Ketamine works its magic on depression by 'stabilizing the brain in a well state'

The anaesthetic drug ketamine might have a reputation as a psychedelic party drug, but in lower doses it's been shown to bring remarkable — almost immediate —  relief to severe and otherwise untreatable cases of depression. And now scientists think they know why: it helps restore synapses in the brain that are destroyed by stress.

"Ketamine is this really exciting drug that is fundamentally different from many of the other antidepressants that we use, in that it has these rapid effects," said Dr. Conor Liston, a neuroscientist and psychiatrist in the Feil Family Brain & Mind Research Institute at Weill Cornell Medicine in New York City, in conversation with Quirks & Quarks host Bob McDonald.

Ketamine is actually acting to restore some of the exact same connections that have been lost during stress.- Dr. Conor Liston, Weill Cornell Medicine

In the last few years, psychedelics like LSD, magic mushrooms and ketamine, have been going through a bit of a renaissance as scientists explore the therapeutic potential these drugs can provide.

Scientists like Dr. Pierre Blier, the director of the mood disorders research unit at the Royal Ottawa Mental Health Centre and a professor at the University of Ottawa, has studied the use of ketamine in reducing suicidal thoughts in patients with severe and treatment-resistant depression.

What is striking is that we also saw, like other researchers, a very important effect — almost everybody experiences a decrease in suicidal ideation. And that's the major impact.- Dr. Pierre Blier, Royal Ottawa Mental Health Centre

"What is striking is that we also saw, like other researchers, a very important effect — almost everybody experiences a decrease in suicidal ideation," said Blier. "And that's the major impact."

Compared to traditional antidepressants, ketamine works very quickly. Most patients who take it for depression experience relief within hours. That relief can last for days, weeks or even months before patients relapse.

Dr. Conor Liston became interested in ketamine because these transitions are similar to what people with episodic depression experience when they get sick, then better, only to relapse again.

"This investigation into ketamine is actually part of a larger project underway in my lab where we're trying to understand the mechanisms that mediate transitions between depressive episodes," said Liston. He's the senior author of a study  looking at these mechanisms, published recently in the journal Science. 

Ketamine restores connections in the brain

Depression is not just bad for the mind, it's bad for the brain. Our bodies release the hormone cortisol when we're stressed, but also during periods of depression. When we're particularly stressed or if there's a chemical imbalance in the brain, cortisol can damage neural connections in key areas of our brain.

"What we showed in our work," said Liston, "is that ketamine and chronic stress are actually doing opposite things — so there's a loss of connections after chronic stress in this brain region. And ketamine is actually acting to restore some of the exact same connections that have been lost during stress."

New brain connections maintain 'well state'

Liston said one surprising part of their study was that changes in behaviour in the mice that indicated a lifting of the effects of depression actually came before restoration of any faulty connections occurred — only hours after the mice had been given the drug.

"That right there told us that they couldn't be required for inducing ketamine's effects initially," said Liston. 

What we found is that those new connections are really important for stabilizing the brain in a 'well state.'- Dr. Conor Liston, Weill Cornell Medicine

Ketamine works on the brain's glutamate neurotransmitter, which is involved in communicating between nerve cells. The researchers think this is what provides the immediate effects of relief, which then becomes reinforced with the formation of new synapses.

"What we found is that those new connections are really important for stabilizing the brain in a 'well state,'" added Liston.

Augmenting ketamine's antidepressant effects

These findings may shed light on the variability in how long ketamine works to keep depression at bay, and also provide a glimpse how episodic depression can start and stop.

"These new connections might explain why it is that some individuals have long lasting benefits from ketamine whereas others do not," said Liston. "what we think our study is showing us is that the formation of these new connections is really important in determining whether — when you get better, you stay better, or do you become depressed again."

If scientists can find a way to stabilize these connections, maybe they can make the effects of ketamine last longer.  This is a concern because it's not yet known if ketamine is safe to take repeatedly on a long-term basis.

According to Liston, there are a number of routes to explore to stabilize the neural connections ketamine helps rebuild. Potentially another drug could work to further stabilize those connections. Or, he suggests, transcranial magnetic stimulation to the brain or perhaps even a behavioural intervention as simple as exercise could help maintain those connections.

Liston plans on testing some of these potential interventions to augment the effects of ketamine.

Ketamine hasn't been approved for psychiatric treatment in Canada. A ketamine nasal spray designed to treat intractable depression has been submitted to Health Canada for approval in January. It is currently being reviewed under the Priority Review Policy.

Anna Beyeler, a neuroscientist from the Université de Bordeaux in France, cautions that although ketamine's "effect on depression is apparent within hours, the drugs can have serious side effects including sedation, detachment from reality, and even addiction to the compound."