Robert Freedman, M. Camille Hoffman, and Randal G. Ross
The Department of Psychiatry that I led as Chair treated a promising neuroscience graduate student, James Holmes. Holmes refused antipsychotic medication, left the University, and killed 12 people in the Aurora Theater Shootings. Theodore Kaczynski received mental health treatment as a mathematics graduate student at the University of Michigan, but left to kill and maim professors as the Unabomber. Doctors knew these individuals were seriously ill, but neither had ever threatened violence. Therefore they could not be confined for further treatment. Their parents recognized that James and Ted were odd and socially isolated from early childhood. Both mothers wondered if their child had autism. Their illnesses progressed during their adolescence, when both made few friends and were considered strange by their classmates. Both later revealed that they were beginning to hallucinate, years before they developed the paranoid delusions that would compel them to murder. Could anything have been done earlier to prevent these and other similar tragedies?
One answer may lie in a woman’s nutrition during her pregnancy. Neuroscience research finds that abnormalities in fetal human brain development are instrumental to the later development of serious mental disorders, including schizophrenia – the condition that both Holmes and Kaczynski suffered from. The symptoms of schizophrenia unfold over decades, but behavior problems can become evident by age 3 or 4 years of age, as they did for Holmes and Kaczynski. Some problems can be detected in infancy as slower development of motor skills. Billions of dollars are spent on psychiatric medications after the disease has taken over the brain and the person is already ill. Yet surprisingly little attention has been focused on what can be done before birth when critical brain development is underway. The National Institute of Mental Health has no funding for clinical trials of interventions before birth in its $1.4 billion budget.
The greatest public health advances in the past 150 years are about preventing illnesses. Cardiac surgery can improve heart function after a heart attack but it has had nowhere near the effect on survival that lowering blood pressure and cholesterol, correcting diets, encouraging exercise, and stopping smoking have had. For schizophrenia, a natural product called choline taken by pregnant women can prevent abnormalities in brain development and childhood behavior associated with later illness.
Targeting treatments to genes
Genetic research in schizophrenia points to a complex set of risks, transmitted through families and involving many genes, including those responsible for the earliest stages of brain development before birth. One of the first genes identified as causing a specific brain deficit in schizophrenia is called CHRNA7, which makes a key brain receptor--the alpha7-nicotinic cholinergic receptor. Receptors are proteins on the surface of nerve cells that receive chemical signals from other nerve cells, enabling these cells to communicate with each other. This receptor is normally activated by a brain chemical called acetylcholine, but as its name implies, nicotine can also activate it.
Because of abnormalities in the CHRNA7 gene, some limited to a single DNA basepair, the number of receptors needed for normal functioning is reduced in the brains of many people with schizophrenia. Patients lose the ability to filter out noise around them and then frequently misperceive voices that become part of their hallucinations and delusions. High rates of smoking among people with schizophrenia point to their need to better activate their decreased numbers of alpha7-nicotinic receptors to quiet their brains. But smoking works only temporarily and causes its own health problems.
Alpha7-nicotinic receptor levels peak in the fetal brain; they then diminish after birth to adult levels. Intervention targeted to CHRNA7 therefore is likely more effective before birth, when the gene is most active and the brain is undergoing its most critical period of development. At this time of life, CHRNA7’s receptors are key to helping other nerve cells mature, including nerve cells that inhibit excess response to noise. Acetylcholine does not reach these alpha7-nicotinic receptors until just before birth. Throughout most of pregnancy, choline in the amniotic fluid or waters surrounding the baby activates the receptors.
Intervening in pregnancy
It is not possible to test fetuses to see if they have any of the hundreds of gene variants associated with schizophrenia, even within one gene like CHRNA7. Treatment must be safe for all pregnant women and their babies, including those who have no risk for illness. Choline is such a treatment. The unique opportunity in pregnancy is that increasing the mother’s choline levels by supplementing choline in her diet activates the fetus’s alpha7-nicotinic receptors and promotes normal brain development even in those at risk for mental illness. (Figure 1).
This supplement approach to prevention is akin to the now widespread use of folic acid supplements during pregnancy to prevent spina bifida. Although spina bifida is rare, folic acid in large amounts is offered to all pregnant women. Even in babies with genetic risk for spina bifida, the folic acid supplement induces the spinal cord to fuse normally and permanently. A second similarity with choline is that folic acid is also effective for a wide variety of developmental defects, from cleft palate to microcephaly. CHRNA7 mutations, active in the development of schizophrenia, are also found in autism spectrum and attention deficit disorder.
Both folic acid and choline are naturally found in food, and both can be safely given to women even if they have no known risk factors for their babies’ development. Folic acid reduces spina bifida from 1 in 1000 to 1 in 10,000 births. Schizophrenia results from 1 in 100 births. The possible impact of even partial prevention on the global burden of mental illness could be quite substantial.
The Department of Psychiatry that I led as Chair treated a promising neuroscience graduate student, James Holmes. Holmes refused antipsychotic medication, left the University, and killed 12 people in the Aurora Theater Shootings. Theodore Kaczynski received mental health treatment as a mathematics graduate student at the University of Michigan, but left to kill and maim professors as the Unabomber. Doctors knew these individuals were seriously ill, but neither had ever threatened violence. Therefore they could not be confined for further treatment. Their parents recognized that James and Ted were odd and socially isolated from early childhood. Both mothers wondered if their child had autism. Their illnesses progressed during their adolescence, when both made few friends and were considered strange by their classmates. Both later revealed that they were beginning to hallucinate, years before they developed the paranoid delusions that would compel them to murder. Could anything have been done earlier to prevent these and other similar tragedies?
One answer may lie in a woman’s nutrition during her pregnancy. Neuroscience research finds that abnormalities in fetal human brain development are instrumental to the later development of serious mental disorders, including schizophrenia – the condition that both Holmes and Kaczynski suffered from. The symptoms of schizophrenia unfold over decades, but behavior problems can become evident by age 3 or 4 years of age, as they did for Holmes and Kaczynski. Some problems can be detected in infancy as slower development of motor skills. Billions of dollars are spent on psychiatric medications after the disease has taken over the brain and the person is already ill. Yet surprisingly little attention has been focused on what can be done before birth when critical brain development is underway. The National Institute of Mental Health has no funding for clinical trials of interventions before birth in its $1.4 billion budget.
The greatest public health advances in the past 150 years are about preventing illnesses. Cardiac surgery can improve heart function after a heart attack but it has had nowhere near the effect on survival that lowering blood pressure and cholesterol, correcting diets, encouraging exercise, and stopping smoking have had. For schizophrenia, a natural product called choline taken by pregnant women can prevent abnormalities in brain development and childhood behavior associated with later illness.
Targeting treatments to genes
Genetic research in schizophrenia points to a complex set of risks, transmitted through families and involving many genes, including those responsible for the earliest stages of brain development before birth. One of the first genes identified as causing a specific brain deficit in schizophrenia is called CHRNA7, which makes a key brain receptor--the alpha7-nicotinic cholinergic receptor. Receptors are proteins on the surface of nerve cells that receive chemical signals from other nerve cells, enabling these cells to communicate with each other. This receptor is normally activated by a brain chemical called acetylcholine, but as its name implies, nicotine can also activate it.
Because of abnormalities in the CHRNA7 gene, some limited to a single DNA basepair, the number of receptors needed for normal functioning is reduced in the brains of many people with schizophrenia. Patients lose the ability to filter out noise around them and then frequently misperceive voices that become part of their hallucinations and delusions. High rates of smoking among people with schizophrenia point to their need to better activate their decreased numbers of alpha7-nicotinic receptors to quiet their brains. But smoking works only temporarily and causes its own health problems.
Alpha7-nicotinic receptor levels peak in the fetal brain; they then diminish after birth to adult levels. Intervention targeted to CHRNA7 therefore is likely more effective before birth, when the gene is most active and the brain is undergoing its most critical period of development. At this time of life, CHRNA7’s receptors are key to helping other nerve cells mature, including nerve cells that inhibit excess response to noise. Acetylcholine does not reach these alpha7-nicotinic receptors until just before birth. Throughout most of pregnancy, choline in the amniotic fluid or waters surrounding the baby activates the receptors.
Intervening in pregnancy
It is not possible to test fetuses to see if they have any of the hundreds of gene variants associated with schizophrenia, even within one gene like CHRNA7. Treatment must be safe for all pregnant women and their babies, including those who have no risk for illness. Choline is such a treatment. The unique opportunity in pregnancy is that increasing the mother’s choline levels by supplementing choline in her diet activates the fetus’s alpha7-nicotinic receptors and promotes normal brain development even in those at risk for mental illness. (Figure 1).
This supplement approach to prevention is akin to the now widespread use of folic acid supplements during pregnancy to prevent spina bifida. Although spina bifida is rare, folic acid in large amounts is offered to all pregnant women. Even in babies with genetic risk for spina bifida, the folic acid supplement induces the spinal cord to fuse normally and permanently. A second similarity with choline is that folic acid is also effective for a wide variety of developmental defects, from cleft palate to microcephaly. CHRNA7 mutations, active in the development of schizophrenia, are also found in autism spectrum and attention deficit disorder.
Both folic acid and choline are naturally found in food, and both can be safely given to women even if they have no known risk factors for their babies’ development. Folic acid reduces spina bifida from 1 in 1000 to 1 in 10,000 births. Schizophrenia results from 1 in 100 births. The possible impact of even partial prevention on the global burden of mental illness could be quite substantial.
Mothers, babies, and choline
Most amniotic fluid choline is used in the construction of the baby’s cells. However, the activation of CHRNA7 requires much higher levels to achieve. Typically, most choline needed by a pregnant mother comes from her diet. Meats, particularly liver and red meat, and egg yolks contain the highest amounts of choline (Table 1).
Choline supplements are given as phosphatidylcholine. Mothers take phosphatidylcholine for their last 6 months of pregnancy in a dose that adds twice the normal dietary choline level. The total is still within the safe guidelines proposed by the National Academy of Medicine for pregnant women.
Mothers can eat more food high in choline (or folic acid) and choose not to take either supplement. However, supplementation has proven to be more effective than diet alone for both nutrients, regardless of the quality of the mother’s diet.
Most amniotic fluid choline is used in the construction of the baby’s cells. However, the activation of CHRNA7 requires much higher levels to achieve. Typically, most choline needed by a pregnant mother comes from her diet. Meats, particularly liver and red meat, and egg yolks contain the highest amounts of choline (Table 1).
Choline supplements are given as phosphatidylcholine. Mothers take phosphatidylcholine for their last 6 months of pregnancy in a dose that adds twice the normal dietary choline level. The total is still within the safe guidelines proposed by the National Academy of Medicine for pregnant women.
Mothers can eat more food high in choline (or folic acid) and choose not to take either supplement. However, supplementation has proven to be more effective than diet alone for both nutrients, regardless of the quality of the mother’s diet.
Positive effects of prenatal choline on child development
Positive effects of choline on the baby’s brain are measureable soon after birth by recording the brain waves to show that the baby is not abnormally responsive to noise. As the baby matures into a child, parents rate the frequency early social isolation and attention problems that Holmes, Kaczynski, and others who develop schizophrenia experience.
A clinical trial randomized pregnant women to choline or placebo. To ensure that no baby was deprived of choline, all women were given dietary instruction in their homes monthly by an obstetrical nurse to encourage them to eat diets high in meat and eggs. Neither the mothers nor the nurses knew who was receiving choline or placebo. In addition, all mothers received folic acid supplements, multivitamins, and regular prenatal care including flu shots, and agreed to abstain from drugs, alcohol, and cigarettes.
By age 3½, Children whose mothers received choline were much less likely to be rated by their parents to be socially isolated or to have problems paying attention that those whose mothers received placebo. The behavior of these children at age 3½ can be compared with the problems that parents whose sons and daughters have developed schizophrenia recall in their children’s behavior at the same age. The increased benefit in social interaction and attention in the children whose mothers received choline is similar in magnitude to the severity of problems recalled from this age by the parents of sons and daughters with schizophrenia. Choline thus moves the needle of risk in the opposite direction (Figure 2).
These 4 year olds are still two decades from the age when Holmes and Kaczynski became seriously ill and dangerous. Most shy, isolated children do not develop schizophrenia or commit murder as adults. The brains of these children have major developmental steps ahead, including more growth in connections in later childhood and then a pruning back of connections during adolescence. Other genes are involved in these later steps. But none of these later steps can compensate fully for deficits established early in life. Holmes, Kaczynski, and others who develop schizophrenia likely had problems at more than one developmental step. We do not know which problems result in people who are disposed to violence, although decreased activation of alpha7-nicotinic receptors has been associated in animals with aggression.
Prevention of mental illness and violence
Violence committed by mentally ill people, including the attacks perpetrated by Holmes and Kaczynski, has provoked national debate on how to respond. The intricate plotting of attacks driven by paranoid, irrational aims on people whom the assailant has never met is horrifying.
In response to public concern, legislative proposals have included restriction of gun ownership and new mental health laws to lower thresholds that allow hospitals to hold patients involuntarily. But both Holmes and Kaczynski had received treatment and neither had histories of mental illness or violence in public records that would have supported their involuntary treatment or firearm restriction. None of these hotly debated and costly measures would have prevented the Aurora Theater and Unabomber attacks.
Population-based prevention, such as choline supplementation during pregnancy, offer an upstream, safe and universal alternative that is less expensive that treating an illness that has advanced. This may seem like a simple proposal compared to calls for more hospitals, prisons, and drugs. But good public health means replacement of heroic, complicated measures by simpler, more effective preventative measures. Polio is an example. Expensive iron lungs, complex neurosurgeries, and lengthy rehabilitation programs were rapidly replaced by a universal effective vaccine.
New England Journal of Medicine Journal Watch noted: “Social and attentional impairments might also be precursors to attention-deficit hyperactivity disorder (ADHD) or autism. Is it a stretch to wonder if choline deficiency is related to the recent increased prevalence of ADHD and autism? Clinically, pregnant women with schizophrenia, familial schizophrenia, or CHRNA7 risk variants may be candidates for phosphatidyl choline supplementation. Whether phosphatidylcholine, like omega-3 fatty acids, should be standard for all pregnancies is an important research question.”
Mothers and Their Babies
Decreasing a child’s chances of developing either ADHD or social isolation is itself a benefit. Whether choline treatment will also decrease the risk for schizophrenia appearing later in life will not be known for decades. Nonetheless, women becoming pregnant can now consider whether or not to take choline supplements. A child has only a 6-month window before birth when choline is effective. Just as folic acid after birth will not reverse spina bifida, choline is not effective at the age when a child already is beginning to have attention and social problems.
Pregnant mothers should check with their doctors that choline is safe for them No fetal or maternal safety concerns have been identified in clinical trials, but choline supplements do not substitute for other important preventative measures before birth, including folic acid, multivitamins, good nutrition, abstention from cigarettes, alcohol, and drugs, immunizations, blood pressure control and regular prenatal care.
During pregnancy, women embark on a maternal role that includes protecting their baby’s future mental health. It is challenging to envision that a simple, affordable and safe change in maternal nutrition might prevent lifelong mental illness. I never want to read of another Aurora Theater shooting.
ABOUT THE AUTHORS
Robert Freedman MD is Scientific Director of the Institute for Children’s Mental Disorders and Professor of Psychiatry, University of Colorado School of Medicine.
M. Camille Hoffman MD, MSCS is Assistant Professor of Obstetrics & Gynecology and Psychiatry, University of Colorado School of Medicine, and Maternal Fetal Medicine sub-specialist at National Jewish Hospital at St. Joseph’s Hospital.
Randal G. Ross MD is Professor of Child Psychiatry and Pediatrics, University of Colorado School of Medicine
Suggested Reading and References:
Freedman R: α7-nicotinic acetylcholine receptor agonists for cognitive enhancement in schizophrenia. Annual Review of Medicine 2014; 65:245-261.
Geller B. Can prenatal choline supplements prevent schizophrenia? New England Journal of Medicine Journal Watch Psychiatry http://www.jwatch.org/na39882/2015/12/18/can-prenatal-choline-supplements-prevent-schizophrenia#sthash.QDQoZ1bo.dpuf
Institute of Medicine of the National Academies of Science of the United States: Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, D.C., USA, 2010
Langman P: Rampage school shooters: a typology. Aggression and Violent Behavior 2009; 14:79–86
Lewis AS, Mineur YS, Smith PH, Cahuzac ELM, Picciotto MR: Modulation of aggressive behavior in mice by nicotinic receptor subtypes. Biochemical Pharmacology 2015; 97:488-497
Ross R, Hunter SK, Hoffman MC, McCarthy L, Chambers B, Law A, Leonard S, Zerbe G O, Freedman R: Perinatal phosphatidylcholine supplementation and early childhood behavior problems: Evidence for CHRNA7 moderation. American Journal of Psychiatry 2016; doi 10.1176/appi.ajp.2015.15091188
Rossi A, Pollice R, Daneluzzo E, Marinangeli MG, Stratta P: Behavioral neurodevelopment abnormalities and schizophrenic disorder: a retrospective evaluation with the Childhood Behavior Checklist (CBCL). Schizophrenia Research 2000; 44:121–128
Zeisel SH: Choline: critical role during fetal development and dietary requirements in adults. Annual Review of Nutrition 2006; 26:229–250
Prevention of mental illness and violence
Violence committed by mentally ill people, including the attacks perpetrated by Holmes and Kaczynski, has provoked national debate on how to respond. The intricate plotting of attacks driven by paranoid, irrational aims on people whom the assailant has never met is horrifying.
In response to public concern, legislative proposals have included restriction of gun ownership and new mental health laws to lower thresholds that allow hospitals to hold patients involuntarily. But both Holmes and Kaczynski had received treatment and neither had histories of mental illness or violence in public records that would have supported their involuntary treatment or firearm restriction. None of these hotly debated and costly measures would have prevented the Aurora Theater and Unabomber attacks.
Population-based prevention, such as choline supplementation during pregnancy, offer an upstream, safe and universal alternative that is less expensive that treating an illness that has advanced. This may seem like a simple proposal compared to calls for more hospitals, prisons, and drugs. But good public health means replacement of heroic, complicated measures by simpler, more effective preventative measures. Polio is an example. Expensive iron lungs, complex neurosurgeries, and lengthy rehabilitation programs were rapidly replaced by a universal effective vaccine.
New England Journal of Medicine Journal Watch noted: “Social and attentional impairments might also be precursors to attention-deficit hyperactivity disorder (ADHD) or autism. Is it a stretch to wonder if choline deficiency is related to the recent increased prevalence of ADHD and autism? Clinically, pregnant women with schizophrenia, familial schizophrenia, or CHRNA7 risk variants may be candidates for phosphatidyl choline supplementation. Whether phosphatidylcholine, like omega-3 fatty acids, should be standard for all pregnancies is an important research question.”
Mothers and Their Babies
Decreasing a child’s chances of developing either ADHD or social isolation is itself a benefit. Whether choline treatment will also decrease the risk for schizophrenia appearing later in life will not be known for decades. Nonetheless, women becoming pregnant can now consider whether or not to take choline supplements. A child has only a 6-month window before birth when choline is effective. Just as folic acid after birth will not reverse spina bifida, choline is not effective at the age when a child already is beginning to have attention and social problems.
Pregnant mothers should check with their doctors that choline is safe for them No fetal or maternal safety concerns have been identified in clinical trials, but choline supplements do not substitute for other important preventative measures before birth, including folic acid, multivitamins, good nutrition, abstention from cigarettes, alcohol, and drugs, immunizations, blood pressure control and regular prenatal care.
During pregnancy, women embark on a maternal role that includes protecting their baby’s future mental health. It is challenging to envision that a simple, affordable and safe change in maternal nutrition might prevent lifelong mental illness. I never want to read of another Aurora Theater shooting.
ABOUT THE AUTHORS
Robert Freedman MD is Scientific Director of the Institute for Children’s Mental Disorders and Professor of Psychiatry, University of Colorado School of Medicine.
M. Camille Hoffman MD, MSCS is Assistant Professor of Obstetrics & Gynecology and Psychiatry, University of Colorado School of Medicine, and Maternal Fetal Medicine sub-specialist at National Jewish Hospital at St. Joseph’s Hospital.
Randal G. Ross MD is Professor of Child Psychiatry and Pediatrics, University of Colorado School of Medicine
Suggested Reading and References:
Freedman R: α7-nicotinic acetylcholine receptor agonists for cognitive enhancement in schizophrenia. Annual Review of Medicine 2014; 65:245-261.
Geller B. Can prenatal choline supplements prevent schizophrenia? New England Journal of Medicine Journal Watch Psychiatry http://www.jwatch.org/na39882/2015/12/18/can-prenatal-choline-supplements-prevent-schizophrenia#sthash.QDQoZ1bo.dpuf
Institute of Medicine of the National Academies of Science of the United States: Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, D.C., USA, 2010
Langman P: Rampage school shooters: a typology. Aggression and Violent Behavior 2009; 14:79–86
Lewis AS, Mineur YS, Smith PH, Cahuzac ELM, Picciotto MR: Modulation of aggressive behavior in mice by nicotinic receptor subtypes. Biochemical Pharmacology 2015; 97:488-497
Ross R, Hunter SK, Hoffman MC, McCarthy L, Chambers B, Law A, Leonard S, Zerbe G O, Freedman R: Perinatal phosphatidylcholine supplementation and early childhood behavior problems: Evidence for CHRNA7 moderation. American Journal of Psychiatry 2016; doi 10.1176/appi.ajp.2015.15091188
Rossi A, Pollice R, Daneluzzo E, Marinangeli MG, Stratta P: Behavioral neurodevelopment abnormalities and schizophrenic disorder: a retrospective evaluation with the Childhood Behavior Checklist (CBCL). Schizophrenia Research 2000; 44:121–128
Zeisel SH: Choline: critical role during fetal development and dietary requirements in adults. Annual Review of Nutrition 2006; 26:229–250