In a webinar broadcast by the Brain & Behavior Research Foundation on June 12, 2018, Dr. Krystal explained how basic research on the biology of PTSD and depression led to a trial he is currently leading focusing on veterans and active-duty military with PTSD. His team will study the dose-related safety and effectiveness of 4 weeks of ketamine infusions. Ketamine “acts rapidly, it’s anti-suicidal, [and] it works for people who don’t respond to other kinds of treatment,” he said.
Dr. Krystal, a member of BBRF’s Scientific Council and the recipient of BBRF Distinguished Investigator grants in 2006 and 2000 and an Independent Investigator grant in 1997, began research with ketamine in the late 1980s. “Ketamine is the tip of an iceberg for potentially a whole new generation of pharmacologic approaches for mood disorders,” he said.
The Need for New Options
This month, the manufacturer of a nasal spray variant of ketamine called esketamine asked the Food and Drug Administration to approve it as a treatment for severe depression. If the agency agrees, esketamine will be the first approved new medication in decades to treat severe depression.
Doctors know ketamine as an intravenous anesthetic used most often on children and animals and abused as the party drug sometimes referred to as “Special K.” In the early 1990s, it became clear that slow infusions of ketamine at very low doses gave quick but brief relief to patients with severe depression.
Dr. Krystal noted evidence that ketamine may work especially quickly in people with bipolar depression and offers hope for others in need of new options: people who fail to respond to electroconvulsive therapy, people with a psychotic depression, people with severe anxiety or agitation as well as those with severe pain.
PTSD patients badly need a new solution, he explained: they only see about a 10% reduction beyond placebo with current anti-depressants. Combat-related symptoms are especially tough. The Department of Veteran Affairs funded two large trials of promising drugs, Prasozin and Risperidone, but they proved ineffective. Moving forward, Dr. Krystal explained, requires turning to “a deeper understanding of the biology” underlying depression and PTSD.
Is Glutamate the Important Neurotransmitter in Depression and PTSD?
Current anti-depressants boost the availability of serotonin or serotonin and norepinephrine, two neurotransmitters that enable neurons in the brain to communicate. It has been proposed that depression involves a paucity of those neurotransmitters. Dr. Krystal, with his colleague Dennis Charney, M.D., also a member of the BBRF Scientific Council and Dean of the Icahn School of Medicine at Mount Sinai in New York, found evidence otherwise. “He led a series of studies showing that depleting the body of serotonin, or depleting the body of norepinephrine, or [both], did not produce depression in people,” Dr. Krystal explained. “This suggested to us that maybe the biology of depression and stress-related disorders didn’t primarily live in the primitive parts of the brain that use serotonin or norepinephrine to communicate, but rather in the higher centers of the brain, the cerebral cortex, where glutamate is the predominant neurotransmitter.”
Both PTSD and depression can be caused by stress. Releasing cortisol is part of the stress response, our reaction to danger. Cortisol “can be harmful if it’s too much for too long, but it may also be harmful if it’s too little for too brief a period,” Dr. Krystal said. In unipolar depression, we get a continual bath of cortisol, which is abnormal. In people with PTSD, not enough cortisol may have been released at moments of extreme stress.
The result may be a loss of connection-points between neurons, called synapses. Dr. Krystal found evidence of this loss in a pioneering MRI brain scan study of PTSD patients published in 1995. “Nowadays, using functional MRI, we can show that functional connections in the brain are reduced in PTSD in relation to or correlated with the overall severity of PTSD, and symptoms such as numbing and hyper arousal,” he said.
In both PTSD and depression, the brain evidently fails to remodel the lost connections. But over months of treatment with anti-depressants, brain scans show regrowth of dendritic spines—connection terminals and key players in the metabolism of glutamate.
Ketamine is thought by some to block the N-methyl-D-aspartate (NMDA) receptor, which binds glutamate. The temporary block may jolt the brain to release glutamate, prompting a cascade of regrowth and reorganization. For some people, a single dose of ketamine can make depression disappear for several days, or for as long as two weeks.
Dr. Krystal points out that this isn’t because of the initial euphoria that explains why people abuse the party drug Special K. “There’s no ketamine in the body at the time when people are reporting the greatest clinical benefit,” he noted. The benefit is an after-effect, not yet understood scientifically.
Dissociation—feeling detached from one’s own body—and occasional nausea, two side-effects of ketamine, are easily managed in a clinic, “and we have not had cases of drug abuse,” Dr. Krystal said, referring to carefully controlled experimental use of ketamine in clinical settings. A many as three-quarters of severe depression patients who have tried ketamine infusions have found some relief. Over time, many need less frequent infusions: 40 percent of Yale’s patients come for infusions once a month or less often. The long-term effectiveness and impact of ketamine remain unproven.
“This new neurobiology of PTSD and depression suggests that there may be other mechanisms for treatment that may come from this line of research,” Dr. Krystal concluded. He hopes to have results from the PTSD trial by early 2020.
Ketamine was originally approved by the US Food and Drug Administration (FDA) as an anesthetic, but is increasingly being used to treat mood disorders, such as treatment-resistant depression, anxiety disorders, and post-traumatic stress disorder (PTSD).1,2 Several studies have also found it to be effective for treating suicidal ideation.3,4
“Ketamine can play an important role in the treatment of anxiety disorders,” according to Prakash Masand, MD, co-founder, chairman, and CEO of Centers of Psychiatric Excellence (COPE) (https://www.copepsychiatry.com) and adjunct professor at the Academic Medicine Education Institute, Duke-National University of Singapore Medical School (Duke-NUS).
“Nowadays, people with anxiety disorders are treated either with a generic antidepressant, such as an SSRI (selective serotonin reuptake inhibitor), an SNRI (selective norepinephrine reuptake inhibitor), or a benzodiazepine and if they don’t respond to one of these, they get a trial of another or several more,” Dr Masand said.
“No good current strategies are available for these non-responders, so novel agents are being studied — including ketamine, which is accumulating an evidence base as [being] rapidly effective for an array of anxiety disorders, including social anxiety disorder (SAD) and PTSD,” he said.
How Does Ketamine Work?
A growing body of evidence points to the role of glutamate, a widely distributed excitatory neurotransmitter, in mediating response to stress and the formation of traumatic memories.2 Ketamine is an ionotropic glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist. Its antidepressant and anti-anxiety effects are presumed to occur through activating synaptic plasticity by increasing brain-derived neutrophic factor translation and secretion and also by inhibiting glycogen synthase kinase-3 and activating mammalian target of rapamycin signaling.5
Brain-derived neutrophic factor plays a role in behavioral responses to classical antidepressants, but the impact on synaptic plasticity may take several weeks to manifest. In contrast, ketamine-mediated synaptic plasticity changes appear to occur within a matter of hours after ketamine administration.5
“The current thinking is that eventually, 6 to 12 weeks after initiating treatment with traditional antidepressants, dendritic growth and increased synaptic connections occur but with ketamine, these can occur within 24 hours of the infusion,” Dr Masand said.
Ketamine and Anxiety: An Increasing Evidence Base
“Ketamine has been studied and shown [to be] effective with an array of anxiety disorders, including SAD, general anxiety disorder (GAD), and PTSD, although the data on its effectiveness in obsessive compulsive disorder (OCD) are more mixed,” Dr Masand observed.
A small study of patients with GAD and/or SAD (n=12) compared 3 ascending ketamine doses to midazolam. Each was given at 1-week intervals, with midazolam counterbalanced in dosing position across patients. Ketamine was found to dose-dependently improve scores on the Fear Questionnaire. Moreover, it’s impact on decreasing theta frequency in the right frontal sites assessed via electroencelphalogram (EEG) was comparable to that of conventional anxiolytics.6
Glue et al evaluated the efficacy and safety of ketamine in 12 patients with refractory GAD and/or SAD who were not currently depressed using an ascending single-dose at weekly intervals study design. Within 1 hour of dosing, patients reported reduced anxiety, which persisted for up to 7 days.7
A continuation of that study evaluated the impact of maintenance treatment ketamine in patients with GAD and/or SAD (n=20) and found that 18 of the 20 patients reported ongoing improvements in social functioning and/or work functioning during maintenance treatment. The researchers concluded that maintenance therapy ”may be a therapeutic alternative for patients with treatment-refractory GAD/SAD.”8
“What is interesting about this study is that the impact of just one infusion lasted for 14 weeks, suggesting that patient[s] with anxiety disorders might have longer maintenance of response than patients with major depression, where the response has been maintained for only one week,” Dr Masand commented.
A study of patients with anxious and non-anxious bipolar depression (n=21 for both groups) found that both anxious and non-anxious patients with bipolar depression had significant antidepressant responses to ketamine, although the anxious depressed group did not show a clear antidepressant response disadvantage over the non-anxious group.9 “Given that anxiety has been shown to be a predictor of poor treatment response in bipolar depression when traditional treatments are used, our findings suggest the need for further investigations into ketamine’s novel role in the treatment of anxious bipolar depression.,” the investigators concluded.9
An open-label trial of ketamine in 10 patients with treatment-refractory OCD found that ketamine’s effects on OCD symptoms, in contrast to depressive symptoms, did not seem to persist or progress after the acute effects of ketamine had dissipated.10
On the other hand, another randomized controlled trial (RCT) of 15 patients with OCD found that anti-OCD effects from a single intravenous dose of ketamine persisted for more than 1 week in some patients with OCD with constant intrusive thoughts, demonstrating that “a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an [SSRI].”11
In PTSD, there is “mounting evidence for a role of the excitatory neurotransmitter glutamate in stress responsiveness, the formation of traumatic memories, and the pathophysiology of PTSD, raising the possibility of identifying novel glutamatergic interventions for this disorder.”12
One double-blind study demonstrated that infusion of ketamine rapidly and significantly reduces symptom severity in patients with PTSD compared with midazolam.2
Another study found that administration of ketamine immediately after witnessing a traumatic event has been shown to prevent the enhancement of passive avoidance learning in mice.13 Ketamine may thus target the mechanisms involved in the consolidation of traumatic memory and may enable the brain to reconsolidate memory and release trauma.14
A case study of a child with PTSD reported remission from behavioral dysregulation after receiving procedural ketamine.15
Drawbacks and Potential Adverse Effects
The main concern regarding the use of ketamine for anxiety disorders is the lack of a road map regarding maintenance, Dr Masand noted.
“At COPE, we have found that roughly 30% to 40% of our patients being treated with ketamine require maintenance infusions, and we highly personalize this approach so that patients can identify early signs of recurrence or relapse and we can devise a treatment schedule to prevent them,” he said.
Some patients continue treatment with pharmacotherapy, including standard antidepressants, benzodiazepines, or a mood stabilizer such as valproate and some patients become more receptive to psychotherapies such as CBT,” he stated.
However, “there is very little data regarding what happens long-term in this patient population.”
“Most side effects are mild and transient,” Dr Masand reported. “Patients must be monitored because of potential increases in blood pressure and pulse.”
Additional adverse events include nausea or vomiting, which are also mild and transient. Patients may be pre-treated with prophylactic anti-nausea medication, such as ondansetron, to pre-empt these symptoms, he said.
Some patients experience dissociation, or an out-of-body experience, which is also usually transient but seen by some patients as “annoying,” he noted. “Dissociative experiences are sometimes seen as a biomarker for insufficient response and suggest that the dose should be increased.”
Providers should be aware that cystitis and lower urinary tract pathologies (eg, detrusor over-activity) have been reported in long-term ketamine users, but typically only at high doses.16
Ketamine’s psychedelic effects make it a” popular recreational drug.”16 At lower doses, the predominant effects are stimulating, and users experience mild dissociation with hallucinations and a distortion of time and space. However, higher doses can induce more severe, schizophrenia-like symptoms and perceptions.16 Although these effects resolve rapidly, long-term use “can cause more pronounced and persistent neuropsychiatric symptoms. For this reason, ketamine should be “used cautiously with other drugs that alter mood and perception, including alcohol, opioids, benzodiazepines and cannabis.”16
“Ketamine for treatment-resistant depression has a robust evidence base and a rapidly-growing evidence base for its use in anxiety disorders,” Dr Masand said.
“Given the gaps in current treatment, this promising agent is occupying a more promising role in treatment of anxiety disorders, such as PTSD. Considering how common PTSD is, ketamine can make an important difference for a large number of people who suffer from this debilitating condition,” he concluded.
First Person Account of Ketamine Therapy: An Interview with Kimberly Palmer
To gain insight into the experience of ketamine treatment in a person with depression and anxiety, Psychiatry Advisor interviewed Kimberly Palmer of Los Angeles, California. Ms Palmer received treatment at the Ketamine Clinics of Los Angeles (https://www.ketamineclinics.com). Ms Palmer works as a program manager for a consulting company where she organizes and runs corporate events for small groups.
Psychiatry Advisor:What made you decide to pursue ketamine treatment?
Ms Palmer:I was raised in an abusive home, and as an adult I had severe major depression, as well as anxiety. I was treated with medications, such as antidepressants, but they had many adverse events and they ended up making me feel like a zombie, so I discontinued them. I managed okay for a while, but then I had another major depressive episode.
I was receiving psychotherapy at the time and it was only moderately helpful — not enough to stop the episode. Fortunately, I knew someone who works at a ketamine clinic. She told me how many patients had been helped by ketamine and I was interested, mostly because the adverse events of ketamine seemed mild and are not long-term.
Psychiatry Advisor: What were your experiences during your infusion?
Ms Palmer: I felt incredible during the infusion. The best way I can describe it is by referring to the movie Avatar, specifically the scene in which the protagonist is walking through a jungle at night for the first time and touching all the plants, which light up with pretty colors—very vivid, colorful, and not linear. There was the sensation of being on a sort of roller coaster, riding through different scenes.
At one point, it felt as though my chair was on a cloud. Then suddenly, the chair disappeared and I was floating on the cloud. It was a wonderful experience.
Psychiatry Advisor: How did the ketamine treatment affect you afterwards?
Ms Palmer: After only one treatment, it was as if a switch had flipped in my brain that allowed me to digest things and move beyond my trauma. Before the infusion, a lot of what was going on with me had to do with self-esteem issues and negative self-talk. These were behaviors learned over many years. After the infusion, the negative self-talk immediately disappeared. All of those thoughts — such as telling myself I am not good enough — that were preventing me from working through emotional issues, were resolved. I was able to start looking at things more objectively rather than taking them personally, and not take on responsibility for other people’s emotions and reactions.
I am currently working with a therapist and a life coach to help me feel more comfortable with communication because I was raised not to ask for things and to put up with anything I’m asked to do. As a result, I have developed a much more positive outlook of myself and the world.
Psychiatry Advisor: How many ketamine treatments have you had?
Ms Palmer: Over a 6-month period I had 6 treatments, which were all very helpful. Then, 6 months after the conclusion of this first series of treatments, some new issues came up, so I received 2 more — one regular 60-minute treatment and one extended 90-minute treatment.
Recently, with the holidays coming up, I decided to pre-empt the effect of some stressors and have another treatment. My most recent infusion took place the day after my father passed away. I noticed that during the infusion, I was able to steer myself away from negative thoughts about that issue. Although I cannot control what visions or experiences I might have, I do have some control over the direction of my thoughts and the after-effects have been positive and helpful.
Psychiatry Advisor: Did you have any adverse events from the treatments?
Ms Palmer: I had no negative physical effects. I had one mild bad reaction, when I came to the treatment session in an agitated state because I had gotten into a fight with someone right before. I was sad and crying by the time I finished the infusion. But I was in a bad headspace before I even walked into the room. And my experience was not scary, only sad.
Psychiatry Advisor: What impact has your treatment had on your day-to-day life?
Ms Palmer: My depression had interrupted my schooling. I was in school for 3 and a half years and then I hit a roadblock. After the treatments, I was able to complete my studies and graduated with a BA in business administration and management.
My job is stressful. I counterbalance the stress with hobbies like surfing and photography. But there are still stressors, and I have a dog who is reaching the end of life, which is affecting me. The ketamine treatments have helped me to manage those stressors.
National Institutes of Health researchers found that a single, low-dose ketamine infusion was relatively free of side effects for patients with treatment-resistant depression. Elia Acevedo-Diaz, M.D., Carlos Zarate, M.D., and colleagues at the NIH’s National Institute of Mental Health (NIMH) report their findings in the Journal of Affective Disorders.
Studies have shown that a single, subanesthetic-dose (a lower dose than would cause anesthesia) ketamine infusion can often rapidly relieve depressive symptoms within hours in people who have not responded to conventional antidepressants, which typically take weeks or months to work. However, widespread off-label use of intravenous subanesthetic-dose ketamine for treatment-resistant depression has raised concerns about side effects, especially given its history as a drug of abuse.
“The most common short-term side effect was feeling strange or loopy,” said Acevedo-Diaz, of the Section on the Neurobiology and Treatment of Mood Disorders, part of the NIMH Intramural Research Program (IRP) in Bethesda, Maryland. “Most side effects peaked within an hour of ketamine administration and were gone within two hours. We did not see any serious, drug-related adverse events or increased ketamine cravings with a single-administration.”
The researchers compiled data on side effects from 163 patients with major depressive disorder or bipolar disorder and 25 healthy controls who participated in one of five placebo-controlled clinical trials conducted at the NIH Clinical Center over 13 years. While past studies have been based mostly on passive monitoring, the NIMH IRP assessment involved active and structured surveillance of emerging side effects in an inpatient setting and used both a standard rating scale and clinician interviews. In addition to dissociative (disconnected, unreal) symptoms, the NIMH IRP assessment examined other potential side effects — including headaches, dizziness, and sleepiness. The study did not address the side effects associated with repeated infusions or long-term use.
Out of 120 possible side effects evaluated, 34 were found to be significantly associated with the treatment. Eight occurred in at least half of the participants: feeling strange, weird, or bizarre; feeling spacey; feeling woozy/loopy; dissociation; floating; visual distortions; difficulty speaking; and numbness. None persisted for more than four hours. No drug-related serious adverse events, cravings, propensity for recreational use, or significant cognitive or memory deficits were seen during a three-month follow-up.
To overcome the limitations associated with side effects and intravenous delivery, ongoing research efforts seek to develop a more practical rapid-acting antidepressant that works in the brain similarly to ketamine. These NIMH researchers, in collaboration with the National Institute on Aging, and the National Center for Advancing Translational Science, are planning a clinical trial of a ketamine metabolite that showed promise as a potentially more specific-acting treatment in pre-clinical studies. Meanwhile, the U.S. Food and Drug Administration earlier this year approved(link is external) an intranasal form of ketamine called esketamine, which can be administered to adults with treatment-resistant depression in a certified doctor’s office or clinic.
About the National Institute of Mental Health (NIMH): The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.
About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
NIH…Turning Discovery Into Health®
Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression. Acevedo-Diaz EE, Cavanaugh GW, Greenstein D, Kraus C, Kadriu B, Zarate CA Jr, Park LT. https://doi.org/10.1016/j.jad.2019.11.028(link is external), Nov. 10, 2019, Journal of Affective Disorders.
Gerard Sanacora, a professor of psychiatry at Yale University, has treated hundreds of severely depressed patients with low doses of ketamine, an anesthetic and popular club drug that isn’t approved for depression.
This sort of “off-label” prescribing is legal. But Sanacora says other doctors sometimes ask him, “How can you be offering this to patients based on the limited amount of information that’s out there and not knowing the potential long-term risk?”
Sanacora has a simple answer.
“If you have patients that are likely to seriously injure themselves or kill themselves within a short period of time, and they’ve tried the standard treatments, how do you not offer this treatment?” he says.
More and more doctors seem to agree with Sanacora.
Dozens of clinics now offer ketamine to patients with depression. And a survey of providers in the U.S. and Canada showed that “well over 3,000” patients have been treated so far, Sanacora says.
A number of small studies have found that ketamine can do something no other drug can: it often relieves even suicidal depression in a matter of hours in patients who have not responded to other treatments.
Ketamine’s potential as an antidepressant was recognized more than a decade ago. And studies done since then provide “compelling evidence that the antidepressant effects of ketamine infusion are both rapid and robust, albeit transient,” according to a consensus statement from a task force of the American Psychiatric Association. Sanacora is one of the task force members.
But there are still a lot of unanswered questions about ketamine, says James Murrough, an assistant professor of psychiatry and neuroscience at the Icahn School of Medicine at Mt. Sinai in New York.
“We haven’t had large-scale trials. We don’t know how much or how often it should be given for it to be effective or safe,” says Murrough, who is an author of a review of ketamine published in the journal Nature Reviews Drug Discovery.
Doctors know a lot about the short-term effects of ketamine because it has been used as an anesthetic in emergency rooms for decades. But there’s still not much information about the effects of using ketamine for years.
That’s worrisome because ketamine’s antidepressant effect tends to wear off after a few days or weeks, meaning patients need repeated infusions to keep depression at bay, Murrough says.
Still, Murrough thinks the case for using ketamine is much stronger than it was just a few years ago.
“There’s warranted caution that’s balanced with an optimism that says we’ve never had a new medication for depression since the era of Prozac,” Murrough says.
Prozac arrived in the 1980s, and became the first of a new class of depression drugs that target the neurotransmitter serotonin.
Ketamine acts on a different neurotransmitter called glutamate. The drug’s success has pharmaceutical companies excited about the possibility of creating a whole new class of drugs for depression, Murrough says.
“Companies are reopening programs,” he says. “They are pulling [old] drugs off the shelf that they know act on the glutamate system.”
One promising candidate is a chemical sibling of ketamine called esketamine. It’s now in the final phase of testing before consideration by the Food and Drug Administration, which designated esketamine as a breakthrough therapy.
And esketamine is just one of several ketamine-like drugs in development, says Sanacora, who consults for companies developing these drugs.
“This is probably the most interesting and exciting new development that I’ve seen in my career, and probably going back over the past 50 to 60 years,” he says.
Party drug’s power to fight depression puzzles scientists.
The anaesthetic ketamine — a hallucinogenic club drug also known as Special K — has tantalized researchers who are seeking new ways to treat depression. The drug can lift a person’s mood in hours, even when depression is severe. But several ‘ketamine-like’ medications have failed to alleviate depression in clinical trials over the past decade.
Now, some researchers think they know why. Emerging evidence suggests that scientists have misunderstood how ketamine fights depression. So they might have attempted to mimic the wrong biological mechanism when designing drugs to improve mood while avoiding the disorienting ketamine high.
On 20 May, researchers at a meeting of the Society of Biological Psychiatry in San Diego, California, will present results suggesting that some of ketamine’s power comes from its ability to affect brain cells called glia, which support neurons. Their finding adds to recent studies contradicting a long-held idea that the drug works mainly by blocking proteins called NMDA receptors, on the surface of brain cells, which transmit signals between those cells.
At the upcoming meeting, a team led by neuroscientist Mark Rasenick of the University of Illinois at Chicago will report on tests of antidepressant drugs in cultured rat glial cells. All of the drugs that the researchers studied caused a cluster of proteins to shift position in the glial cells’ membranes, signalling to the cells to form new connections with their neighbours. But ketamine produced this effect in 15 minutes, as compared to 3 days for conventional antidepressants.
Moreover, drugs that block NMDA receptors but are not antidepressants did not show the effect at all. This suggests that ketamine’s ability to bind to NMDA receptors might not be its primary weapon against depression.
Rasenick’s team is not the first to suggest a different target for ketamine. A paper published in Nature in May 2016 concluded that one of ketamine’s breakdown products — not the drug itself — probably lifted depression in mice1. And this compound affected cell proteins called AMPA receptors, instead of NMDA receptors.
The team behind the study plans to test the breakdown product in clinical trials later this year. But study co-author Carlos Zarate, a psychiatrist at the US National Institute of Mental Health in Bethesda, Maryland, says that it is too early to abandon the NMDA-receptor hypothesis, and more data are needed.
Others agree. “We have to be careful not to interpret [the latest] clinical findings as definitively negative,” says Gerard Sanacora, a psychiatrist at Yale University in New Haven, Connecticut. Rodent studies have shown, for example, that blocking NMDA receptors can have an antidepressant effect2.
And there could be more-prosaic explanations for why so many ketamine-like drugs that target NMDA receptors — including candidates from the drug giants Roche, Pfizer and AstraZeneca — have failed in clinical trials. Participants might have received doses that were too small or infrequent to buoy their moods. And in trials with control groups, the placebo effect can make it difficult to determine whether a psychiatric drug is working.
The companies that are still testing drugs to inhibit NMDA receptors are trying to make sense of the latest findings on ketamine and its would-be imitators. “We do need to tease all this apart,” says David Nicholson, chief research-and-development officer at Allergan in Parsippany, New Jersey. In February, Allergan began treating around 500 people with a molecule called rapastinel, which binds to NMDA receptors and showed promising results in earlier trials.
Yet, the most enduring mystery involves ketamine itself, as researchers try to untangle what makes the drug so potent. Alan Schatzberg, a psychiatrist at Stanford University in California suspects that ketamine could act against depression in many ways: jump-starting the process by some as-yet-unknown mechanism, perhaps, and then blocking NMDA receptors to permanently rewire the brain.
Schatzberg also points out that ketamine can act similarly to morphine and rapidly bind to opioid receptors in the brain, which could explain why its effects are apparent within hours. And some studies have found that people with depression are more likely to benefit from ketamine if they do experience that out-of-body feeling, suggesting that it might be related to the drug’s main mechanism3.
In the meantime, the hunt continues for drugs that can replicate ketamine’s mood-boosting power. That could be difficult, says Steven Levine, a psychiatrist and president of Ketamine Treatment Centers in New York City. “Ketamine is a dirty, dirty drug,” he says. “It goes a lot of places, it does a lot of things.”