As then-chairman of the University of Colorado School of Medicine's Department of Psychiatry, Robert Freedman, MD, oversaw the treatment of James Holmes, a promising neuroscience graduate student who, in 2012, walked into an Aurora movie theater and shot 12 people dead. Although mentally ill persons are far more likely to be the victims of violence than its perpetrators, as Dr Freedman points out, these tragic, all-too-common instances of mass violence do often involve a psychiatric component.
Dr Freedman feels that such events as the Aurora shooting may be preventable with pre- and postnatal interventions to reduce the risk for mental illness. In particular, early and ongoing work by Dr Freedman and his colleagues suggests that supplementation with the B vitamin choline may lessen the childhood risk for behavioral symptoms that predict future psychosis. Medscape recently spoke with Dr Freedman about his research and the idea of preventive psychiatry.
Medscape: What inspired your research into how perinatal choline supplementation influences childhood development?
Dr Freedman: We wanted to figure out what is wrong in the brains of people who have schizophrenia. We discovered that these patients are missing a very specific mechanism that normally allows people to screen noise from meaningful sounds; we also discovered that this circuit is turned on by a previously unknown nicotinic acetylcholine receptor, genetic defects in which increase the risk for schizophrenia. Of course, there are other genes involved in the disorder, but the gene for this receptor—the CHRNA7 gene—is one of them.
Because this is a nicotinic receptor, it could explain the very heavy rates of smoking in patients with schizophrenia; they might be self-medicating to increase activity of the faulty receptor. It has also been a possible treatment target under investigation.
We got interested in developing a medication that would do better than nicotine at stimulating this circuit, and I had an epiphany one day: Chances are that this gene is active not only during adult life, but also during brain development. One of the miracles of the brain and the body is that the program that builds it is in the same genes that run it; its operating system is its blueprint at the same time.
We got interested in how exactly this receptor influences the development of the brain, and there was a mystery in that the acetylcholine, along with nicotine, should normally activate it. Although this innervation doesn't grow in until right before birth—as has been well established in rodent models, and in some human studies—the receptor appeared to be active throughout development. We realized from some of our other animal and human work that choline in the amniotic fluid was activating the receptor.
Obviously, to do detailed electrophysiology, we have to use animals, and this work was performed in slices of rat hippocampus in vitro. The effects of choline actually complicated these experiments, because choline is a usual constituent of the fluid used to bathe the slices. Investigators eventually realized that the effects of choline on the cholinergic receptors were preventing them from seeing the effect of applying test substances, such as acetylcholine, to the neurons under study. They then realized that choline itself was activating the receptors.
Then we discovered that other researchers had long ago identified choline as one of the things that pregnant women can be deficient in.It's usually not deficient in adults or children except during pregnancy, when moms need extra choline to build the baby. There are also genetically abnormalities in the regulation of choline, some of which are also associated with schizophrenia.
It occurred to us that this could be just like folic acid, which is necessary for brain and spinal cord development and is supplemented during pregnancy. There are several genetic defects that give rise to these problems, and yet the easiest way to overcome them is by supplementing mothers with folate. Thus, we tried choline supplementation in animals first, and then began experimenting with it humans.
Medscape: What did you find?
Dr Freedman: In mice, we found that when we supplemented mothers during gestation, their babies would then have a normal physiology, and also that we could actually reverse genetic defects that would normally cause developmental problems by supplementing choline before the babies were born. It appeared that the mice's brains were developing normally and remained normal for the rest of their lives. We also found that supplementing newborn mice with choline did not have the same results—it was too late.
Next, we applied to the US Food and Drug Administration to try this in humans. Now we've completed the first randomized, placebo-controlled study, and it turned out that, very much as we predicted, if we supplemented choline during gestation, babies were born that electrophysiologically appeared to be at lower risk for schizophrenia. Specifically, we found that supplemented infants exhibited greater degrees of inhibition, meaning that their brains gradually stop responding to subsequent presentations of the same tone; impaired inhibition is a risk factor for schizophrenia.
We also did a follow-up study 4 years out showing that supplemented children have a significantly lower degree of attention and behavioral problems as well as social isolation, which are predictors of future schizophrenia.
Ideally, we would follow these children for another 20 or 25 years to see whether and how many develop schizophrenia, and that's of course beyond the scope of most imaginable experiments. On the other hand, not to make these data public at this point means that 25 years go by, and we have many babies who will eventually develop a mental illness. By continuing to study the effects of choline, perhaps we'll be able to prevent this.
Medscape: In your experience, how aware are doctors—whether obstetricians, psychiatrists, or primary care physicians—of the benefits of perinatal choline supplementation? How much choline is typically obtained through diet?
Dr Freedman: I don't think that doctors and patients are really aware of this. But we're hoping that as we do more and more research—and a larger trial—that they will be. We're starting new studies and aiming to get larger numbers. We also want to use the power of social media to better stay in touch with patients in the long term.
Medscape: How much choline is typically obtained through diet?
Dr Freedman: It is certainly possible to get enough choline through diet; such foods as liver, eggs, and red meat are high in it. And all of the women in our study, including the placebo group, received the same degree of dietary encouragement. But we found that choline supplementation was more successful than attempts to have a very good diet. The same thing turned out to be true with folic acid years ago.
Medscape: Has any past work investigated the effects of choline on development?
Dr Freedman: Other groups have looked at choline, primarily for cognitive development, but not for the prevention of mental illness.
Steve Zeisel at the University of North Carolina is the acknowledged guru of choline and the first to seriously advocate its use during pregnancy. A trial by him and his colleagues—the only other trial that had a placebo control—was for cognitive development, not mental illness. Cognitive development at 1 year is not highly stable, so the investigators probably picked a suboptimal age at which to measure this outcome. We also reported that there was no difference in cognitive outcome at 1 year, for the same reason. Also, their patients were highly educated and ate healthy diets high in choline, which were assessed by measuring plasma levels of betaine, a metabolite.
The other studies out there are observational and found that higher plasma levels of choline predicted better development—but again, not better cognition. One study assessed maternal choline intake by dietary questionnaires and did not detect any effects on childhood cognition at 3 years of age. However, in a subsequent study of the same children at 7 years of age, estimated maternal choline intake above 400 mg/day did have significant positive effects on cognition.
Another observational study that measured plasma choline and betaine in the early second trimester found a range between 8.10 and 11.3 µmol/L, with a mean level of 9.40 µmol/L. The mean estimated choline dietary intake was 383 mg/day, lower than the recommended 450 mg/day. Both plasma free choline and betaine levels were significantly related to infant neurodevelopmental milestones at 18 months. Other nutrients, including vitamin B12 and folate, were not related to this outcome.
Finally, an observational study that measured both serum free choline and phosphatidylcholine found high levels in relatively advantaged mothers; phosphatidylcholine levels correlated highly with the child's performance IQ at age 5 years.
Adequate choline intake is likely to be more difficult in underdeveloped regions. In a study of choline measurements during pregnancy in the context of impoverished diets in Jamaica, estimated mean dietary choline intake was 278 mg/day. Mean plasma choline levels were 8.4 µmol/L, which is the low end of the range observed in the United States. At age 18 years, youth in Jamaica had developed 25% more behavioral problems than US youths.
Medscape: You oversaw the department that treated James Holmes, the graduate student who, in 2012, murdered 12 people in a movie theater and injured 70 others. You feel that if choline supplementation pans out, it could help prevent these acts of extreme violence, correct?
Dr Freedman: Yes. We know that most violent crime is not committed by mentally ill people and that most mentally ill people don't commit violent crime. But these very bizarre shootings that have grabbed the public attention do have a preponderance of mentally ill people involved. We don't want all mentally ill people labeled as violent. But we need to try to prevent this aspect of violence in our society.
We definitely need some new preventive approaches to mental illness, because we haven't been too successful with our current approaches. Most people who commit violence are doing it very early in the course of their illness, often before their illness is even recognized. We desperately need prevention.
Medscape: What other preventive measures for mental illness have been studied?
Dr Freedman: There's not much out there. It's a daunting task, if you think about it, because you have to intervene and then wait 25 years to see whether it's going to work. But there are at least problems in pregnancy that we know give rise to increased rates of mental illness.
One is infection; some infections are preventable, and that's one of the reasons there's a strong campaign to get women to have flu shots even if they're pregnant. Fetuses are very sensitive to the flu; they don't actually get it, but the mother's reaction to the flu stunts their development, including their development of their brain.
There's also an experiment you can do to entirely inactivate nicotinic receptors—in other words, the opposite of giving choline—and that is to give high-dose nicotine. We obviously couldn't do this experimentally in people, but unfortunately they do it to themselves all the time by smoking. High levels of nicotine in the plasma of pregnant women is associated with future schizophrenia.
There has also been a lot of talk about vitamin D deficiency increasing the risk for mental illness, but more work needs to be done here.
Medscape: How about any childhood interventions?
Dr Freedman: In people who are already showing early signs of schizophrenia, early psychotherapy will decrease the risk for suicide in particular, which is often a first presentation of mental illness. But it doesn't have a dramatic effect on the overall conversion rate or the overall rate of schizophrenia. For adolescents who are already developing symptoms, there is a small, inconsistent benefit of treatment with antipsychotic drugs, cognitive therapy, and omega-3 fatty acids (fish oil).
Medscape: What does the future of this research look like?
Dr Freedman: The National Institutes of Health are not currently funding any trials of interventions in humans during pregnancy to prevent mental health problems, and there are no trials of choline listed on ClinicalTrials.gov. Other groups are beginning to look at this, and me and my colleagues in this work—Camille Hoffman, MD, an obstetrician, and Randall Ross, MD, a child psychiatrist—will continue to do so.
We are currently receiving final regulatory approval for a second trial in 200 women. Like the first trial, it will be placebo-controlled and double-blind, with all women getting dietary advice. We are planning to follow the babies for 8 years to track their development through an age at which the risk for attention-deficit/hyperactivity disorder arises. We are also establishing a social media presence to help us to keep in contact with women for the next several decades, to see what happens as their children enter the age of risk for schizophrenia and bipolar disorder.
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Cite this: Can a Prenatal Supplement Prevent Mental Illness? - Medscape - Nov 08, 2016.