Researchers at Carleton University are illuminating how the anesthetic drug ketamine works in the brain and whether it could be a model for future antidepressants.
The research at Carleton, which was published in Nature in December, focused on ketamine at the molecular and cellular level. It explored the impact of the drug on the 4E-BP proteins, which play a large role in producing other proteins in the brain.
The research is part of a broader effort to develop treatments for depression that work in similar ways to ketamine without the drug’s detrimental side effects.
“We’re trying to understand how ketamine has these effects,” said Carleton neuroscience professor Argel Aguilar-Valles, who is leading the research. “Our study is one additional piece in the puzzle to understand it.”
Ketamine is used for anesthesia in medical and veterinary settings, and is also used as a street drug. Over the past decades, research on ketamine has shown small doses have an antidepressant effect.
More than 30 per cent of patients with depression find first-line treatment—often selective serotonin reuptake inhibitors such as Prozac—to be ineffective at working as an antidepressant. The researchers say studying ketamine is important because it could reveal new ways to treat depression in these individuals.
Ketamine is already being used as an antidepressant. Last year, a ketamine-based nasal spray was approved by Health Canada, and the same treatment was approved by the Food and Drug Administration (FDA) in the United States in 2019.
Ketamine is legal in Canada for medical purposes.
Ketamine’s side effects can include hallucination and dissociation, which is the feeling of disconnection from one’s body. The drug can also be addictive.
The researchers conducted a “forced swim test” on both normal mice and mice genetically modified to not have the proteins the researchers were studying.
Normal mice were placed in a beaker of water to stimulate a mildly stressful situation. The researchers recorded the amount of active swimming, finding that the mice’s movement increased after receiving ketamine.
“It’s a very quick method to determine if a drug has a potential antidepressant effect,” Aguilar-Valles said.
This process was repeated with the genetically modified mice. Aguilar-Valles said they found that the genetically-modified mice were “no longer responding to ketamine in the same way as a normal mouse with the intact protein.”
The researchers concluded the proteins are fundamental in ketamine’s effects as an antidepressant. By discovering how ketamine treats depression at a molecular level, researchers can design other drugs that work in similar ways but don’t have ketamine’s side effects.
Aguilar-Valles said he started his research on ketamine’s antidepressant effects six years ago as a research associate at McGill University in Montreal. He continued his study in his own lab at Carleton when he came to the university in January 2019.
The Nature paper’s initial experimentation was finished and submitted for peer-review in 2019 and published late last year after additional experimentation.
When the pandemic shut down Carleton’s labs in March 2020, Aguilar-Valles said the research stopped for months until it was able to resume in the summer.
“Our research basically went into standby,” Aguilar-Valles said. “It really slowed us down.”
Future research
The research published in Nature was conducted primarily on mice that were not chronically stressed. The next step is to conduct chronic stress experiments because studies show that psychological stress affects depression.
Emily Arsenault, a fourth-year neuroscience and mental health student, is conducting a follow-up study as part of her honour’s thesis. Arsenault is looking at whether the hypothesis from the initial research—that the proteins being studied play a key role in ketamine’s effects as an antidepressant—remains true in conditions that mimic depression in humans.
In her study, the normal and genetically-modified mice are placed through a chronic stress procedure with mild, unpredictable stressors. Then, they are treated with ketamine and their behaviour is observed.
Recent research shows that conditions associated with depression—such as chronic stress—decrease the ability of the brain to form new neural connections. Most antidepressants increase that ability.
From the preliminary results, Arsenault found that ketamine can restore the brain’s ability to form new neural connections lost due to chronic stress. However, the genetically-modified mice do not exhibit any increase in this ability.
These results indicate that the proteins being studied play a key role in stress reception.
While these studies shine a light on ketamine’s functions, the research is not yet complete. Arsenault is planning on staying at Carleton for her master’s degree.
“I hope that I’ll be able to continue doing my research,” she said.
Aguilar-Valles said this type of preclinical research is crucial for clinical studies.
“Without basic research, you would not be able to understand clinical circumstances,” he said. “Basic research is the backbone of medicine and clinical advancement, so it’s very important to continue to do it and not disregard it as something that is purely academic.”
