A set of chemical imbalances in the brains of people with schizophrenia related to the chemical glutamate has been elucidated by Johns Hopkins Medicine researchers in recently published studies using animals and people. They have also dicovered how to regulate the levels using a compound derived from broccoli sprouts.
The results advance the hope that supplementing with broccoli sprout extract, which contains high levels of the chemical sulforaphane, may someday provide a way to lower the doses of traditional antipsychotic medicines needed to manage schizophrenia symptoms, thus reducing unwanted side effects of the medicines.
“It’s possible that future studies could show sulforaphane to be a safe supplement to give people at risk of developing schizophrenia as a way to prevent, delay or blunt the onset of symptoms,"
said Akira Sawa, M.D., Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and director of the Johns Hopkins Schizophrenia Center.
Brain Metabolism Differences
The researchers looked for differences in brain metabolism between people with schizophrenia and healthy controls.
They recruited 81 people from the Johns Hopkins Schizophrenia Center within 24 months of their first psychosis episode, which can be a characteristic symptom of schizophrenia, as well as 91 healthy controls from the community. The participants were an average of 22 years old, and 58% were men.
The study used a powerful magnet to measure and compare five regions in the brain between the people with and without psychosis. A computer analysis of 7-Tesla magnetic resonance spectroscopy (MRS) data identified individual chemical metabolites and their quantities.
Schizophrenia is marked by hallucinations, delusions and disordered thinking, feeling, behavior, perception and speaking. Drugs used to treat schizophrenia don’t work completely for everyone, and they can cause a variety of undesirable side effects.
Glutamate And Glutathione
On average, 4% significantly lower levels of the brain chemical glutamate were found in the anterior cingulate cortex region of the brain in people with psychosis compared to healthy people.
Glutamate is known for its role in sending messages between brain cells, and has been linked to depression and schizophrenia, so these findings added to evidence that glutamate levels have a role in schizophrenia.
Additionally, the researchers found a significant reduction of 3% of the chemical glutathione in the brain’s anterior cingulate cortex and 8% in the thalamus. Glutathione is made of three smaller molecules, and one of them is glutamate.
Next, the researchers asked how glutamate might be managed in the brain and whether that management is faulty in disease. They first looked at how it’s stored.
Because glutamate is a building block of glutathione, the researchers wondered if the brain might use glutathione as a way to store extra glutamate. And if so, the researchers questioned if they could use known drugs to shift this balance to either release glutamate from storage when there isn’t enough, or send it into storage if there is too much.
Shifting The Balance With A Bigger Gas Tank
In separate study, the team used the drug L-Buthionine sulfoximine in rat brain cells to block an enzyme that turns glutamate into glutathione, allowing it to be used up. The researchers found that theses nerves were more excited and fired faster, which means they were sending more messages to other brain cells.
Shifting the balance this way is akin to shifting the brain cells to a pattern similar to one found in the brains of people with schizophrenia.
Next, the researchers wanted to see if they could do the opposite and shift the balance to get more glutamate stored in the form of glutathione. They used the chemical sulforaphane found in broccoli sprouts, which is known to turn on a gene that makes more of the enzyme that sticks glutamate with another molecule to make glutathione.
When they treated rat brain cells with glutathione, it slowed the speed at which the nerve cells fired, meaning they were sending fewer messages. The researchers say this pushed the brain cells to behave less like the pattern found in brains with schizophrenia.
“We are thinking of glutathione as glutamate stored in a gas tank. If you have a bigger gas tank, you have more leeway on how far you can drive, but as soon as you take the gas out of the tank it’s burned up quickly. We can think of those with schizophrenia as having a smaller gas tank,"
said Thomas Sedlak, M.D., Ph.D., assistant professor of psychiatry and behavioral sciences.
Because sulforaphane changed the glutamate imbalance in the rat brains and affected how messages were transmitted between the rat brain cells, the researchers wanted to test whether sulforaphane could change glutathione levels in healthy people’s brains and see if this could eventually be a strategy for people with mental disorders.
For another study, the researchers recruited nine healthy volunteers (four women, five men) to take two capsules with 100 micromoles daily of sulforaphane in the form of broccoli sprout extract for seven days.
The volunteers reported that a few of them were gassy and some had stomach upset when eating the capsules on an empty stomach, but overall the sulforaphane was relatively well tolerated.
[caption id=“attachment_98822” align=“aligncenter” width=“680”] Organic broccoli sprouts
Credit: Julie Gibbons CC-BY[/caption]
The researchers used MRS again to monitor three brain regions for glutathione levels in the healthy volunteers before and after taking sulforaphane. They found that after seven days, there was about a 30% increase in average glutathione levels in the subjects' brains.
For example, in the hippocampus, glutathione levels rose an average of 0.27 millimolar from a baseline of 1.1 millimolar after seven days of taking sulforaphane.
Don’t Try This At Home
Further research is needed to learn whether sulforaphane can safely reduce symptoms of psychosis or hallucinations in people with schizophrenia. They would need to determine an optimal dose and see how long people must take it to observe an effect.
The researchers caution that their studies don’t justify or demonstrate the value of using commercially available sulforaphane supplements to treat or prevent schizophrenia, and patients should consult their physicians before trying any kind of over-the-counter supplement. Versions of sulforaphane supplementsare sold in health food stores and at vitamin counters, and aren’t regulated by the U.S. Food and Drug Administration.
“For people predisposed to heart disease, we know that changes in diet and exercise can help stave off the disease, but there isn’t anything like that for severe mental disorders yet,” said Sedlak. “We are hoping that we will one day make some mental illness preventable to a certain extent."
Sulforaphane is found in a variety of cruciferous vegetables, and was first identified as a “chemoprotective” substance decades ago by Paul Talalay and Jed Fahey at Johns Hopkins.
Wang AM, Pradhan S, Coughlin JM, et al. Assessing Brain Metabolism With 7-T Proton Magnetic Resonance Spectroscopy in Patients With First-Episode Psychosis JAMA Psychiatry. 2019;76(3):314–323. doi:10.1001/jamapsychiatry.2018.3637
Thomas W. Sedlak, Bindu D. Paul, Gregory M. Parker, Lynda D. Hester, Adele M. Snowman, Yu Taniguchi, Atsushi Kamiya, Solomon H. Snyder, Akira Sawa The glutathione cycle shapes synaptic glutamate activity Proceedings of the National Academy of Sciences Feb 2019, 116 (7) 2701-2706; DOI: 10.1073/pnas.1817885116
Thomas W. Sedlak, Leslie G. Nucifora, Minori Koga, Lindsay S. Shaffer, Cecilia Higgs, Teppei Tanaka, Anna M. Wang, Jennifer M. Coughlin, Peter B. Barker, Jed W. Fahey, Akira Sawa Sulforaphane Augments Glutathione and Influences Brain Metabolites in Human Subjects: A Clinical Pilot Study Molecular Neuropsychiatry, 2017; 3 (4): 214 DOI: 10.1159/000487639