Long Career Studying Choline Leads to Public Health Payoff

Back in 1997, a team of researchers identified a molecular link between a nicotine receptor and an auditory defect common in people with schizophrenia. At the time, the discovery that this α7-nicotinic cholinergic receptor was involved in schizophrenia physiology was found interesting since it potentially helped explain why smoking was so prevalent among people with schizophrenia.

But over the years, this receptor became the catalyst for a major change in thought: schizophrenia is not an adult-onset disease; its origins begin in early development.

Leading that mission to unlock the developmental origins of schizophrenia for the past two decades has been Robert Freedman, M.D., a professor of psychiatry at the University of Colorado (CU) School of Medicine.

The efforts of Freedman, who is also editor of the American Journal of Psychiatry (AJP), and his colleagues at Colorado have received much recognition in academic circles over the years –such as the 2015 Lieber Prize for Schizophrenia Research (Psychiatric News, November 13, 2015). Now, the research has made a public health impact. Earlier this year, the AMA approved a resolution that prenatal vitamins should include higher levels of choline to help prevent the onset of schizophrenia and other neurodevelopmental disorders.

The AMA’s decision heartened Freedman, who told Psychiatric News, “Our whole goal was to do the kind of thorough work that would be widely accepted and prescribed by physicians.”

The choline connection emerged after Freedman had established the importance of the α7 receptor in neural development. This receptor is expressed 10 times higher in prenatal brains compared with the brains of adults. However, the regions where these receptors are located are not fully innervated until just before birth, so the receptor is not turned on by neurotransmitters in the fetal brain itself.

Freedman surmised that choline—a nutrient found in foods like spinach and soybeans and a precursor to the neurotransmitter acetylcholine—in the amniotic fluid was attaching to these receptors. Sure enough, studies in mice confirmed that choline levels during pregnancy dropped at the same time the fetal brain was undergoing rapid development. Further research using mouse models deficient in choline production showed that choline supplements could eliminate schizophrenia-like defects.

That set the stage for a trial with humans. As Freedman told Psychiatric News, conducting an intervention study in humans could be potentially problematic given that psychosis symptoms typically emerge in young adulthood. “Most organizations don’t want to fund a project that will take a generation before results are seen,” he said. Fortunately, there was an alternative way to measure choline’s effect, and it goes back to that α7 receptor-auditory connection.

Many people with schizophrenia have a hearing problem known as P50 inhibition. Generally, when two similar sounds occur very close together, the brain considers the second sound redundant and produces a lower electrical response (the electrical signal occurs 50 milliseconds after the sound, hence the P50 name). In people with schizophrenia, this ability to filter out redundancy is defective, and all sounds illicit a large P50 response. P50 inhibition can be measured in early childhood, and in infants it is considered a risk factor for schizophrenia or other developmental disorders.

In a landmark study published in AJP in 2013, Freedman and his team recruited 100 pregnant women and gave them either daily placebo or choline (900 mg, twice the recommended daily dosage) starting in their second trimester. When the newborns were 5 weeks old, they were given P50 tests, and the results showed that the choline group had a much higher percentage of babies with normal P50 activity—76 percent compared with 43 percent in the placebo group. In a follow-up assessment four years later, Freedman found that the children who had received choline prenatally had fewer social and attentional problems on average.

“That clinical study was a great example of merging multidisciplinary research fields to answer an important clinical question,” said Camille Hoffman-Shuler, M.D., an assistant professor of obstetrics and gynecology and psychiatry at CU School of Medicine. “I am thrilled that the AMA has recommended that choline be a part of prenatal care.”

Hoffman-Shuler, who cited Freedman as a valued colleague and mentor, compared the potential impact of choline supplementation with another important nutrient for pregnant women: folate. “Thanks to folate supplementation, we reduced neural tube defects from about 1 in 1,000 newborns to 1 in 10,000. The current prevalence of schizophrenia is around 1 in 100, an order of magnitude higher than neural tube defects were. Imagine the public health impact if choline can get a similar reduction of incidence.”

And it’s not just schizophrenia that might be prevented, she said. Autism, fetal alcohol syndrome, depression, and other psychiatric conditions have also been associated to some extent with prenatal choline deficiencies.

Freedman also acknowledged the contributions of the dedicated team at CU that has investigated the developmental origins of schizophrenia for all the years. He also thanked the tireless advocacy of fellow APA member Carl Bell, M.D., a clinical psychiatrist emeritus at the University of Illinois at Chicago who undoubtedly helped influence the AMA decision.

The work is not over yet, and Freedman and his colleagues already have a new choline prevention trial under way to supply further proof of choline’s effectiveness. The investigators are adding steps to the protocol to enable better social contact with the mothers; this will help improve retention and provide more long-term data. They are also increasing the dose by about 15 percent to see whether that increases P50 normalization in infants even further.

The goal, Freedman said, is to find a level where 100 percent of infants have normal P50 responses without adverse side effects. “Remember, a baby’s brain develops only once, and you can’t undo mistakes,” he said. “We have to help protect it as best we can.” ■

Freedman’s seminal nicotinic receptor study, “Linkage of a Neurophysiological Deficit in Schizophrenia to a Chromosome 15 Locus,” can be accessed here. The landmark clinical trial, “Perinatal Choline Effects on Neonatal Pathophysiology Related to Later Schizophrenia Risk,” is available here.