New research hints at the biology behind ketamine's antidepressant effects

laudia Kieffer remembers the first time she encountered the drug she describes as having “saved my life”. Eight years ago, Kieffer, who had suffered from treatment-resistant depression for decades, was given ketamine as a routine anaesthetic, as part of a post-mastectomy breast reconstruction procedure.

“The researchers were astounded at how well it worked for me,” she says. “There were other patients for whom the effects lasted for maybe a day, but for me it was two weeks. So after that I began going to a treatment centre once a month for an infusion and now that’s how I live. If I go too long without it, things can quickly slip back. But I have hope now.”

Kieffer is far from alone. There are thousands of similar stories, both in the US and the UK, where psychiatrists sometimes prescribe Order ketamine off-label as a last-ditch treatment for the estimated 12-20% of depression patients for whom every other medication has failed. For while ketamine is best known in modern culture as either a powerful anaesthetic – when applied in large doses – or “Special K”, the club drug with mind-bending psychedelic effects, its new use is rapidly gaining momentum.

In the US, the Food and Drug Administration (FDA) recently made the landmark decision to officially license a ketamine-related drug called Spravato as a medication for depression. As the first novel regulatory-approved treatment for the condition in more than 30 years, it comes with vast expectations. But experts warn that it isn’t necessarily a “miracle cure” – it can come with side-effects and nothing is known about the risks of using it long term.

But as well as alleviating the pain, Kieffer noticed an instantaneous change in her state of mind.

“My head suddenly felt different to any previous time in my entire life,” she says. “I wasn’t high. It wasn’t like I had smoked a joint or had morphine. It was like a spring breeze had blown through my head and just cleaned out all the detritus that had built up over years and years. And when you’ve suffered from depression for as long as I had, it feels like you’re drowning. So when something comes along that makes you feel so very different and healthy, you want to know what that drug is.”

At the time, Kieffer had tried almost every depression-related treatment available, without success. “I’d had three nervous breakdowns and been hospitalised three times,” she remembers. “I’d had 13 rounds of electric-shock therapy and it didn’t help. When I was in my 20s and 30s, I would self-medicate, just because that’s what you do when you don’t know what else to do. I was thinking about taking my life every single day. I just wanted to fall asleep and not wake up.”

But unbeknown to her at the time, a growing number of clinical trials was already investigating the potential benefits of ketamine infusions as a treatment for depression. Two years after her operation, Kieffer enrolled in one such study, run by the US National Institutes for Health.

The main reason why ketamine has attracted so much attention is the rapid effect it can have on patients who have exhausted all other treatment options. While traditional antidepressants take several weeks before patients feel any relief, ketamine works in a matter of hours and the benefits of a single dose can last for up to a week. Because of the speed with which it works, doctors in the US will often administer ketamine infusions to emergency room patients who have attempted to kill themselves.

One of the complexities of depression is how diverse it is. There can be a spectrum of symptoms and, unlike other antidepressants, ketamine appears to have wide-ranging benefits across many of them. Studies have shown positive effects in patients with anxious bipolar depression, PTSD, anhedonia or loss of pleasure and suicidal thoughts. All this led Thomas Insel, the former director of the US National Institutes of Mental Health, to describe ketamine as potentially “the most important breakthrough in antidepressant treatment in decades”.