Can Ketamine Improve ‘Electroshock’ Therapy?

By Troy Farah 01/23/18

Researchers thought that ketamine might mitigate the cognitive side effects of ECT as well as boosting good effects like improvement in mood.

A hand holding a vial of ketamine.

Two controversial treatments for depression—ketamine infusion and electroconvulsive therapy, once called “electroshock” therapy—have been studied to see if they would create a beneficial outcome when used together. This may seem like a strange pairing, but it’s actually long been common to combine them.

“People sort of said, ‘Hey, if [ketamine is] being used on its own and it's helpful, what if we use it as the anesthetic for ECT?’” Ian Anderson, Professor of Psychiatry at the University of Manchester and the study’s lead author, told The Fix. “Maybe we'll get kind of double bang for our buck, so to speak.”

Electroconvulsive therapy (ECT) is often conflated with images of writhing patients hooked up to machines delivering painful electric shocks. In movies and TV, ECT is inevitably used as a diabolical plot device to torture non-conforming mental patients, such as in One Flew Over The Cuckoo’s Nest or Requiem For A Dream.

A 2001 study analyzed 20 films with such depictions and found, “ECT on film has become a progressively more negative and cruel treatment, leaving the impression of a brutal, harmful, and abusive maneuver with no therapeutic benefit.”

In reality, ECT is rarely, if ever, used without anesthetic, the shocks are much milder and it's only given with informed consent, not as a punishment. It works by intentionally giving sleeping patients seizures—which sounds terrifying, but really isn’t—and has a 50 percent remission rate for patients with unipolar or bipolar major depression.

There are some short-term side effects, especially memory loss and confusion, and some controversy about the long-term effects; but for some, it’s a last resort for treatment-resistant depression.

On the other hand, ketamine, a dissociative painkiller often equated with kaleidoscopic hallucinations and rave culture, has seen a renaissance as of late because of its almost miraculous reversal of migraines, obsessive-compulsive disorder, PTSD and most notably, treatment-resistant depression, although results are usually short-lived.

Since its discovery in 1962, ketamine has seen widespread, low-cost use as an anesthetic—it’s on the World Health Organization’s list of essential medicines—but its off-label application in treating depression is attracting fierce attention. Small clinical trials come out at a regular pace—here’s one from last December, published in The American Journal of Psychiatry, that found ketamine rapidly reduced suicidal thoughts.

So, when you combine the two, is there a cumulative and beneficial result?

A study published last year in Lancet Psychiatry explored the relationship between the two treatments and reported, “No evidence of benefit for ketamine was found, although the sample size (N = 79) used was small.”

Anderson’s team thought that, because ketamine is an NMDA receptor antagonist (meaning it regulates glutamate, the body’s most abundant neurotransmitter, which is associated with synaptic plasticity, including learning and memory), that it would mitigate the cognitive side effects of ECT.

“The idea was that it maybe would stop some of those bad effects and perhaps boost the good effects i.e. the improvement in mood,” Anderson explains. But what they found was disappointing. Compared to saline, which they used as a placebo in their double-blind, randomized trial, ketamine did slightly worse when used with ECT.

“It did suggest that even with 95 percent confidence, any benefit from ketamine couldn't be more than quite a small effect…which means it's unlikely to be clinically very helpful,” Anderson says. “We did a battery of tests of thinking, memory and verbal fluency, spatial memory and didn't find any benefit from that nor on how quickly you improved in your depression. So it was a negative study.”

There are a couple of reasons why. It could have been difficult to successfully blind patients, as ketamine’s hallucinations are quite profound. Or maybe dose had something to do with it—the researchers used 0.5 mg/kg, the same amount often given in depression treatment—but Anderson doesn’t think that higher doses will work either.

“The other option is it might just be that ECT is working through the glutamate system the same way the ketamine is, so if you give them both together they're both kind of working on the same brain you're not actually getting any benefit from adding one to the other,” Anderson says. “That’s another possibility, but at the moment we don't know why we don't seem to see the benefits that you see with ketamine on its own.”

This gives further weight to the novel effect of ketamine on glutamate levels and could guide the development of other drugs that work similarly and have a more permanent effect. This research may also help us learn more about how ECT works, which isn’t fully understood yet.

Anderson, who has been studying depression for much of his career, describes the whole process of this study as “a nightmare.” Use of ECT has significantly declined in recent years, thanks in part to its stigma, which made it difficult to find willing patients in the first place. Around 20,000 patients in England and Wales were receiving ECT yearly in the ‘80s, compared to less than 5000 in 2006.

So Anderson’s team “had to go to seven different organizations with eleven ECT suites because they just weren't doing enough ECT.” They also had trouble sourcing ketamine because Pfizer experienced a supply shortage. Finally, they had a few incidents of worsening depression amongst their study participants, including four with self-harm, although no one died.

“More of these [self-harm incidents] occurred in the saline group than the ketamine group, so certainly it didn't seem to be even any hint that ketamine was making it worse,” Anderson explains. “And when we looked into each one, they seem to fit in with the illness the person had. So it was more related to their depression than the treatment, as far as we could tell.”

“The place of ketamine in combination with ECT has not been finally defined,” the researchers conclude, “but our study suggests that there is no beneficial effect when it is given at a standard dose of 0.5 mg during ECT as it is routinely given in the UK.”

In other words, this isn’t the end for the ketamine-ECT combo, but unless a much larger, costly study is done, we won’t have a clear answer on the benefits. But given the many practical difficulties in doing ECT research—its cost, availability and the stigma against it—it may not be easy to find answers.

“I would still be interested in how you improve the outcomes of ECT,” Anderson says. “We basically need a better network of people giving ECT. [They] should really all be taking part in low-level research to try and kind of look at outcomes and improve the way one does it.”

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Troy Farah is a journalist from the Southwest. His reporting has appeared in Undark, The Outline, VICE, Motherboard, and others. His website is and he can be shadowed on Twitter.