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.
Supplements for the Treatment of Schizophrenia
At the 2018 meeting of the North Carolina Psychiatric Association, researcher Karen Graham reviewed evidence for adjunctive treatments that may help treat schizophrenia when added to antipsychotic medications.
Graham endorsed omega-3-fatty acids, saying that they may delay the conversion to schizophrenia in young people at high risk for the illness. Data in chronic schizophrenia are more equivocal.
Data on the effects of vitamin D3 in schizophrenia are mixed, but D3 is often low in patients with psychotic disorders, and supplementation with vitamin D3 in the general population has been associated with decreases in cancer and all-cause mortality.
Graham indicated that in three studies vitamin B6 (pyridoxine) decreased tardive dyskinesia, a side effect of antipsychotic medication that is characterized by repetitive or jerky involuntary movements of the face and body. B6 also reduced the severity of akathisia or restless legs, which is comparable to the effects of 40mg/day of the beta blocker drug propranolol. Graham recommended a dose of 300mg/day of B6 that could be increased up to 600mg twice per day. The onset of effects usually begins by week three, and the cost ranges from 25 to 80 cents per day.
The antioxidant supplement N-acetylcysteine (NAC) may also help. Graham described six studies that found NAC had positive effects on negative symptoms (apathy, blunted emotions, etc.) and/or cognition in patients with schizophrenia. The dosage in these studies was usually 2 grams/day for 24 weeks. The cost was 50 cents per day.
Two 8-week trials of L-theanine (an amino acid found in green and black tea) at doses of 400mg/day improved negative symptoms and anxiety in 40 patients with schizophrenia. The rationale for the study was that L-theanine increases inhibitory neurotransmitters, modulates the amino acid 5-HTP and the neurotransmitter dopamine, increases brain-derived neurotrophic factor (BDNF), and may be neuroprotective after a heart attack or a traumatic brain injury. The cost is 40 cents per day.
Graham reported that the supplement ginkgo biloba produced significant improvement in negative symptoms and total symptoms in eight clinical trials that included a total of 1,033 patients with schizophrenia. Doses ranged from 240 to 360 mg/day. These supplements (usually extracted from leaves of the ginkgo tree) have not been found to have many side effects, but they can reportedly increase post-operative bleeding. Gingko biloba supplements cost 20 to 80 cents per day. There is also at least one positive study of ginkgo biloba in tardive dyskinesia.
Three of four studies of cannabidiol in schizophrenia have been positive (at doses of 600, 800, and 1,000 mg/day in studies that lasted four to six weeks). There are now six additional ongoing studies listed on the website clinicaltrials.gov. There is little of this diol component in regular marijuana, and the cost of pure cannabidiol is unfortunately an exorbitant $60 to $100/day.
There is a positive controlled study of the herb ashwagandha in 66 patients with schizophrenia.
Not included in Dr. Graham’s review was the prenatal treatment of women with phosphatidylcholine (900mg/day) followed by supplements in the newborn, which normalized an aspect of sensory gating known as P50 in patients with 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. This has been suggested by researchers Robert Freedman and Randal G. Ross in a 2015 article in the Shanghai Archives of Psychiatry as a possible primary preventive approach to schizophrenia.
Pregnant women in their second and third trimesters should at least consume foods high in choline, especially if the fetus is at high risk for schizophrenia because of a family history of schizophrenia.
Beef liver is very high in choline, providing 420mg per slice. Other animal products provide significant choline, such as eggs (120 mg/egg), beef (90mg/100g), chicken liver (85mg/liver), fish (85mg/100g), bacon (35mg/strip) or other pork, chicken (67mg/100g). Tofu (36mg/half cup) and cereal (22mg/half cup) are also sources of choline.
Foods High in Choline
| Beef liver | 1 slice | 420mg choline; |
| Egg | 1 egg | 120; |
| Beef | 100 gm | 90; |
| Chicken liver | 1 liver | 85; |
| Fish | 100 gm | 85; |
| Bacon or pork | 2 strips bacon | 70; |
| Chicken | 100 gm | 67; |
| Tofu | 120 ml (0.5 cup) | 36; |
| Cereal | 120 ml (0.5 cup) | 22 |
Choline Treatment For Pregnant Mothers And Newborns Improves Babies’ Cognition and Normalizes a Risk Factor for Schizophrenia
Deficiencies in GABA inhibition have been linked to the risk of schizophrenia (and perhaps bipolar disorder). GABA receptors are initially excitatory but switch to being inhibitory early in life. Choline derived from phosphatidylcholine or from eggs and meat in the diet is important in increasing GABA receptor development and maturity.
Ross et al. reported this year in the American Journal of Psychiatry that in a placebo-controlled study in which mothers took phosphatidylcholine in the last 2 trimesters of pregnancy (at doses of 3,600mg in the morning plus 2,700mg in the evening) and infants took 100mg/day for 12 weeks, the infants who received choline showed better neuronal inhibition than infants who did not receive choline on a P50 test of auditory evoked potential, in which the brain’s response to a series of beeps is recorded. An overactive P50 response is a sign of deficiencies in GABA inhibition.
In infants with a common gene variant in the alpha 7 nicotinic receptor that makes it function less well (which also may be a risk factor for the development of schizophrenia), the choline regimen normalized the P50 test, while placebo had no effect. However, in a recent study by Cabranes et al. published in Psychiatry Research, there was no association of the alpha 7 gene variant and schizophrenia or bipolar disorder, although patients with bipolar disorder and patients with schizophrenia did perform differently on the P50 evoked potential test than controls did.
Editor’s Note: In an editorial by Judy Rapoport that accompanied the Ross et al. study, the difficulty of using the findings in clinical practice are discussed. Meck et al. showed in 1999 that choline supplementation enhanced spatial memory, and in several cases nutritional supplements can have beneficial effects on the brain. Rapoport notes the success of perinatal folate in preventing neural tube defects and the likelihood that Vitamin D supplementation can prevent some cases of schizophrenia.
However, extrapolating the choline findings of Ross et al. to clinical practice, especially given the lack of association of the alpha 7 gene variation to psychiatric illness in the study by Cabranes et al., might be premature. Instead, Rapoport recommends a good diet and prevention of infection as first steps for treatment. Choline supplementation would be roughly equivalent to three eggs a day.
