Stanford researchers are learning how ketamine works for depression

Daiana Lorenz/Youtube

• A new study from Stanford sheds light on
  how ketamine works in the brain to
  alleviate depression.
• The research suggests that the drug not only impacts a
  network of switches called the glutamate system, but also
  engages the opioid system — the same one that’s activated by
  opioid painkillers.
• The finding could have big implications for plans to
  turn ketamine into the
  next blockbuster antidepressant.

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Ketamine’s unique ability to staunch the symptoms of depression
has earned it a new reputation in recent months. No longer seen
solely as an illicit party drug, the compound is the focus of
research into a
novel class of antidepressants that could yield the
first new depression drug in more than 30 years.

But the science of how ketamine stonewalls depression symptoms
has remained murky. For years, researchers believed it worked by
acting on a network of brain receptors called the glutamate
system, which other popular antidepressants ignore. But a new
study suggests that ketamine also influences the brain’s opioid
network — the same one engaged by opioid painkillers.

That could have implications for plans to turn the drug into a
pharmaceutical. Drug companies including Allergan, Johnson &
Johnson, and a San Francisco-based drug maker called VistaGen

have all been looking to ketamine as inspiration for the next
blockbuster antidepressant. 

“When we say this is a new generation of drugs, we mean it. This
drug is fundamentally different from all the other
antidepressants that have been approved so far,” Shawn Singh,
VistaGen’s CEO,
told Business Insider in May.

The new paper,
published Tuesday night in the American Journal of Psychiatry
and funded by the National Institutes of Health, is the first to
illuminate how ketamine exerts its effects in the brain.

Alan Schatzberg, a co-author on the paper and a professor of
psychiatry at Stanford, told Business Insider that he hopes drug
makers can use his team’s discovery to streamline their efforts
and avoid the pitfalls of antidepressant drug candidates that
have failed. 

“Before we did the study, I had some doubts about ketamine’s use
for treating depression,” Schatzberg said. “Now I’ve seen the
drug work, but I’ve also seen it doesn’t work the way people
originally thought.”

How ketamine is distinct from existing depression drugs

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Most existing antidepressants, from Abilify to Zoloft, work by
plugging up the places where our brain takes up serotonin, a
chemical messenger that plays a key role in mood. The result is
more free-floating serotonin and, in some people, relief from a
dark curtain of depressive symptoms.

But those effects don’t occur in everyone who tries the drugs. In
fact, up to 80%
of the people who try existing antidepressants fail to see
results. Plus, the drugs take four to six weeks to work. As a
result, depression remains one of the world’s leading
causes of death.

Ketamine, on the other hand, affects key switches in the brain
called NMDA receptors. Collectively, these switches are part of a
larger network in the brain called the glutamate system. Like
serotonin receptors, those for NMDA play an important role in our
mood and help keep our emotions in check. But NMDA receptors also
keep our brain’s synapses — the delicate branches that serve as
the ecosystem for our thoughts — flexible and resilient.

Depression appears to cause those synaptic branches to shrivel up
and in some cases even die. Scientists think existing
antidepressant drugs send help to those branches indirectly over
time by way of serotonin. Ketamine, by contrast, delivers its aid
directly by plugging up NMDA receptors like a cork and nipping
depressive symptoms within hours.

This mechanism of action spurred some scientists to call ketamine
“the most
important discovery in half a century” in 2012.

The new study suggests that in addition to affecting the
glutamate system, ketamine also impacts the same switches that
are targeted by opioid painkillers.

For their work, the Stanford researchers gave 12 adults whose
depression failed to respond to multiple treatments two infusions
of ketamine. Before the first infusion, the participants took a
drug that blocks the brain’s opioid receptors. Before the second
infusion, the participants got a placebo. (The participants and
researchers were never told whether they were getting the drug or
the placebo — a double-blind setup designed to minimize the
chance that observed results were merely psychological.)

In more than half the cases in which the participants got the
placebo, the ketamine appeared to reduce depressive symptoms by
roughly 90%; the effects lasted about three days. Conversely,
when the patients got the opioid-blocker before the ketamine, the
ketamine had virtually no antidepressant effects.

This finding led the researchers to hypothesize that ketamine’s
activity takes place in different phases. In the first, the drug
activates the brain’s opioid receptors, quickly smothering
depressive symptoms, one of the researchers suggested in the
paper. In the second phase — which is thought to be key for
ketamine’s lasting antidepressant qualities — the drug appears to
engage the brain’s glutamate system.

What the next blockbuster antidepressant needs

Several drug companies have tried and failed to create a new
depression drug that targets the NMDA receptors in the glutamate
system. Pharmaceutical giant Roche pulled the plug on a drug
called basimglurant in 2016 after it failed to show
results in a Phase II study; AstraZeneca discontinued
its work on a heavily-promoted candidate called lanicemine in
2013.

Yet ketamine’s rapid-fire ability to stymie depressive symptoms
has continued to baffle and inspire researchers looking for an
alternative to current treatments.

Allergan,
Johnson & Johnson, and VistaGen are all currently working
to develop new ketamine-inspired drugs. In fact, two of the
authors on the latest paper previously consulted for these
companies: Schatzberg received a grant from Janssen, Johnson
& Johnson’s neuroscience partner, and study author Carolyn
Rodriguez has consulted for Allergan.

None of the three drug candidates target the brain’s opioid
system, however.

Mark Smith, VistaGen’s chief medical officer, said that although
the results of the study are “intriguing,” they would not
directly impact the company’s work on
its new drug.

Similarly, a representative from Janssen, whose work with Johnson
& Johnson has focused on a
nasal-spray version of esketamine (the chemical mirror image
of ketamine), told Business Insider in a statement that the
Stanford study would not impact the direction of their work. They
added that there were several issues with the study, including
the fact that it was small and did not include “relevant control
conditions.”

But overall, the new study sheds light on important questions
about why — and how — ketamine works to fight depression in the
brain.

“I think this paper points us in the direction that the [opioid
system] is an area for potential interest,” Schatzberg said. “The
question is, can we have a rational discussion about this in an
era when there’s an opioid crisis?”