It’s been way too long since there was a new class of drugs to treat depression. Ketamine might be the solution.
By Moises Velasquez-Manoff
In May of 2017, Louise decided that her life was just too difficult, so she’d end it. In the previous four years, three siblings and a half-sibling had died, two from disease, one from fire and one from choking. Close friends had moved away. She felt painfully, unbearably alone. It would be the fourth time Louise (I’m using her middle name to protect her privacy), then 68, would attempt suicide, and she was determined to get it right.
She wrote a letter with instructions on where to find important documents and who should inherit what. She packed up her jewelry and artwork, addressing each box to particular friends and family members. Then she checked into a motel — homes where people have committed suicide lose value and she didn’t want hers to sell below market — put a plastic sheet on the bed, lay down and swallowed what she figured was an overdose of prescription pills with champagne.
A few days later, she woke up in a psychiatric ward in Albuquerque. The motel maid had found her. “I was very upset I had failed,” she told me recently. So she tried to cut her wrists with a bracelet she was wearing — unsuccessfully.
The suicide rate has been rising in the United States since the beginning of the century, and is now the 10th leading cause of death, according to the Centers for Disease Control and Prevention. It’s often called a public health crisis. And yet no new classes of drugs have been developed to treat depression (and by extension suicidality) in about 30 years, since the advent of selective serotonin reuptake inhibitors like Prozac.
The trend most likely has social causes — lack of access to mental health care, economic stress, loneliness and despair, the opioid epidemic, and the unique difficulties facing small-town America. These are serious problems that need long-term solutions. But in the meantime, the field of psychiatry desperately needs new treatment options for patients who show up with a stomach full of pills.
Now, scientists think that they may have found one — an old anesthetic called ketamine that, at low doses, can halt suicidal thoughts almost immediately.
Depression ran in Louise’s family. It had afflicted all her siblings, both of her parents and her grandmother. Prozac had helped Louise for a time, but stopped working for her in the late 2000s, as it sometimes does. No other drug seemed able to lift her dark moods.
After her suicide attempt, Louise’s psychiatrist suggested she try ketamine. She agreed, and received an infusion intravenously. Within hours, her sense of well-being improved. The hospital discharged her. Back home, she discovered that going to the market was no longer a “herculean task.” Getting her car washed wasn’t an insurmountable chore. “Life was better,” she said. “Life was doable.”
Using ketamine to treat depression and suicidality is somewhat controversial. Numerous small studies suggest that it holds great promise, but it’s only now being tested in placebo-controlled trials with hundreds of patients. It is also popular as a club drug in some circles. Like morphine, it may operate on the opioid system, and it can induce feelings of euphoria. Occasionally ketamine abusers develop severe symptoms, including brain damage, persistent hallucinations and a painful inflammation of the bladder called cystitis.
Nonetheless, if proven safe and effective in small doses, ketamine stands to transform how doctors deal with suicidal patients and depression generally.
The drug seems to address a longstanding problem in emergency psychiatry. Sedation and physical restraint aside, doctors have few ways to quickly stop suicidal ideation, or thoughts of killing oneself. The current crop of anti-depressants can take weeks and sometimes months to work, if they work at all. They may also, paradoxically, increase suicidality in some patients. Talk therapy takes time to help as well (assuming it does). Here’s a sobering fact: Some studies indicate that suicide risk peaks soon after patients have been discharged from a medical facility.
Researchers at Yale discovered ketamine’s potential as an antidepressant in the late 1990s and scientists at the National Institute of Mental Health confirmed it the mid 2000s. Numerous studies followed suggesting that the drug helps precisely with that subset of depressive patients — about a third — for whom nothing else works. It doesn’t work for everyone in this group, but when it does, it works within hours, not weeks.
Suicidality doesn’t perfectly overlap with depression. Many people attempt suicide not because they’re clinically depressed, but rather impulsively, because they’ve been fired or they’ve broken up with girl- and boyfriends, or sometimes because they’re just really drunk. I’ve heard people who show up in the hospital in this state — despondent, angry and uninhibited more than depressed — described as “drunkicidal.”
Many are fine once they sober up. For those who aren’t, ketamine may help independent of its effect on depression. And because ketamine is already approved by the Food and Drug Administration, doctors can prescribe it off-label. Meaning that not only does a drug exist right now that could help with depression and suicidality, it’s theoretically available to patients.
I kept thinking about this during the recent spate of high-profile suicides: the chef Anthony Bourdain, the designer Kate Spade, the actress Margot Kidder. Could ketamine have saved any of them? Did they know about it? Did their psychiatrists?
More patients should be aware of this,” Louise told me. “It really is a godsend.”
Earlier this year, I wrote about ketamine and depression for Wired, and patients I interviewed told me some version of the same thing — that ketamine changed their lives and, in some cases, saved it.
Ketamine works differently from other antidepressants. The prevailing theory is that it affects the brain’s glutamate system, which scientists now realize may be involved in depression, rather than the better-known serotonin pathway used by drugs like Prozac. Animal research suggests that partly blocking certain glutamate receptors increases brain plasticity — the ability of the brain to make new neuronal connections — and corrects some of the abnormalities that result from chronic stress. These salutary effects on the brain, coupled with how quickly ketamine works, have inspired a flurry of research. A number of drugs either derived from ketamine, or based on how scientists think it works, are in development. The pharmaceutical company Janssen is working on a nasal spray.
But ketamine has what many view as a major flaw. It can produce dissociative and hallucinatory side effects while it is being administered. Patients can feel as if they’ve left their bodies or that they’re dying. Louise described her first ketamine experience as being like Picasso’s painting “Guernica” — disjointed and unpleasant. But subsequent treatments, she said, were “wonderful” — full of images of birds, fish and whales.
Questions also remain about the safety of long-term use. Depressed patients often have to return for “booster” treatments (Louise finds that she needs an infusion once a month). The drug is considered safe when given once, but no one is sure how repeated doses may affect the brain. And ketamine can be addictive, too.
Nonetheless, dozens of clinics have opened around the country offering ketamine infusions as an off-label treatment for depression. Views on these clinics run the gamut from concerns about profiteering (Louise’s treatments cost $500 out-of-pocket; most insurance companies don’t cover ketamine when it is prescribed off-label) to acknowledgment that they may be helping desperately ill patients.
Dr. Jeffrey Lieberman, the psychiatrist in chief of Columbia University Medical Center, told the health care news site STAT that some patients may be “getting fleeced.”
Dr. Samuel Wilkinson, a Yale psychiatrist who studies ketamine, worries that some of these clinic operators forgo more established treatments to try ketamine. Case in point: Louise refused electroconvulsive therapy, because she remembers it making her mother and grandmother into “living zombies.” In Dr. Wilkinson’s view, patients should strongly consider all other reasonable possibilities before moving to ketamine. (And electroconvulsive therapy, which retains a gruesome reputation, has in fact improved greatly, he said.) He also worries that patients’ suicidal impulses could seem to disappear after ketamine treatment, leading to discharge from the hospital, but then rebound after the ketamine is stopped or tapered — something he’s seen happen in a research setting.
The deeper issue here is one of weighing the risks of new treatment that hasn’t been fully vetted and has unclear long-term side effects against a condition whose primary symptom is the urge to kill oneself.
Dr. Michael Grunebaum, a Columbia psychiatrist who studies ketamine, thinks the drug should no longer be relegated to a last-line treatment. “It makes sense that it move up in the treatment algorithm in E.R.s and inpatient units,” he told me. (Although if emergency rooms everywhere began offering ketamine, it could create new problems, he adds. As has occurred with opioids, people might claim to be suicidal when, in reality, they’re trying to get high.)
The most ringing endorsement of ketamine may come from those on the front lines of medicine: E.R. doctors. I met Louise through a doctor friend, Lowan Stewart, who works at the emergency room in Santa Fe, N.M., where she was first admitted after overdosing. He also treats patients at the ketamine clinic where Louise ended up going. Generally speaking, the protocol in emergency rooms doesn’t include giving suicidal patients ketamine, and he argues that this should change.
His view, informed by the extreme backdrop of the E.R., is worth considering. He regularly sees patients with gunshot and knife wounds, people experiencing psychotic episodes, car accident and drug overdose victims — and of course suicidal patients. Sometimes these patients beg him to kill them. Other times they threaten or attack police officers — an attempt at “suicide by cop.” Once he stabilizes them, he often has to lock them in a padded room for up to 24 hours dressed only in tearable paper pajamas, perhaps sedated, until a psychiatrist arrives. “It’s horrible,” he told me. The reality of a busy E.R. is that these patients often end up crying alone, he said.
E.R. doctors are often quite familiar with ketamine; Dr. Stewart uses it as an anesthetic regularly on children precisely because it’s considered so safe. Now that research has revealed its potential to treat depression and stop suicidal impulses, he thinks that doctors should offer it to suicidal patients in the E.R. “We could help so many people,” he said.
Moises Velasquez-Manoff, the author of “An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases” and an editor at Bay Nature magazine, is a contributing opinion writer.
Peter Grinspoon went to rehab for his opioid addiction—and realized that current faith-based abstinence programs often lack scientific research.
Kathy Jean Schultz
11.27.18 5:04 AM ET
We’re in the midst of an opioid epidemic. In the U.S., deaths spiked from 10,000 in 2002 to more than 49,000 in 2017. Canada’s steady uptick in opioid-linked deaths is highest for ages 30-39.
Treatments vary, and most of them use faith-based initiatives to attempt to stem addiction in the bud, and rely on an abstinence-only method.
The problem, say a growing number of scientists, is that these faith-based options don’t work—especially given new knowledge about how addiction affects our bodies through our brains.
The movement to redefine and understand opioid use disorder, or OUD, is welcomed by Peter Grinspoon.
A little more than a decade ago, Grinspoon had the veneer of success. He had a medical degree, a family, and was doing well in his practice. But, as he chronicled in his 2016 memoir, Free Refills: A Doctor Confronts His Addiction, he was hiding a secret: he was addicted to opioids.
Now Grinspoon, who is 11 years sober, is advocating for medication-assisted treatment, called MAT, which combines behavioral therapy with FDA-approved medications to help stem addiction.
Last month, Grinspoon published a post on Harvard Health Blog that questioned the very medical basis of addiction. Titled “Does Addiction Last a Lifetime?,” the post questions what mental health professionals understand about an “addictive personality,” a concept that he argues saddles people with lifelong vulnerability to relapse, or to re-addiction to new substances.
For one thing, he supports the use of buprenorphine. Drugs like buprenorphine lessen withdrawal symptoms and the cravings that lead to relapse and overdose.
While in rehab, Grinspoon was told, ‘A drug is a drug is a drug.’ “This mentality does not allow for a difference between the powerful opiate fentanyl, which kills thousands of people every year, and buprenorphine, which is a widely-accepted treatment for OUD,” he posted.
Grinspoon also sees a problem with the abstinence-only approach many rehabilitation centers have adopted.
“I have come to believe that an uncompromising ‘abstinence-only’ model is a holdover from the very beginnings of the recovery movement, almost 100 years ago, and our understanding has greatly evolved since then,” Grinspoon said. “The concepts of addiction and recovery that made sense in 1935, when Alcoholics Anonymous was founded, and which have been carried on by tradition, might not still hold true in the modern age of neurochemistry and functional MRIs.”
Given the opioid-overdose death rate, “uncompromising” is the key word.
“It seems as if it’s just what we’ve been doing since 1935 because there was nothing else,” he told the Daily Beast. “Now we have multi-faceted approaches to treatment, including the use of drugs like buprenorphine, which fuels OUD recovery.”
The problem, according to Grinspoon, is the very basis by which we think about and treat opioid addiction. “You treat opiate withdrawal differently than you treat alcohol withdrawal,” he said. “Yet the rehabs tend to treat every addiction the same. Most rehab centers are not using cutting-edge science.”
MAT could change that. It includes not only buprenorphine for opioid addiction, but also acamprosate for alcoholism, and naltrexone for opiates and/or alcohol. None of these drug treatments were discovered until recently, and definitely weren’t known in 1935.
But implementing change here is difficult, thanks to court-mandated NA and AA meeting attendance. Courts and probation officers, as well as police, prosecutors and local, state and federal agencies, often order OUD-related offenders to attend abstinence-only, faith-based NA or AA meetings, and have done so for decades. Yet people within the U.S. criminal justice system experience high rates of OUD and overdose, according to a recent Johns Hopkins University study.
That study, published last December in the journal Health Affairs, looked at 72,000 adults in an OUD treatment program, including 17,000 referred by criminal justice agencies.
The researchers found that less than 5 percent of OUD-related offenders ordered into treatment received MAT. In contrast, 40 percent of people referred by employers or healthcare providers received MAT.
That potentially set them up for failure. The study authors found that MAT’s behavioral therapy-fueled approach could decrease overdose risk within the court-ordered population, many of whom lack homes, jobs, medical care or other factors that contribute to OUD upon release from jail. Despite its promise, researchers found that courts were unlikely to refer misusers to MAT.
That doesn’t surprise Grinspoon.
“Judges are vastly under-educated about modern addiction, both the disease and the treatment,” Grinspoon said. “I was forced, by my professional medical society, into a pretty religious 12-step rehab program for 90 days and, as an atheist, I found it counterproductive at best. Judges need to enable people to access modern treatments, not the old-fashioned, non-evidence-based mush that is called ‘treatment’ at many rehab centers.”
Nora Volkow, the Director of the U.S. National Institute on Drug Abuse, agrees. “In general, studies show abstinence-only programs do not work with opioids,” Volkow told the Daily Beast. “There may be some misusers for whom it does work, but in the majority of cases it does not. People with OUD have a very high rate of relapse in abstinence-only programs, and the death rate during relapse can be as high as 90 percent.”
Volkow said that many treatment options don’t take into account the fact that OUD acts differently from that of other disorders from common addictive substances. “What opioids do is to kidnap the system that drives our motivation for survival,” she explained. “For example, if you have not eaten for days your brain will make getting food a priority, for survival. But when you are opioid-addicted your brain is not able to do any of the things we normally do to survive.”
Laura Schmidt is a University of California San Francisco School of Medicine professor who recently wrote a paper published in Drug and Alcohol Review on alternative methods of opioid addiction treatment. She says addiction remains surprisingly misunderstood.
“The addictive-personality concept has pretty much been debunked by research,” Schmidt told The Daily Beast. “The biggest problem now is capacity. We simply don’t have enough treatment slots for everyone who needs them.” Analyses have shown OUDs far exceed treatment need: in 2017, more than 450,000 people with OUD were unable to access treatment.
Schmidt, like Grinspoon, points out that addiction has been freighted by history, ever since the 19th century temperance movement that saw alcohol consumption as abhorrent. “With that framework in place, treatment providers strategically deploy what’s called a moral/medical model, depending upon the patient,” Schmidt explained. “When providers decide patients need to be held morally accountable, they get patients to stay sober by shaming them.
“In the very process of doing that, they continue to promulgate the idea that addiction is the addicts’ fault,” Schmidt added. “Providers think by shaming patients they can get them clean.”
That approach is problematic, and leads to a vicious circle of further stigmatization, which Schmidt said could also lead to the significant barrier to funding treatment patients face in dealing with insurance companies.
It’s something Schmidt has, in fact, seen in her own work.
“I worked on a study of a healthcare organization offering OUD treatment to their members,” Schmidt said. “There was a waiting list, and while people were waiting to enroll in our study, a few were able to receive MAT. They told others on the waiting list that MAT had helped them stay off opioids, and eventually through word-of-mouth, OUD misusers began asking us if they could get into MAT. So the word spread that it helped to quell craving and withdrawal sickness.
“This was really notable to me,” Schmidt continued. “The misusers themselves were more open-minded about treatment alternatives than NA suggestions. They wanted what works.”
Advances in MAT grew out of investigation into the science of brain imaging. Scientists were able to see inside the brain of an addicted person and pinpoint parts affected by drug abuse. The discovery of brain circuits underlying addiction has resulted in development of effective medications — including buprenorphine, naloxone, and acamprosate. One study actually mapped out what appear to be relapse pathways in the brains of opiate-dependent users.
New research has shown how those neural circuits are detectable via functional magnetic resonance imaging, or fMRI. fMRI can show whether oxygen levels and electricity flows inside a misuser’s brain are normal or abnormal. fMRIs have shown how craving contributes to cocaine relapse, for example. Cocaine users’ own feelings of craving matched their fMRI images, which showed activity in the craving area of their brains.
It’s a critical discovery in the science of addiction, one that Schmidt said was “hard to deny.”
Multi-pronged approaches that combine fMRI, recovery program meetings and MAT, along with other new techniques, are beginning to gain acceptance. They’re already in place in states from Washington to Vermont.
But will that actually stem the deaths resulting from the opioid crisis? “There is a pervasive bias in the rehab network against this kind of medicine-assisted treatment,” Grinspoon said—but he’s optimistic that MAT and other medically based treatments might help reverse the upward spike of opioid deaths every year.