In a series of recently published studies using animals and people, Johns
Hopkins Medicine researchers say they have further characterized a set of
chemical imbalances in the brains of people with schizophrenia related to the
chemical glutamate. And they figured out how to tweak the level using a
compound derived from broccoli sprouts.
They say 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,” adds 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.
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, including metabolic problems increasing
cardiovascular risk, involuntary movements, restlessness, stiffness and “the
shakes.”
In a study described in the Jan. 9 edition of the journal JAMA
Psychiatry, 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 researchers 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.
The researchers found on average 4% significantly lower levels of the brain
chemical glutamate 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.
In another study, described in the Feb. 12 issue of 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
researchers found that theses 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 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,” says
Thomas Sedlak, M.D., Ph.D., 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.”
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 their study, published in April 2018 in 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.
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.
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.
The scientists say 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,” says 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.
According to the World Health Organization, schizophrenia affects about 21
million people worldwide.
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