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Though suicide rates have declined slightly over the last few years, death by suicide remains a public health crisis in the United States and throughout the world—and we still don’t have great treatments for it. In recent years, clinicians have begun using the mind-altering psychedelic ketamine as an off-label therapy for people who are having dark ruminations about harming themselves. But while the effects set in quickly—within a couple of days, or even hours—they typically begin to wear off after a week.
Now a team of scientists from Stanford University has figured out a way to potentially extend these effects for up to a month—giving people who are struggling with suicidal thoughts enough of a reprieve to try other long-term therapies, such as antidepressants, which typically take a few weeks to kick in, or to connect with a good therapist.
Periodic infusions of ketamine carry certain risks, including increased blood pressure and heart rate, possible dependency, higher cost and inconvenience, and dissociative effects, such as feeling detached from oneself or the world. So the Stanford team decided to test whether another drug, called buprenorphine, that is often used in pain management and opioid replacement therapy, could help.
The scientists recruited 45 patients who were suffering from major depressive disorder and suicidal ideation for a small double-blind placebo-controlled trial. They all got a 40-minute infusion of ketamine, a common surgical anesthetic that acts on opioid receptors. Then, 48 hours later, they began taking a daily pill that contained either a placebo or low-dose buprenorphine—a fraction of that used for pain management or opioid replacement. After a month, about half of patients who got the placebo after ketamine were no longer clinically suicidal, according to their scores on a standard scale. But among patients who got buprenorphine, nearly 80 percent were no longer clinically suicidal. The team published their finding in the American Journal of Psychiatry. It’s a promising early-stage result that justifies a larger trial with longer treatment times and follow-ups.
I spoke with Stanford psychiatry professor and study co-author Alan Schatzberg about what’s happening in the brains of people who are having suicidal thoughts, why depression and suicidality don’t always overlap, and what’s driving the current epidemic.
Read more: “A Vaccine for Depression?”
Why is it so difficult to study suicidality?
Most studies in major depression don’t include actively suicidal people or people who have moderate suicidal ideation. They tend to exclude them for a variety of reasons. One is that the studies are often placebo controlled. You don’t want to give a placebo to somebody who is imminently at risk. So that’s one issue. The acute risk of self-harm also makes it much more challenging for the people who conduct trials to study them [and to keep them safe]. That’s why you have relatively few studies of suicidal ideation, particularly with pharmacological approaches.
How do clinicians realistically diagnose suicidality?
It’s mainly based on clinical symptoms and an interview regarding the nature of the person’s self-destructive thoughts. A clinician will ask them, “What kind of thoughts have you had? Have you had thoughts that life isn’t worth living?” That’s a mild suicidal thought. It’s very different than someone who spends a lot of their day thinking of how to harm themselves or how to die by suicide. So personal history is extremely important. You have to ask the right questions and ascertain whether the person has recently tried to hurt themselves. We’ve developed some rating instruments.
There are also implicit cognitive tests that have been developed where you can ask people to respond to visual cues or words that may suggest some interest in self-harm. You can then look at how quickly or slowly they react to these words. These have been shown in some studies to be sensitive tools for hospitalized patients, for example. They’re largely used in research studies, but there are efforts to use cognitive testing to elicit responses that appear to suggest suicide risk.
You found a way to prolong the anti-suicide effects of ketamine by a few weeks. How much of a difference does that kind of timeline make when it comes to prevention and treatment?
The anti-suicide effect of ketamine is often quite dramatic. You see that within a couple of days, so anything that extends it is quite helpful, particularly if you can go out a few weeks. In the case of someone who has imminent risk in the next day or so, you may still need to hospitalize them. There’s nothing that will necessarily substitute for that in terms of ensuring safety. But otherwise, people who are suicidal are largely suicidal for long periods of time, and they suffer with it for long periods of time. They live outside of hospitals, but they live at risk to themselves.
How difficult is it to get someone who is contemplating suicide into a clinic?
Well, the clinic is an outpatient program, and psychiatric clinics aren’t the easiest to access if there’s an immediate risk. Generally speaking, if somebody is at immediate risk, they ought to go to an emergency room, where they can be assessed as to whether they need to be hospitalized. Those aren’t simple assignments either—there are limited psychiatric beds—so the treatment of suicidal people largely occurs on an ambulatory basis. Having something that’s actually effective pharmacologically is of great use.
Read more: “Does Depression Have an Evolutionary Purpose?”
You found that your drug combo extended ketamine’s anti-suicidal effects, but not its antidepressant effects. What does this tell us about the relationship between depression and suicide?
It tells us they’re not entirely overlapping. We’ve tended to think of suicide as the most severe form of depression, but we know that there are people who try to kill themselves or die by suicide who weren’t necessarily all that depressed. Depression has all sorts of other symptoms that contribute to severity, such as lack of pleasure, lack of energy, inability to concentrate, and inability to sleep. There are a lot of patients with those symptoms who aren’t particularly suicidal. They feel horrible. They may feel like life isn’t worth living with those symptoms, but they’re not necessarily actively suicidal.
So suicidal thinking and depression overlap to some extent, but not entirely. And there are many patients who succumb to suicide who aren’t overtly depressed. They have other issues going on—personality issues, substance abuse issues, life circumstance issues.
Do we know anything about differences in the underlying neurobiology between depression and suicidal thinking?
We know a little bit more about the cognitive style that’s involved: Many of these patients constantly dwell on the potential for self-harm. But we need to know a lot more about the biology. This kind of pharmacologic finding may in fact lead to a lot more study of suicide, particularly of the opioid system in depression and in suicidality.
My hypothesis is that there’s probably a disturbance of the hedonic capacity, or the ability to feel pleasure, along with disturbances in the ability to suppress thoughts. A lot of these patients can’t really enjoy themselves, which may be tied more toward the pleasure centers of the brain, which are often opioid mediated. We tend not to have thought about the opioid system so much in depression or suicide. These findings could prompt more interest.
Suicide is often framed as a social and economic phenomenon as much as a medical one in the U.S. Does finding a drug combination that helps even in the short-term change how we understand what’s driving it?
It looks like suicide numbers are going down overall in the U.S., but going up in young people over the last few years. So we have a medical-sociological phenomenon that we haven’t been able to control. And while our findings do tell you something about a biological system that’s involved potentially in feeling better, they don’t necessarily mean that system is disordered. The only way we find out is if people pick up on these findings and use them for further study. We think it’s an important observation, and we think it could have a dramatic effect on risk of death due to a terrible cause. 
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