Professor of psychiatry and the Director of the Yale Depression Research Program Gerard Sanacora is investigating the use of the anesthetic ketamine as a treatment for depression. Currently, most antidepressants take weeks to have an effect, but ketamine’s antidepressant effects kick in within hours. Sanacora is currently conducting experiments to determine the optimal dosage level, as well as the exact rapidity of ketamine’s antidepressant effects. The News sat down with Sanacora to understand how ketamine works and what it could mean for the future of depression treatment.

Q: Why is it important to speed up the delivery of drugs that treat depression?

A: The problem is, right now, most treatments for depression require weeks to have a clinically meaningful effect. For many people, that wouldn’t be a terrible problem. Depression runs a large range of severity. For a person with mild, even moderate depression, it’s not urgent. But for people with severe depression, four weeks is an incredibly long time. Especially when it reaches the point where people are seriously considering suicide, or where people have stopped performing daily functions, like stopped eating.

Q: How does the ketamine treatment work?

A: That would be nice if we knew exactly. The real answer for any of our treatments is that we don’t really know — including drugs like Prozac.

Q: What’s the current hypothesis?

A: It looks like ketamine is having its acute effects by binding to a specific receptor for the neurotransmitter glutamate. Then it’s actually triggering a neuroplastic effect — so the way the brain cells talk to each other actually changes.

Q: So do all drugs that treat depression work the same way or is it only ketamine?

A: They don’t all work the same way. Let’s say, for example, Prozac most typically would take weeks to work. We would say that Prozac works by binding and blocking the transport of the serotonin reuptake transporter. But that’s not what causes the antidepressant effect. That happens within 15 minutes of taking the drug, and nobody feels better after only 15 minutes of taking the drug. We think [taking the drug] just initiates the process and there are downstream effects that start initiating the antidepressant effect. So there might be many ways of going through the front door, but do they all lead through the same backdoor?

Q: Why does ketamine work faster than Prozac?

A: One of the thoughts is that you might be entering the system closer to the point that’s actually generating the actual antidepressant effect. So let’s say that Prozac is initiating a series of 20 events that result in the antidepressant effect. Ketamine might be entering the system at a much closer point — much closer to the actual thing where the antidepressant effect is coming from.

Q: So I’m guessing that clinical trials have been conducted already?

A: Yes, quite a few.

Q: To what extent have these trials been conducted?

A: The first clinical trial was published in 2000 here at Yale. And since then there have been a large number of studies that have been published. At this point there have been a few hundred patients in total treated in clinical trials with ketamine.

Q: Have they been treated these 14 years, from 2000 to now, or solely through your study?

A: These are including all studies. There have been several smaller studies. There really hasn’t been one large definitive study that has been done.

Q: What distinguishes your clinical trial from the other ones?

A: Right now we’re just starting a large study sponsored by the National Institute of Health. We’re trying to understand what would be the optimal dose of the medication to give. The studies to date have all used the same dose of medication that was figured out more than 15 years ago. No one has tried to figure out [what happens] if we use a larger dose of medication, or if we could use smaller doses of the medication and have the same effect.

Q: What about the other study?

A: We’re trying to figure out if there’s a real acute benefit [very rapid effects] of the medicine for patients with severe depression.

Q: How rapid?

A: Very rapidly. Within a few hours.

Q: When do you think that treatments involving ketamine will be available on the market?

A: So the scary thing is that it’s available on the market right now. You can get [it] from your pharmacy. It’s been available as an FDA approved drug for many years.

Q: Is it available for the treatment of depression?

A: No, as an anesthetic agent. It’s used very commonly in pediatric anesthesia and it’s used in the emergency room quite frequently. There’s no law against people using it. It’s just not indicated for depression. But doctors can use medications off label if they want to. So I think the question we’re getting more at is when do we think that the FDA indication for the use of ketamine will include depression. I think that will depend on the results of the next few studies, [which will determine] the safety of the drug.

Q: So if the studies go according to plan, will it just be a few years?

A: I think that because it’s a drug that’s readily available and has been out for 80 years, it wouldn’t have a long delay in making it to the clinic. But it really depends on the FDA. It’s such a different approach to treatment that the FDA is going to have to come to some decisions on how they think it should be used. I don’t think this is going to be the type of drug that people will be getting at the local pharmacy and taking home. This will probably be, especially initially, used more in a hospital setting. That could happen very quickly, easily within a five-year time period.

Q: What are some of the risks of using ketamine?

A: Ketamine itself — with a higher dose — is an anesthetic agent. There are significant changes in your heart rate and blood pressure that accompany ketamine, so it really has to be given in a situation that is medically monitored. And also, there are some dangers in cognition and perception that would limit its use as a dosage for outpatients. So it really needs to be monitored.