For those with stubbornly resistant forms of severe depression, ketamine was looking more and more like a solution. Years of research has hinted at the dissociative anesthetic's treatment potential where other medications failed, promising the benefits of electroshock therapy with far fewer risks.
For all of the excitement, separating the hope from the hype has been challenged by the drug's strong psychoactive effects. How can you conduct a blind test for a drug that so overtly detaches the mind from the body?
By taking advantage of the unconscious state of patients under general anesthesia, researchers from Stanford University School of Medicine in the US put ketamine to the ultimate, gold standard test.
Their randomized, triple-masked study found a single dose of ketamine is as likely as an infusion of saline to improve the mood of patients diagnosed with moderate-to-severe depression in the following days.
"I was very surprised to see this result, especially having talked to some of those patients who said "My life is changed, I've never felt this way before," but they were in the placebo group," says the study's senior author Boris Heifets, an anesthesiologist at Stanford University School of Medicine.
Developed in the 1960s in a search for new anesthetics and analgesics, ketamine has quite a history in medicine. Still used in emergency care to this day as a quick and reliable means of treating patients in pain and extreme states of distress, its illicit use for recreational purposes – thanks to its dreamy, dissociative effects – has also slowly risen over the years.
Over the past decade, its potential as an antidepressant has drawn renewed interest in the pharmaceutical sector. Clinically speaking, relatively small amounts of the psychedelic were found to improve moods in rats, even after just a single dose.
Potential explanations were quickly identified in various anatomical and animal model studies, linking the compound's effects with changes in functional connectivity and activity in regions associated with depression.
Studies involving patients diagnosed with severe depression have subsequently found significant reductions in suicidal thoughts and reported improvements in mood, leading to the FDA approval of ketamine as a nasal spray for treatment-resistant depression.
Behind the headlines of hope, there has remained the possibility that the experience of taking a powerful psychoactive substance could itself be critical to its therapeutic benefits.
To 'mask' the drug's mind-altering effects from other possible mechanisms, Heifets and his team assigned 40 surgical patients to one of two groups; one to receive ketamine while under general anesthesia, the other saline.
Neither the patient, the investigators, nor the care staff knew which they received. Two weeks after their surgery, at the end of the trial, just over a third of the total number of recruits correctly guessed which group they'd belonged to.
Yet in the days following their infusion, a number of patients in both groups showed improvements in their mood based on the Montgomery–Åsberg Depression Rating Scale, suggesting ketamine's benefits may largely come down to the psychology of medical treatment in general.
This doesn't necessarily mean ketamine is a complete bust in treating depression, though it does imply any influence it might have could be more a consequence of general experience than biochemical fine-tuning.
"We also considered the possibility that surgery and general anesthesia without ketamine has an antidepressant effect," the researchers write. "However, our review of previous studies measuring symptoms of depression in the perioperative period strongly suggests otherwise."
Brains are complex engines, with depression itself proving to be a complicated phenomenon defying simple explanations of 'chemical imbalances' or maladjusted circuitry.
Just as we're finding MDMA mixed with therapy can deliver healing experiences for patients with PTSD, controlled doses of ketamine in the right surroundings just might help individuals with severe depression find a way forward.
"There is most definitely a physiological mechanism, something that happens between your ears, when you instill hope," says Heifets.
This research was published in Nature Mental Health.
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