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‘Nothing less than transformational:’ Ketamine brings relief to people with severe depression

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Ketamine gave Rachel Morgan her life back.

The 33 year old has struggled to beat back severe depression and post-traumatic stress disorder for much of her life. She’s tried more than 30 psychiatric medications, none of which helped. Her inner pain reached a level so unbearable that she retreated from the world. She stayed in bed. She stopped doing the dishes and taking out the trash, which piled up in her San Francisco apartment. She stopped socializing.

She lost the will to live.

“I had gotten to a point where I disappeared, mentally and physically,” Morgan said. “My psychiatrist kind of put his hands up in the air and said, ‘There’s nothing else I can do for you.'”

But he did suggest something different she could try, albeit not through him: ketamine. The only legally available psychedelic in the U.S., the drug is widely used as an anesthetic in hospitals and medical settings. But it has been found to give people with severe mood disorders, including treatment-resistant depression and suicidal ideation, almost unbelievably fast-acting relief from their symptoms — some with a single dose, though more commonly it takes several treatments.

Morgan received her first ketamine infusion in a Palo Alto psychiatry clinic in June. By her second treatment, she took out the trash for the first time in months. After several infusions, friends told her she was talking more than she had in a year.

For the first time in her life, “I felt like there is a future for me,” Morgan said. “It’s left me a different person than I was a year ago.”

Ketamine is starting to shed its reputation as a psychedelic club drug and experimental mental health treatment as more patients like Morgan see results and more research is conducted on the drug’s impact on the brain. A watershed moment came in March when the U.S. Food and Drug Administration (FDA) approved Spravato, or esketamine, a ketamine nasal spray for adults with treatment-resistant major depression. One short-term clinical trial showed the spray had a statistically significant effect on depression compared to a placebo, and patients saw some effect within two days, according to the FDA.

A handful of local private psychiatry clinics, including in Palo Alto, Menlo Park and Woodside, have in recent years started offering ketamine. They are working at the forefront of a promising new treatment in psychiatry, a field that has seen little medication innovation for decades.

Many of the psychiatrists who run these clinics said they were initially skeptical of the drug’s potential, with little still known about how exactly ketamine works as an antidepressant and its long-term effects, but became believers when they saw life-changing improvements in patients for whom nothing else had worked.

“I think we’re on the brink of an amazing revolution in psychiatry,” said Alex Dimitriu, who offers ketamine treatments at his Menlo Park private psychiatry clinic. “We’re on the brink of understanding that a lot of drugs that previously we thought were drugs of abuse are actually turning out to be some very powerful agents.”

Exploring ketamine’s potential

Ketamine was developed in 1962 as a fast-acting anesthetic and continues to be widely used as such today, particularly for surgery and pain relief, including with children and in veterinary medicine. The drug is a schedule III controlled substance, meaning its medical use is accepted and it has moderate to low potential for abuse. The World Health Organization has included ketamine on its list of essential medicines since 1985 and calls it “possibly the most widely used anesthetic in the world.” As an anesthetic, it is incredibly safe (it does not depress breathing or blood pressure) and is easy to administer, according to the World Health Organization.

In higher doses, ketamine produces a “dissociative” state that can include hallucinations and out-of-body experiences. The drug’s conscious-altering potential led to its recreational use in the psychedelic era of the 1960s and 1970s.

Reports of ketamine use to treat psychological or psychiatric disorders first emerged in the 1970s, including in Argentina, Mexico and Russia, according to a study co-authored by Jennifer Dore, who offers ketamine at her private Helios Psychiatry practice in Woodside.

In 2000, a group of Yale University researchers published a seminal but small-scale study that found seven patients with major depression who received ketamine showed significant improvement in their symptoms within 72 hours, suggesting the drug could be used as an antidepressant.

Six years later, a National Institute of Mental Health study showed that ketamine reduced depression symptoms more quickly than a placebo.

Dore, who trained as a resident at the Stanford University Department of Psychiatry, became curious about ketamine several years ago while treating patients with severe PTSD and treatment-resistant depression. They simply weren’t getting better.

Dore dug into the available research on the drug’s antidepressant effects, which suggested that ketamine inhibits the action of the brain’s NMDA receptors and triggers glutamate production, which causes the brain to form new neural connections. She reached out to Phil Wolfson, director of the Center for Transformational Psychotherapy in San Anselmo, who pioneered ketamine-assisted psychotherapy, in which ketamine is administered while simultaneously patients receive therapy. She was compelled by taking this approach rather than the more medical model of providing the drug in isolation.

The results with her early patients in 2016 were like nothing she had ever seen.

“They had immediate relief,” she said.

Dore said her clinic was the first on the Peninsula to offer ketamine-assisted psychotherapy. She now offers trainings for other providers and sits on the board of the Ketamine Research Foundation.

In March, Dore published a five-year study with two other psychiatry practices that found patients who received ketamine saw clinically significant improvements in depression and anxiety, particularly so for people who came in with more severe symptoms like suicidality and a history of psychiatric hospitalization. At their clinics, they saw the drug help people suffering from obsessive compulsive disorder, bipolar disorder, personality disorders, substance abuse, psychological reactions to physical illness and even relationship issues and social anxiety.

“Ketamine promotes a time-out from (the) ordinary, usual mind, relief from negativity, and an openness to the expansiveness of mind with access to self in the larger sense,” Dore’s study states. “These effects enhance a patient’s ability to engage in meaningful psychotherapy during and after administration.”

Dore is a staunch champion of combining ketamine with psychotherapy, which she believes is necessary to harness the full potential of the drug. She doesn’t see ketamine as a magic bullet, but rather one tool she can use in concert with others — talk therapy, medication, nutrition — to treat people in serious psychological pain.

Before patients start ketamine, Dore carefully evaluates them to determine if it’s an appropriate next step in their treatment, as recommended by the American Psychiatric Association, including through therapy sessions, psychological tests and a review of their medical history. If they choose to proceed, Dore requires patients to sign a lengthy consent form that explains how ketamine works and its potential benefits and risks.

During a patient’s initial treatment, Dore monitors their physical and emotional responses, including blood pressure and heart rate, to decide on an appropriate dose going forward. The highest doses can produce the dissociative state, or the dream-like sensation of disconnecting from reality, Dore said. (Some people believe they have died and are in a new reality, she said. One patient described it as being in a lucid dream.) At lower doses, it can feel more like having a glass of wine, she said. The peak effects last about 15 to 30 minutes, according to Dore.

Patients can take the ketamine via a small lozenge that dissolves under their tongues, intravenously or an intra-muscular injection.

They receive the ketamine in a large second-floor space at Dore’s practice. It resembles a homey living room more than a psychiatric setting — a reflection of the importance of creating “set and setting” for a psychedelic experience, including a comforting physical environment. A large, soft corner couch is strewn with pillows, including one that says “anger” and another, “love.” During treatments, Dore pulls down the blinds on the windows, adjusts the temperature and offers patients weighted blankets, eyeshades and quiet music. The sessions last two to three hours.

Gaining a new perspective

Andy Mathis was at the end of his mental rope when he found Dore. A father, husband and successful tech industry executive, he had quietly suffered from self-doubt and insomnia since he was a young child. By the time he reached his mid-40s, it had escalated to depression. He felt his well-being and very brain chemistry was at risk.

A friend of a friend referred him to Dore, who prescribed him antidepressant and anti-anxiety medications that finally helped him sleep. But she suspected there was more to understand about the root causes of his symptoms, he said, and suggested ketamine as a means for exploring that.

A former professional tennis player, Mathis said he had never taken any drugs before. He did his own research on ketamine and thought it sounded “groundbreaking.” He was more curious than fearful about embarking on a psychedelic experience.

He received his first infusion two and a half years ago and continues to get ketamine every four to eight weeks today.

“It was indeed transformational,” Mathis said. “Nothing less than transformational.”

Mathis described the experience as taking him out of his own ego, a “tilt(ing) of the prism on how I see things.”

“It allowed me to have a detached, philosophical view on all things — me, my place in the world, my relationships,” he said.

This helps him make sense of his emotions “in a way that can be extremely difficult and sometimes even impossible to do when I am inside of myself,” referring to his default, day-to-day mental state.

Over the course of the infusions, Mathis started feeling more comfortable in his own skin, which he said improved his relationships and even his work performance. He realized he has a love for music and at age 47, started to learn how to play the saxophone. He came to a better understanding of his relationship to food and how he had used it as a coping mechanism.

Combining the ketamine-induced realizations with therapy was crucial, Mathis said.

“It was the post-experience discussions that we would have that would also unravel and unwind some of the unhealthy habits,” he said. “I’m 47 now, almost 48. I am healthier now than I was probably, maybe, ever.”

Dore likened ketamine’s power as a catalyst for psychological change to “a year of psychotherapy in three hours.”

Unlike antidepressants, patients don’t have to take ketamine every day and do not experience significant side effects; they can become nauseous or slur their words during the treatment, psychiatrists said. They require patients to have someone to drive them home after the treatment.

Mathis, for his part, did not experience any negative side effects. A patient at another local psychiatry clinic, Lisa Ward, however, said her mind feels “foggy” if she has two infusions in a single week. According to the FDA, the most common side effects experienced by patients treated with Spravato, the esketamine nasal spray, in clinical trials including disassociation, dizziness, nausea, lethargy and increased blood pressure.

“It would be inhumane,” Dore said, to not offer ketamine to people in intractable mental anguish. “We need things that are transformative, that aren’t putting a Band-Aid on a problem.”

Psychiatrist calls it ‘life-changing’

When Rameen Ghorieshi first looked into ketamine as an option for a patient with treatment-resistant depression about five years ago, it was still “very much fringe,” he said. His colleagues at Stanford, where he completed his psychiatric training, knew about the drug but had no idea how to actually use it as a treatment.

He decided to offer ketamine at his small private practice in downtown Palo Alto, Palo Alto Mind Body. He trained with an anesthesiologist and started with two patients. One suicidal young woman who had dealt with a chronic illness since childhood and didn’t intend to live past 30 years old, he said, got to the point where she was working four days a week, socializing and planning to go back to school.

“That just blew my mind,” Ghorieshi said. “I knew it would help just reading the studies but seeing it firsthand was pretty incredible.”

He has done more than 1,000 ketamine infusions at his downtown Palo Alto practice. Eighty-seven percent of patients rated their improvements as significant and 35% of those described it as “life-changing.” It particularly helped suicidal patients, he said. About 13% of patients said the improvement in their symptoms was not worth the time and effort of the infusions.

“This is a bit of a departure for me. I’m a very conservative prescriber,” Ghorieshi said. “My patients tend to be on one, two, maybe three medications. … But it was so remarkable that it seemed hard not to offer it to people.”

Ghorieshi said his was the first clinic in the Bay Area to treat someone with the tightly controlled, FDA-approved nasal spray. A handful of his patients have since received it, with good results, he said.

Esketamine is attached to a federal Risk Evaluation and Mitigation Strategy, which the FDA “can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks.” Providers and patients must register and the drug must be administered in a certified medical office under the supervision of a health care professional.

At Palo Alto Mind Body, patients receive eight ketamine infusions over several weeks. They are strongly encouraged to also pursue therapy but it’s not part of the treatment itself, Ghorieshi said.

He or a nurse supervises patients over the course of the 90-minute appointments. Morgan likes to sit upright on the couch in Ghorieshi’s office, covered by a blanket that keeps her warm and gives her a sense of emotional security. She listens to relaxing elevator music. After, she goes home and naps off the residual effects.

Years ago, she was given much higher doses of ketamine as a pain treatment for chronic physical illnesses and had horrible hallucinations, which she described as “having my head slammed against a wall repeatedly by a slime monster from a deep black bog.”

At the dose Ghorieshi gives her, she feels like the floor and ceiling switch. Her inhibitions dissolve. Afterwards, she feels more open to trying new experiences, from coping mechanisms for her depression to new foods. She feels her perfectionism, which for a long time had prevented her from being vulnerable with others, soften.

“To me, that’s the magic of ketamine,” Menlo Park psychiatrist Dimitriu said of the drug’s tendency to destabilize entrenched behaviors. “I think that speaks to the magic of future psychedelic research, which is down the pipeline, in that it increases our openness to new experience. The general belief here is if you’re depressed severely, you get stuck in maladaptive patterns.”

Lisa Ward didn’t see immediate relief from her life-long depression after her first ketamine infusion with Ghorieshi in March.

Then, a week later as the drug continued to work in her system, “the whole cloud just lifted,” she said. (It takes most patients several treatments to see results, according to Ghorieshi.)

She had more energy. She felt more productive. The benefits extended to her loved ones, as she’s engaged more with her two young children, husband, her parents and her sister.

“It’s enough for me to have more fun with my kids. It’s enough for me to spend more time with my husband instead of going to bed because I just can’t deal with the day anymore,” she said. “Being in depression you don’t realize it but it takes a big toll on other people.”

For Ward, a photographer, the effects of ketamine last about five weeks before she feels the cloud returning. There was one period where the ketamine seemed to stop working all together. Because she lives in Hollister — a three-hour round trip drive from Palo Alto, not including the time of the session itself — and pays out of pocket for the expensive treatment, gaps between her appointments stretch longer than she’d like.

She actually doesn’t enjoy the experience of being on ketamine, which she described as mind-bending and often intense. But she said the disruption of her depression allows her to focus on shifting the underpinning behavior and thought patterns.

Ketamine “doesn’t magically lift all … your problems away,” Ward said. “You’re more apt to make changes when you’re thinking clearly and you’re not so focused on the depression.”

While esketamine, the nasal spray, is covered by insurance because of the FDA approval, most other ketamine administrations are not. Morgan pays almost $1,000 out of pocket for each infusion, though Ghorieshi said some of his patients have been reimbursed for their treatments. Dore charges patients for her time as a provider, about $1,000 for a several-hour session, rather than for the drug itself.

Morgan felt strongly about using her full name in this article to dispel stigma around ketamine in the hopes it will be more widely accepted — and thus available to more people in need.

“Just because you hear something in one context, like ketamine being used as an illicit drug, doesn’t mean it doesn’t exist in another,” she said. “I think that’s what scares insurance companies away from covering it for patients. And that’s what makes me angry because I wish this treatment was out there for everybody to see. I’m lucky enough to be able to handle the financial portion, but the average person might not be.”

The as-yet-unknown risks

Despite the success stories, ketamine has not yet been fully accepted by the broader psychiatric community. The unanswered questions and possible risks that surround ketamine — how it works as an antidepressant, the long-term effects, the potential for abuse — are cause for caution, said Alan Schatzberg, a Stanford School of Medicine psychiatry professor and former president of the American Psychiatric Association.

“Rarely has there been so much anticipation for a new antidepressant as has been seen for intranasal esketamine,” he wrote in the American Journal of Psychiatry in May about the newly FDA-approved ketamine nasal spray.

“Do we have clear evidence of efficacy? Maybe. How strong is the efficacy? Apparently mild. Do we have a real sense of how long and how often to prescribe it? It’s not entirely clear.

“Taken together,” he wrote, “there are more questions than answers with intranasal esketamine, and care should be exercised in its application in clinical practice.”

In an interview, Schatzberg said he’s concerned about repetitive, extended use of any form of ketamine and the drug’s potential for dependence. The American Psychiatric Association has said that the literature on ketamine’s longer-term effectiveness and safety is so limited that the organization cannot “make a meaningful statement” on such use.

“The scarcity of this information is one of the major drawbacks to be considered before initiating ketamine therapy for patients with mood disorders and should be discussed with the patient before beginning treatment,” an American Psychiatric Association task force wrote in a consensus statement on ketamine in 2017.

Schatzberg co-authored a 2018 study that suggests ketamine’s antidepressant effects are tied to the brain’s opioid system and said the implications of this for dependency should be studied further.

“This is the same as any potential drug of abuse, any kind of opioid type drug. Serial use is less the issue. It’s when you get into repetitive use that one needs to be careful,” Schatzberg said. “That’s the clarion call that we’ve been sounding.”

One of his study co-authors, Carolyn Rodriguez, a Stanford associate professor of psychiatry and behavioral sciences, has been blown away by the rapid benefits of ketamine in studies she’s conducted with patients with obsessive compulsive order, or OCD. In the first-ever randomized clinical trial of ketamine compared to placebo in OCD, she found that a single low dose of ketamine prompted a decrease in OCD symptoms within hours for all participants.

Yet she remains cautious and said more research is needed to fully understand the powerful drug. She’s currently studying the mechanisms of how ketamine works so quickly on OCD patients, with funding from the National Institute of Mental Health.

“I believe that the state of the field of ketamine and how it works on OCD is not at the point yet where I would recommend it clinically because I always like to see science, (including) my own science, replicated,” Rodriguez said.

With pause about the long-term effects, she and other researchers have suggested a national registry be created to monitor side effects.

Ghorieshi said he is frank with his patients about the unknowns and potential downsides of ketamine, which must be weighed against other risks.

“We do know the immediate mortality and morbidity of things like suicide and depression.

I think that’s, as with anything, the risk-benefit. What are the risks of suicide, but also depression and anxiety in general?” he said. “You have to balance that versus these unknown risks of ketamine.”

Mathis, for his part, said he’s not concerned about the long-term effects of taking ketamine.

“What I worry about,” Mathis said, “is what my health would have done without it.”

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NOVA Health Recovery | Alexandria, Va 22306 | Call for esketamine and nasal ketamine as well as IV Ketamine for depression, PTSD, anxiety  703-844-0184 < Link

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.



KETAMINE CENTER NORTHERN VIRGINIA | 703-844-0184 | NOVA HEALTH RECOVERY | SPRAVATO KETAMINE NASAL SPRAY CENTER |ALEXANDRIA, VA 22306 | KETAMINE FOR DEPRESSION AND PTSD | 22304 |20176 | 703-844-0184 | 22101 | 22102 | FAIRFAX KETAMINE INFUSION CENTER 22304 | DR. SENDI | Ketamine and OCD, PTSD, Depression, Anxiety



Call NOVA Health Recovery at 703-844-0184 for a free consultation for a Ketamine infusion. No referral needed. We offer intranasal Ketamine follow up therapy as well. Alexandria, Va 22306.

Call NOVA Health Recovery at 703-844-0184 for a free consultation for a Ketamine infusion. No referral needed. We offer intranasal Ketamine follow up therapy as well. Alexandria, Va 22306.

Ketamine: A Promising Novel Therapy for Anxiety and PTSD

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.

However, between 30% and 40% of these patients will not achieve remission, despite 3 or 4 different traditional agents, and even with evidence-based nonpharmacologic therapies, such as cognitive behavioral therapy (CBT) or mentalization-based therapy (MBT), he noted.

“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.

GAD/SAD

  • 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.

Anxious Depression

  • 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

Related Articles

OCD

  • 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

PTSD

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.13Ketamine 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

Promising Role

“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. 

References

  1. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disordersJAMA Psychiatry. 2017;74(4):399-405.
  2. Feder A, Parides M, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trialJAMA Psychiatry. 2014;71(6):681-688.
  3. Murrough JW, Soleimani L, DeWilde KE, et al. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trialPsychol Med. 2015;45(16):3571-3580.
  4. Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysisAm J Psychiatry. 2018;175(2):150-158.
  5. Schwartz J, Murrough JW, Iosifescu DV. Ketamine for treatment-resistant depression: recent developments and clinical applicationsEvid Based Ment Health. 2016;19(2):35-38.
  6. Shadli SM, Kawe T, Martin D, McNaughton N, Neehoff S, Glue P. Ketamine effects on EEG during therapy of treatment-resistant generalized anxiety and social anxiety [published online April 24,2018]. Int J Neuropsychopharmacology. doi:10.1093/ijnp/pyy032
  7. Glue P, Medlicott NJ, Harland S, et al. Ketamine’s dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders. J Psychopharmacol. 2017;31(10):1302-1305.
  8. Glue P, Neehoff SM, Medlicott NJ, Gray A, Kibby G, McNaughton N. Safety and efficacy of maintenance ketamine treatment in patients with treatment-refractory generalised anxiety and social anxiety disordersJ Psychopharmacol. 2018;32(6):663-667.
  9. Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM, Zarate CA. A single infusion of ketamine improves depression scores in patients with anxious bipolar depressionBipolar Disord. 2014;17(4):438-443.
  10. Bloch MH, Wasylink S, Landeros-Weisenberger A, et al. Effects of ketamine in treatment-refractory obsessive-compulsive disorderBiol Psychiatry. 2012;72(11):964-970.
  11. Rodriguez CI, Kegeles LS, Levinson A, et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology. 2013;38(12):2475-2483.
  12. Girgenti MJ, Ghosal S, LoPresto D, Taylor JR, Duman RS. Ketamine accelerates fear extinction via mTORC1 signalingNeurobiol Dis. 2016;100:1-8.
  13. Ito W, Erisir A, Morozov AObservation of distressed conspecific as a model of emotional trauma generates silent synapses in the prefrontal-amygdala pathway and enhances fear learning, but ketamine abolishes those effects. Neuropsychopharmacology. 2015; 40(11):2536-2545.
  14. Fattore L, Piva A, Zanda MT, Fumagalli G, Chiamulera C. Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketaminePsychopharmacology (Berl). 2018;235(2):433-445.
  15. Donoghue AC, Roback MG, Cullen KR. Remission from behavioral dysregulation in a child with PTSD after receiving procedural ketaminePediatrics. 2015;136(3):e694-e696.
  16. Li L, Vlisides PE. Ketamine: 50 years of modulating the mindFront Hum Neurosci. 2016;10:612.

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Ketamine Works as a Fast-Acting Antidepressant, But the Full Effects Are Still Unknown

Ketamine Works as a Fast-Acting Antidepressant, But the Full Effects Are Still Unknown

etamine leads something of a double life, straddling the line between medical science and party drug. Since it’s invention in the early 1960s, ketamine has enjoyed a quiet existence as a veterinary and pediatric anesthetic given in high doses. But in a second, wilder life, ketamine’s effects at lower doses—a profound sense of dissociation from self and body—became an illicit favorite among psychedelic enthusiasts. Pioneering neuroscientist John Lilly, who famously attempted to facilitate communication between humans and dolphins, used the drug in the late 1970s during experiments in sensory deprivation tanks. By the 1990s, the drug had made its way to the dance floor as “special K.”

More recently, ketamine has taken on a third, wholly unexpected role. Since the early 2000s, the drug has been studied as a uniquely powerful medication for treating severe depression and obsessive-compulsive disorder (OCD). When given as an intravenous infusion, ketamine can lift symptoms of depression and OCD from patients who fail to respond to common antidepressants like Prozac and even resist treatments like electroconvulsive therapy (ECT).

Exactly how ketamine produces antidepressant effects remains unclear, however. Antidepressants like Prozac are Serotonin Reuptake Inhibitors (SSRIs) that increase levels of the neurotransmitter serotonin in the brain, which is believed to boost mood. Ketamine’s main mechanism of action to produce dissociative anesthetic effects, on the other hand, depends on another neurotransmitter, glutamate.

“The prevailing hypothesis for ketamine’s antidepressant effect is that it blocks a receptor (or docking port) for glutamate,” says Carolyn Rodriguez, a professor of psychiatry at Stanford who has conducted some of the pioneering research into ketamine as an OCD treatment.

However, new research suggests that ketamine’s influence on glutamate receptors, and specifically the NMDA receptor, may not be the sole cause of its antidepressant effects. According to a recent study in the American Journal of Psychiatry by Rodriguez and her Stanford colleagues, ketamine might also activate a third system in the brain: opioid receptors.

Ketamine is known to bind weakly to the mu opioid receptor, acting as an agonist to produce a physiological response at the same site in the brain where narcotics like morphine exert their influence. It’s also known that opioids can have antidepressant effects, says Alan Schatzberg, a professor of psychiatry at Stanford and co-author of the new study.

It never made sense to Schatzberg that ketamine’s antidepressant effects were a result of blocking the glutamate receptors, as attempts to use other glutamate-blocking drugs as antidepressants have largely failed. The Stanford psychiatrist, who has spent his career studying depression, wondered if researchers were unknowingly activating opioid receptors with ketamine.

“You could test this by using an antagonist of the opioid system to see if you blocked the effect in people who are ketamine responders,” he says. “And that’s what we did.”

The researchers enlisted 12 subjects with treatment-resistant depression and gave them either an infusion of ketamine preceded by a placebo, or ketamine preceded by a dose of naltrexone, an opioid receptor blocker. Of those, seven subjects responded to the ketamine with placebo, “and it was very dramatic,” Schatzberg says, with depression lifting by the next day. “But in the other condition, they showed no effect,” suggesting it was the opioid receptor activity, not blocking glutamate receptors, that was responsible.

While opioid blockers prevented ketamine from activating the associated receptors, it did not block the drugs dissociative effects, suggesting dissociation alone won’t affect depression. “It’s not that, ‘hey, we’ll get you a little weird and you’ll get the effect,’” Schatzberg says.

The appeal of ketamine’s use as an antidepressant is clear enough. While more typical antidepressants may require six to eight weeks to produce benefits, ketamine works within hours.

“Our patients are asked to hang in there until the medication and talk therapy takes effect,” says Carlos Zarate, chief of the experimental therapeutics and pathophysiology branch of the National Institute of Mental Health (NIMH) who was not associated with the new study. While waiting for traditional treatments to kick in, patients “may lose their friends or even attempt suicide.”

But the study linking ketamine to opioid activity means an extra dose of caution is required. While ketamine acts quickly, the anti-depressive effects of the drug only last for a few days to a week, meaning repeat doses would be needed in practice. Researchers and clinicians should consider the risk of addiction in long-term use, Schatzberg says. “You’re going to eventually get into some form of tolerance I think, and that’s not good.”

However, the new finding is based on just seven subjects, and it still needs to be replicated by other scientists, says Yale professor of psychiatry Greg Sanacora, who was not involved in the new study. And even if the trial is replicated, it would not prove ketamine’s opioid activity is responsible for its antidepressant effects.

“It doesn’t show that at all,” says Sanacora, who studies glutamate, mood disorders and ketamine. “It shows that the opioid system needs to be functioning in order to get this response.”

Sanacora compares the new study to using antibiotics to treat an ear infection. If you administered an additional drug that blocks absorption of antibiotics in the stomach, you would block treatment of the ear infection, but you wouldn’t conclude that antibiotics fight ear infections through stomach absorption—you just need a normally functioning stomach to allow the antibiotic to do its job. Similarly, opioid receptors might need to be functioning normally for ketamine to produce antidepressant effects, even if opioid activity is not directly responsible for those effects.

Complicating matters further, placebos often cause patients to experience less pain, but opioid blockers like naltrexone have been shown to prevent this response, according to Sanacora. It could be, he suggests, that all the apparatus of the clinic—the nursing staff, the equipment—exerted a placebo effect that is mediated by the brain’s opioid system, and the patients who received naltrexone simply did not respond to that placebo effect

“That’s a very important and powerful tool that is in all of medicine, not just in psychiatry,” Sanacora says. “And we know that the opiate system is involved, to some extent, in that type of response.”

It’s also possible, the researchers note in the paper, that ketamine’s action at the glutamate receptor is still important. “Ketamine acts in three distinct phases—rapid effects, sustained effects and return to baseline,” Rodriguez says. Opioid signaling may turn out to mediate ketamine’s rapid effects, while “the glutamate system may be responsible for the sustaining effects after ketamine is metabolized.”

One interpretation is that ketamine blocks glutamate receptors on neurons that are inhibitory, meaning they signal other neurons to fire fewer signals. By blocking these neurons from firing, ketamine may enhance glutamate activity in the rest of the brain, producing anti-depressive effects that persist after the opioid activity dies down.

“The reality is it’s in a gray zone,” Sanacora says. “This is just one small piece of a very large puzzle or concern that we really need to look at the data in total.”

That data is forthcoming. Results from a Janssen Pharmaceuticals clinical trial using esketamine, an isomer of ketamine, and involving hundreds of subjects will soon become public, according to Sanacora, who has consulted for the company. And at NIMH, Zarate and colleagues are studying hydroxynorketamine, a metabolite of ketamine that may provide the same benefits but without the dissociative side effects

Ketamine Works as a Fast-Acting Antidepressant, But the Full Effects Are Still Unknown

A new study suggests that ketamine activates the brain’s opioid receptors, complicating its use to treat clinical depression

Ketamine Syringe
Ketamine syringe, 10mg held by a healthcare professional. (Peter Cripps / Alamy Stock Photo)

By Jon KelveySEPTEMBER 11, 2018777110231.1K

Ketamine leads something of a double life, straddling the line between medical science and party drug. Since it’s invention in the early 1960s, ketamine has enjoyed a quiet existence as a veterinary and pediatric anesthetic given in high doses. But in a second, wilder life, ketamine’s effects at lower doses—a profound sense of dissociation from self and body—became an illicit favorite among psychedelic enthusiasts. Pioneering neuroscientist John Lilly, who famously attempted to facilitate communication between humans and dolphins, used the drug in the late 1970s during experiments in sensory deprivation tanks. By the 1990s, the drug had made its way to the dance floor as “special K.”

More recently, ketamine has taken on a third, wholly unexpected role. Since the early 2000s, the drug has been studied as a uniquely powerful medication for treating severe depression and obsessive-compulsive disorder (OCD). When given as an intravenous infusion, ketamine can lift symptoms of depression and OCD from patients who fail to respond to common antidepressants like Prozac and even resist treatments like electroconvulsive therapy (ECT).

Exactly how ketamine produces antidepressant effects remains unclear, however. Antidepressants like Prozac are Serotonin Reuptake Inhibitors (SSRIs) that increase levels of the neurotransmitter serotonin in the brain, which is believed to boost mood. Ketamine’s main mechanism of action to produce dissociative anesthetic effects, on the other hand, depends on another neurotransmitter, glutamate.

“The prevailing hypothesis for ketamine’s antidepressant effect is that it blocks a receptor (or docking port) for glutamate,” says Carolyn Rodriguez, a professor of psychiatry at Stanford who has conducted some of the pioneering research into ketamine as an OCD treatment.

However, new research suggests that ketamine’s influence on glutamate receptors, and specifically the NMDA receptor, may not be the sole cause of its antidepressant effects. According to a recent study in the American Journal of Psychiatry by Rodriguez and her Stanford colleagues, ketamine might also activate a third system in the brain: opioid receptors.

Ketamine is known to bind weakly to the mu opioid receptor, acting as an agonist to produce a physiological response at the same site in the brain where narcotics like morphine exert their influence. It’s also known that opioids can have antidepressant effects, says Alan Schatzberg, a professor of psychiatry at Stanford and co-author of the new study.

It never made sense to Schatzberg that ketamine’s antidepressant effects were a result of blocking the glutamate receptors, as attempts to use other glutamate-blocking drugs as antidepressants have largely failed. The Stanford psychiatrist, who has spent his career studying depression, wondered if researchers were unknowingly activating opioid receptors with ketamine.

“You could test this by using an antagonist of the opioid system to see if you blocked the effect in people who are ketamine responders,” he says. “And that’s what we did.”

The researchers enlisted 12 subjects with treatment-resistant depression and gave them either an infusion of ketamine preceded by a placebo, or ketamine preceded by a dose of naltrexone, an opioid receptor blocker. Of those, seven subjects responded to the ketamine with placebo, “and it was very dramatic,” Schatzberg says, with depression lifting by the next day. “But in the other condition, they showed no effect,” suggesting it was the opioid receptor activity, not blocking glutamate receptors, that was responsible.

While opioid blockers prevented ketamine from activating the associated receptors, it did not block the drugs dissociative effects, suggesting dissociation alone won’t affect depression. “It’s not that, ‘hey, we’ll get you a little weird and you’ll get the effect,’” Schatzberg says.

The appeal of ketamine’s use as an antidepressant is clear enough. While more typical antidepressants may require six to eight weeks to produce benefits, ketamine works within hours.

“Our patients are asked to hang in there until the medication and talk therapy takes effect,” says Carlos Zarate, chief of the experimental therapeutics and pathophysiology branch of the National Institute of Mental Health (NIMH) who was not associated with the new study. While waiting for traditional treatments to kick in, patients “may lose their friends or even attempt suicide.”

<

A treatment that works within 24 hours? “That’s huge.”

A vial of ketamine. The drug is used primarily as an anesthetic but is gaining popularity as an effective antidepressant.
A vial of ketamine. The drug is used primarily as an anesthetic but is gaining popularity as an effective antidepressant. (Wikimedia Commons)

But the study linking ketamine to opioid activity means an extra dose of caution is required. While ketamine acts quickly, the anti-depressive effects of the drug only last for a few days to a week, meaning repeat doses would be needed in practice. Researchers and clinicians should consider the risk of addiction in long-term use, Schatzberg says. “You’re going to eventually get into some form of tolerance I think, and that’s not good.”

However, the new finding is based on just seven subjects, and it still needs to be replicated by other scientists, says Yale professor of psychiatry Greg Sanacora, who was not involved in the new study. And even if the trial is replicated, it would not prove ketamine’s opioid activity is responsible for its antidepressant effects.

“It doesn’t show that at all,” says Sanacora, who studies glutamate, mood disorders and ketamine. “It shows that the opioid system needs to be functioning in order to get this response.”

Sanacora compares the new study to using antibiotics to treat an ear infection. If you administered an additional drug that blocks absorption of antibiotics in the stomach, you would block treatment of the ear infection, but you wouldn’t conclude that antibiotics fight ear infections through stomach absorption—you just need a normally functioning stomach to allow the antibiotic to do its job. Similarly, opioid receptors might need to be functioning normally for ketamine to produce antidepressant effects, even if opioid activity is not directly responsible for those effects.

Complicating matters further, placebos often cause patients to experience less pain, but opioid blockers like naltrexone have been shown to prevent this response, according to Sanacora. It could be, he suggests, that all the apparatus of the clinic—the nursing staff, the equipment—exerted a placebo effect that is mediated by the brain’s opioid system, and the patients who received naltrexone simply did not respond to that placebo effect.

“That’s a very important and powerful tool that is in all of medicine, not just in psychiatry,” Sanacora says. “And we know that the opiate system is involved, to some extent, in that type of response.”

It’s also possible, the researchers note in the paper, that ketamine’s action at the glutamate receptor is still important. “Ketamine acts in three distinct phases—rapid effects, sustained effects and return to baseline,” Rodriguez says. Opioid signaling may turn out to mediate ketamine’s rapid effects, while “the glutamate system may be responsible for the sustaining effects after ketamine is metabolized.”

One interpretation is that ketamine blocks glutamate receptors on neurons that are inhibitory, meaning they signal other neurons to fire fewer signals. By blocking these neurons from firing, ketamine may enhance glutamate activity in the rest of the brain, producing anti-depressive effects that persist after the opioid activity dies down.

“The reality is it’s in a gray zone,” Sanacora says. “This is just one small piece of a very large puzzle or concern that we really need to look at the data in total.”

That data is forthcoming. Results from a Janssen Pharmaceuticals clinical trial using esketamine, an isomer of ketamine, and involving hundreds of subjects will soon become public, according to Sanacora, who has consulted for the company. And at NIMH, Zarate and colleagues are studying hydroxynorketamine, a metabolite of ketamine that may provide the same benefits but without the dissociative side effects.

The ultimate goal of all this research is to find a ketamine-like drug with fewer liabilities, and that aim is bringing researchers back to the fundamentals of science.

“For me, one of the exciting parts of this study is that it suggests that ketamine’s mechanism is complicated, it acts on different receptors beyond glutamate and is the start of this exciting dialogue,” Rodriguez says. “Sometimes great science raises more questions than answers.”











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Ketamine-like depression treatment on track for FDA approval

CNN)A ketamine-like drug for treatment-resistant depression was backed by a US Food and Drug Administration advisory committee on Tuesday. If it is then approved by the FDA, the drug — called esketamine — may provide a new option for patients with major depressive disorder who have tried at least two other antidepressants without success.A panel of experts voted to endorse the drug, which is made in nasal spray form by the pharmaceutical company Janssen, a division of Johnson & Johnson. Fourteen members voted that the benefits outweighed the risk, with two opposed and one abstaining.

Ketamine offers lifeline for people with severe depression, suicidal thoughts
703-844-0184 | NOVA Health Recovery | Alexandria, Va 22306

Ketamine offers lifeline for people with severe depression, suicidal thoughtsThe drug is a close relative of ketamine, a powerful medication used in hospitals primarily as an anesthetic; recent scientific studies have also shown its potential with treatment-resistant depression and suicidal ideation. Ketamine is also used recreationally — and illegally — as a club drug known as Special K. It generates an intense high and dissociative effects.Esketamine, which is not FDA-approved for any conditions, targets a different brain pathway than approved antidepressants, many of which have been around for decades. It is expected to be used in combination with antidepressants, but the latter can take a month or two to take effect. Esketamine, on the other hand, might have an effect within hours or days, according to an FDA briefing document.The drug was designated as a breakthrough therapy in 2013, intending to “expedite the development and review of drugs for serious or life-threatening conditions,” the FDA says. First-line treatments don’t work for roughly 30% to 40% of patients with major depressive disorder, according to the briefing document.The FDA does not have to follow the recommendation of advisory committees, though it often does.

ERs 'flooded' with mentally ill patients with no place else to turn

ERs ‘flooded’ with mentally ill patients with no place else to turnHowever, the research behind esketamine has come under some criticism, with two of five key studies failing to meet their primary endpoints. Only one of these studies is a positive short-term trial, whereas most FDA-approved antidepressants are backed by at least two, according to the briefing document. But Janssen has maintained that the overall picture is positive.Adverse events tended to occur in the first two hours patients received the drug, including sedation, blood pressure increases and dissociation. For this reason, patients wouldn’t be able to pick it up at a local pharmacy; it would be given under the supervision of health care professionals who can keep an eye on the person during those first two hours.Because of the drug’s close relationship to ketamine, experts have also raised concerns about its potential for misuse and abuse. The clinical trials have not seen evidence of this risk, according to presentations made during the meeting.Advisory panelists also expressed concern that not enough long-term data was available to characterize the drug’s cognitive effects and other health impacts down the line.Get CNN Health’s weekly newsletter

There were six deaths of patients taking esketamine in trials, including three suicides, but FDA materials concluded “it is difficult to consider these deaths as drug-related.”The only current FDA-approved medication for treatment-resistant depression combines two other drugs already on the market. Other non-pharmaceutical treatments exist, such as electroconvulsive therapy.Janssen spokesman Greg Panico said no information about pricing would be available at this time. An FDA decision is expected in early March, he added.

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A Randomized Controlled Trial of Intranasal Ketamine in Major
Depressive Disorder

A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder

Abstract
Background—The N-methyl-d-aspartate glutamate receptor antagonist ketamine, delivered via
an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant
depression. The current study was designed to test the safety, tolerability and efficacy of intranasal
ketamine in patients with depression who had failed at least one prior antidepressant trial.
Methods—Twenty patients with major depression were randomized and 18 completed two
treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution in a randomized,
double-blind, crossover study. The primary efficacy outcome measure was change in depression
severity 24 hours following ketamine or placebo, measured using the Montgomery-Asberg
Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in selfreports of depression, changes in anxiety, and proportion of responders. Potential
psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with
ketamine were also measured.

Results—Patients showed significant improvement in depressive symptoms at 24 hours
following ketamine compared to placebo [t=4.39, p<0.001; estimated mean MADRS score
difference of 7.6 ± 3.7 (95% CI: 3.9 – 11.3)]. Eight of 18 patients (44%) met response criteria 24
hours following ketamine administration, compared to 1 of 18 (6%) following placebo (p=0.033).
Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and
was not associated with clinically significant changes in hemodynamic parameters.

Conclusions—This study provides the first controlled evidence for the rapid antidepressant
effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If
replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients
with major depression

Intranasal ketamine has shown safety and efficacy as an anesthetic and analgesic agent (16–
20). In particular, intranasal ketamine has been successfully used in the treatment of
headache and pain in ambulatory patients (21–23). In one study, 50 mg of ketamine
administered intranasally was well tolerated and led to symptomatic improvement in chronic
pain (23). The objective of the current proof of concept clinical trial was to test the rapid
antidepressant effect of a single 50 mg administration of ketamine via an intranasal route in
patients with major depression who had failed to respond to at least one prior antidepressant
trial. Based on accumulating evidence supporting the efficacy and tolerability of ketamine
administered IV in depression, and prior research examining intranasal ketamine in pain, we
hypothesized that a dose of 50 mg, administered via an intranasal route, would be safe, well
tolerated and lead to a rapid reduction in depressive symptoms.

DISCUSSION
In the current study we found that a single dose of 50 mg of ketamine administered via
intranasal route was associated with a rapid antidepressant response in patients with major
depression who had failed at least one prior antidepressant trial. A significant antidepressant
effect of ketamine was detected as early as 40 min following administration and there was a
large difference in depression severity between the treatment conditions at the 24-hour
primary outcome (mean difference in MADRS score of 7.6 ± 3.7). In aggregate, there was
significant antidepressant benefit following ketamine compared to placebo over the full 7-
day assessment period, although when comparing individual time points the treatment
conditions no longer separated at 72 hours or 7 days. Ketamine was associated with
significant improvement in anxiety symptoms and self-reports of depressive symptoms at 24
hours. Intranasal ketamine was well tolerated with only very minimal increases in
dissociation, psychosis-like symptoms or hemodynamic parameters. This study provides the
first randomized, controlled evidence that intranasal ketamine is safe, well tolerated, and
effective for rapid reduction of depressive symptoms in patients with MDD and at least mild
treatment resistance.
In comparison with prior studies of ketamine administered IV (at a dose of 0.5 mg/kg) in
depression, our observed magnitude of antidepressant effect with intranasal administration
may be somewhat reduced. Murrough et al. reported a mean ketamine-placebo difference of
7.95 points (95% CI: 3.20–12.71) on the MADRS 24 hours following a single IV infusion
and a response rate of 64% (15). Response rates as high as 70% following IV administration
have been reported in some studies (11, 15), though other studies have reported response
rates from 50% to as low as 30% following IV ketamine (28, 29). Our mean drug-placebo
difference is in line with what has been previously reported (7.6 ± 3.7 points on the
MADRS), although the proportion of responders in our study may be somewhat lower at
44%. This lower proportion of treatment responders may be consistent with the lower blood
ketamine levels achieved in our study compared to levels previously reported following IV
administration. In our sample, the mean ketamine blood level was 72 ng/mL at 20 min and
84 ng/mL at 40 min. In contrast, mean ketamine levels reported following IV infusion
(0.5mg/kg) are approximately 150 ng/mL at 30 min and 200 ng/mL at 40 min. (27, 30, 31).
It is currently not known if efficacy equivalent to IV administration can be obtained by
intranasal administration in the case that comparable blood levels can be achieved.

We report a significant improvement in anxiety symptoms at 24 hours, assessed with the
HAM-A. Two studies of IV ketamine for bipolar depression reported a significant
improvement in anxiety symptoms measured with the HAM-A and a visual analog scale(27,
32). However, previous studies of patients with unipolar TRD have not described effects of
IV ketamine on anxiety, with the exception of an early RCT (11) and an open label study
(33) reporting significant improvement in psychic anxiety measured as an individual
symptom on the Hamilton Depression Rating Scale, and another open-label study reporting
significant decrease in anxiety symptoms on the HAM-A at +230 minutes (34).
Previous studies of IV ketamine in depression have reported elevations in measures of
psychotomimetic, dissociative and hemodynamic parameters (11, 13, 35). In our study, the
ketamine group experienced a very limited increase in dissociation at +40 min as measured
by the CADSS (mean 1.4 points; scale range 0–92). In comparison, Murrough et al. reported
a larger dissociative effect 40 min following ketamine administered IV [mean CADSS score
of 14.7 points (95% CI: 10.6–18.8)] (15). A similar pattern was observed for psychotic-like
effects measured using the BPRS+ (11, 15). We also observed comparatively small changes
in hemodynamic parameters. No patient met protocol criteria for interventions. Studies of IV
ketamine in depression have reported relatively greater changes in hemodynamic parameters
(mean systolic BP increase of 19.0 versus our 7.6 mmHg at +40mins relative to baseline)
(15). The reduced magnitude of acute behavioral and hemodynamic changes observed in the
current study may be consistent with the lower blood levels achieved compared to prior
studies with ketamine administered IV, as discussed above.
The bioavailability of ketamine administered via an intranasal route has been reported to be
between 25–50% (36). A study in healthy volunteers comparing administration methods
found intranasal ketamine bioavailability of 45%, higher than subligual, oral, or rectal
administration and found no significant differences in pharmacokinetics between
preparations, including injection (37). Additionally, this study found conversion to
norketamine was more similar between intranasal and injection than the other administration
methods, suggesting that first-pass metabolism is relatively absent with intranasal
administration. The area under the ketamine and norketamine plasma concentration-time
curves in that study was lowest for intranasal administration but was found to increase
almost linearly with doses from 25 to 50mg (37). In previous studies of IV ketamine in
depression, peak norketamine blood levels of approximately 20–50 ng/mL have been
reported (30, 31). In line with these findings, the mean norketamine level in our study was
46 ng/mL at 40 min.
We selected our dose of 50 mg largely based on a previous study using a similar design and
the same dose in patients with a chronic pain disorder (23). Based on an expected
bioavailability of intranasal ketamine between 25–50% (36), our dose may be approximately
equivalent to 0.15 – 0.34 mg/kg administered IV. Although this is lower than the standard
0.5 mg/kg IV frequently used in ketamine depression studies, we reasoned that this dose was
appropriate from a safety perspective given that the administration period in the current
study is relatively short (20 min versus 40 min or longer in IV studies). Clearly, much more
research is required in order to determine the optimal dose, duration, frequency and route of
administration of ketamine for depression



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Allergan and Lundbeck await depression and mania data

Allergan needs a win with rapastinel, while Lundbeck’s chief exec faces her second clinical challenge.

Calendar pin 14th

Welcome to your weekly digest of approaching regulatory and clinical readouts. After a tough 2018 Allergan needs some good news, and it will soon find out if its depression project rapastinel will provide it. Three phase III trials of the project are due to yield topline data in the first half of this year.

Rapastinel targets the NMDA receptor, making it similar to Johnson & Johnson’s ketamine enantiomer esketamine. The J&J candidate is under US review with a PDUFA date of May 2019, though continuing US government shutdown could put approval in doubt.

Although the two projects are often mentioned in the same breath they act differently: rapastinel is a partial agonist of the NMDA receptor, while esketamine blocks it. This way, Allergan hopes, its project might not have the same psychomimetic effects as ketamine and, to a lesser extent, esketamine.

Dissociation – becoming less aware of one’s surroundings – has been seen with the J&J project. Allergan will want to show a safety edge with rapastinel, but stronger efficacy versus esketamine would not go amiss either. Still, Bernstein analysts only give rapastinel a 50% chance of success.

The three phase III trials of rapastinel test the project on top of standard antidepressants in patients with a partial response to the existing drugs. The primary endpoint of all three is change in Montgomery-Asberg depression rating scale (MADRS) at three weeks.

Esketamine itself had mixed results in its pivotal programme: the Transform-2 trial met its primary endpoint, but Transform-3 and Transform-1 did not. Across the three studies, which tested esketamine on top of an oral antidepressant, the reduction in MADRS score at four weeks was 3.2-4.1 points.

Allergan is also developing an oral NMDA modulator, AGN-241751, but this has only just entered phase II. The company, which faced calls for a break-up last year, needs a nearer-term boost, and with 2024 sales forecasts of $505m rapastinel is its biggest pipeline hope.

Selected upcoming rapastinel phase III readouts
NameSetting Trial ID Primary completion
RAP-MD-01Adjunctive therapy NCT02932943Nov 2018
RAP-MD-02Adjunctive therapy NCT02943564Nov 2018
RAP-MD-03Adjunctive therapy NCT02943577Nov 2018
RAP-MD-06 Long-term safety study, adjunctive therapyNCT03002077Nov 2018
RAP-MD-04 Adjunctive therapy, relapse preventionNCT02951988Sep 2019
RAP-MD-32MonotherapyNCT03560518Feb 2020
RAP-MD-30 MonotherapyNCT03675776Dec 2020
RAP-MD-99 Adjunctive or monotherapyNCT03668600Feb 2021
RAP-MD-33 Monotherapy, relapse preventionNCT03614156Jul 2021
Source: EvaluatePharma, Clinicaltrials.gov.

Second test

The two upcoming phase III readouts for Lundbeck’s antipsychotic Rexulti in bipolar mania might not be game changing: there are already approved drugs for this indication, and existing off-label use of antipsychotics is being fuelled by increasing genericisation.

Still, the data will be interesting as they represent the second clinical stock catalyst for Lundbeck’s new chief executive, Deborah Dunsire. The first was the failure of Lu AF35700 in treatment-resistant schizophrenia, and drove shares down almost 30%.

Some analysts do not think that success in bipolar mania will add materially to Rexulti sales, but the downside risk of a second negative trial readout is substantially greater given the lack of other catalysts.

The two bipolar trials have enrolled 322 and 333 patients, the active cohorts given 2-4mg of Rexulti for 21 days, with a six-month follow-up. The primary endpoint is change in the Young-mania rating scale, and a key secondary endpoint is clinical global impression-bipolar (CGI BP) severity-of-illness score in mania.

Even if there is improvement in severity of illness, success in bipolar mania will at best be a nice-to-have addition to Rexulti’s current uses in schizophrenia and major depressive disorder, according to analysts at Leerink.

A more exciting event for Lundbeck will be whether Rexulti can have an impact on agitation in Alzheimer’s disease, where Bernstein analysts reckon success could add $1bn of sales. However, previous data have been mixed.

For now, if Rexulti does not deliver the goods in the more immediate bipolar indication, the market could seize it as an opportunity to punish the stock further.

Selected upcoming Rexulti phase III readouts
SettingTrial IDData due
Bipolar manic episodesNCT03259555Q1 2019
Bipolar manic episodesNCT03257865Q1 2019
Alzheimer’s agitationNCT035485842020
Alzheimer’s agitationNCT035941232021
Alzheimer’s agitationNCT037249422021
Source: EvaluatePharma, Clinicaltrials.gov.



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Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate

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Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate

A version of the club drug is expected to be approved for depression in March. Researchers think it could help treat suicidal thinking.

Joe Wright has no doubt that ketamine saved his life. A 34-year-old high school teacher who writes poetry every day on a typewriter, Wright was plagued by suicidal impulses for years. The thoughts started coming on when he was a high schooler himself, on Staten Island, N.Y., and intensified during his first year of college. “It was an internal monologue, emphatic on how pointless it is to exist,” he says. “It’s like being ambushed by your own brain.”

He first tried to kill himself by swallowing a bottle of sleeping pills the summer after his sophomore year. Years of treatment with Prozac, Zoloft, Wellbutrin, and other antidepressants followed, but the desire for an end was never fully resolved. He started cutting himself on his arms and legs with a pencil-sharpener blade. Sometimes he’d burn himself with cigarettes. He remembers few details about his second and third suicide attempts. They were halfhearted; he drank himself into a stupor and once added Xanax into the mix.

Wright decided to try again in 2016, this time using a cocktail of drugs he’d ground into a powder. As he tells the story now, he was preparing to mix the powder into water and drink it when his dog jumped onto his lap. Suddenly he had a moment of clarity that shocked him into action. He started doing research and came upon a Columbia University study of a pharmaceutical treatment for severe depression and suicidality. It involved an infusion of ketamine, a decades-old anesthetic that’s also an infamous party drug. He immediately volunteered.

His first—and only—ketamine infusion made him feel dreamlike, goofy, and euphoric. He almost immediately started feeling more hopeful about life. He was more receptive to therapy. Less than a year later, he married. Today he says his dark moods are remote and manageable. Suicidal thoughts are largely gone. “If they had told me how much it would affect me, I wouldn’t have believed it,” Wright says. “It is unconscionable that it is not already approved for suicidal patients.”

The reasons it isn’t aren’t strictly medical. Over the past three decades, pharmaceutical companies have conducted hundreds of trials for at least 10 antidepressants to treat severe PMS, social anxiety disorder, and any number of conditions. What they’ve almost never done is test their drugs on the sickest people, those on the verge of suicide. There are ethical considerations: Doctors don’t want to give a placebo to a person who’s about to kill himself. And reputational concerns: A suicide in a drug trial could hurt a medication’s sales prospects.

The risk-benefit calculation has changed amid the suicide epidemic in the U.S. From 1999 to 2016, the rate of suicides increased by 30 percent. It’s now the second-leading cause of death for 10- to 34-year-olds, behind accidents. (Globally the opposite is true: Suicide is decreasing.) Growing economic disparity, returning veterans traumatized by war, the opioid crisis, easy access to guns—these have all been cited as reasons for the rise in America. There’s been no breakthrough in easing any of these circumstances.

But there is, finally, a serious quest for a suicide cure. Ketamine is at the center, and crucially the pharmaceutical industry now sees a path. The first ketamine-based drug, from Johnson & Johnson, could be approved for treatment-resistant depression by March and suicidal thinking within two years. Allergan Plc is not far behind in developing its own fast-acting antidepressant that could help suicidal patients. How this happened is one of the most hopeful tales of scientific research in recent memory.

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate
Dennis Charney at Mount Sinai.PHOTOGRAPHER: MAX AGUILERA-HELLWEG FOR BLOOMBERG BUSINESSWEEK

Dennis Charney, dean of the Icahn School of Medicine at Mount Sinai in New York, works from an office filled with family pictures, diplomas, and awards from a long career in research. One thing on the wall is different from the rest: a patent for the use of a nasal-spray form of ketamine as a treatment for suicidal patients. The story of the drug is in some ways the story of Charney’s career.

In the 1990s he was a psychiatry professor, mentoring then associate professor John Krystal at Yale and trying to figure out how a deficit of serotonin played into depression. Back then, depression research was all about serotonin. The 1987 approval of Prozac, the first selective serotonin reuptake inhibitor, or SSRI, ushered in an era of what people in the industry call me-too drug development, research that seeks to improve on existing medicines rather than exploring new approaches. Within this narrow range, pharmaceutical companies churned out blockbuster after blockbuster. One in eight Americans age 12 and older reported using antidepressants within the past month, according to a survey conducted from 2011 to 2014 by the U.S. Centers for Disease Control and Prevention.

Charney was a depression guy; Krystal was interested in schizophrenia. Their curiosity led them to the same place: the glutamate system, what Krystal calls the “main information highway of the higher brain.” (Glutamate is an excitatory neurotransmitter, which helps brain cells communicate. It’s considered crucial in learning and memory formation.) They had already used ketamine to temporarily produce schizophrenia-like symptoms, to better understand glutamate’s role in that condition. In the mid-1990s they decided to conduct a single-dose study of ketamine on nine patients (two ultimately dropped out) at the Yale-affiliated VA Connecticut Healthcare System in West Haven to see how depressed people would react to the drug.

“If we had done the typical thing … we would have completely missed the antidepressant effect”

Outside the field of anesthesiology, ketamine is known, if it’s known at all, for its abuse potential. Street users sometimes take doses large enough to enter what’s known as a “K hole,” a state in which they’re unable to interact with the world around them. Over the course of a day, those recreational doses can be as much as 100 times greater than the tiny amount Charney and Krystal were planning to give to patients. Nonetheless, they decided to monitor patients for 72 hours—well beyond the two hours that ketamine produces obvious behavioral effects—just to be careful not to miss any negative effects that might crop up. “If we had done the typical thing that we do with these drug tests,” Krystal says, “we would have completely missed the antidepressant effect of ketamine.”

Checking on patients four hours after the drug had been administered, the researchers saw something unexpected. “To our surprise,” Charney says, “the patients started saying they were better, they were better in a few hours.” This was unheard of. Antidepressants are known for taking weeks or months to work, and about a third of patients aren’t sufficiently helped by the drugs. “We were shocked,” says Krystal, who now chairs the Yale psychiatry department. “We didn’t submit the results for publication for several years.”

When Charney and Krystal did publish their findings, in 2000, they attracted almost no notice. Perhaps that was because the trial was so small and the results were almost too good to be true. Or maybe it was ketamine’s reputation as an illicit drug. Or the side effects, which have always been problematic: Ketamine can cause patients to disassociate, meaning they enter a state in which they feel as if their mind and body aren’t connected.

But probably none of these factors mattered as much as the bald economic reality. The pharmaceutical industry is not in the business of spending hundreds of millions of dollars to do large-scale studies of an old, cheap drug like ketamine. Originally developed as a safer alternative to the anesthetic phencyclidine, better known as PCP or angel dust, ketamine has been approved since 1970. There’s rarely profit in developing a medication that’s been off patent a long time, even if scientists find an entirely new use for it.

Somehow, even with all of this baggage, research into ketamine inched forward. The small study that almost wasn’t published has now been cited more than 2,000 times.

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate
John Mann in his office at Columbia’s New York State Psychiatric Institute. 

Suicide is described in medicine as resulting from a range of mental disorders and hardships—a tragedy with many possible roots. Conditions such as severe depression, bipolar disorder, and schizophrenia are known risk factors. Childhood trauma or abuse may also be a contributor, and there may be genetic risk factors as well.

From these facts, John Mann, an Australian-born psychiatrist with a doctorate in neurochemistry, made a leap. If suicide has many causes, he hypothesized, then all suicidal brains might have certain characteristics in common. He’s since done some of the most high-profile work to illuminate what researchers call the biology of suicide. The phrase itself represents a bold idea—that there’s an underlying physiological susceptibility to suicide, apart from depression or another psychiatric disorder.

Mann moved to New York in 1978, and in 1982, at Cornell University, he started collecting the brains of people who’d killed themselves. He recruited Victoria Arango, now a leading expert in the field of suicide biology. The practice of studying postmortem brain tissue had largely fallen out of favor, and Mann wanted to reboot it. “He was very proud to take me to the freezer,” Arango says of the day Mann introduced her to the brain collection, which then numbered about 15. “I said, ‘What am I supposed to do with this?’ ”

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate
Some of Mann’s brain collection. 

They took the work, and the brains, first to the University of Pittsburgh, and then, in 1994, to Columbia. They’ve now amassed a collection of some 1,000 human brains—some from suicide victims, the others, control brains—filed neatly in freezers kept at –112F. The small Balkan country of Macedonia contributes the newest brains, thanks to a Columbia faculty member from there who helped arrange it. The Macedonian brains are frozen immediately after being removed and flown in trunks, chaperoned, some 4,700 miles to end up in shoe-box-size, QR-coded black boxes. Inside are dissected sections of pink tissue in plastic bags notated with markers: right side, left side, date of collection.

In the early 1990s, Mann and Arango discovered that depressed patients who killed themselves have subtle alterations in serotonin in certain regions of the brain. Mann remembers sitting with Arango and neurophysiologist Mark Underwood, her husband and longtime research partner, and analyzing the parts of the brain affected by the deficit. They struggled to make sense of it, until it dawned on them that these were the same brain regions described in a famous psychiatric case study. In 1848, Phineas Gage, an American railroad worker, was impaled through the skull by a 43-inch-long tamping iron when the explosives he was working with went off prematurely. He survived, but his personality was permanently altered. In a paper titled “Recovery From the Passage of an Iron Bar Through the Head,” his doctor wrote that Gage’s “animal propensities” had emerged and described him as using the “grossest profanity.” Modern research has shown that the tamping iron destroyed key areas of the brain involved in inhibition—the same areas that were altered in the depressed patients who’d committed suicide. For the group, this was a clue that the differences in the brain of suicidal patients were anatomically important.

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate
Columbia’s Victoria Arango. 

“Most people inhibit suicide. They find a reason not to do it,” Underwood says. Thanks to subtle changes in the part of the brain that might normally control inhibition and top-down control, people who kill themselves “don’t find a reason not to do it,” he says.

About eight years ago, Mann saw ketamine research taking off in other corners of the scientific world and added the drug to his own work. In one trial, his group found that ketamine treatment could ease suicidal thoughts in 24 hours more effectively than a control drug. Crucially, they found that the antisuicidal effects of ketamine were to some extent independent of the antidepressant effect of the drug, which helped support their thesis that suicidal impulses aren’t necessarily just a byproduct of depression. It was this study, led by Michael Grunebaum, a colleague of Mann’s, that made a believer of Joe Wright.

“It’s like you have 50 pounds on your shoulders, and the ketamine takes 40 pounds off”

In 2000, the National Institutes of Health hired Charney to run both mood disorder and experimental drug research. It was the perfect place for him to forge ahead with ketamine. There he did the work to replicate what he and his colleagues at Yale had discovered. In a study published in 2006, led by researcher Carlos Zarate Jr., who now oversees NIH studies of ketamine and suicidality, an NIH team found that patients had “robust and rapid antidepressant effects” from a single dose of the drug within two hours. “We could not believe it. In the first few subjects we were like, ‘Oh, you can always find one patient or two who gets better,’ ” Zarate recalls.

In a 2009 study done at Mount Sinai, patients suffering from treatment-resistant depression showed rapid improvement in suicidal thinking within 24 hours. The next year, Zarate’s group demonstrated antisuicidal effects within 40 minutes. “That you could replicate the findings, the rapid findings, was quite eerie,” Zarate says.

Finally ketamine crossed back into commercial drug development. In 2009, Johnson & Johnson lured away Husseini Manji, a prominent NIH researcher who’d worked on the drug, to run its neuroscience division. J&J didn’t hire him explicitly to develop ketamine into a new pharmaceutical, but a few years into his tenure, Manji decided to look into it. This time it would come in a nasal-spray form of esketamine, a close chemical cousin. That would allow for patent protection. Further, the nasal spray removes some of the challenges that an IV form of the drug would present. Psychiatrists, for one thing, aren’t typically equipped to administer IV drugs in their offices.

While these wheels were slowly turning, some doctors—mostly psychiatrists and anesthesiologists—took action. Around 2012 they started opening ketamine clinics. Dozens have now popped up in major metropolitan areas. Insurance typically won’t touch it, but at these centers people can pay about $500 for an infusion of the drug. It was at one time a cultural phenomenon—a 2015 Bloomberg Businessweek story called it “the club drug cure.” Since then, the sense of novelty has dissipated. In September the American Society of Ketamine Physicians convened its first medical meeting about the unconventional use of the drug.

“You are literally saving lives,” Steven Mandel, an anesthesiologist-turned-ketamine provider, told a room of about 100 people, mostly doctors and nurse practitioners, who gathered in Austin to hear him and other early adopters talk about how they use the drug. Sporadic cheers interrupted the speakers as they presented anecdotes about its effectiveness.

There were also issues to address. A consensus statementin JAMA Psychiatry published in 2017 said there was an “urgent need for some guidance” on ketamine use. The authors were particularly concerned with the lack of data about the safety of prolonged use of the drug in people with mood disorders, citing “major gaps” in the medical community’s knowledge about its long-term impact.

The context for the off-label use of ketamine is a shrinking landscape for psychiatry treatment. An effort to deinstitutionalize the U.S. mental health system, which took hold in the 1960s, has almost resulted in the disappearance of psychiatric hospitals and even psychiatric beds within general hospitals. There were 37,679 psychiatric beds in state hospitals in 2016, down from 558,922 in 1955, according to the Treatment Advocacy Center. Today a person is often discharged from a hospital within days of a suicide attempt, setting up a risky situation in which someone who may not have fully recovered ends up at home with a bunch of antidepressants that could take weeks to lift his mood, if they work at all.

A ketamine clinic can be the way out of this scenario—for people with access and means. For Dana Manning, a 53-year-old Maine resident who suffers from bipolar disorder, $500 is out of reach. “I want to die every day,” she says.

After trying to end her life in 2003 by overdosing on a cocktail of drugs including Xanax and Percocet, Manning tried virtually every drug approved for bipolar disorder. None stopped the mood swings. In 2010 the depression came back so intensely that she could barely get out of bed and had to quit her job as a medical records specialist. Electroconvulsive therapy, the last-ditch treatment for depressed patients who don’t respond to drugs, didn’t help.

Her psychiatrist went deep into the medical literature to find options and finally suggested ketamine. He was even able to get the state Medicaid program to cover it, she says. She received a total of four weekly infusions before she moved to Pennsylvania, where there were more family members nearby to care for her.

The first several weeks following her ketamine regimen were “the only time I can say I have felt normal” in 15 years, she says. “It’s like you have 50 pounds on your shoulders, and the ketamine takes 40 pounds off.”

She’s now back in Maine, and the depression has returned. Her current Medicare insurance won’t cover ketamine. She lives on $1,300 a month in disability income. “Knowing it is there and I can’t have it is beyond frustrating,” she says.

relates to Ketamine Could Be the Key to Reversing America’s Rising Suicide Rate
Mark Underwood at the New York State Psychiatric Institute. 

Ketamine is considered a “dirty” drug by scientists—it affects so many pathways and systems in the brain at the same time that it’s hard to single out the exact reason it works in the patients it does help. That’s one reason researchers continue to look for better versions of the drug. Another, of course, is that new versions are patentable. Should Johnson & Johnson’s esketamine hit the market, the ketamine pioneers and their research institutions stand to benefit. Yale’s Krystal, NIH’s Zarate, and Sinai’s Charney, all of whom are on the patent on Charney’s wall, will collect royalties based on the drug’s sales. J&J hasn’t said anything about potential pricing, but there’s every reason to believe the biggest breakthrough in depression treatment since Prozac will be expensive.

The company’s initial esketamine study in suicidal patients involved 68 people at high risk. To avoid concerns about using placebos on actively suicidal subjects, everyone received antidepressants and other standard treatments. About 40 percent of those who received esketamine were deemed no longer at risk of killing themselves within 24 hours. Two much larger trials are under way.

When Johnson & Johnson unveiled data from its esketamine study in treatment-resistant depression at the American Psychiatric Association meeting in May, the presentation was jammed. Esketamine could become the first-ever rapid-acting antidepressant, and physicians and investors are clamoring for any information about how it works. The results in suicidal patients should come later this year and could pave the way for a Food and Drug Administration filing for use in suicidal depressed patients in 2020. Allergan expects to have results from its suicide study next year, too.

“The truth is, what everybody cares about is, do they decrease suicide attempts?” says Gregory Simon, a psychiatrist and mental health researcher at Kaiser Permanente Washington Health Research Institute. “That is an incredibly important question that we hope to be able to answer, and we are planning for when these treatments become available.”

Exactly how ketamine and its cousin esketamine work is still the subject of intense debate. In essence, the drugs appear to provide a quick molecular reset button for brains impaired by stress or depression. Both ketamine and esketamine release a burst of glutamate. This, in turn, may trigger the growth of synapses, or neural connections, in brain areas that may play a role in mood and the ability to feel pleasure. It’s possible the drug works to prevent suicide by boosting those circuits while also reestablishing some of the inhibition needed to prevent a person from killing himself. “We certainly think that esketamine is working exactly on the circuitry of depression,” Manji says. “Are we homing in exactly on where suicidal ideation resides?” His former colleagues at NIH are trying to find that spot in the brain as well. Using polysomnography—sleep tests in which patients have nodes connected to various parts of their head to monitor brain activity—as well as MRIs and positron emission tomography, or PET scans, researchers can see how a patient’s brain responds to ketamine, to better understand exactly what it’s doing to quash suicidal thinking.

Concerns about the side effects of ketamine-style drugs linger. Some patients taking esketamine have reported experiencing disassociation symptoms. Johnson & Johnson calls the effects manageable and says they cropped up within an hour of the treatment, a period in which a person on the drug would likely be kept in the doctor’s office for monitoring. Some patients also experienced modest spikes in blood pressure within the same timeframe.

Nasal-spray dosing brings other issues. The Black Dog Institute in Australia and the University of New South Wales in Sydney, which teamed up to study a nasal-spray form of ketamine, published their findings last March in the Journal of Psychopharmacology. The researchers found that absorption rates were variable among patients. J&J says its own studies with esketamine contradict these findings.

But in the wake of the opioid crisis, perhaps the biggest worry is that loosening the reins too much on the use of ketamine and similar drugs could lead to a new abuse crisis. That’s why Wall Street analysts are particularly excited by Allergan’s rapid-acting antidepressant, rapastinel, which is about a year behind esketamine in testing. Researchers say it likely acts on the same target in the brain as ketamine, the NMDA receptor, but in a more subtle way that may avoid the disassociation side effects and abuse potential. Studies in lab animals show the drug doesn’t lead creatures to seek more of it, as they sometimes do with ketamine, says Allergan Vice President Armin Szegedi. Allergan’s medicine is an IV drug, but the company is developing an oral drug.

For its suicide study, Allergan is working hard to enroll veterans, one of the populations most affected by the recent spike in suicides, and has included several U.S. Department of Veterans Affairs medical centers as sites in the trial. More than 6,000 veterans died by suicide each year from 2008 to 2016, a rate that’s 50 percent higher than in the general population even after adjusting for demographics, according to VA data.

“How the brain mediates what makes us who we are is still a mystery, and maybe we will never fully understand it,” Szegedi says. “What really changed the landscape here is you had clinical data showing ‘This really does the trick.’ Once you find something in the darkness, you really have to figure out: Can you do something better, faster, safer?”

If you or someone you know is having suicidal thoughts, the National Suicide Prevention hotline is 1 (800) 273 8255.

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Depression Therapy With Party-Drug Roots Faces FDA Panel Review

Depression Therapy With Party-Drug Roots Faces FDA Panel Review



Depression Therapy With Party-Drug Roots Faces FDA Panel Review

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Potential for abuse and strategies for containing any risks from an experimental depression treatment from Johnson & Johnson will be in focus at an Food and Drug Administration panel next week.

J&J’s nasal spray, esketamine, a close cousin of the party drug ketamine, will be considered by an FDA advisory panel on Feb. 12. While agency staff seemed satisfied that the likelihood of abuse is low, they raised questions about safety issues connected to a dreamlike sensation the medication can create in some users.

“Ketamine abuse is relatively uncommon in the general population,” agency staff said in a report ahead of next week’s meeting. Just 1.3 percent of people over age 12 abuse the drug, lower than abuse rates for other hallucinogens like ecstasy and LSD.

At the same time, reviewers worried that patients could get into accidents or otherwise be harmed if they leave a doctor’s office while still experiencing disassociation, a known side effect of ketamine — and a sought-after experience for casual users who have dubbed the spacey feeling the “K-hole.”

It takes roughly 90 minutes for disassociation symptoms from esketamine to resolve, according to the report. FDA staff also cited elevated blood pressure as a safety concern.

Esketamine is a key part of J&J’s pharmaceutical pipeline, as the company faces flagging sales this year weighed down by drug pricing scrutiny and looming generic competition. Its shares, which rose 2.3 percent this year through Thursday’s close, were were little changed in early trading on Friday.

In addition to weighing in on the drug’s safety and a proposed risk-evaluation and mitigation strategy, FDA staff will ask advisers to vote on whether esketamine effectively treated the depression of patients who weren’t helped by other therapies. They’ll also discuss whether additional studies are needed before or after the drug is potentially approved.

The staff report noted there were six deaths among patients taking the J&J drug, of which three were suicide in the esketamine depression program, but they didn’t see a clear link to the drug itself.

“Given the small number of cases, the severity of the patients’ underlying illness, and the lack of a consistent pattern among these cases, it is difficult to consider these deaths as drug related,” staff reviewers noted.

A decision on whether to allow the drug on the market is expected by March 4. Esketamine has the FDA’s breakthrough-therapy designation in treatment-resistant depression as well as for depressed people at risk of suicide. Results from a study in suicidal patients are expected this year. Allergan is also testing a fast-acting antidepressant, rapastinel, which is about a year behind esketamine in testing.