Esketamine, antidepressants, mental health - black and white photo of a hooded, blurred figure.
Photo: Dave

An Extra-Potent Ketamine Spray Could Help Treat Depression

"Let’s face it, nasal spray is a more appealing prospect than electric shocks and anaesthesia."
Brussels, BE

This piece originally appeared on VICE Belgium.

In recent years, ketamine has made its way from dancefloors to the treatment room. In addition to fuelling nights out (when clubs are open, anyway), the drug is currently being used as a treatment for clinical depression in hospitals and mental health units. Experts argue that its dissociative and anaesthetic effects can ease severe depression quicker than more traditional treatments like SSRIs, a type of widely-used antidepressants that boost serotonin levels in the brain.


Traditional anti-depressants tend to increase levels of serotonin – the hormone that stabilises mood and regulates happiness, sadness and anxiety – and chemicals like dopamine and norepinephrine, which are responsible for communication between brain cells. Ketamine and esketamine, its close pharmacological cousin, work with glutamate, a different chemical messenger that allows cells to communicate along new pathways. In both cases, the drugs effectively reprogramme the way your cells talk, affecting your mood and thought patterns.

Ketamine clinics have popped up across the US, Canada and the UK, but they tend to be reserved for individuals who are yet to respond to other depression treatments. Treatments take the form of regular infusions of either ketamine or esketamine over the course of several weeks.

Esketamine, ketamine’s more potent relative, can be administered as a simple nasal spray. Some professionals believe that it may, theoretically anyway, have fewer side effects. We say “theoretically”, because, to date, there have been no head-to-head clinical trials that measure the comparative side effects.

Despite 15 years’ worth of research into treating severe depression with ketamine, it’s still early days for clinics that use these drugs. In the UK, NHS guidance stresses that “ketamine is not a licensed treatment for depression” and that the drug can only officially be used at the moment as an anaesthetic or a painkiller.


We spoke about this new treatment with Koen Demyttenaere, a psychiatrist at the KU Leuven University in Belgium. Demyttenaere is a teacher, a researcher and an expert on different forms of depression. He has spent much of the past year successfully treating severely depressed patients using a ketamine derivative.

VICE: Why is ketamine effective in fighting depression?
Koen Demyttenaere:
There are a lot of antidepressants on the market that work on neurotransmitters with different levels of intensity. Around only 60 percent of the patients who use them see improvement, and you have to wait between four and six weeks for them to begin working. In the past decade or so, there hasn’t been a huge amount of development in terms of treatments. It is only very recently that options have begun to open up and start making a difference. 

Like esketamine?
Yes, but we need to be clear that ketamine isn’t officially recognised as an antidepressant and esketamine is currently only used for treatment-resistant depression. They’re costly products which, in Belgium at least, have to be taken under medical supervision in a hospital setting. They’re not for patients just starting treatment.

What makes ketamine and esketamine different from other antidepressants?
We have found that both can ease depression considerably in just a few hours. This is because they’re acting on a completely different neurotransmitter to those targeted by conventional antidepressants. We’ve also found using both ketamine and esketamine results in a rapid decrease in suicidal thoughts, but it should be noted that this is sort of independent from the general antidepressant effect.


There are a lot of ketamine clinics now in the U.S. and UK. How do they work?
Usually, patients visit once or twice a week. They receive either ketamine intravenously or esketamine by nasal spray. Again, this is administered by medical professionals – it has to be, because the patient can find themselves in a state of dissociation as a result of the dosage, and there is also a risk of elevated blood pressure. Right now, the data are still insufficient to determine if there’s a risk of long-term dependence. 

How do your patients find the initial nasal spray administrations?
I should start by saying it’s not a miracle solution. It doesn’t work for everybody. But some people feel much better after just a few hours. What we have to consider is, are we looking at an antidepressant effect alone, or does euphoria also play a role? In general, though, any new product that works on a different mechanism is welcome in the medical field, if it can help more patients.

Is the dissociative aspect of esketamine milder than with ketamine?
There have been a number of studies suggesting that it’s not the case. However, we currently don’t have enough data to tell us about long-term effects, so that’s still the big question. For people with bad depression who’ve had no luck with the “usual” treatments, we often try ECT [electroconvulsive therapy, meaning sending electric shockwaves through the brain], which is still the most powerful treatment. But now, I think esketamine could be a viable alternative to ECT for some patients.


So you’re saying that esketamine could potentially be an alternative to the most powerful depression treatment there is? 
Maybe in an acute phase — and, again, only for some patients. There are still indications that ECT is more powerful, but generally speaking, electric shocks are scarier to people. Esketamine may not be as potent, but let’s face it, nasal spray is a more appealing prospect than electric shocks and anaesthesia.

Have you seen any patients have an extreme reaction to the dissociation?
Here in Kortenberg [a small Belgian town where Demyttenaere’s campus is located], we try to make sure the patients’ rooms are nicely decorated; we let them listen to music of their choice through headphones. Thanks to these things — plus the presence of an empathetic nurse — we haven’t yet treated any cases of dissociation problems. The effects that do occur are mild and temporary. 

Do you think new medications like this are becoming more necessary?
I wouldn’t say there is an increasing number of patients with severe depression. What’s significant is that a certain percentage respond positively to the first antidepressant they try, others react well to the second — and ultimately, the goal is to need fewer different treatments for depression.

But if you try three different treatments and don’t see results, my advice is still not to give up. Some patients try four different treatments before they find relief. Even if a new medication like esketamine doesn’t work out for you, we know we can help people get better, even after five years of severe depression. Also, you have to remember that in cases of severe depression, a course of psychotherapy can be really helpful, in addition to medication.

I think that in a case of a major depressive disorder that goes on for a long time, you have to make a distinction between the treatments we might use in an acute phase, like ECT or esketamine, and the ones we use afterwards. We could keep going with ECT or esketamine, or we could start a neuromodulation treatment, for instance [a type of treatment that stimulates the brain and nervous system to change their activity].

Do you think ketamine and esketamine treatment will gain popularity in the future?
That’s something we all have to figure out together. On our end, we can decide when to offer such treatments. We can give medical and technical explanations; we can tell patients what we know or don’t know about a given product. But in the end, it’s up to the patient to figure out what they want out of their treatment. They’re the ones who have to examine their expectations and their life environment. After that, it’s a matter of finding common ground. Making that choice is a really important step for a patient.