What Patients Need to Know About Ketamine

This is part 2 in a multi-part series. Click here for part 1.

As rates of depression and anxiety have increased dramatically, people have sought therapies outside the standard regimen of oral antidepressants and talk therapy. Beginning in the mid-2010s (see figure 1 in this paper), more doctors started offering ketamine as a treatment for depression. In 2019, the Food and Drug Administration (FDA) approved esketamine as a treatment for forms of depression that haven’t improved with standard antidepressants (like citalopram/Celexa or bupropion/Wellbutrin). Given over 10 years of experience with ketamine as a researcher and physician, in this article I try to answer some basic questions prospective patients often have about ketamine/esketamine.

When Is It Right to Try Ketamine?

Despite the fact that antidepressants can be immensely helpful for people, they don’t work for everyone. Ketamine and esketamine were approved for forms of depression that haven’t responded to traditional oral antidepresants (such as fluoxetine/Prozac, sertraline/Zoloft, etc.). In circumstances where insurance pays for treatment (more common with esketamine than ketamine), patients are often required to have tried at least two oral antidepressants before starting treatment with ketamine/esketmaine. (The exception would be when a patient is imminently suicidal, in which case the treatment would often be started while the patient is hospitalized.) What counts as “trying” an oral antidepressant? As a general rule, at least 4 weeks of treatment are required before it can be known if an antidepressant is helpful.

When friends and family who are depressed ask me if they should seek out ketamine as a potential option, I tell them that it doesn’t make sense unless they have tried oral antidepressants. The reasons for this are that ketamine/esketamine are riskier than standard antidepressants, require substantial commitments of time, and are more expensive.

Is Ketamine Safe?

Especially since the news media reported that ketamine played a significant role in the death of actor Matthew Perry, a lot of patients wonder if ketamine/esketamine is actually safe. The short answer is yes, when it’s done with the proper safeguards. What are the proper safeguards? The most important one is that ketamine/esketamine should be administered while the patient is in a clinic (as opposed to at home). Further details of Matthew Perry’s death illustrate why this is so important.

The amount of ketamine found in Perry’s deceased body was fairly high (anesthetic level), to the point that it would have caused him to lose consciousness. This, combined with the fact that he was near a swimming pool, means that the ketamine caused him to lose consciousness while in the water, and then he drowned. Even with such a large amount of ketamine in his body, if he had been in a doctor’s office (instead of near a swimming pool) he would not have died. Perry’s case is a tragic example of why it’s not a good idea for doctors to prescribe, or patients to take, ketamine at home—a practice that my colleagues and I have warned against.

Another important safeguard is that the frequency and dosing of ketamine be appropriate. The clinical evidence shows that there’s no added benefit to receiving ketamine/esketamine more than twice per week. If patients take ketamine several times a week at high doses for an extended period, this can result in irreversible problems with memory and thinking, and increase their risk of delusions. We know this from studies of people who excessively use ketamine recreationally.

Treatment Patterns

The best clinical evidence shows that patients should start treatment twice per week for 4 weeks. If a patient experiences substantial improvement (generally around 50% improvement in symptoms), the treatment pattern would shift to once per week for another four weeks. To sustain improvement, it’s often helpful to then shift to a maintenance schedule. At the Interventional Psychiatry Service at Yale, where I work, we often find that a pattern of one treatment every 3-4 weeks is sufficient for helping patients maintain the treatment’s antidepressant effects. If patients have consistent and substantial improvement in symptoms for at least 4-6 months, they may opt to then stop ketamine/esketamine after a discussion with their provider.

Ketamine and Esketamine Are Not Cure-Alls

As psychiatrists, we probably don’t pay enough attention to patients’ social and economic circumstances as well as their lifestyle choices, which can all have huge effects on mental health. Ketamine/esketamine is not a cure-all or "magic bullet" that will somehow alleviate all of a suffering patient’s problems. When I counsel with prospective patients, I try to strike a balance between optimism and realism: Ketamine/esketamine can be immensely helpful for some patients, but if the root cause of your depression is a recent and acrimonious divorce, then the drug’s benefits will be limited. Nonetheless, this treatment can often help patients to reclaim the energy and motivation they need to better address their own personal problems themselves, which in turn can lead to better mental health. It’s important to have a treatment plan that addresses what might be the root causes of a patient’s depression, whether that be a plan to reduce screen time and social media (a key culprit in young patients) or a rigorous course of cognitive behavioral therapy. Ketamine/esketamine should not be the only aspect of a treatment plan.

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