Scientists think long-term ketamine use might
harm the brain. Here, the brain of a person who
abused ketamine for four years shows signs of
shrinkage (arrow), though this damage could
have been caused by other factors.
he asks. “That, to me, is a worry.”
What’s more, the lack of long-term data
on the drug’s effects raises hard questions
about what to do after esketamine treat-
ment has started. “There is very, very,
very little data for what happens after a
lot of ketamine use,” Iosifescu says.
The data that do exist are concerning.
MRI scans of people who have abused
ketamine for a long time reveal brain
damage (though other factors could
be sources of that damage). Animal
studies show ketamine-induced brain
damage, too. But not much is known about
esketamine’s long-term effects in people taking it for depression. “If you take
ketamine for too long — and it’s unclear
what too long is — that’s going to be a
problem,” Iosifescu says. “Nobody can
really tell you where this boundary is.”
As more is learned about how ketamine
and esketamine alleviate depression,
scientists may come up with other drugs
that are perhaps less concerning. Carlos
Zarate Jr., a clinical neuroscientist at the
National Institute of Mental Health in
Bethesda, Md., helped make some of the
early discoveries about ketamine’s fast
antidepressant effects. These days, he is
studying a molecule that’s made when
ketamine gets broken down in the body.
Tests in animals hint that this molecule
has rapid antidepressant properties
without ketamine’s baggage.
But Zarate is circumspect: “We still
aren’t really sure what the key targets
are in depression.” Ketamine and esketamine, many scientists suspect, work by
spurring brain cells to release a chemical
messenger called glutamate, which might
spur nerve cell connections to form. But a
small study by Schatzberg and colleagues
suggested that ketamine’s antidepressant
effects somehow work through the body’s
opioid system. That’s a contested idea,
but it hints that ketamine may be addictive in a way similar to opioids.
For now, clinicians and patients
are moving forward without all of the
answers. Ultimately, “it’s not about being
a fan of ketamine or a hater of ketamine,”
Iosifescu says. “It’s about understanding
what is it good for.” s
BODY & BRAIN
Sound, light may
Plaques shrank in mice’s
brains after clicks and flashes
BY LAURA SANDERS
Fast clicking sounds can boost brainpower in mice with signs of Alzheimer’s
disease. Like flickering lights, these
external sounds spur a type of brain
wave that seemed to sweep disease-related plaques from mice’s brains,
researchers report in the March 14 Cell.
It’s too early to say whether flick-ers and clicks could help people with
Alzheimer’s. If so, the treatment would
represent a fundamentally new way to
target the neurodegenerative disease.
An earlier study by MIT neuro-
scientist Li-Huei Tsai and colleagues
focused on the eyes. Lights that flick-
ered exactly 40 times a second kicked off
gamma waves, a brain wave thought to
happen during concentration. In mice,
the brain waves seemed to somehow
reduce amyloid-beta, a protein that piles
up in the brains of Alzheimer’s patients
(SN: 1/21/17, p. 13). But A-beta was
reduced only in the part of the brain that
handles vision — an area not thought to
be key to Alzheimer’s progression.
Sounds that hum at a rate of 40 clicks
per second, or 40 hertz, also spur gamma
waves that appeared to clear mice’s
A-beta, Tsai and colleagues now find. But
that happens in a more relevant brain
area: the hippocampus, which is involved
in memory and affected by Alzheimer’s.
A daily hour of fast clicks for a week
also improved the memories of mice
genetically engineered to have signs of
Alzheimer’s. Compared with mice that
heard randomly spaced clicks, mice that
listened to 40-hertz clicks found a hidden
platform in a water maze faster and better
recognized a previously seen object.
“That’s a very exciting finding, that it
can actually affect cognition,” says neuroscientist Tara Tracy of the Buck Institute
for Research on Aging in Novato, Calif.
Sound-triggered gamma waves appear
to kick off other beneficial changes, too.
Brain levels of a harmful form of tau,
another protein implicated in Alzheim-
er’s, dropped, and blood vessels in the
brain expanded, perhaps easing A-beta’s
disposal. Immune cells called microglia
also grew more active, attacking A-beta.
When mice were treated with both
flickering lights and clicks, the effect
was even stronger, Tsai says. There were
fewer A-beta plaques across a big stretch
of the brain, including the hippocampus
and the prefrontal cortex, an area impor-
tant for complex thinking. And microglia
swarmed into a feeding frenzy. “Microg-
lia pile up on each other, all congregated
around the amyloid plaques,” Tsai says.
It’s not yet clear how increasing
gamma waves led to these effects. “How
is this particular stimulation affecting all
of these properties?” Tracy asks.
Also unknown is whether results from
mice that mimic a rare and aggressive
form of Alzheimer’s apply to people.
Tsai has cofounded a company, Cognito
Therapeutics, that is testing the light-and-sound approach in older people
with mild to moderate cognitive impairment. So far, Tsai says, “we haven’t seen
any undesirable effects.” s