In a series of recently published studies in humans and animals, Johns Hopkins Medicine researchers say they have identified certain glutamate-related chemical imbalances in the brains of schizophrenia patients — and that these imbalances may potentially be reversed using a compound derived from broccoli sprouts, known as sulforaphane.
“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,” says Akira Sawa, MD, PhD, professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and director of the Johns Hopkins Schizophrenia Center.
Schizophrenia is a debilitating disorder characterized by hallucinations, delusions and disordered thinking, feelings, behaviors, perception and speaking. The current medications used to treat schizophrenia don’t work for everyone, and they can cause a variety of adverse side effects, including metabolic problems increasing cardiovascular risk, involuntary movements, restlessness, stiffness and “the shakes.”
In the first study, published in the journal JAMA Psychiatry, the research team looked for differences in brain metabolism between people with schizophrenia and healthy controls. They recruited 81 patients from the Johns Hopkins Schizophrenia Center within 24 months of their first psychosis episode, as well as 91 healthy controls from the community. The participants were an average of 22 years old, and 58% were men.
The researchers used a powerful magnet to measure and compare five regions in the brain between participants with and without psychosis. A computer analysis of 7-Tesla magnetic resonance spectroscopy (MRS) data identified individual chemical metabolites and their quantities.
On average, patients with psychosis had 4 percent less glutamate in the anterior cingulate cortex region of the brain, 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.
Further, the researchers found a 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 investigated how glutamate is managed in the brain and whether that management is faulty in disease. They first looked at how it’s stored. Since glutamate is a building block of glutathione, the researchers wanted to know if the brain might use glutathione as a way to store extra glutamate. And if so, the researchers wondered 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.
In another study, appearing in the journal PNAS, 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 team discovered that these nerves were more excited and fired faster, which means they were sending more messages to other brain cells. The researchers say shifting the balance this way is similar to the pattern 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. 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,” says Thomas Sedlak, MD, PhD, assistant professor of psychiatry and behavioral sciences. “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.”
Next, 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.
In this experiment, published in the journal Molecular Neuropsychiatry, 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.
A few of the participants said they were gassy and some had stomach upset when eating the capsules on an empty stomach, but overall the sulforaphane was relatively well tolerated.
The researchers found that after seven days, there was about a 30% increase in average glutathione levels in the healthy 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.
The scientists say further research is needed to determine whether sulforaphane can safely reduce symptoms of psychosis or hallucinations in people with schizophrenia. They would also need to determine an optimal dose and see how long people must take it to observe an effect.
The researchers warn that the findings 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 supplements are 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,” says Sedlak. “We are hoping that we will one day make some mental illness preventable to a certain extent.”
Source: Johns Hopkins Medicine