 systematic review by Paola Bozzatello and colleagues in the Journal of Clinical Psychiatry found only seven studies of omega-3 fatty acid supplementation in bipolar disorder. The studies had small sample sizes and widely varying dosage parameters, so the evidence that can be drawn from them is not strong, but the review did find a modest benefit on bipolar depression (but not mania) when omega-3 fatty acids were added to a treatment regimen, compared to treatment as usual.
The same review found that studies of omega-3 fatty acid supplementation in unipolar depression also varied widely, and thus it was difficult to draw inferences from them. Some meta-analyses found no benefit to omega-3 fatty acid supplementation, while others suggested that omega-3s could improve depression. The review found that the type of omega-3 fatty acids used might matter. Supplementation with EPA seemed to improve depression more than supplementation with DHA. The review also cited a 2014 comprehensive meta-analysis by Giuseppe Grosso and colleagues in the journal PLoS One that analyzed the findings from 19 studies in people with depression or depressive symptoms. Grosso and colleagues found that people with more severe depression seemed to benefit more from omega-3s.
Preventing Illness in the Offspring of a Parent with Bipolar Disorder
A 2018 article by researcher Robert Freedman and colleagues in the American Journal of Psychiatry reported that prenatal nutritional supplements can reduce mental illness in at-risk offspring. The article made a good case for supplementation with folate, phosphatidylcholine, and vitamins A and D.
Here we describe some additional ways to minimize risk of mental illness in children who are at risk for bipolar disorder or other mental illnesses.
Some efforts at prevention can begin even before a child is conceived. Avoiding smoking or drinking alcohol and maintaining a nutritious diet to prevent inflammation and excessive weight gain before conception could reduce adverse epigenetic effects on the offspring. Epigenetics refers to environmental influences on gene transcription. The impact of life experiences such as a mother or father’s substance use is not registered in their child’s DNA sequence, but can influence the structure of the child’s DNA or its packaging.
Maternal good health and wellbeing during pregnancy has also been shown to improve neonatal health and functioning.
Once a child is born, they can be encouraged in healthy habits, including a nutritious diet, good sleeping habits, regular vigorous exercise, and mindfulness/meditation training (which pediatric psychiatrist James Hudziak has suggested should be universal).
For a child who is beginning to develop mood or behavioral symptoms, more intensive intervention may be prudent. Research supports the effectiveness of family interventions such as family-focused therapy (FFT) for youth with depression, cyclothymia, or bipolar disorder not otherwise specified (BP-NOS) and a family history of bipolar disorder. Researcher David J. Miklowitz described the effects of this intervention in a 2013 article in the Journal of the American Academy of Child and Adolescent Psychiatry.
Depression in children 3 to 6 years of age is as common as depression in older children (with rates around 1–2%), and robust improvements have been observed when families engage in parent child interaction therapy (PCIT) with a focus on emotional development. In PCIT, parents are coached while interacting with their children and encouraged to establish warm interactions while setting appropriate limits. In a study by Joan L. Luby and colleagues published in the American Journal of Psychiatry in 2018, using PCIT modified to include an emotional development component improved depression and associated symptoms in children aged 3 to 11, and it also improved mothers’ mood and behavior. Read more
Prenatal Prevention of Psychiatric Illness with Nutritional Supplements
In a 2018 article in the American Journal of Psychiatry, researcher Robert Freedman and colleagues shared the results of a systematic review of data on nutritional supplements during pregnancy for the primary prevention of psychiatric illness in the child. Freedman and colleagues concluded that the evidence is robust that prenatal folic acid supplementation plus multivitamins not only can prevent birth defects such as cleft palate, spina bifida, and microcephaly, but also social withdrawal, decreased attention, and aggression at age 18 months. They wrote, “Supplements of up to 4 mg [of folic acid] before 12 weeks gestation have been found to be safe and effective.”
The effects of omega-3 fatty acid supplementation depended on when the supplements were taken. Taking omega-3 fatty acid supplements early in pregnancy was linked to an increase in schizophrenia and more symptoms of attention deficit hyperactivity disorder (ADHD) in the offspring. However, supplementation after 20 weeks of pregnancy decreased preterm delivery, low birth weight, and asthma.
As of 2017, choline supplementation during pregnancy is recommended by the American Medical Association. Their recommendation is based on research in which the choline precursor phosphatidylcholine (5,000-6,300 mg/day) was given to mothers beginning in the 18th week of pregnancy and continued in the newborn for two weeks to three months after birth in the form of 100mg of liquid phosphatidylcholine. This supplementation regimen normalized the P50 auditory evoked potential, a measure of inhibitory sensory gating that is abnormal in patients with schizophrenia and bipolar disorder and infants whose parents had psychosis, depression, or smoked (all risk factors for a later diagnosis of schizophrenia).
Healthy individuals show a reduced response to an auditory cue when it is repeated 50 milliseconds after the initial cue. In people with schizophrenia, response to the repeated cue is not suppressed. Not only did the P50 auditory evoked potential normalize with phosphatidylcholine supplementation, but at 3.5 years of age, those who received phosphatidylcholine supplements in utero and as newborns had fewer problems with attention and social interactions. The findings were even more robust in those with the CHRNA7 genotype (a genetic variation in the alpha 7 nicotinic receptor), which is a risk factor for schizophrenia.
Supplementation with vitamins A and D during gestation also decreased the risk for schizophrenia and autism spectrum disorders in offspring. Recommendations include Vitamin D at doses of 600 to 4,000 IU for pregnant mothers and 400 to 1,000 IU for infants. Because of potential toxicity, vitamin A should be limited to 8,000 units from diet and supplements combined. (Supplements typically contain 2,500 units.)
While there are some methodological limitations to the findings, Freedman and colleagues conclude, “As part of comprehensive maternal and fetal care, prenatal nutrient interventions should be further considered as uniquely effective first steps in decreasing risk for future psychiatric and other illnesses in newborn children.”
Editor’s Note: Given the high risk of psychiatric illness (74%) in the offspring of a parent with bipolar disorder and the finding of abnormal P50 auditory evoked potential in patients with bipolar disorder, the recommended nutritional supplements should be given special consideration during gestation of a child who has a parent with bipolar disorder. According to the 2018 article by Freedman and colleagues, this would include folate, phosphatidylcholine, vitamin A and vitamin D.
Eating Beef Jerky and Other Nitrate-Cured Meats Linked to Increased Mania Risk
In a 2018 article in the journal Molecular Psychiatry, researcher Seva G. Khambadkone and colleagues reported that a history of eating nitrated dry cured meat, such as beef jerky, was associated with a more than threefold increase in the risk of current mania. Eating other types of meat and fish products was not linked to mania.
The study included 217 people with mania, 91 with bipolar depression, 79 with unipolar depression, and 371 with schizophrenia, plus 343 control participants without a psychiatric disorder. Each participant responded to a questionnaire assessing whether they had ever eaten certain foods. The researchers had the idea that eating foods such as undercooked meat or fish, which might carry infectious agents, could be connected with mania, since inflammation seems to be linked to psychiatric illness. To the researchers’ surprise, their analysis found an independent link between eating nitrated dry cured meat (such as beef jerky, turkey jerky, or meat sticks) and being admitted to a hospital with acute mania.
Having eaten other cured meats such as salami or prosciutto was not linked to mania, nor was having eaten any other food.
Following these findings, Khambadkone and colleagues designed a study in which rats were given meat with added nitrate. The rats showed hyperactivity that resembled human mania, alterations in brain pathways that have been linked to bipolar disorder, and changes to gut microbes.
