Depression Esketamine Ketamine

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Ketamine Study Reveals How to Make It an Even Better Depression Treatment

In early March, the FDA approved a nasal spray for depression based on ketamine, a substance once known only as a rave drug. Despite its reputation, ketamine is so promising as an anti-depressant that it will soon be available in licensed clinics throughout the country. A study published in Science on Thursday proposes the new treatment can be made even better.

In their paper, a team of scientists at Weill Cornell’s Medicine’s Feil Family Brain and Mind Research Institute show that ketamine can help the brain reform synapses, crucial connections between neurons, that can alleviate depressive symptoms. Ketamine is already famous for working quickly to relieve depressive symptoms — within days or hours — co-author Conor Liston, Ph.D., tells Inverse, but maintaining those crucial connections is key to extending its effects.

“Our study shows that the formation of new connections (synapses) between brain cells is required for sustaining ketamine’s antidepressant effects in the days after treatment,” says Liston, also professor of neuroscience at Weill Cornell. “Ketamine is an exciting new treatment for depression that differs from drugs like SSRIs in that it relieves symptoms rapidly. However, those effects are not always sustained.”

upset, depressed
Ketamine-based nasal spray is a new FDA-licensed drug for treatment-resistant depression.

Growing Back Dendritic Spines

In a mouse model, Liston and his co-authors demonstrated that doses of ketamine helped mouse brains regrow dendritic spines, small protrusions on neurons that help them pick up signals rom other cells that, crucially, degrade during exposure to chronic stress. These dendritic spines are a key part of synapse formation.

The degradation of these spines is not a perfect analog to human depression, but humans have them as well, and Liston points out that some of the most important features of depression in humans are also present in chronically stressed mice.

To create depression-like conditions, the team degraded the dendritic spines in their mice using stress hormones. Then, they gave one group a dose of ketamine, which they expected to have anti-depressive effects.

dendritic spine
A dendritic spine helps form a synapse — a connection to another neuron.

The dose of ketamine not only changed the mice’s behavior — they tried harder to escape their cages — it also helped reform the dendritic spines in their brains. Interestingly, the ketamine didn’t form random dendritic spines but actually seemed to replace the old ones that had been degraded by constant stress. Of the new spines formed, 47.7 percent grew within two micrometers of where the old ones once were.

Why Dendritic Spines Are Important

The new dendritic spines serve an important purpose in the mouse brains. Within three hours of treatment, previously damaged circuits in the prefrontal cortex were starting to come back online, but this happened before new synapses form. At the end of the experiment, an estimated 20.4 to 31.0 percent of the lost synapses were restored after the mice took ketamine.

The fact that the circuits were restored before the synapses reformed suggests that ketamine jump-starts a two-step process that fights depression. The first step is the rapid anti-depressant effect that is seen in so many studies. The second step — regrowing the spines and restoring synapses — occurs more slowly, which means it’s the one scientists should focus on if they’re looking to make ketamine’s effects on depression last longer, Liston says.

When Liston used blue light to artificially remove the newly grown spines in a follow-up experiment, the mice relapsed into depressive symptoms. It suggested that maintaining these dendritic spines is important in keeping depression at bay.

“Our results suggest that interventions aimed at enhancing the survival of newly formed connections in prefrontal brain circuits could be useful for augmenting ketamine’s antidepressant effects by increasing their durability in the days and weeks after treatments.”

The FDA’s approval of a ketamine-based drug to treat depression was groundbreaking in itself, especially since it works differently than other anti-depressant drugs. But just because it’s been approved doesn’t mean there aren’t ways to improve it. Depression can be alleviated with ketamine, but for now the illness constantly threatens individuals with remission. Preventing the potential for a relapse with the promise of longer-lasting effects is one way to make this already remarkable drug even more helpful.

tructured Abstract

INTRODUCTION

Depression is an episodic form of mental illness, yet the circuit-level mechanisms driving the induction, remission, and recurrence of depressive episodes over time are not well understood. Ketamine relieves depressive symptoms rapidly, providing an opportunity to study the neurobiological substrates of transitions from depression to remission and to test whether mechanisms that induce antidepressant effects acutely are distinct from those that sustain them.

RATIONALE

Contrasting changes in dendritic spine density in prefrontal cortical pyramidal cells have been associated with the emergence of depression-related behaviors in chronic stress models and with ketamine’s antidepressant effects. But whether and how dendritic spine remodeling is causally involved, or whether it is merely correlated with these effects, is unclear. To answer these questions, we used two-photon imaging to study how chronic stress and ketamine affect dendritic spine remodeling and neuronal activity dynamics in the living prefrontal cortex (PFC), as well as a recently developed optogenetic tool to manipulate the survival of newly formed spines after ketamine treatment.

RESULTS

The induction of depression-related behavior in multiple chronic stress models was associated with targeted, branch-specific elimination of postsynaptic dendritic spines and a loss of correlated multicellular ensemble activity in PFC projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predicted motivated escape behavior. Unexpectedly, ketamine’s effects on behavior and ensemble activity preceded its effects on spine formation, indicating that spine formation was not required for inducing these effects acutely. However, individual differences in the restoration of lost spines were correlated with behavior 2 to 7 days after treatment, suggesting that spinogenesis may be important for the long-term maintenance of these effects. To test this, we used a photoactivatable probe to selectively reverse the effects of ketamine on spine formation in the PFC and found that the newly formed spines play a necessary and specific role in sustaining ketamine’s antidepressant effects on motivated escape behavior. By contrast, optically deleting a random subset of spines unrelated to ketamine treatment had no effect on behavior.

CONCLUSION

Prefrontal cortical spine formation sustains the remission of specific depression-related behaviors after ketamine treatment by restoring lost spines and rescuing coordinated ensemble activity in PFC microcircuits. Pharmacological and neurostimulatory interventions for enhancing and preserving the rescue of lost synapses may therefore be useful for promoting sustained remission.

Why is ketamine an antidepressant?

A better understanding of the mechanisms underlying the action of antidepressants is urgently needed. Moda-Sava et al. explored a possible mode of action for the drug ketamine, which has recently been shown to help patients recover from depression (see the Perspective by Beyeler). Ketamine rescued behavior in mice that was associated with depression-like phenotypes by selectively reversing stress-induced spine loss and restoring coordinated multicellular ensemble activity in prefrontal microcircuits. The initial induction of ketamine’s antidepressant effect on mouse behavior occurred independently of effects on spine formation. Instead, synaptogenesis in the prefrontal region played a critical role in nourishing these effects over time. Interventions aimed at enhancing the survival of restored synapses may thus be useful for sustaining the behavioral effects of fast-acting antidepressants.

Structured Abstract

INTRODUCTION

Depression is an episodic form of mental illness, yet the circuit-level mechanisms driving the induction, remission, and recurrence of depressive episodes over time are not well understood. Ketamine relieves depressive symptoms rapidly, providing an opportunity to study the neurobiological substrates of transitions from depression to remission and to test whether mechanisms that induce antidepressant effects acutely are distinct from those that sustain them.

RATIONALE

Contrasting changes in dendritic spine density in prefrontal cortical pyramidal cells have been associated with the emergence of depression-related behaviors in chronic stress models and with ketamine’s antidepressant effects. But whether and how dendritic spine remodeling is causally involved, or whether it is merely correlated with these effects, is unclear. To answer these questions, we used two-photon imaging to study how chronic stress and ketamine affect dendritic spine remodeling and neuronal activity dynamics in the living prefrontal cortex (PFC), as well as a recently developed optogenetic tool to manipulate the survival of newly formed spines after ketamine treatment.

RESULTS

The induction of depression-related behavior in multiple chronic stress models was associated with targeted, branch-specific elimination of postsynaptic dendritic spines and a loss of correlated multicellular ensemble activity in PFC projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predicted motivated escape behavior. Unexpectedly, ketamine’s effects on behavior and ensemble activity preceded its effects on spine formation, indicating that spine formation was not required for inducing these effects acutely. However, individual differences in the restoration of lost spines were correlated with behavior 2 to 7 days after treatment, suggesting that spinogenesis may be important for the long-term maintenance of these effects. To test this, we used a photoactivatable probe to selectively reverse the effects of ketamine on spine formation in the PFC and found that the newly formed spines play a necessary and specific role in sustaining ketamine’s antidepressant effects on motivated escape behavior. By contrast, optically deleting a random subset of spines unrelated to ketamine treatment had no effect on behavior.

CONCLUSION

Prefrontal cortical spine formation sustains the remission of specific depression-related behaviors after ketamine treatment by restoring lost spines and rescuing coordinated ensemble activity in PFC microcircuits. Pharmacological and neurostimulatory interventions for enhancing and preserving the rescue of lost synapses may therefore be useful for promoting sustained remission.



Depression Esketamine Ketamine

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Ketamine Virginia Link

Long known as a party drug, ketamine now used for depression, but concerns remain

A decades-old anesthetic made notorious as a party drug in the 1980s is resurfacing as a potential “game-changing” treatment for severe depression, patients and psychiatrists say, but they remain wary about potential long-term problems.

The Food and Drug Administration earlier this month OKd use of Spravato for patients with depression who have not benefited from other currently available medications. Spravato, the brand name given to the drug esketamine, is a molecule derived from ketamine — known as Special K on the club scene.

Ketamine has been shown in some studies to be useful for treating a wide variety of neurological disorders including depression. Regular, longtime use of it isn’t well understood, psychiatrists say, but the need for a new drug to treat depression is so great that the FDA put Spravato on a fast-track course for approval.

The drug likely will be commercially available in a few weeks, and patients already are requesting it. Restrictions around its use, though — the drug must be administered in a doctor’s office by providers who are certified with the company making it — mean it may be months before it’s widely available, and longer than that before insurers start paying for it.

“I don’t think we know at this point how effective it’s going to be,” said Dr. Craig Nelson, a psychiatrist at the UCSF Depression Center. “There have been a number of studies of ketamine, sometimes showing effects in people who were resistant to other drugs. If we can treat a different group of people, it would be a great advantage.”

Ketamine was developed in the 1960s as a surgical anesthetic for people and animals. The drug can cause hallucinations and a feeling of “dissociation” or unreality, and in the 1980s it took off as a party drug among people seeking those effects. It remained a common anesthetic, though, and in the early 2000s doctors began to notice a connection between ketamine and relief from symptoms of depression and other mood disorders.

Spravato is delivered by nasal spray, which patients give themselves in a doctor’s office. Patients must be monitored while they get the drug and for two hours after to make sure they don’t suffer immediate complications. At the start, patients will get the nasal spray twice a week for four weeks, then taper to regular boosters every few weeks for an indefinite period of time.

Studies of ketamine — and specifically of Spravato — have produced encouraging but inconsistent results. Psychiatrists say that, like most other antidepressants, the drug probably won’t help everyone with difficult-to-treat depression. But there likely will be a subset of patients who get substantial benefits, and that alone may make it an incredible new tool.

About 16 million Americans experience depression every year, and roughly a quarter of them get no benefit from antidepressants on the market. Thought scientists haven’t determined exactly how ketamine works on the brains of people with depression or other mood disorders, it appears to take a different path of attack than any drug already available. That means that people who don’t respond to other antidepressants may find this one works for them.

But a concern among some psychiatrists is that studies have suggested that ketamine may affect the same receptors in the brain that respond to opioids. Ketamine and its derivations may then put patients at risk of addiction — but research so far hasn’t explored that kind of long-term effect.

“There might be some potential problems if you used it too aggressively,” said Dr. Alan Schatzberg, director of the Stanford Mood Disorders Center, who led the research that identified a connection with opioid receptors. “The issue is not so much the short-term use, it’s the repetitive use, and the use over time, as to whether there are going to be untoward consequences.

“It would be hard for me to recommend the use of this drug for chronically depressed people without knowing what the endgame is here,” he added.

Dr. Carolyn Rodriguez, a Stanford psychiatrist who was part of the studies of ketamine and opioid receptors, said she shares Schatzberg’s concerns. But she’s been studying the use of ketamine to treat obsessive-compulsive disorder, and for some patients the results have been so remarkable that the benefits may exceed the risks.

“When I gave ketamine to my first patient, I nearly fell off my chair. Somebody said it was like a vacation from their OCD, and I was just, ‘Wow, this is really possible,’” Rodriguez said. “I want to make sure patients have their eyes wide open. I hope (the FDA approval) spurs more research, so we can really inform consumers.”

Though the new nasal spray is the first formal FDA approval of a ketamine-derived drug, psychiatrists have been using the generic anesthetic for years to study its effect on depression and other mood disorders.

In recent years, clinics have opened around the country offering intravenous infusions of ketamine to people with hard-to-treat depression and other problems. These treatments aren’t specifically FDA-approved but are allowed as off-label use of ketamine. The clinics have faced skepticism from some traditional psychiatrists, but there’s a growing ream of anecdotal evidence that the ketamine IVs work — for some people.

Aptos resident Mary, who suffers from depression and other mood disorders and asked that her last name not be used to protect her privacy, said the already available antidepressants weren’t keeping her symptoms at bay, and she frequently felt “one step away from the abyss.” When she first heard about ketamine, from a support group for people with depression and other mood disorders, she was hesitant.

“I kind of hemmed and hawed, because I’d heard that K was a street drug,” Mary said. “But then I said, ‘What do I have to lose?’ So I went and did it.”

The results were quick: Within four days, “the cloud had lifted,” she said. More than a year later, she is still feeling good with regular infusions every three or four weeks. During the ketamine infusion, Mary said she’ll feel the dissociation, which she described as feeling like she’s viewing the world around her as though it were a movie and not her own life.

She said she’s pleased the FDA approved Spravato, though she hasn’t decided whether she’ll switch from the IV ketamine to the nasal spray. She hopes that the FDA approval will give some validation to ketamine and encourage others to try it.

Mary gets her infusions at Palo Alto Mind Body, where Dr. M Rameen Ghorieshi started offering ketamine two years ago. He’s certified with the maker of Spravato — Janssen Pharmaceuticals, a branch of Johnson and Johnson — to provide the drug, though he doesn’t know when he’ll actually start giving the nasal spray to patients.

Ghorieshi said that although he’s been offering IV ketamine for more than two years, he shares his colleagues’ wariness of the long-term effects of regular use of the drug. He hopes FDA approval will encourage further research.

“At this point we’ve done 1,000 infusions. The outcomes have exceeded my own expectations,” Ghorieshi said. “But anecdotes are not clinical trials. I approach this very cautiously. What I don’t want is 20 or 30 years from now to look back and say, ‘What did we do?’”

Depression Esketamine

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Listening to ketamine

The fast-acting drug offers a new way to treat depression and fathom its origins. Recent approval of a nasal spray promises to expand access, but much remains unknown about long-term use and the potential for abuse.

t 32, Raquel Bennett was looking for a reason to live. She’d struggled with severe depression for more than a decade, trying multiple antidepressants and years of talk therapy. The treatment helped, but not enough to make it seem worth living with a debilitating mental illness, she says. “I was desperate.”

In 2002, following a friend’s suggestion, Bennett received an injection of ketamine, an anesthetic and psychedelic party drug also known as Special K. During her first ketamine trip, Bennett hallucinated that God inserted a giant golden key into her ear, turning on her brain. “It was as if I was living in a dark house and suddenly the lights came on,” she says. “Suddenly everything seemed illuminated.”

The drug lifted Bennett’s depression and dispelled her thoughts of suicide within minutes. The effect lasted for several months, and, she says, the respite saved her life. She was fascinated by the drug’s rapid effects and went on to earn a doctoral degree in psychology, writing her dissertation about ketamine. Today, she works at a clinic in Berkeley, California, that specializes in using ketamine to treat depression. “This medicine works differently and better than any other medication I’ve tried,” she says.

When Bennett experimented with ketamine, the notion of using a psychedelic rave drug for depression was still decidedly fringe. Since the first clinical trials in the early 2000s, however, dozens of studies have shown that a low dose of ketamine delivered via IV can relieve the symptoms of depression, including thoughts of suicide, within hours.

Even a low dose can have intense side effects, such as the sensation of being outside one’s body, vivid hallucinations, confusion and nausea. The antidepressant effects of ketamine typically don’t last more than a week or two. But the drug appears to work where no others have — in the roughly 30 percent of people with major depression who, like Bennett, don’t respond to other treatments. It also works fast, a major advantage for suicidal patients who can’t wait weeks for traditional antidepressants to kick in.

Infographic shows the relatively small percentage of people who suffer from depression who may be helped by ketamine, according to clinical studies. Of the 17 million people in the US estimated to suffer from depression, only 10 million receive treatment. Half of those are helped by that treatment, with only about a third experiencing full recovery. Treatment-resistant patients have severe disease and don’t respond to current medications. Studies suggest that about 60 percent of this group may find relief with ketamine.

“When you prescribe Prozac, you have to convince people that it’s worth taking a medication for several weeks,” says John Krystal, a psychiatrist and neuroscientist at Yale University in New Haven, Connecticut. “With ketamine, patients may feel better that day, or by the next morning.”

The buzz around ketamine can drown out just how little is known about the drug. In the April 2017 JAMA Psychiatry, the American Psychiatric Association published an analysis of the evidence for ketamine treatment noting that there are few published data on the safety of repeated use, although studies of ketamine abusers — who typically use much higher doses — show that the drug can cause memory loss and bladder damage. Most clinical trials of the low dose used for depression have looked at only a single dose, following up on patients for just a week or two, so scientists don’t know if it’s safe to take the drug repeatedly over long periods. But that’s exactly what might be necessary to keep depression at bay.

The analysis also warned about ketamine’s well-established potential for abuse. Used recreationally, large doses of the drug are known to be addictive — there’s some evidence that ketamine can bind to opioid receptors, raising alarms that even low doses could lead to dependence.

Bennett has now been receiving regular ketamine injections for 17 years, with few negative side effects, she says. She doesn’t consider herself addicted to ketamine because she feels no desire to take it between scheduled appointments. But she does feel dependent on the drug, in the same way that a person with high blood pressure takes medication for hypertension, she says.

Still, she acknowledges what most clinicians and researchers contend: There simply aren’t enough data to know what the optimal dose for depression is, who is most likely to benefit from ketamine treatment and what long-term treatment should look like. “There’s a lot that we don’t know about how to use this tool,” Bennett says. “What’s the best dose? What’s the best route of administration? How frequently do you give ketamine treatment? What does maintenance look like? Is it OK to use this in an ongoing way?”

Despite the unknowns, pharmaceutical companies have been racing to bring the first ketamine-based antidepressant to market. In March, the US Food and Drug Administration approved a ketamine-derived nasal spray, esketamine, developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. Only two of Janssen’s five phase III trials had shown a benefit greater than taking a placebo. Still, in February an independent panel recommended FDA approval. That makes ketamine the first novel depression drug to hit the market in more than 50 years, notes Carlos Zarate Jr, a psychiatrist who studies mood disorder therapies at the National Institute of Mental Health.

Photo shows the mechanized assembly line at Janssen Pharmaceutical as bottles of Spravato, the esketamine nasal spray are manufactured.
Although clinicians are hopeful that Janssen Pharmaceutical’s newly approved esketamine nasal spray, Spravato, will expand access to treatment, many also worry about the drug’s potential for abuse.CREDIT: JANSSEN PHARMACEUTICALS, INC.

Thousands of people are already flocking to private clinics like Bennett’s, which provide intravenous ketamine infusions. Because the drug was approved in the 1970s as an anesthetic, physicians can legally provide the drug as an “off-label” depression treatment. Many ketamine clinics have long waiting lists or are so swamped that they aren’t accepting new patients, and Janssen’s nasal spray could rapidly expand access to treatment.

But some researchers worry that the nasal spray won’t solve many of ketamine’s problems and could create new ones. Although the FDA is requiring that the nasal spray be administered only in a certified doctor’s office or clinic, esketamine is “every bit as habit forming as regular ketamine,” and will be difficult to keep out of the hands of abusers, says Scott Thompson, a neuroscientist at the University of Maryland and a coauthor with Zarate of a 2019 review on fast-acting antidepressants in the Annual Review of Pharmacology and Toxicology. A nasal spray can’t deliver as precise a dose as an IV infusion, Thompson notes. “If someone has got a cold, they’re not going to get the same dose.”

Scott Thompson of the University of Maryland discusses how ketamine is changing the landscape of the psychiatric treatment of severe depression.

CREDIT: VIDEO PRODUCED BY HUNNI MEDIA FOR KNOWABLE

In Thompson’s view, esketamine holds few advantages over generic ketamine, which costs less than a dollar per dose, although the IV infusions in private clinics often cost hundreds of dollars per visit. Janssen has indicated that each esketamine treatment will range from $590 to $885, not including the costs of administration and observation.

Zarate and others are still thrilled to see big pharma investing in ketamine, after decades of stalled efforts to find new psychiatric drugs. “As esketamine hits the market, venture capitalists will come up with better versions and move the field forward,” Zarate says. Several drug companies are now testing other ketamine-like compounds in hopes of developing drugs that have its potent antidepressant potential without its psychedelic and dissociative side effects.

Illustration shows a high-tech version of a neural network, with signals represented as lights. Depression, many now think, is caused by problems in the neural circuitry.

Depression, fast and slow

In 2001, writer Andrew Solomon published a haunting description of the depression that derailed his early 30s: “If one imagines a soul of iron that weathers with grief and rusts with mild depression, then major depression is the startling collapse of a whole structure,” he wrote.

When Solomon first fell ill, in the 1990s, many clinicians and researchers presumed that the pathological brain changes underlying depression were inherently slow to repair. This mind-set was rooted in the modest but controversial success of a class of slow-acting drugs that includes Prozac.

Developed in the 1950s, the drugs were first inspired by the chance observation that a hypertension drug called reserpine – an extract of the plant Rauwolfia serpentina, or devil pepper — made people intensely depressed. After discovering that reserpine depletes monoamine neurotransmitters in the brain, including serotonin and norepinephrine, scientists hypothesized that low neurotransmitter levels causedepression. They went on to develop monoaminergic antidepressants, drugs designed to increase circulating levels of these chemicals in the brain.

Today, monoaminergic antidepressants include selective serotonin reuptake inhibitors (SSRIs) such as Prozac, Lexapro and Zoloft, as well as the older and less commonly prescribed monoamine oxidase inhibitors (MAOIs) and tricyclic and tetracyclic antidepressants. Scientists have long debated whether the drugs work at all, but the most comprehensive study to date — published in The Lancet in 2018 — suggests that they do lower depression symptoms in about 60 percent of depressed people, albeit only modestly more than taking a placebo.

The benefits start to show up only after several weeks of treatment, however, and roughly a third of people with major depression disorder – called treatment-resistant patients — don’t respond to at least two types of monoaminergic antidepressant.

By the early 2000s, the monoamine hypothesis had unraveled. This was partly due to the antidepressants’ mediocre performance in patients, and partly to experiments which showed that depleting neurotransmitter levels in healthy people does not make people depressed. Scientists now believe that drugs like Prozac do not directly treat depression’s root cause. Instead, they think the drugs work via an indirect mechanism to subtly boost the growth of synapses and the birth of new neurons, and that this somehow relieves symptoms.

Solomon’s bleak metaphor of corrosion was at least partly grounded in science. Many scientists now agree that depression slowly eats away at the neural pathways underlying our sense of worth and well-being, our desire to go to the movies or get out of bed. But research into ketamine holds out new hope that — unlike rusted iron — the depressed brain can be restored, by repairing and strengthening the neural circuits that regulate mood. —Emily Underwood

Some researchers are also testing whether ketamine works for conditions beyond depression, such as obsessive-compulsive disorder, as well as in specific subsets of patients, such as severely depressed teenagers. Other scientists are using ketamine to help untangle one of the biggest mysteries in neuroscience: What causes depression? (See sidebar.)

Seeking answers in neural wiring

Thirty years ago, the prevailing thought was that low levels of certain brain chemicals, such as serotonin, caused depression. Boosting those could remove symptoms.

“I felt that depression needed months or weeks of treatment — that the plastic changes involved in the healing process would require weeks to reset themselves,” says Todd Gould, a neuropharmacologist at the University of Maryland and a coauthor of the recent review paper. But ketamine’s speed of action casts doubt on that idea.

Newer evidence suggests that depression is caused by problems in the neural circuits that regulate mood, Gould notes. Much of the evidence for this faulty-wiring hypothesis comes from rodents. Starting in the 1990s, scientists began to discover intriguing abnormalities in the brains of mice and rats that had been exposed to certain stressors, such as bullying by a big, aggressive male.

Stress and trauma are strong predictors of depression in people, but scientists can’t ask rats or mice if they are depressed. Instead, they use behavioral tests for classic depression symptoms such as anhedonia, the inability to take joy in pleasurable activities, Thompson says. Depressed animals “give up easily” in experiments that test their willingness to work for rewards like sugar water, or their interest in the intoxicating scent of a potential mate’s urine. “They can’t be bothered to cross the cage,” he says.

Thompson and others have found that there are fewer connections, or synapses, between neurons that communicate reward signals in the brain in depressed animals. Other labs have found shriveled connections in neuronal circuits key to decision-making, attention and memory. Brain imaging studies in people with depression have also revealed abnormal activity in neural circuits that regulate emotion, suggesting that the findings in rodents may also apply to humans.

If faulty neural connections are to blame for depression, the next question is, “How do we get atrophied neural pathways to regrow?” Krystal says.

Circuit training

The answer, many scientists now believe, is the brain’s most abundant neurotransmitter, glutamate.

Glutamate is the workhorse of the brain. It relays fleeting thoughts and feelings, and enables the formation of memories by strengthening synaptic connections. Glutamate is the reason you can still ride a bike years after you learned, even if you never practiced.

Not all glutamate activity is good. Too much can cause the equivalent of an electrical storm in the brain — a seizure — and chronically high levels may lead to dementia. Abnormalities in glutamate receptors — specialized proteins on the surface of brain cells where glutamate can dock and bind — are linked to a wide array of psychiatric diseases, including depression and schizophrenia.

To maintain balance, cells called inhibitory interneurons act like brakes, releasing a neurotransmitter called GABA that quiets brain activity. Most mind-altering drugs work by changing the balance between GABA and glutamate — amphetamines and PCP enhance glutamate signaling, for example, while alcohol inhibits glutamate and boosts GABA.

By the 1990s, scientists had discovered that ketamine triggers a gush of glutamate in the brain’s prefrontal cortex. This region governs attention and plays an important role in emotional regulation. The out-of-body sensations that some people experience when they take ketamine may occur because this rapid release of glutamate “excites the heck out of a whole bunch of neurons” in the prefrontal cortex, says Bita Moghaddam, a neuroscientist at Oregon Health & Science University who discovered the drug’s glutamate-revving effect on rats while studying schizophrenia.

Scientists aren’t sure yet how ketamine forms stronger neural circuits. But the hypothesis goes roughly like this: When ketamine enters the brain, it causes a short-term burst of neuronal activity that triggers a series of biochemical reactions that create stronger, more plentiful synaptic connections between brain cells.

At first, many researchers thought ketamine’s antidepressant effects relied on a structure located on the surface of neurons, called the NMDA receptor. Like a key that fits into different locks, ketamine can bind to several types of NMDA receptor, making neurons release the excitatory glutamate neurotransmitter.

This hypothesis suffered a blow, however, when several drugs designed to bind to the NMDA receptor (as ketamine does) failed in clinical trials for depression.

A space-filling ribbon model shows the 3-D structure of the NMDA receptor, which binds glutamate in the brain and is thought to play a key role in the symptoms of depression.
Central to the controversy over how ketamine works in the brain is the NMDA receptor (illustrated here), which binds to the neurotransmitter glutamate. Some scientists believe ketamine’s antidepressant effects hinge on its ability to block NMDA receptors, but others believe the drug works via other mechanisms. Resolving that mystery is key to developing similar drugs with fewer side effects, scientists say.CREDIT: FURUKAWA LAB, CSHL

Esketamine also complicates the story. Ketamine is made up of two molecules that form mirror images of each other, R- and S-ketamine. Esketamine is made up of just the S form and binds roughly four times as effectively as R-ketamine to the NMDA receptor. Despite acting much more powerfully on the NMDA receptor, studies in rodents suggest that S-ketamine is a less potent antidepressant than R-ketamine, although it’s not yet clear whether or not R-ketamine could work better in humans.

Zarate and others now believe ketamine may work through a different receptor that binds glutamate, called AMPA. By pinpointing which receptor ketamine acts on, researchers hope to develop a similar drug with fewer side effects. One hot lead is a compound called hydroxynorketamine (HNK) — a metabolic byproduct of ketamine that does not affect NMDA receptors but still produces rapid antidepressant effects in rodents. The drug appears to lack ketamine’s disorienting side effects, and Zarate and Gould plan to launch the first small clinical trials to establish HNK’s safety in humans this year, likely in around 70 people. “I think we have a very good drug candidate,” Gould says. (Zarate and Gould, among others, have disclosed that they are listed on patents for HNK, so they stand to share in any future royalties received by their employers.)

Plastic synaptic remodelers

To alter how the brain processes mood, scientists believe ketamine must ultimately change synapses. In experiments in rodents, Ron Duman of Yale University has shown that both ketamine and HNK can harness one of the brain’s most important tools for synaptic remodeling: brain-derived neurotrophic factor, or BDNF.

BDNF is a protein intimately involved in shaping synapses during brain development and throughout the lifespan. Healthy brain function depends on having just the right amount of BDNF in the right place at the right time. Many mental illnesses, including depression, are associated with low or abnormal amounts of the protein. For example, samples of brain tissue from people who have died by suicide often contain abnormally low amounts of BDNF.

Duman and colleagues have found that both ketamine and HNK cause a sharp uptick in the amount of BDNF that is released from neurons. This increase is required for the drugs’ antidepressant effects, and for the increase in dendritic spines — the stubby protrusions that form synaptic connections with other neurons. Both ketamine and HNK also seem to reduce inflammation, which has been linked repeatedly to the stress-induced loss of synapses.

A micrograph of a portion of a rat neuron, in false colors, shows how ketamine coaxes the budding of new dendritic spines from the neuron. In a control, two dendritic spines are visible. In the ketamine-treated neuron, six dendritic spines are visible
Ketamine strengthens connections between brain cells. Compared with a control, a rat neuron (red) treated with ketamine has grown more dendritic spines (shown by yellow arrows).CREDIT: R.J. LIU, G. AGHAJANIAN & R. DUMAN

Ketamine is not the only compound that can induce rapid synaptic plasticity: Other psychedelics, such as ecstasy (MDMA), acid (LSD), and DMT also trigger similar structural changes in neurons and rapid antidepressant effects in rodents, researchers at the University of California at Davis recently found. The effects don’t hinge on getting high, the team reported in March in ACS Chemical Neuroscience. Even very small doses — too low to cause perceptual distortions — can increase synapse density and lift depression.

Traditional antidepressants such as Prozac also increase BDNF levels in the brain, but not nearly as fast as ketamine does, Duman says. That is why most antidepressants take so long to remodel synapses and relieve depression symptoms, he says.

Dissecting depression

Beyond promising new treatments, Zarate and other researchers see ketamine as a powerful tool for probing depression’s tangled neurobiology. Studies in mice and rats are a good start, but scientists need to study the drug in people to truly understand how ketamine affects the brain. Unlike traditional, slower-acting antidepressants, ketamine lends itself to short-term lab experiments.

Zarate is using neuroimaging tools such as fMRI to study the human brain on ketamine. Past studies have shown that in people with depression, communication among several key brain networks is disrupted. One network, called the default-mode network (DMN), is involved in self-referential thoughts such as ruminating about one’s problems or flaws. This network tends to be hyperactive in people with depression, and less connected to more outwardly attuned brain networks such as the salience network, which helps the brain notice and respond to its surroundings.

Before and after images show averaged brain activity of people with treatment-resistant major depression while their index finger is stroked. Before an infusion of ketamine, the patients show some activity in the front of the brain. After ketamine, the activity is more widespread and the intense, as shown in false colors on the image of the brain, and representing enhanced cortical excitability.
Ketamine appears to strengthen connections between neural networks in people with severe depression. In a study comparing neural activity prior to a ketamine infusion (left) and six to nine hours after an infusion (right), a single dose made the brain more responsive to a simple sensory stimulus, the light stroking of a finger.

In one recent study, Zarate and his colleagues found that after receiving an IV dose of ketamine, people with depression had more normal activity in the default mode network, and that it was better connected to the salience network. At least temporarily, the drug seems to help people get unstuck from patterns of brain activity associated with repetitive, negative thoughts. Zarate does caution that the study results need to be replicated.

The team has also used brain imaging to study how ketamine affects suicidal thoughts. About four hours after an infusion of ketamine, a chunk of the prefrontal cortex that is hyperactive in people with depression had calmed down, researchers found, which correlated with people reporting fewer thoughts of suicide.

Ketamine also seems to tune other brain regions that are key to effective treatment. Last year, scientists published a study in mice showing that ketamine quiets abnormal activity in the lateral habenula, a small nodule wedged deep under the cortex. Some researchers have described the lateral habenula as the brain’s “disappointment center.” The region is responsible for learning from negative experiences, and is hyperactive in people with depression, as if “broadcasting negative feelings and thoughts,” Thompson says.

Such studies remain exploratory. As to why ketamine works — and just as important, why its effects are transient — scientists are still speculating. “I think ketamine is resetting neural circuits in a way that improves the symptoms of depression, but the risk factors — whether genetic, environmental or other risk factors — are still present,” Gould says. “It seems to help reset things temporarily, but the underlying cause is not necessarily resolved.”

Helen Mayberg, a neurologist at Mount Sinai Hospital in New York who specializes in using an experimental procedure called deep brain stimulation to treat depression, suggests that ketamine may be like using a defibrillator on someone experiencing cardiac arrhythmia. “I am not addressing the fact that you have underlying heart disease, but now that your arrhythmia is gone, I can concentrate on other treatments.”

It’s important to put the potential risks of ketamine into perspective, particularly for people contemplating suicide, researchers emphasize. Most people are willing to tolerate severe side effects for other life-saving treatments, such as cancer drugs, Mayberg points out. “If you can interrupt an extreme suicidal plan and ideation, I’ll take that.”

Ketamine in teens?

For Krystal, weighing ketamine’s still largely uncharted risks and potential rewards ultimately comes down to a deeply personal question: “What would we want for ourselves? For our families? Do we want them to have to go through several failed trials over several months, or even a year, before taking a medication that might make their depression better in 24 hours?”

Some of the hardest decisions are likely to involve children and adolescents. Hospitalization for youth suicide attempts and ideation nearly doubled between 2008 and 2015, leaving many clinicians — and parents — desperate for more effective and rapid treatments. Left untreated, depression is “really bad for the brain” and can cause serious, long-term cognitive and developmental problems when it starts young, Zarate says. “The question is, is that going to be better than the long-term side effects of ketamine?”

Untreated depression is really bad for the brain, especially in the young. The question is, is that going to be better than the long-term side effects of ketamine?

Scientists don’t yet know. Ketamine has been deemed safe to use as an anesthetic in children, but there aren’t yet sufficient clinical data to show how low, repeated doses of ketamine used for depression could affect the developing brain.

On a more fundamental level, scientists don’t fully understand the neurobiology of adolescent depression, notes psychiatrist Kathryn Cullen of the University of Minnesota. It may involve abnormalities in brain development, such as the way the prefrontal cortex connects to brain regions that process emotion, but “we don’t know if the brain connection abnormalities emerge because of toxic stress induced by depression, or if these abnormalities predispose people to develop depression, or if depression itself reflects abnormal development,” Cullen says. “It’s critical to figure out how to alleviate the biological changes that are associated with [teen] depression so that the brain can get back on a healthy trajectory.”

Two recent clinical trials — one at Yale and another at Minnesota run by Cullen — have found that ketamine can lower symptoms in severely depressed teenagers, but neither study was set up to follow the teenagers long-term, says Cullen. Janssen is currently running a trial of its esketamine nasal spray with 145 youths who are suicidal, but the results of that study have not been published yet. Cullen thinks ketamine has potential for use in teens, particularly to avoid suicide, but “there are still a lot of unknowns.”

Not just a quick fix

Worldwide, depression afflicts more than 300 million people, making it the leading global cause of disability. When contemplating such overwhelming misery, the vision of a world in which depression can be cured with a single injection or squirt of nasal spray holds obvious appeal.

A photo shows a woman as she receives an infusion of the drug ketamine during a 45-minute session at an outpatient clinic in Chicago on July 25, 2018. She struggled with depression and anxiety and made several suicide attempts before starting ketamine treatments earlier in the year.
Thousands of private clinics in the United States, such as this outpatient clinic in Chicago, are offering repeated ketamine treatment off-label for depression and suicidal thoughts, but the drug’s effects are temporary and scientists still don’t know whether taking the drug over long periods is safe.CREDIT: AP PHOTO / TERESA CRAWFORD

But — despite the hype — that is not what ketamine offers, Bennett says. Based on her own experience as a patient, and her clinical work, she is troubled by the framing of ketamine as a “rapid” depression treatment if that precludes the slower, more effortful process of psychotherapy. Without psychotherapy, she says, “you’re not giving patients any tools to help themselves, just making them dependent on a molecule that has temporary effects. When the effect wears off, they have to go back for more medicine. This is going to be lucrative for the pharmaceutical company but probably not in the patient’s best interest.”

In Bennett’s clinic, ketamine is administered only alongside talk therapy, which she uses to prepare patients before they take ketamine, and afterward to help them process the experience. “I think this is the only ethical way” to administer a drug that can trigger disorienting psychedelic experiences, she says. “This isn’t a ‘take two and call me in the morning’ situation.”

There’s growing scientific interest in whether ketamine can enhance the effectiveness of therapy by increasing the brain’s ability to remodel circuits through experience, Krystal notes. And in 2017 a small Yale study found that providing cognitive behavioral therapy in tandem with ketamine can extend the drug’s antidepressant effects.

Unlike some researchers and pharmaceutical companies, which consider ketamine’s and esketamine’s hallucinogenic side effects inherently negative, Bennett thinks that for some people the visions can be positive — particularly in the context of therapy. There’s scant scientific evidence to support the idea that such hallucinations are therapeutic, and they can be deeply disturbing for some people. (If people who experience hallucinations do better, it may simply be because they have received a higher dose of ketamine, Krystal points out.)

Still, Bennett thinks researchers and clinicians need to stay open-minded about why ketamine is helping people — and be more attentive to the settings in which ketamine and esketamine are administered. “People consistently report that they experience the presence of God, or their own sacredness,” she says. “When someone comes to my office wanting to kill themselves, ready to die — and then they have a transformational moment where they believe their life is sacred — it’s indescribable how exciting that is as a clinician.”



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