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.
Folate Supplements Reduce Autism Rates in Offspring of Women Taking Anti-Epileptic Drugs During Pregnancy
A 2017 study form Norway suggests that the offspring of women taking anti-epileptic drugs during pregnancy are less likely to develop autism if the women also take folic acid supplements.
The study by Marte Bjørk and colleagues in the journal JAMA Neurology used data from 104,936 children aged 18 to 36 months. Those whose mothers took anti-epileptic drugs during pregnancy had elevated autism rates, but only if their mothers did not use folic acid supplements. The mothers’ folate levels in weeks 17 to 19 of their pregnancies were inversely related to the degree of autistic traits in their offspring.
Women without epilepsy and women whose epilepsy went untreated during pregnancy had children with similarly low rates of autism to those whose mothers supplemented their anti-epileptic medications with folic acid during pregnancy.
Lamotrigine potentiates the antidepressant effects of quetiapine in bipolar depression
At the 2015 meeting of the International Society for Bipolar Disorders, researcher John Geddes presented an important study showing in inadequate responders to quetiapine that compared to adding placebo, adding the anticonvulsant lamotrigine to their treatment improved depression rapidly and lastingly. Some psychiatrists have been prescribing this combination to patients for some time, but this is the first formal clinical trial documenting its efficacy. The article was published online in December in the journal Lancet Psychiatry.
Researcher Guy Goodwin described details of the study, called CEQUEL, at the meeting. It included 202 patients with bipolar I or II disorder who required treatment for a depressive episode. Participants who did not respond completely to 14 days of treatment with quetiapine were prescribed either an additional dose of lamotrigine or a placebo. Lamotrigine was very slowly titrated up to maximum doses of 200mg/day. Its antidepressant effects were striking. They began early and persisted for 50 weeks. (The published article covers only the first 12 weeks.) Response rates for the combination of quetiapine and lamotrigine were 52%, compared to 22% for quetiapine alone. Remission rates were 35% for quetiapine and lamotrigine and 12% for quetiapine alone.
Folic acid interaction
Another part of the study assessed whether folic acid supplements could improve outcomes, but in fact they did the opposite, reversing the benefits of adding lamotrigine. Geddes did not have an explanation for why this might be the case. Lamotrigine can inhibit folate metabolism, and it had been thought that adding folate would be useful. Until further data are gathered on folate augmentation in patients taking the combination of lamotrigine and quetiapine, folate should be used cautiously if at all in these patients.
Possible combination with lithium
In Goodwin’s talk, he also noted lithium’s potential to lower suicide rates, premature mortality, and cognitive impairment, and to increase hippocampal and cortical volume.
Since lamotrigine was shown to potentiate the antidepressant effects of lithium in a study by Van der Loos and colleagues, and quetiapine is approved by the Food and Drug Administration for the prevention of depression as an adjunct to lithium (or valproate), there might be theoretical acute and long-term benefits to combining the three: lithium, quetiapine, and lamotrigine.
Folic Acid Supplementation Not Linked To Cancer
Folic acid is often recommended for patients with difficult-to-treat depression and for pregnant women. A recent study suggested that when taken before and in the first weeks of pregnancy, the vitamin supplement can reduce the risk of autism in the child. However, some concern was raised after a 2007 study that suggested a possible link between folic acid and cancer risk. New research indicates that cancer is not a risk of folic acid supplementation.
In a meta-analysis that analyzed data from 13 different trials of folic acid that included a total of over 49,000 patients, no increased risk of cancer was found in patients taking folic acid. The meta-analysis was published this year in the Lancet.
Editor’s Note: In addition to folic acid’s beneficial effects during pregnancy, it can also enhance the effects of antidepressants and mood stabilizers. The dose typically recommended for depression is 1mg for women and 2mg for men.
Fifteen percent of the population has an inefficient form of the enzyme methylenetetrahydrofolate reductase (MTHFR), which converts folate to methylfolate. For treatment of depression in these individuals, l-methylfolate should be used instead of regular folic acid.
Folic Acid During Pregnancy May Lower Autism Risk
A study of 85,000 children in Norway that was recently published in the Journal of the American Medical Association showed that women who took folic acid during pregnancy were 40% less likely to have a child who developed autism.
A summary of the research by National Public Radio explained:
Folic acid is the synthetic version of a B vitamin called folate. It’s found naturally in foods such as spinach, black-eyed peas and rice. Public health officials recommend that women who may become pregnant take at least 400 micrograms of folic acid every day to reduce the chance of having a child with spina bifida.
The folic acid’s effect reduced the most severe cases of autism but did not seem to have an effect on the incidence of more mild forms, such as Asperger syndrome. The benefits were seen in those women who had been taking folic acid for 4 weeks before conception and continued to take the supplement during the first 8 weeks of pregnancy.
Dopamine D2 and D3 Agonist Pramipexole May Enhance Cognitive Function in Bipolar I Disorder
Anil Malhotra from the Zucker Hillside Hospital found that pramipexole (Mirapex), a dopamine D2 and D3 agonist used in the treatment of Parkinson’s disease, improved measures of processing speed and working memory in euthymic bipolar patients (whose average age was 42) when compared with placebo in an adjunctive clinical trial.
Editor’s Note: Bipolar patients in a euthymic phase have consistently been shown to have some degree of cognitive dysfunction that is typically correlated with the number of prior depressive and/or manic episodes they have experienced. This is one of the first studies to directly target this cognitive dysfunction with a pharmacotherapeutic agent.
Pramipexole may be of additional value among depressed patients, because in two small, placebo-controlled studies, one led by Carlos Zarate at the National Institute of Mental Health and one led by Joseph F. Goldberg in New York, pramipexole has been shown to exert acute antidepressant effects in bipolar patients in the depressive phase of the illness. The new data from Malhotra raise the possibility that there could be a two-for-one benefit when pramipexole is used in the depressive phase of bipolar illness—improvement in both depression and cognition.
