Ketamine and esketamine: an option for treatment-resistant depression?

For many people with depression, the first antidepressant does not work well enough, and neither does the second. Ketamine, an anesthetic that has been used in medicine for decades, can lift depression within hours to days, much faster than standard antidepressants, which usually take weeks. Since 2020, a nasal spray form called esketamine has been approved in Canada, and large trials have compared ketamine with other treatments. This article explains what treatment-resistant depression is, what the evidence shows for ketamine and esketamine, their risks, and how genes and other medications affect them.

What is treatment-resistant depression?

Depression is usually called treatment-resistant when it has not improved enough after at least two adequate trials of antidepressants, taken at a proper dose for long enough. It is common: in the large STAR*D study, only about two in three people reached remission even after up to four treatment steps, so about one in three did not. People with treatment-resistant depression may be offered a different antidepressant, an add-on medication, psychotherapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) or, more recently, ketamine or esketamine. Read more in what to do when antidepressants are not working.

How does ketamine work in the brain?

Standard antidepressants act mainly on serotonin and norepinephrine. Ketamine works differently: it blocks NMDA receptors, which respond to glutamate, the brain's main excitatory messenger. This sets off a chain of changes, including increased activity of AMPA receptors, release of growth factors such as BDNF and the rapid formation of new connections between nerve cells in brain regions that regulate mood.

Animal studies have also shown that ketamine quiets bursts of activity in the lateral habenula, a small brain region sometimes called the "anti-reward centre". Overactivity in this region drives despair and the loss of pleasure (anhedonia) in depressed animals, and blocking it with ketamine relieved these behaviours within hours. These findings help explain ketamine's speed, although they still need to be confirmed in people.

What do studies show about ketamine for depression?

• Rapid response. In a two-site trial in New York and Houston, 73 people with treatment-resistant depression received a single intravenous (IV) infusion of ketamine or of midazolam, a sedative used as a comparison. After 24 hours, 64% responded to ketamine, compared with 28% to midazolam.
• Suicidal thoughts. In a trial of 80 adults with depression and significant suicidal thoughts, 55% of those given ketamine had at least a 50% reduction in suicidal thoughts the next day, compared with 30% given midazolam.
• Repeated infusions in routine care. In Oxford, 28 people with treatment-resistant depression received three or six low-dose ketamine infusions over three weeks in a routine ECT clinic. Eight (29%) responded, and four of them reached remission. The benefit lasted a median of 70 days after the last infusion, ranging from 25 to 168 days.
• Ketamine compared with ECT. In the ELEKT-D trial of 403 people with treatment-resistant depression without psychosis, 55% responded to six ketamine infusions over three weeks, compared with 41% with nine ECT treatments. Ketamine was at least as effective as ECT, ECT was more likely to affect memory in the short term, and ketamine was more likely to cause dissociation.

The main limitation is that the effect of a single dose often fades within days to weeks. Repeated or maintenance treatment, usually every 1 to 4 weeks, can help keep the benefit.

What is esketamine and how well does it work?

Ketamine is a mixture of two mirror-image forms. Esketamine is one of them, given as a nasal spray together with an oral antidepressant. It is approved in Canada for adults with treatment-resistant depression and is given in a certified clinic, where the person is monitored after each dose.

In the ESCAPE-TRD trial of 676 people with treatment-resistant depression who continued their antidepressant, esketamine was compared with quetiapine extended release, a commonly used add-on medication. Esketamine led to remission sooner and more often: by week 32, 34.5% of people treated with esketamine reported remission on a standard depression questionnaire, compared with 18.2% with quetiapine. Side effects were more common with esketamine but were usually mild and passed the same day, and fewer people stopped esketamine because of them. Read more about esketamine and other options in treatment-resistant depression: what helps beyond antidepressants.

What do Canadian guidelines recommend?

The 2023 Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines recommend IV ketamine and intranasal esketamine as second-line add-on treatments for people whose depression has not responded to at least two adequate antidepressant trials. CANMAT notes that both can rapidly reduce suicidal thoughts. They are not first-line mainly because of their side effects and the need to monitor blood pressure and dissociation after each dose. Other forms of ketamine, such as tablets, nasal or intramuscular ketamine, are third-line because treatment protocols vary widely and results are mixed.

What are the risks of ketamine and esketamine?

• Dissociation, a feeling of being detached from your body or surroundings, as well as dizziness, nausea and sleepiness, usually in the first hours after a dose.
• Higher blood pressure for a short time after each dose, which is why blood pressure is checked before and after treatment.
• Misuse. Ketamine is also used recreationally, so treatment is given and monitored in a clinic.
• Bladder problems. Long-term ketamine use can irritate the bladder (cystitis), and CANMAT recommends periodic urine tests for people on longer-term treatment.
• Driving. People should not drive or operate machinery for the rest of the day after a dose.

Ketamine and esketamine are not suitable for everyone, for example people with uncontrolled high blood pressure or certain blood vessel conditions in the brain. A psychiatrist can help decide whether they are a good option.

How do genes and other medications affect ketamine?

Ketamine is broken down in the liver mainly by the CYP2B6 enzyme, with a contribution from CYP3A4. The CYP2B6 gene varies a lot between people, and the common CYP2B6*6 variant reduces the enzyme's activity:

• In laboratory studies, several CYP2B6 variants, including the one encoded by CYP2B6*6, broke down ketamine much more slowly than the usual form of the enzyme.
• In people with chronic pain who received 24-hour ketamine infusions, those with one or two copies of CYP2B6*6 cleared ketamine much more slowly, and slower clearance was linked to more side effects.
• After a single low dose of ketamine taken by mouth, however, CYP2B6*6 did not change ketamine levels in healthy volunteers.

Genetic effects may therefore matter most with repeated or prolonged dosing. There is no clinical guideline yet that recommends adjusting ketamine or esketamine based on genes, but a pharmacogenetic result can help a care team understand unusually strong side effects. Medications that strongly speed up or slow down CYP2B6 or CYP3A4 can also change ketamine levels, so the full medication list should be reviewed before treatment.

How can a Pillcheck test help?

Many people reach treatment-resistant depression after several antidepressants did not work or caused side effects. Genes such as CYP2D6, CYP2C19 and CYP2B6 affect how the body handles many antidepressants, and using them to guide treatment can help more people respond and recover. Read more in a randomized trial of Pillcheck-guided pharmacist care.

With Pillcheck, a pharmacist reviews your results together with all of your current medications, including add-on treatments, accounts for drug-drug-gene interactions and prepares recommendations that you can share with your psychiatrist or family doctor. Pillcheck reports CYP2B6 and CYP3A4, the main enzymes that break down ketamine.

Pillcheck testing is performed in CAP- and COLA-accredited clinical genetic laboratories located in Canada. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. The Pillcheck test panel ensures high accuracy for people of non-European and admixed ancestries. Your results last a lifetime, and report updates are free of charge.

Summary

• About one in three people with depression do not reach remission even after several treatment steps.
• Ketamine can relieve depression and suicidal thoughts within hours to days; in a large trial, IV ketamine was at least as effective as ECT.
• Esketamine nasal spray is approved in Canada for treatment-resistant depression and led to remission more often than quetiapine in a large trial.
• CANMAT 2023 recommends IV ketamine and esketamine as second-line add-on treatments, with monitoring for blood pressure and dissociation.
• Ketamine is broken down mainly by CYP2B6 and CYP3A4; genes and other medications can change its levels, especially with repeated dosing.

Frequently asked questions

How fast does ketamine work for depression?

Some people feel better within 24 hours of an infusion, but for others the benefit builds over several treatments. The effect of a single dose often fades within days to weeks, so repeated treatment is usually needed.

Is ketamine for depression the same as recreational ketamine?

No. Treatment uses low doses given and monitored in a clinic. Recreational use involves uncontrolled doses and carries a risk of misuse and bladder damage.

Can a genetic test tell me whether ketamine will work?

No. Genes such as CYP2B6 and CYP3A4 affect how quickly ketamine is broken down and may help explain side effects, but no genetic test predicts whether ketamine will relieve your depression.

Can I take ketamine with my antidepressant?

Yes. In most studies and in CANMAT recommendations, ketamine and esketamine are given in addition to an antidepressant. Your care team should review all of your medications before treatment.

References

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